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In healthcare, a differential diagnosis (DDx) is a method of analysis that distinguishes a particular disease or condition from others that present with similar clinical features. Differential diagnostic procedures are used by clinicians to diagnose the specific disease in a patient, or, at least, to consider any imminently life-threatening conditions. Often, each possible disease is called a differential diagnosis (e.g., acute bronchitis could be a differential diagnosis in the evaluation of a cough, even if the final diagnosis is common cold).
More generally, a differential diagnostic procedure is a systematic diagnostic method used to identify the presence of a disease entity where multiple alternatives are possible. This method may employ algorithms, akin to the process of elimination, or at least a process of obtaining information that decreases the "probabilities" of candidate conditions to negligible levels, by using evidence such as symptoms, patient history, and medical knowledge to adjust epistemic confidences in the mind of the diagnostician (or, for computerized or computer-assisted diagnosis, the software of the system).
Differential diagnosis can be regarded as implementing aspects of the hypothetico-deductive method, in the sense that the potential presence of candidate diseases or conditions can be viewed as hypotheses that clinicians further determine as being true or false.
A differential diagnosis is also commonly used within the field of psychiatry/psychology, where two different diagnoses can be attached to a patient who is exhibiting symptoms that could fit into either diagnosis. For example, a patient who has been diagnosed with bipolar disorder may also be given a differential diagnosis of borderline personality disorder, given the similarity in the symptoms of both conditions.
Strategies used in preparing a differential diagnosis list vary with the experience of the healthcare provider. While novice providers may work systemically to assess all possible explanations for a patient's concerns, those with more experience often draw on clinical experience and pattern recognition to protect the patient from delays, risks, and cost of inefficient strategies or tests. Effective providers utilize an evidence-based approach, complementing their clinical experience with knowledge from clinical research.
== General components ==
A differential diagnosis has four general steps. The clinician will:
Gather relevant information about the person's medical history and present signs and/or symptoms list.
List possible causes (candidate conditions) for the symptoms. The list need not be in writing.
Prioritize the list by balancing the risks of a diagnosis with the probability. These are subjective, not objective parameters.
Perform tests to determine the actual diagnosis. This is known by the colloquial phrase "to Rule Out". Even after the process, the diagnosis is not clear. The clinician again considers the risks and may treat them empirically, often called "Educated Best Guess."
A mnemonic to help in considering multiple possible pathological processes is VINDICATEM:
Vascular
Inflammatory / Infectious
Neoplastic
Degenerative / Deficiency / Drugs
Idiopathic / Intoxication / Iatrogenic
Congenital
Autoimmune / Allergic / Anatomic
Traumatic
Endocrine / Environmental
Metabolic
== Specific methods ==
There are several methods for differential diagnostic procedures and several variants among those. Furthermore, a differential diagnostic procedure can be used concomitantly or alternately with protocols, guidelines, or other diagnostic procedures (such as pattern recognition or using medical algorithms).
For example, in case of medical emergency, there may not be enough time to do any detailed calculations or estimations of different probabilities, in which case the ABC protocol (airway, breathing and circulation) may be more appropriate. Later, when the situation is less acute, a more comprehensive differential diagnostic procedure may be adopted.
The differential diagnostic procedure may be simplified if a "pathognomonic" sign or symptom is found (in which case it is almost certain that the target condition is present) or in the absence of a sine qua non sign or symptom (in which case it is almost certain that the target condition is absent).
A diagnostician can be selective, considering first those disorders that are more likely (a probabilistic approach), more serious if left undiagnosed and untreated (a prognostic approach), or more responsive to treatment if offered (a pragmatic approach). Since the subjective probability of the presence of a condition is never exactly 100% or 0%, the differential diagnostic procedure may aim at specifying these various probabilities to form indications for further action.
The following are two methods of differential diagnosis, being based on epidemiology and likelihood ratios, respectively.
=== Epidemiology-based method ===
One method of performing a differential diagnosis by epidemiology aims to estimate the probability of each candidate condition by comparing their probabilities to have occurred in the first place in the individual. It is based on probabilities related both to the presentation (such as pain) and probabilities of the various candidate conditions (such as diseases).
==== Theory ====
The statistical basis for differential diagnosis is Bayes' theorem. As an analogy, when a die has landed the outcome is certain by 100%, but the probability that it Would Have Occurred in the First Place (hereafter abbreviated WHOIFP) is still 1/6. In the same way, the probability that a presentation or condition would have occurred in the first place in an individual (WHOIFPI) is not same as the probability that the presentation or condition has occurred in the individual, because the presentation has occurred by 100% certainty in the individual. Yet, the contributive probability fractions of each condition are assumed the same, relatively:
Pr
(
Presentation is caused by condition in individual
)
Pr
(
Presentation has occurred in individual
)
=
Pr
(
Presentation WHOIFPI by condition
)
Pr
(
Presentation WHOIFPI
)
{\displaystyle {\begin{aligned}&{\frac {\Pr({\text{Presentation is caused by condition in individual}})}{\Pr({\text{Presentation has occurred in individual}})}}={\frac {\Pr({\text{Presentation WHOIFPI by condition}})}{\Pr({\text{Presentation WHOIFPI}})}}\end{aligned}}}
where:
Pr(Presentation is caused by condition in individual) is the probability that the presentation is caused by condition in the individual; condition without further specification refers to any candidate condition
Pr(Presentation has occurred in individual) is the probability that the presentation has occurred in the individual, which can be perceived and thereby set at 100%
Pr(Presentation WHOIFPI by condition) is the probability that the presentation Would Have Occurred in the First Place in the Individual by condition
Pr(Presentation WHOIFPI) is the probability that the presentation Would Have Occurred in the First Place in the Individual
When an individual presents with a symptom or sign, Pr(Presentation has occurred in individual) is 100% and can therefore be replaced by 1, and can be ignored since division by 1 does not make any difference:
Pr
(
Presentation is caused by condition in individual
)
=
Pr
(
Presentation WHOIFPI by condition
)
Pr
(
Presentation WHOIFPI
)
{\displaystyle \Pr({\text{Presentation is caused by condition in individual}})={\frac {\Pr({\text{Presentation WHOIFPI by condition}})}{\Pr({\text{Presentation WHOIFPI}})}}}
The total probability of the presentation to have occurred in the individual can be approximated as the sum of the individual candidate conditions:
Pr
(
Presentation WHOIFPI
)
=
Pr
(
Presentation WHOIFPI by condition 1
)
+
Pr
(
Presentation WHOIFPI by condition 2
)
+
Pr
(
Presentation WHOIFPI by condition 3
)
+
etc.
{\displaystyle {\begin{aligned}\Pr({\text{Presentation WHOIFPI}})&=\Pr({\text{Presentation WHOIFPI by condition 1}})\\&{}+\Pr({\text{Presentation WHOIFPI by condition 2}})\\&{}+\Pr({\text{Presentation WHOIFPI by condition 3}})+{\text{etc.}}\end{aligned}}}
Also, the probability of the presentation to have been caused by any candidate condition is proportional to the probability of the condition, depending on what rate it causes the presentation:
Pr
(
Presentation WHOIFPI by condition
)
=
Pr
(
Condition WHOIFPI
)
⋅
r
condition
→
presentation
,
{\displaystyle \Pr({\text{Presentation WHOIFPI by condition}})=\Pr({\text{Condition WHOIFPI}})\cdot r_{{\text{condition}}\rightarrow {\text{presentation}}},}
where:
Pr(Presentation WHOIFPI by condition) is the probability that the presentation Would Have Occurred in the First Place in the Individual by condition
Pr(Condition WHOIFPI) is the probability that the condition Would Have Occurred in the First Place in the Individual
rCondition → presentation is the rate at which a condition causes the presentation, that is, the fraction of people with conditions that manifests with the presentation.
The probability that a condition would have occurred in the first place in an individual is approximately equal to that of a population that is as similar to the individual as possible except for the current presentation, compensated where possible by relative risks given by known risk factor that distinguish the individual from the population:
Pr
(
Condition WHOIFPI
)
≈
R
R
condition
⋅
Pr
(
Condition in population
)
,
{\displaystyle \Pr({\text{Condition WHOIFPI}})\approx RR_{\text{condition}}\cdot \Pr({\text{Condition in population}}),}
where:
Pr(Condition WHOIFPI) is the probability that the condition Would Have Occurred in the First Place in the Individual
RRcondition is the relative risk for condition conferred by known risk factors in the individual that are not present in the population
Pr(Condition in population) is the probability that the condition occurs in a population that is as similar to the individual as possible except for the presentation
The following table demonstrates how these relations can be made for a series of candidate conditions:
One additional "candidate condition" is the instance of there being no abnormality, and the presentation is only a (usually relatively unlikely) appearance of a basically normal state. Its probability in the population (P(No abnormality in population)) is complementary to the sum of probabilities of "abnormal" candidate conditions.
==== Example ====
This example case demonstrates how this method is applied but does not represent a guideline for handling similar real-world cases. Also, the example uses relatively specified numbers with sometimes several decimals, while in reality, there are often simply rough estimations, such as of likelihoods being very high, high, low or very low, but still using the general principles of the method.
For an individual (who becomes the "patient" in this example), a blood test of, for example, serum calcium shows a result above the standard reference range, which, by most definitions, classifies as hypercalcemia, which becomes the "presentation" in this case. A clinician (who becomes the "diagnostician" in this example), who does not currently see the patient, gets to know about his finding.
By practical reasons, the clinician considers that there is enough test indication to have a look at the patient's medical records. For simplicity, let's say that the only information given in the medical records is a family history of primary hyperparathyroidism (here abbreviated as PH), which may explain the finding of hypercalcemia. For this patient, let's say that the resultant hereditary risk factor is estimated to confer a relative risk of 10 (RRPH = 10).
The clinician considers that there is enough motivation to perform a differential diagnostic procedure for the finding of hypercalcemia. The main causes of hypercalcemia are primary hyperparathyroidism (PH) and cancer, so for simplicity, the list of candidate conditions that the clinician could think of can be given as:
Primary hyperparathyroidism (PH)
Cancer
Other diseases that the clinician could think of (which is simply termed "other conditions" for the rest of this example)
No disease (or no abnormality), and the finding is caused entirely by statistical variability
The probability that 'primary hyperparathyroidism' (PH) would have occurred in the first place in the individual (P(PH WHOIFPI)) can be calculated as follows:
Let's say that the last blood test taken by the patient was half a year ago and was normal and that the incidence of primary hyperparathyroidism in a general population appropriately matches the individual (except for the presentation and mentioned heredity) is 1 in 4000 per year. Ignoring more detailed retrospective analyses (such as including speed of disease progress and lag time of medical diagnosis), the time-at-risk for having developed primary hyperparathyroidism can roughly be regarded as being the last half-year because a previously developed hypercalcemia would probably have been caught up by the previous blood test. This corresponds to a probability of primary hyperparathyroidism (PH) in the population of:
Pr
(
PH in population
)
=
0.5
years
⋅
1
4000 per year
=
1
8000
{\displaystyle \Pr({\text{PH in population}})=0.5{\text{ years}}\cdot {\frac {1}{\text{4000 per year}}}={\frac {1}{8000}}}
With the relative risk conferred from the family history, the probability that primary hyperparathyroidism (PH) would have occurred in the first place in the individual given from the currently available information becomes:
Pr
(
PH WHOIFPI
)
≈
R
R
P
H
⋅
Pr
(
PH in population
)
=
10
⋅
1
8000
=
1
800
=
0.00125
{\displaystyle \Pr({\text{PH WHOIFPI}})\approx RR_{PH}\cdot \Pr({\text{PH in population}})=10\cdot {\frac {1}{8000}}={\frac {1}{800}}=0.00125}
Primary hyperparathyroidism can be assumed to cause hypercalcemia essentially 100% of the time (rPH → hypercalcemia = 1), so this independently calculated probability of primary hyperparathyroidism (PH) can be assumed to be the same as the probability of being a cause of the presentation:
Pr
(
Hypercalcemia WHOIFPI by PH
)
=
Pr
(
PH WHOIFPI
)
⋅
r
PH
→
hypercalcemia
=
0.00125
⋅
1
=
0.00125
{\displaystyle {\begin{aligned}\Pr({\text{Hypercalcemia WHOIFPI by PH}})&=\Pr({\text{PH WHOIFPI}})\cdot r_{{\text{PH}}\rightarrow {\text{hypercalcemia}}}\\&=0.00125\cdot 1=0.00125\end{aligned}}}
For cancer, the same time-at-risk is assumed for simplicity, and let's say that the incidence of cancer in the area is estimated at 1 in 250 per year, giving a population probability of cancer of:
Pr
(
cancer in population
)
=
0.5
years
⋅
1
250 per year
=
1
500
{\displaystyle \Pr({\text{cancer in population}})=0.5{\text{ years}}\cdot {\frac {1}{\text{250 per year}}}={\frac {1}{500}}}
For simplicity, let's say that any association between a family history of primary hyperparathyroidism and risk of cancer is ignored, so the relative risk for the individual to have contracted cancer in the first place is similar to that of the population (RRcancer = 1):
Pr
(
cancer WHOIFPI
)
≈
R
R
cancer
⋅
Pr
(
cancer in population
)
=
1
⋅
1
500
=
1
500
=
0.002.
{\displaystyle \Pr({\text{cancer WHOIFPI}})\approx RR_{\text{cancer}}\cdot \Pr({\text{cancer in population}})=1\cdot {\frac {1}{500}}={\frac {1}{500}}=0.002.}
However, hypercalcemia only occurs in, very approximately, 10% of cancers, (rcancer → hypercalcemia = 0.1), so:
Pr
(
Hypercalcemia WHOIFPI by cancer
)
=
Pr
(
cancer WHOIFPI
)
⋅
r
cancer
→
hypercalcemia
=
0.002
⋅
0.1
=
0.0002.
{\displaystyle {\begin{aligned}&\Pr({\text{Hypercalcemia WHOIFPI by cancer}})\\=&\Pr({\text{cancer WHOIFPI}})\cdot r_{{\text{cancer}}\rightarrow {\text{hypercalcemia}}}\\=&0.002\cdot 0.1=0.0002.\end{aligned}}}
The probabilities that hypercalcemia would have occurred in the first place by other candidate conditions can be calculated in a similar manner. However, for simplicity, let's say that the probability that any of these would have occurred in the first place is calculated at 0.0005 in this example.
For the instance of there being no disease, the corresponding probability in the population is complementary to the sum of probabilities for other conditions:
Pr
(
no disease in population
)
=
1
−
Pr
(
PH in population
)
−
Pr
(
cancer in population
)
−
Pr
(
other conditions in population
)
=
0.997.
{\displaystyle {\begin{aligned}\Pr({\text{no disease in population}})&=1-\Pr({\text{PH in population}})-\Pr({\text{cancer in population}})\\&{}\quad -\Pr({\text{other conditions in population}})\\&{}=0.997.\end{aligned}}}
The probability that the individual would be healthy in the first place can be assumed to be the same:
Pr
(
no disease WHOIFPI
)
=
0.997.
{\displaystyle \Pr({\text{no disease WHOIFPI}})=0.997.\,}
The rate at which the case of no abnormal condition still ends up in measurement of serum calcium of being above the standard reference range (thereby classifying as hypercalcemia) is, by the definition of standard reference range, less than 2.5%. However, this probability can be further specified by considering how much the measurement deviates from the mean in the standard reference range. Let's say that the serum calcium measurement was 1.30 mmol/L, which, with a standard reference range established at 1.05 to 1.25 mmol/L, corresponds to a standard score of 3 and a corresponding probability of 0.14% that such degree of hypercalcemia would have occurred in the first place in the case of no abnormality:
r
no disease
→
hypercalcemia
=
0.0014
{\displaystyle r_{{\text{no disease}}\rightarrow {\text{hypercalcemia}}}=0.0014}
Subsequently, the probability that hypercalcemia would have resulted from no disease can be calculated as:
Pr
(
Hypercalcemia WHOIFPI by no disease
)
=
Pr
(
no disease WHOIFPI
)
⋅
r
no disease
→
hypercalcemia
=
0.997
⋅
0.0014
≈
0.0014
{\displaystyle {\begin{aligned}&\Pr({\text{Hypercalcemia WHOIFPI by no disease}})\\=&\Pr({\text{no disease WHOIFPI}})\cdot r_{{\text{no disease}}\rightarrow {\text{hypercalcemia}}}\\=&0.997\cdot 0.0014\approx 0.0014\end{aligned}}}
The probability that hypercalcemia would have occurred in the first place in the individual can thus be calculated as:
Pr
(
hypercalcemia WHOIFPI
)
=
Pr
(
hypercalcemia WHOIFPI by PH
)
+
Pr
(
hypercalcemia WHOIFPI by cancer
)
+
Pr
(
hypercalcemia WHOIFPI by other conditions
)
+
Pr
(
hypercalcemia WHOIFPI by no disease
)
=
0.00125
+
0.0002
+
0.0005
+
0.0014
=
0.00335
{\displaystyle {\begin{aligned}&\Pr({\text{hypercalcemia WHOIFPI}})\\=&\Pr({\text{hypercalcemia WHOIFPI by PH}})+\Pr({\text{hypercalcemia WHOIFPI by cancer}})\\&{}+\Pr({\text{hypercalcemia WHOIFPI by other conditions}})+\Pr({\text{hypercalcemia WHOIFPI by no disease}})\\=&0.00125+0.0002+0.0005+0.0014=0.00335\end{aligned}}}
Subsequently, the probability that hypercalcemia is caused by primary hyperparathyroidism (PH) in the individual can be calculated as:
Pr
(
hypercalcemia is caused by PH in individual
)
=
Pr
(
hypercalcemia WHOIFPI by PH
)
Pr
(
hypercalcemia WHOIFPI
)
=
0.00125
0.00335
=
0.373
=
37.3
%
{\displaystyle {\begin{aligned}&\Pr({\text{hypercalcemia is caused by PH in individual}})\\=&{\frac {\Pr({\text{hypercalcemia WHOIFPI by PH}})}{\Pr({\text{hypercalcemia WHOIFPI}})}}\\=&{\frac {0.00125}{0.00335}}=0.373=37.3\%\end{aligned}}}
Similarly, the probability that hypercalcemia is caused by cancer in the individual can be calculated as:
Pr
(
hypercalcemia is caused by cancer in individual
)
=
Pr
(
hypercalcemia WHOIFPI by cancer
)
Pr
(
hypercalcemia WHOIFPI
)
=
0.0002
0.00335
=
0.060
=
6.0
%
,
{\displaystyle {\begin{aligned}&\Pr({\text{hypercalcemia is caused by cancer in individual}})\\=&{\frac {\Pr({\text{hypercalcemia WHOIFPI by cancer}})}{\Pr({\text{hypercalcemia WHOIFPI}})}}\\=&{\frac {0.0002}{0.00335}}=0.060=6.0\%,\end{aligned}}}
and for other candidate conditions:
Pr
(
hypercalcemia is caused by other conditions in individual
)
=
Pr
(
hypercalcemia WHOIFPI by other conditions
)
Pr
(
hypercalcemia WHOIFPI
)
=
0.0005
0.00335
=
0.149
=
14.9
%
,
{\displaystyle {\begin{aligned}&\Pr({\text{hypercalcemia is caused by other conditions in individual}})\\=&{\frac {\Pr({\text{hypercalcemia WHOIFPI by other conditions}})}{\Pr({\text{hypercalcemia WHOIFPI}})}}\\=&{\frac {0.0005}{0.00335}}=0.149=14.9\%,\end{aligned}}}
and the probability that there actually is no disease:
Pr
(
hypercalcemia is present despite no disease in individual
)
=
Pr
(
hypercalcemia WHOIFPI by no disease
)
Pr
(
hypercalcemia WHOIFPI
)
=
0.0014
0.00335
=
0.418
=
41.8
%
{\displaystyle {\begin{aligned}&\Pr({\text{hypercalcemia is present despite no disease in individual}})\\=&{\frac {\Pr({\text{hypercalcemia WHOIFPI by no disease}})}{\Pr({\text{hypercalcemia WHOIFPI}})}}\\=&{\frac {0.0014}{0.00335}}=0.418=41.8\%\end{aligned}}}
For clarification, these calculations are given as the table in the method description:
Thus, this method estimates that the probability that the hypercalcemia is caused by primary hyperparathyroidism, cancer, other conditions or no disease at all are 37.3%, 6.0%, 14.9%, and 41.8%, respectively, which may be used in estimating further test indications.
This case is continued in the example of the method described in the next section.
=== Likelihood ratio-based method ===
The procedure of differential diagnosis can become extremely complex when fully taking additional tests and treatments into consideration. One method that is somewhat a tradeoff between being clinically perfect and being relatively simple to calculate is one that uses likelihood ratios to derive subsequent post-test likelihoods.
==== Theory ====
The initial likelihoods for each candidate condition can be estimated by various methods, such as:
By epidemiology as described in the previous section.
By clinic-specific pattern recognition, such as statistically knowing that patients coming into a particular clinic with a particular complaint statistically has a particular likelihood of each candidate condition.
One method of estimating likelihoods even after further tests uses likelihood ratios (which is derived from sensitivities and specificities) as a multiplication factor after each test or procedure. In an ideal world, sensitivities and specificities would be established for all tests for all possible pathological conditions. In reality, however, these parameters may only be established for one of the candidate conditions. Multiplying with likelihood ratios necessitates conversion of likelihoods from probabilities to odds in favor (hereafter simply termed "odds") by:
odds
=
probability
1
−
probability
{\displaystyle {\text{odds}}={\frac {\text{probability}}{1-{\text{probability}}}}}
However, only the candidate conditions with known likelihood ratio need this conversion. After multiplication, conversion back to probability is calculated by:
probability
=
odds
odds
+
1
{\displaystyle {\text{probability}}={\frac {\text{odds}}{{\text{odds}}+1}}}
The rest of the candidate conditions (for which there is no established likelihood ratio for the test at hand) can, for simplicity, be adjusted by subsequently multiplying all candidate conditions with a common factor to again yield a sum of 100%.
The resulting probabilities are used for estimating the indications for further medical tests, treatments or other actions. If there is an indication for an additional test, and it returns with a result, then the procedure is repeated using the likelihood ratio of the additional test. With updated probabilities for each of the candidate conditions, the indications for further tests, treatments, or other actions change as well, and so the procedure can be repeated until an endpoint where there no longer is any indication for currently performing further actions. Such an endpoint mainly occurs when one candidate condition becomes so certain that no test can be found that is powerful enough to change the relative probability profile enough to motivate any change in further actions. Tactics for reaching such an endpoint with as few tests as possible includes making tests with high specificity for conditions of already outstandingly high-profile-relative probability, because the high likelihood ratio positive for such tests is very high, bringing all less likely conditions to relatively lower probabilities. Alternatively, tests with high sensitivity for competing candidate conditions have a high likelihood ratio negative, potentially bringing the probabilities for competing candidate conditions to negligible levels. If such negligible probabilities are achieved, the clinician can rule out these conditions, and continue the differential diagnostic procedure with only the remaining candidate conditions.
==== Example ====
This example continues for the same patient as in the example for the epidemiology-based method. As with the previous example of epidemiology-based method, this example case is made to demonstrate how this method is applied but does not represent a guideline for handling similar real-world cases. Also, the example uses relatively specified numbers, while in reality, there are often just rough estimations. In this example, the probabilities for each candidate condition were established by an epidemiology-based method to be as follows:
These percentages could also have been established by experience at the particular clinic by knowing that these are the percentages for final diagnosis for people presenting to the clinic with hypercalcemia and having a family history of primary hyperparathyroidism.
The condition of highest profile-relative probability (except "no disease") is primary hyperparathyroidism (PH), but cancer is still of major concern, because if it is the actual causative condition for the hypercalcemia, then the choice of whether to treat or not likely means life or death for the patient, in effect potentially putting the indication at a similar level for further tests for both of these conditions.
Here, let's say that the clinician considers the profile-relative probabilities of being of enough concern to indicate sending the patient a call for a clinician visit, with an additional visit to the medical laboratory for an additional blood test complemented with further analyses, including parathyroid hormone for the suspicion of primary hyperparathyroidism.
For simplicity, let's say that the clinician first receives the blood test (in formulas abbreviated as "BT") result for the parathyroid hormone analysis and that it showed a parathyroid hormone level that is elevated relative to what would be expected by the calcium level.
Such a constellation can be estimated to have a sensitivity of approximately 70% and a specificity of approximately 90% for primary hyperparathyroidism. This confers a likelihood ratio positive of 7 for primary hyperparathyroidism.
The probability of primary hyperparathyroidism is now termed Pre-BTPH because it corresponds to before the blood test (Latin preposition prae means before). It was estimated at 37.3%, corresponding to an odds of 0.595. With the likelihood ratio positive of 7 for the blood test, the post-test odds is calculated as:
Odds
(
PostBT
P
H
)
=
Odds
(
PreBT
P
H
)
⋅
L
H
(
B
T
)
=
0.595
⋅
7
=
4.16
,
{\displaystyle \operatorname {Odds} ({\text{PostBT}}_{PH})=\operatorname {Odds} ({\text{PreBT}}_{PH})\cdot LH(BT)=0.595\cdot 7=4.16,}
where:
Odds(PostBTPH) is the odds for primary hyperparathyroidism after the blood test for parathyroid hormone
Odds(PreBTPH is the odds in favor of primary hyperparathyroidism before the blood test for parathyroid hormone
LH(BT) is the likelihood ratio positive for the blood test for parathyroid hormone
An Odds(PostBTPH) of 4.16 is again converted to the corresponding probability by:
Pr
(
PostBT
P
H
)
=
Odds
(
PostBT
P
H
)
Odds
(
PostBT
P
H
)
+
1
=
4.16
4.16
+
1
=
0.806
=
80.6
%
{\displaystyle \Pr({\text{PostBT}}_{PH})={\frac {\operatorname {Odds} ({\text{PostBT}}_{PH})}{\operatorname {Odds} ({\text{PostBT}}_{PH})+1}}={\frac {4.16}{4.16+1}}=0.806=80.6\%}
The sum of the probabilities for the rest of the candidate conditions should therefore be:
Pr
(
PostBT
r
e
s
t
)
=
100
%
−
80.6
%
=
19.4
%
{\displaystyle \Pr({\text{PostBT}}_{rest})=100\%-80.6\%=19.4\%}
Before the blood test for parathyroid hormone, the sum of their probabilities were:
Pr
(
PreBT
rest
)
=
6.0
%
+
14.9
%
+
41.8
%
=
62.7
%
{\displaystyle \Pr({\text{PreBT}}_{\text{rest}})=6.0\%+14.9\%+41.8\%=62.7\%}
Therefore, to conform to a sum of 100% for all candidate conditions, each of the other candidates must be multiplied by a correcting factor:
Correcting factor
=
Pr
(
PostBT
rest
)
Pr
(
PreBT
rest
)
=
19.4
62.7
=
0.309
{\displaystyle {\text{Correcting factor}}={\frac {\Pr({\text{PostBT}}_{\text{rest}})}{\Pr({\text{PreBT}}_{\text{rest}})}}={\frac {19.4}{62.7}}=0.309}
For example, the probability of cancer after the test is calculated as:
Pr
(
PostBT
cancer
)
=
Pr
(
PreBT
cancer
)
⋅
Correcting factor
=
6.0
%
⋅
0.309
=
1.9
%
{\displaystyle \Pr({\text{PostBT}}_{\text{cancer}})=\Pr({\text{PreBT}}_{\text{cancer}})\cdot {\text{Correcting factor}}=6.0\%\cdot 0.309=1.9\%}
The probabilities for each candidate conditions before and after the blood test are given in following table:
These "new" percentages, including a profile-relative probability of 80% for primary hyperparathyroidism, underlie any indications for further tests, treatments, or other actions. In this case, let's say that the clinician continues the plan for the patient to attend a clinician visit for a further checkup, especially focused on primary hyperparathyroidism.
A clinician visit can, theoretically, be regarded as a series of tests, including both questions in a medical history, as well as components of a physical examination, where the post-test probability of a previous test, can be used as the pre-test probability of the next. The indications for choosing the next test are dynamically influenced by the results of previous tests.
Let's say that the patient in this example is revealed to have at least some of the symptoms and signs of depression, bone pain, joint pain or constipation of more severity than what would be expected by the hypercalcemia itself, supporting the suspicion of primary hyperparathyroidism, and let's say that the likelihood ratios for the tests, when multiplied together, roughly results in a product of 6 for primary hyperparathyroidism.
The presence of unspecific pathologic symptoms and signs in the history and examination are often concurrently indicative of cancer as well, and let's say that the tests gave an overall likelihood ratio estimated at 1.5 for cancer. For other conditions, as well as the instance of not having any disease at all, let's say that it is unknown how they are affected by the tests at hand, as often happens in reality. This gives the following results for the history and physical examination (abbreviated as P&E):
These probabilities after the history and examination may make the physician confident enough to plan the patient for surgery for a parathyroidectomy to resect the affected tissue.
At this point, the probability of "other conditions" is so low that the physician cannot think of any test for them that could make a difference that would be substantial enough to form an indication for such a test, and the physician thereby practically regards "other conditions" as ruled out, in this case not primarily by any specific test for such other conditions that were negative, but rather by the absence of positive tests so far.
For "cancer", the cutoff at which to confidently regard it as ruled out maybe more stringent because of severe consequences of missing it, so the physician may consider that at least a histopathologic examination of the resected tissue is indicated.
This case is continued in the example of Combinations in the corresponding section below.
== Coverage of candidate conditions ==
The validity of both the initial estimation of probabilities by epidemiology and further workup by likelihood ratios are dependent on the inclusion of candidate conditions that are responsible for a large part as possible of the probability of having developed the condition, and it is clinically important to include those where relatively fast initiation of therapy is most likely to result in the greatest benefit. If an important candidate condition is missed, no method of differential diagnosis will supply the correct conclusion. The need to find more candidate conditions for inclusion increases with the increasing severity of the presentation itself. For example, if the only presentation is a deviating laboratory parameter and all common harmful underlying conditions have been ruled out, then it may be acceptable to stop finding more candidate conditions, but this would much more likely be unacceptable if the presentation would have been severe pain.
== Combinations ==
If two conditions get high post-test probabilities, especially if the sum of the probabilities for conditions with known likelihood ratios becomes higher than 100%, then the actual condition is a combination of the two. In such cases, that combined condition can be added to the list of candidate conditions, and the calculations should start over from the beginning.
To continue the example used above, let's say that the history and physical examination were indicative of cancer as well, with a likelihood ratio of 3, giving an Odds(PostH&E) of 0.057, corresponding to a P(PostH&E) of 5.4%. This would correspond to a "Sum of known P(PostH&E)" of 101.5%. This is an indication for considering a combination of primary hyperparathyroidism and cancer, such as, in this case, a parathyroid hormone-producing parathyroid carcinoma. A recalculation may therefore be needed, with the first two conditions being separated into "primary hyperparathyroidism without cancer", "cancer without primary hyperparathyroidism" as well as "combined primary hyperparathyroidism and cancer", and likelihood ratios being applied to each condition separately. In this case, however, tissue has already been resected, wherein a histopathologic examination can be performed that includes the possibility of parathyroid carcinoma in the examination (which may entail appropriate sample staining).
Let's say that the histopathologic examination confirms primary hyperparathyroidism, but also showed a malignant pattern. By an initial method by epidemiology, the incidence of parathyroid carcinoma is estimated at 1 in 6 million people per year, giving a very low probability before taking any tests into consideration. In comparison, the probability that non-malignant primary hyperparathyroidism would have occurred at the same time as an unrelated non-carcinoma cancer that presents with malignant cells in the parathyroid gland is calculated by multiplying the probabilities of the two. The resultant probability is, however, much smaller than the 1 in 6 million. Therefore, the probability of parathyroid carcinoma may still be close to 100% after histopathologic examination despite the low probability of occurring in the first place.
== Machine differential diagnosis ==
Machine differential diagnosis is the use of computer software to partly or fully make a differential diagnosis. It may be regarded as an application of artificial intelligence. Alternatively, it may be seen as "augmented intelligence" if it meets the FDA criteria, namely that (1) it reveals the underlying data, (2) reveals the underlying logic, and (3) leaves the clinician in charge to shape and make the decision. Machine learning AI is generally seen as a device by the FDA, whereas augmented intelligence applications are not.
Many studies demonstrate improvement of quality of care and reduction of medical errors by using such decision support systems. Some of these systems are designed for a specific medical problem such as schizophrenia, Lyme disease or ventilator-associated pneumonia. Others are designed to cover all major clinical and diagnostic findings to assist physicians with faster and more accurate diagnosis.
However, these tools all still require advanced medical skills to rate symptoms and choose additional tests to deduce the probabilities of different diagnoses. Machine differential diagnosis is also currently unable to diagnose multiple concurrent disorders. Their usage by non-experts is therefore not a substitute for professional diagnosis.
== History ==
The method of differential diagnosis was first suggested for use in the diagnosis of mental disorders by Emil Kraepelin. It is more systematic than the old-fashioned method of diagnosis by gestalt (impression).
== Alternative medical meanings ==
"Differential diagnosis" is also used more loosely to refer simply to a list of the most common causes of a given symptom, to a list of disorders similar to a given disorder, or to such lists when they are annotated with advice on how to narrow the list down (French's Index of Differential Diagnosis is an example). Thus, a differential diagnosis in this sense is medical information specially organized to aid in diagnosis.
== Usage apart from in medicine ==
Methods similar to those of differential diagnostic processes in medicine are also used by biological taxonomists to identify and classify organisms, living and extinct. For example, after finding an unknown species, there can first be a listing of all potential species, followed by ruling out of one by one until, optimally, only one potential choice remains.
Similar procedures may be used by plant and maintenance engineers and automotive mechanics and used to be used in diagnosing faulty electronic circuitry.
== In popular culture ==
In the American television medical drama House, the main protagonist Dr. Gregory House leads a team of diagnosticians who regularly use differential diagnostics procedures.
== See also ==
Comorbidity
Diagnosis of exclusion
Dual diagnosis
Gender-bias in medical diagnosis
List of medical symptoms
== References == | Wikipedia/Differential_diagnosis |
A non-communicable disease (NCD) is a disease that is not transmissible directly from one person to another. NCDs include Parkinson's disease, autoimmune diseases, strokes, heart diseases, cancers, diabetes, chronic kidney disease, osteoarthritis, osteoporosis, Alzheimer's disease, cataracts, and others. NCDs may be chronic or acute. Most are non-infectious, although there are some non-communicable infectious diseases, such as parasitic diseases in which the parasite's life cycle does not include direct host-to-host transmission.
The four main NCDs that are the leading causes of death globally are cardiovascular disease, cancer, chronic respiratory diseases, and diabetes. NCDs account for seven out of the ten leading causes of death worldwide. Figures given for 2019 are 41 million deaths due to NCDs worldwide. Of these 17.9 million were due to cardiovascular disease; 9.3 million due to cancer; 4.1 million to chronic respiratory diseases, and 2.0 million to diabetes. Over 80% of the deaths from these four groups were premature, not reaching the age of 70.
Risk factors such as a person's background, lifestyle and environment increase the likelihood of certain NCDs. Every year, at least 5 million people die because of tobacco use and about 2.8 million die from being overweight. High cholesterol accounts for roughly 2.6 million deaths and 7.5 million die because of high blood pressure.
== Risk factors ==
Risk factors such as a person's background; lifestyle and environment are known to increase the likelihood of certain non-communicable diseases. They include age, gender, genetics, exposure to air pollution, and behaviors such as smoking, unhealthy diet and physical inactivity which can lead to hypertension and obesity, in turn leading to increased risk of many NCDs. Most NCDs are considered preventable because they are caused by modifiable risk factors.
The WHO's World Health Report 2002 identified five important risk factors for non-communicable disease in the top ten leading risks to health. These are raised blood pressure, raised cholesterol, tobacco use, alcohol consumption, and being overweight. The other factors associated with higher risk of NCDs include a person's economic and social conditions, also known as the social determinants of health.
It has been estimated that if the primary risk factors were eliminated, 80% of the cases of heart disease, stroke and type 2 diabetes and 40% of cancers could be prevented. Interventions targeting the main risk factors could have a significant impact on reducing the burden of disease worldwide. Efforts focused on better diet and increased physical activity have been shown to control the prevalence of NCDs .
== Environmental diseases ==
NCDs include many environmental diseases covering a broad category of avoidable and unavoidable human health conditions caused by external factors, such as sunlight, nutrition, pollution, and lifestyle choices. The diseases of affluence are non-infectious diseases with environmental causes. Examples include:
Many types of cardiovascular disease (CVD)
Chronic obstructive pulmonary disease (COPD) caused by smoking tobacco
Diabetes mellitus type 2
Noise-induced hearing loss
Lower back pain caused by too little exercise
Malnutrition caused by too little food, or eating the wrong kinds of food (e.g. scurvy from lack of Vitamin C)
Skin cancer caused by radiation from the sun
Obesity
=== Inherited diseases ===
Genetic disorders are caused by errors in genetic information that produce diseases in the affected people.
The origin of these genetic errors can be:
Spontaneous errors or mutations to the genome:
A change in chromosome numbers, such as Down syndrome.
A defect in a gene caused by mutation, such as Cystic fibrosis.
An increase in the amount of genetic information, such as Chimerism or Heterochromia.
Cystic fibrosis is an example of an inherited disease that is caused by a mutation on a gene. The faulty gene impairs the normal movement of sodium chloride in and out of cells, which causes the mucus-secreting organs to produce abnormally thick mucus. The gene is recessive, meaning that a person must have two copies of the faulty gene for them to develop the disease. Cystic fibrosis affects the respiratory, digestive and reproductive systems, as well as the sweat glands. The mucus secreted is very thick and blocks passageways in the lungs and digestive tracts. This mucus causes problems with breathing and with the digestion and absorption of nutrients.
Inherited genetic errors from parents:
Dominant genetic diseases, such as Huntingtons, require the inheritance of one erroneous gene to be expressed.
Recessive genetic diseases require the inheritance of erroneous genes to be expressed and this is one reason they work together.
== Global health ==
Referred to as a "lifestyle" disease, because the majority of these diseases are preventable illnesses, the most common causes for non-communicable diseases (NCD) include tobacco use (smoking), hazardous alcohol use, poor diets (high consumption of sugar, salt, saturated fats, and trans fatty acids) and physical inactivity. Currently, NCD kills 36 million people a year, a number that by some estimates is expected to rise by 17–24% within the next decade.
The World Health Organization has reported that, "At a global level, 7 of the 10 leading causes of deaths in 2021 were noncommunicable diseases, accounting for 38% of all deaths, or 68% of the top 10 causes."
Historically, many NCDs were associated with economic development and were so-called a "diseases of the rich". The burden of non-communicable diseases in developing countries has increased however, with an estimated 80% of the four main types of NCDs — cardiovascular diseases, cancers, chronic respiratory diseases and diabetes — now occurring in low- and middle-income countries. Action Plan for the Global Strategy for the Prevention and Control of non-communicable Diseases and with two-thirds of people who are affected by diabetes now residing in developing nations, NCD can no longer be considered just a problem affecting affluent estimation of the economic impact of chronic non-communicable diseases in selected countries. New WHO report: deaths from non-communicable diseases are on the rise, with developing world hit hardest. As previously stated, in 2008 alone, NCD's were the cause of 63% of deaths worldwide; a number that is expected to rise considerably in the near future if measures are not taken.
If present growth trends are maintained, by 2020, NCDs will attribute to 7 out of every 10 deaths in developing countries, killing 52 million people annually worldwide by 2030. With statistics such as these, it comes as no surprise that international entities such as the World Health Organization & World Bank Human Development Network have identified the prevention and control of NCDs as an increasingly important discussion item on the global health agenda.
Thus, should policy makers and communities mobilize "and make prevention and targeted treatment of such diseases a priority," sustainable measures can be implemented to stagnate (and eventually even reverse) this emerging global health threat. Potential measures currently being discussed by the(World Health Organization)-Food and Agriculture Organization includes reducing the levels of salt in foods, limiting inappropriate marketing of unhealthy foods and non-alcoholic beverages to children, imposing controls on harmful alcohol use, raising taxes on tobacco, and legislating to curb smoking in public places.
=== United Nations ===
The World Health Organization is the specialized agency of the United Nations (UN) that acts as coordinating authority on international public health issues, including NCDs. In May 2008, the 193 Member States of the WHO approved a six-year plan to address non-communicable diseases, especially the rapidly increasing burden in low- and middle-income countries. The plan calls for raising the priority given to NCDs in international development work'.
During the 64th session of the United Nations General Assembly in 2010, a resolution was passed to call for a high-level meeting of the General Assembly on the prevention and treatment NCDs with the participation of heads of state and government. The resolution also encouraged UN Member States to address the issue of non-communicable diseases at the 2010 Review Summit for the Millennium Development Goals.
=== Global Non-communicable Disease Network ===
In order to better coordinate efforts around the globe, in 2009 the WHO announced the launch of the Global Non-communicable Disease Network (NCDnet). NCDnet will consist of leading health organizations and experts from around the world in order to fight against diseases such as cancer, cardiovascular disease, and diabetes. Ala Alwan, assistant director-general for Non-communicable Diseases and Mental Health at the WHO, said: "integrating the prevention of non-communicable diseases and injuries into the national and global development agendas is not only achievable but also a priority for developing countries."
=== NCD Alliance ===
The NCD Alliance is a global partnership founded in May 2009 by four international federations representing cardiovascular disease, diabetes, cancer, and chronic respiratory disease. The NCD Alliance brings together roughly 900 national member associations to fight non-communicable disease. Long-term aims of the Alliance include:
NCD/disease national plans for all
A tobacco free world
Improved lifestyles
Strengthened health systems
Global access to affordable and good quality medicines and technologies
Human rights for people with NCDs.
=== Task Force ===
The United Nations Interagency Task Force on the Prevention and Control of Non-communicable Diseases (UNIATF) was established by the United Nations Secretary-General in 2013 in order to provide scaled up action across the UN system to support governments, in particular in low- and middle-income countries, to tackle non-communicable diseases.
=== Young Professionals Chronic Disease Network ===
The Young Professionals Chronic Disease Network, or commonly referred to as YP-CDN, is a global network of roughly 5000 young professionals across 157 countries. The organization aims to mobilize these young people "to take action against social injustice driven by NCDs.".
Now redirected to the Sustainable development knowledge platform.
== Economics ==
Previously, chronic NCDs were considered a problem limited mostly to high income countries, while infectious diseases seemed to affect low income countries. The burden of disease attributed to NCDs has been estimated at 85% in industrialized nations, 70% in middle income nations, and nearly 50% in countries with the lowest national incomes. In 2008, chronic NCDs accounted for more than 60% (over 35 million) of the 57 million deaths worldwide. Given the global population distribution, almost 80% of deaths due to chronic NCDs worldwide now occur in low and middle income countries, while only 20% occur in higher income countries.
National economies are reportedly suffering significant losses due to premature deaths or inability to work resulting from heart disease, stroke, diabetes, and the broader impacts of physical inactivity, which is a significant contributor to NCDs globally. For instance, China is expected to lose roughly $558 billion in national income between 2005 and 2015 due to early deaths. In 2005, heart disease, stroke and diabetes caused an estimated loss in international dollars of national income of 9 billion in India and 3 billion in Brazil.
Following up on the 2023 edition of the FAO report – The State of Food and Agriculture – the subsequent edition provides a detailed breakdown of the hidden costs associated with unhealthy dietary patterns and non-communicable diseases for 156 countries. These hidden costs were measured as productivity losses due to disease-burden. The report finds that in 2020, global health hidden costs amounted 8.1 trillion 2020 PPP dollars, 70 percent of all of the hidden costs of agrifood systems. Diets low in whole grains are the leading concern (18 percent of global quantified health hidden costs), alongside diets high in sodium and low in fruits (16 percent each), although there is significant variation across countries.
=== Absenteeism and presenteeism ===
The burden of chronic NCDs including mental health conditions is felt in workplaces around the world, notably due to elevated levels of absenteeism, or absence from work because of illness, and presenteeism, or productivity lost from staff coming to work and performing below normal standards due to poor health. For example, the United Kingdom experienced a loss of about 175 million days in 2006 to absence from illness among a working population of 37.7 million people. The estimated cost of absences due to illness was over 20 billion pounds in the same year. The cost due to presenteeism is likely even larger, although methods of analyzing the economic impacts of presenteeism are still being developed. Methods for analyzing the distinct workplace impacts of NCDs versus other types of health conditions are also still being developed.
== Key diseases ==
=== Cancer ===
For the vast majority of cancers, risk factors are environmental or lifestyle-related, thus cancers are mostly preventable NCD. Greater than 30% of cancer is preventable via avoiding risk factors including: tobacco, being overweight or obesity, low fruit and vegetable intake, physical inactivity, alcohol, sexually transmitted infections, and air pollution. Infectious agents are responsible for some cancers, for instance almost all cervical cancers are caused by human papillomavirus infection.
=== Cardiovascular disease ===
The first studies on cardiovascular health were performed in 1949 by Jerry Morris using occupational health data and were published in 1958. The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis. A trend has emerged, particularly in the early 2000s, in which numerous studies have revealed a link between fast food and an increase in heart disease. These studies include those conducted by the Ryan Mackey Memorial Research Institute, Harvard University and the Sydney Center for Cardiovascular Health. Many major fast food chains, particularly McDonald's, have protested the methods used in these studies and have responded with healthier menu options.
A fairly recent emphasis is on the link between low-grade inflammation that hallmarks atherosclerosis and its possible interventions. C-reactive protein (CRP) is a common inflammatory marker that has been found to be present in increased levels in patients at risk for cardiovascular disease. Also osteoprotegerin which involved with regulation of a key inflammatory transcription factor called NF-κB has been found to be a risk factor of cardiovascular disease and mortality.
=== Diabetes ===
Type 2 Diabetes Mellitus is a chronic condition which is largely preventable and manageable but difficult to cure. Management concentrates on keeping blood sugar levels as close to normal ("euglycemia") as possible without presenting undue patient danger. This can usually be with close dietary management, exercise, and use of appropriate medications (insulin only in the case of type 1 diabetes mellitus. Oral medications may be used in the case of type 2 diabetes, as well as insulin).
Patient education, understanding, and participation is vital since the complications of diabetes are far less common and less severe in people who have well-managed blood sugar levels.
Wider health problems may accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.
=== Chronic kidney disease ===
Although chronic kidney disease (CKD) is not currently identified as one of WHO's main targets for global NCD control, there is compelling evidence that CKD is not only common, harmful and treatable but also a major contributing factor to the incidence and outcomes of at least three of the diseases targeted by WHO (diabetes, hypertension and CVD).
CKD strongly predisposes to hypertension and CVD; diabetes, hypertension and CVD are all major causes of CKD; and major risk factors for diabetes, hypertension and CVD (such as obesity and smoking) also cause or exacerbate CKD. In addition, among people with diabetes, hypertension, or CVD, the subset who also have CKD are at highest risk of adverse outcomes and high health care costs. Thus, CKD, diabetes and cardiovascular disease are closely associated conditions that often coexist; share common risk factors and treatments; and would benefit from a coordinated global approach to prevention and control.
=== Chronic respiratory disease ===
Chronic respiratory diseases (CRDs) are diseases of the lungs and airways. According to the World Health Organization (WHO) hundreds of millions of people have CRDs. Common CRDs are: asthma, chronic obstructive pulmonary disease, occupational lung disease, and pulmonary hypertension. While CRDs are not curable, various treatments are available to help improve quality of life for individuals who have them. Most treatments involve dilating major airways to improve shortness of breath among other symptoms. The main risk factors for developing CRDs are: tobacco smoking, indoor and outdoor air pollution, allergens, and occupational risks.
WHO helped launch the Global Alliance against Chronic Respiratory Diseases (GARD) in 2006. GARD is voluntarily composed of national and international organizations and works toward "reducing the global burden of chronic respiratory diseases" and focus mainly on vulnerable populations and low and middle-income countries.
== See also ==
List of countries by risk of death from non-communicable disease
Chronic disease
Global health
The INCTR Challenge Fund project of the International Network for Cancer Treatment and Research
== References ==
This article incorporates text from a free content work. Licensed under CC BY 4.0 (license statement/permission). Text taken from In Brief to The State of Food and Agriculture 2024, FAO, FAO.
== Further reading ==
== External links ==
WHO fact sheet on non-communicable diseases
WHO Regional Office for the Eastern Mediterranean website on non-communicable diseases
"NCDnet — Global Noncommunicable Disease Network". World Health Organization. Archived from the original on December 23, 2009. | Wikipedia/Non-infectious_disease |
A male genital disease is a condition that affects the male reproductive system. The human male genitals consist of testicles and epididymides, ductus deferentes, seminal vesicles and ejaculatory ducts, prostate, bulbourethral glands, and penis.
== Classification by type of disease ==
=== Infection ===
==== Aetiological agents ====
===== Bacterial =====
Erythrasma
Balanoposthitis
Fournier's Gangrene
===== Fungus =====
Candidiasis
Tinea cruris
===== Parasites =====
Cutaneous larva migrans
Pubic lice
Scabies
Tick
===== Virus =====
Molluscum contagiosum
Herpes: simplex, zoster
=== Cancers ===
The probability of contracting a cancerous development depends on age, ethnicity and the existence, or non-existence, of environmental causation. Unlike all other genitally situated cancers, the incidence of penis cancer is related to the sexual mode of transmission.
=== Inflammation ===
An example of a male genital disease is orchitis.
== Classification by location of disease ==
=== Penis ===
Mondor's disease is a non-common disease
Peyronie's disease is diagnosed when there is evidence of scar tissue formation within the tunica albuginea, tissue which contributes to the maintenance of the erectile state
=== Prostate ===
The three most statistically frequently occurring diseases of the prostate gland are benign hyperplasia (a swelling of the gland, not due to cancerous accumulation), prostatitis (inflammation), and cancer (which is the accumulation of malignant cells in the gland).
== See also ==
Female genital disease
== References ==
== External links == | Wikipedia/Male_genital_disease |
Disseminated disease can refer to disseminated cancer which is the movement of cancerous cells from the original tumor to other areas of the body, or disseminated infection which is the pathogen's entry into the host, growth, and dissemination, which results in illness.
After exiting the main tumor, cancer cells circulate throughout the body. They are known as circulating tumor cells once they are in the blood. Few circulating tumor cells can disseminate to distant locations and remain tumor cells. The amount of disseminated tumor cells that can develop into metastases is even lower.
== See also ==
Metastasis
Localized disease
== References ==
== Further reading ==
Albert, WH; Hauch, S; Zieglschmid, V (2005). "Detection of Disseminated Cancer Cells in Blood". EJIFCC. 16 (2). International Federation of Clinical Chemistry and Laboratory Medicine: 81–85. PMC 6008966. PMID 29942243.
Ramamoorthi, Ganesan; Kodumudi, Krithika; Gallen, Corey; Zachariah, Nadia Nocera; Basu, Amrita; Albert, Gabriella; Beyer, Amber; Snyder, Colin; Wiener, Doris; Costa, Ricardo L.B.; Czerniecki, Brian J. (2022). "Disseminated cancer cells in breast cancer: Mechanism of dissemination and dormancy and emerging insights on therapeutic opportunities". Seminars in Cancer Biology. 78. Elsevier BV: 78–89. doi:10.1016/j.semcancer.2021.02.004. ISSN 1044-579X. PMID 33626407.
== External links == | Wikipedia/Disseminated_disease |
Airborne transmission or aerosol transmission is transmission of an infectious disease through small particles suspended in the air. Infectious diseases capable of airborne transmission include many of considerable importance both in human and veterinary medicine. The relevant infectious agent may be viruses, bacteria, or fungi, and they may be spread through breathing, talking, coughing, sneezing, raising of dust, spraying of liquids, flushing toilets, or any activities which generate aerosol particles or droplets.
== Infectious aerosols: physical terminology ==
Aerosol transmission has traditionally been considered distinct from transmission by droplets, but this distinction is no longer used. Respiratory droplets were thought to rapidly fall to the ground after emission: but smaller droplets and aerosols also contain live infectious agents, and can remain in the air longer and travel farther. Individuals generate aerosols and droplets across a wide range of sizes and concentrations, and the amount produced varies widely by person and activity. Larger droplets greater than 100 μm usually settle within 2 m. Smaller particles can carry airborne pathogens for extended periods of time. While the concentration of airborne pathogens is greater within 2m, they can travel farther and concentrate in a room.
The traditional size cutoff of 5 μm between airborne and respiratory droplets has been discarded, as exhaled particles form a continuum of sizes whose fates depend on environmental conditions in addition to their initial sizes. This error has informed hospital based transmission based precautions for decades. Indoor respiratory secretion transfer data suggest that droplets/aerosols in the 20 μm size range initially travel with the air flow from cough jets and air conditioning like aerosols, but fall out gravitationally at a greater distance as "jet riders". As this size range is most efficiently filtered out in the nasal mucosa, the primordial infection site in COVID-19, aerosols/droplets in this size range may contribute to driving the COVID-19 pandemic.
== Overview ==
Airborne diseases can be transmitted from one individual to another through the air. The pathogens transmitted may be any kind of microbe, and they may be spread in aerosols, dust or droplets. The aerosols might be generated from sources of infection such as the bodily secretions of an infected individual, or biological wastes. Infectious aerosols may stay suspended in air currents long enough to travel for considerable distances; sneezes, for example, can easily project infectious droplets for dozens of feet (ten or more meters).
Airborne pathogens or allergens typically enter the body via the nose, throat, sinuses and lungs. Inhalation of these pathogens affects the respiratory system and can then spread to the rest of the body. Sinus congestion, coughing and sore throats are examples of inflammation of the upper respiratory airway. Air pollution plays a significant role in airborne diseases. Pollutants can influence lung function by increasing air way inflammation.
Common infections that spread by airborne transmission include SARS-CoV-2; measles morbillivirus, chickenpox virus; Mycobacterium tuberculosis, influenza virus, enterovirus, norovirus and less commonly other species of coronavirus, adenovirus, and possibly respiratory syncytial virus. Some pathogens which have more than one mode of transmission are also anisotropic, meaning that their different modes of transmission can cause different kinds of diseases, with different levels of severity. Two examples are the bacterias Yersinia pestis (which causes plague) and Francisella tularensis (which causes tularaemia), which both can cause severe pneumonia, if transmitted via the airborne route through inhalation.
Poor ventilation enhances transmission by allowing aerosols to spread undisturbed in an indoor space. Crowded rooms are more likely to contain an infected person. The longer a susceptible person stays in such a space, the greater chance of transmission. Airborne transmission is complex, and hard to demonstrate unequivocally but the Wells-Riley model can be used to make simple estimates of infection probability.
Some airborne diseases can affect non-humans. For example, Newcastle disease is an avian disease that affects many types of domestic poultry worldwide that is airborne.
It has been suggested that airborne transmission should be classified as being either obligate, preferential, or opportunistic, although there is limited research that show the importance of each of these categories. Obligate airborne infections spread only through aerosols; the most common example of this category is tuberculosis. Preferential airborne infections, such as chicken pox, can be obtained through different routes, but mainly by aerosols. Opportunistic airborne infections such as influenza typically transmit through other routes; however, under favourable conditions, aerosol transmission can occur.
== Transmission efficiency ==
Environmental factors influence the efficacy of airborne disease transmission; the most evident environmental conditions are temperature and relative humidity.
The transmission of airborne diseases is affected by all the factors that influence temperature and humidity, in both meteorological (outdoor) and human (indoor) environments. Circumstances influencing the spread of droplets containing infectious particles can include pH, salinity, wind, air pollution, and solar radiation as well as human behavior.
Airborne infections usually land in the respiratory system, with the agent present in aerosols (infectious particles < 5 μm in diameter). This includes dry particles, often the remnant of an evaporated wet particle called nuclei, and wet particles.
Relative humidity (RH) plays an important role in the evaporation of droplets and the distance they travel. 30 μm droplets evaporate in seconds. The CDC recommends a minimum of 40% RH indoors to significantly reduce the infectivity of aerosolized virus. An ideal humidity for preventing aerosol respiratory viral transmission at room temperature appears to be between 40% and 60% RH. If the relative humidity goes below 35% RH, infectious virus stays longer in the air.
The number of rainy days (more important than total precipitation); mean daily sunshine hours; latitude and altitude are relevant when assessing the possibility of spread of airborne disease. Some infrequent or exceptional events influence the dissemination of airborne diseases, including tropical storms, hurricanes, typhoons, or monsoons.
Climate affects temperature, winds and relative humidity, the main factors affecting the spread, duration and infectiousness of droplets containing infectious particles. The influenza virus spreads easily in the Northern Hemisphere winter due to climate conditions that favour the infectiousness of the virus.
Isolated weather events decrease the concentration of airborne fungal spores; a few days later, number of spores increases exponentially.
Socioeconomics has a minor role in airborne disease transmission. In cities, airborne disease spreads more rapidly than in rural areas and urban outskirts. Rural areas generally favor higher airborne fungal dissemination.
Proximity to large bodies of water such as rivers and lakes can enhance airborne disease.
A direct association between insufficient ventilation rates and increased COVID-19 transmission has been observed. Prior to COVID-19, standards for ventilation systems focused more on supplying sufficient oxygen to a room, rather than disease-related aspects of air quality.
Poor maintenance of air conditioning systems has led to outbreaks of Legionella pneumophila.
Hospital-acquired airborne diseases are associated with poorly-resourced and maintained medical systems.
Air conditioning may reduce transmission by removing contaminated air, but may also contribute to the spread of respiratory secretions inside a room.
The new findings reveal that understanding airflow patterns is even more crucial than simply increasing air changes per hour. During the COVID-19 pandemic, the common advice was to maximize ventilation, but this may not always be the most effective approach. A room can be well-prepared to prevent the spread of infectious diseases even at a low ACH. This insight could lead to safer building designs and significant energy savings during future pandemics.
== Prevention ==
A layered risk-management approach to slowing the spread of a transmissible disease attempts to minimize risk through multiple layers of interventions. Each intervention has the potential to reduce risk. A layered approach can include interventions by individuals (e.g. mask wearing, hand hygiene), institutions (e.g. surface disinfection, ventilation, and air filtration measures to control the indoor environment), the medical system (e.g. vaccination) and public health at the population level (e.g. testing, quarantine, and contact tracing).
Preventive techniques can include disease-specific immunization as well as nonpharmaceutical interventions such as wearing a respirator and limiting time spent in the presence of infected individuals. Wearing a face mask can lower the risk of airborne transmission to the extent that it limits the transfer of airborne particles between individuals. The type of mask that is effective against airborne transmission is dependent on the size of the particles. While fluid-resistant surgical masks prevent large droplet inhalation, smaller particles which form aerosols require a higher level of protection with filtration masks rated at N95 (US) or FFP3 (EU) required. Use of FFP3 masks by staff managing patients with COVID-19 reduced acquisition of COVID-19 by staff members.
Engineering solutions which aim to control or eliminate exposure to a hazard are higher on the hierarchy of control than personal protective equipment (PPE). At the level of physically based engineering interventions, effective ventilation and high frequency air changes, or air filtration through high efficiency particulate filters, reduce detectable levels of virus and other bioaerosols, improving conditions for everyone in an area. Portable air filters, such as those tested in Conway Morris A et al. present a readily deployable solution when existing ventilation is inadequate, for instance in repurposed COVID-19 hospital facilities.
The United States Centers for Disease Control and Prevention (CDC) advises the public about vaccination and following careful hygiene and sanitation protocols for airborne disease prevention. Many public health specialists recommend physical distancing (also known as social distancing) to reduce transmission.
A 2011 study concluded that vuvuzelas (a type of air horn popular e.g. with fans at football games) presented a particularly high risk of airborne transmission, as they were spreading a much higher number of aerosol particles than e.g., the act of shouting.
Exposure does not guarantee infection. The generation of aerosols, adequate transport of aerosols through the air, inhalation by a susceptible host, and deposition in the respiratory tract are all important factors contributing to the over-all risk for infection. Furthermore, the infective ability of the virus must be maintained throughout all these stages. In addition the risk for infection is also dependent on host immune system competency plus the quantity of infectious particles ingested.
Antibiotics may be used in dealing with airborne bacterial primary infections, such as pneumonic plague.
== See also ==
Aeroplankton
Basic reproduction number
Miasma theory
Vector (epidemiology)
Waterborne diseases
Zoonosis
== References == | Wikipedia/Airborne_disease |
Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology. Interconnected
== Types of disease ==
Broadly speaking, endocrine disorders may be subdivided into three groups:
Endocrine gland hypofunction/hyposecretion (leading to hormone deficiency)
Endocrine gland hyperfunction/hypersecretion (leading to hormone excess)
Tumours (benign or malignant) of endocrine glands
Endocrine disorders are often quite complex, involving a mixed picture of hyposecretion and hypersecretion because of the feedback mechanisms involved in the endocrine system. For example, most forms of hyperthyroidism are associated with an excess of thyroid hormone and a low level of thyroid stimulating hormone.
== List of diseases ==
=== Glucose homeostasis disorders ===
Diabetes
Type 1 Diabetes
Type 2 Diabetes
Gestational Diabetes
Mature Onset Diabetes of the Young
Diabetic myopathy
Hypoglycemia
Idiopathic hypoglycemia
Insulinoma
Glucagonoma
=== Thyroid disorders ===
Goitre
Hyperthyroidism
Graves-Basedow disease
Toxic multinodular goitre
Thyrotoxic myopathy
Hypothyroidism
Hypothyroid myopathies
Kocher-Debre-Semelaigne syndrome
Hoffmann syndrome
Myasthenic syndrome
Atrophic form
Thyroiditis
Hashimoto's thyroiditis
Thyroid cancer
Thyroid hormone resistance
=== Calcium homeostasis disorders and Metabolic bone disease ===
Parathyroid gland disorders
Hyperparathyroidism
Primary hyperparathyroidism
Secondary hyperparathyroidism
Tertiary hyperparathyroidism
Hyperparathyroid myopathy
Hypoparathyroidism
Pseudohypoparathyroidism
Hypoparathyroid myopathy
Osteoporosis
Osteitis deformans (Paget's disease of bone)
Rickets
Osteomalacia
=== Pituitary gland disorders ===
==== Posterior pituitary ====
Diabetes insipidus
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
==== Anterior pituitary ====
Hypopituitarism (or Panhypopituitarism)
Pituitary tumors
Pituitary adenomas
Prolactinoma (or Hyperprolactinemia)
Acromegaly, gigantism, dwarfism
Cushing's disease
=== Adrenal gland disorders ===
Addison's disease
Adrenal crisis
Adrenal insufficiency
Adrenal tumour
Congenital adrenal hyperplasia
Hypercortisolism (Cushing's disease)
Steroid myopathy
Hypoaldosteronism
Hyperaldosteronism
=== Sex hormone disorders ===
Disorders of sex development or intersex disorders
Hermaphroditism
Gonadal dysgenesis
Androgen insensitivity syndromes
Hypogonadism (Gonadotropin deficiency)
Inherited (genetic and chromosomal) disorders
Kallmann syndrome
Klinefelter syndrome
Turner syndrome
Acquired disorders
Ovarian failure (also known as Premature Menopause)
Testicular failure
Testosterone deficiency myopathy
Disorders of Puberty
Delayed puberty
Precocious puberty
Menstrual function or fertility disorders
Amenorrhea
Polycystic ovary syndrome (PCOS)
=== Tumours of the endocrine glands not mentioned elsewhere ===
Multiple endocrine neoplasia
MEN type 1
MEN type 2a
MEN type 2b
Carcinoid syndrome
=== See also separate organs ===
Autoimmune polyendocrine syndromes
Incidentaloma - an unexpected finding on diagnostic imaging, often of endocrine glands
== Endocrine emergencies ==
In endocrinology, medical emergencies include diabetic ketoacidosis, hyperosmolar hyperglycemic state, hypoglycemic coma, acute adrenocortical insufficiency, phaeochromocytoma crisis, hypercalcemic crisis, thyroid storm, myxoedema coma and pituitary apoplexy.
Emergencies arising from decompensated pheochromocytomas or parathyroid adenomas are sometimes referred for emergency resection when aggressive medical therapies fail to control the patient's state, however the surgical risks are significant, especially blood pressure lability and the possibility of cardiovascular collapse after resection (due to a brutal drop in respectively catecholamines and calcium, which must be compensated with gradual normalization). It remains debated when emergency surgery is appropriate as opposed to urgent or elective surgery after continued attempts to stabilize the patient, notably in view of newer and more efficient medications and protocols.
== See also ==
List of MeSH codes (C19)
List of ICD-9 codes 240-279: Endocrine, nutritional and metabolic diseases, and immunity disorders
Diabetes self-management
== References ==
== External links ==
Endocrine+system+diseases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
MedlinePlus Overview endocrinediseases | Wikipedia/Endocrine_disease |
Maternal–fetal medicine (MFM), also known as perinatology, is a branch of medicine that focuses on managing health concerns of the mother and fetus prior to, during, and shortly after pregnancy.
Maternal–fetal medicine specialists are physicians who subspecialize within the field of obstetrics. Their training typically includes a four-year residency in obstetrics and gynecology followed by a three-year fellowship. They may perform prenatal tests, provide treatments, and perform surgeries. They act both as a consultant during lower-risk pregnancies and as the primary obstetrician in especially high-risk pregnancies. After birth, they may work closely with pediatricians or neonatologists. For the mother, perinatologists assist with pre-existing health concerns, as well as complications caused by pregnancy.
== History ==
Maternal–fetal medicine began to emerge as a discipline in the 1960s. Advances in research and technology allowed physicians to diagnose and treat fetal complications in utero, whereas previously, obstetricians could only rely on heart rate monitoring and maternal reports of fetal movement. The development of amniocentesis in 1952, fetal blood sampling during labor in the early 1960s, more precise fetal heart monitoring in 1968, and real-time ultrasound in 1971 resulted in early intervention and lower mortality rates. In 1963, Albert William Liley developed a course of intrauterine transfusions for Rh incompatibility at the National Women's Hospital in Australia, regarded as the first fetal treatment. Other antenatal treatments, such as the administration of glucocorticoids to speed lung maturation in neonates at risk for respiratory distress syndrome, led to improved outcomes for premature infants.
Consequently, organizations were developed to focus on these emerging medical practices, and in 1991, the First International Congress of Perinatal Medicine was held, at which the World Association of Perinatal Medicine was founded.
Today, maternal-fetal medicine specialists can be found in major hospitals internationally. They may work in privately owned clinics, or in larger, government-funded institutions.
The field of maternal-fetal medicine is one of the most rapidly evolving fields in medicine, especially with respect to the fetus. Research is being carried on in the field of fetal gene and stem cell therapy in hope to provide early treatment for genetic disorders, open fetal surgery for the correction of birth defects like congenital heart disease, and the prevention of preeclampsia.
== Scope of practice ==
Maternal–fetal medicine specialists attend to patients who fall within certain levels of maternal care. These levels correspond to health risks for the baby, mother, or both, during pregnancy.
They take care of pregnant women who have chronic conditions (e.g. heart or kidney disease, hypertension, diabetes, and thrombophilia), pregnant women who are at risk for pregnancy-related complications (e.g. preterm labor, pre-eclampsia, and twin or triplet pregnancies), and pregnant women with fetuses at risk. Fetuses may be at risk due to chromosomal or congenital abnormalities, maternal disease, infections, genetic diseases and growth restriction.
Expecting mothers with chronic conditions, such as high blood pressure, drug use during or before pregnancy, or a diagnosed medical condition may require a consult with a maternal-fetal specialist. In addition, women who experience difficulty conceiving may be referred to a maternal-fetal specialist for assistance.
During pregnancy, a variety of complications of pregnancy can arise. Depending on the severity of the complication, a maternal-fetal specialist may meet with the patient intermittently, or become the primary obstetrician for the length of the pregnancy. Post-partum, maternal-fetal specialists may follow up with a patient and monitor any medical complications that may arise.
The rates of maternal and infant mortality due to complications of pregnancy have decreased by over 23% since 1990, from 377,000 deaths to 293,000 deaths. Most deaths can be attributed to infection, maternal bleeding, and obstructed labor, and their incidence of mortality vary widely internationally. The Society for Maternal-fetal Medicine (SMFM) strives to improve maternal and child outcomes by standards of prevention, diagnosis and treatment through research, education and training.
== Training ==
Maternal–fetal medicine specialists are obstetrician-gynecologists who undergo an additional three years of specialized training in the assessment and management of high-risk pregnancies. In the United States, such obstetrician-gynecologists are certified by the American Board of Obstetrician Gynecologists (ABOG) or the American Osteopathic Board of Obstetrics and Gynecology.
Maternal–fetal medicine specialists have training in obstetric ultrasound, invasive prenatal diagnosis using amniocentesis and chorionic villus sampling, and the management of high-risk pregnancies. Some are further trained in the field of fetal diagnosis and prenatal therapy where they become competent in advanced procedures such as targeted fetal assessment using ultrasound and Doppler, fetal blood sampling and transfusion, fetoscopy, and open fetal surgery.
For the ABOG, MFM subspecialists are required to do a minimum of 12 months in clinical rotation and 18-months in research activities. They are encouraged to use simulation and case-based learning incorporated in their training, a certification in advanced cardiac life support (ACLS) is required, they are required to develop in-service examination and expand leadership training. Obstetrical care and service has been improved to provide academic advancement for MFM in-patient directorships, improve skills in coding and reimbursement for maternal care, establish national, stratified system for levels of maternal care, develop specific, proscriptive guidelines on complications with highest maternal morbidity and mortality, and finally, increase departmental and divisional support for MFM subspecialists with maternal focus. As Maternal–fetal medicine subspecialists improve their work ethics and knowledge of this advancing field, they are capable of reducing the rate of maternal mortality and maternal morbidity.
== See also ==
Advanced Life Support in Obstetrics (ALSO)
Roberto Caldeyro-Barcia
== References ==
== External links ==
World Congress on Controversies in Obstetrics, Gynecology & Infertility (COGI)
British Maternal and Fetal Medicine Society
The Society for Maternal–Fetal Medicine | Wikipedia/Fetal_disease |
There are several scoring systems in intensive care units (ICUs) today.
== Adult scoring systems ==
APACHE II was designed to provide a morbidity score for a patient. It is useful to decide what kind of treatment or medicine is given. Methods exist to derive a predicted mortality from this score, but these methods are not too well defined and rather imprecise.
APACHE III is an updated version.
SAPS II was designed to provide a predicted mortality, that does not reflect the expected mortality for a particular patient, but is good for benchmarking. In a rather simple way, it makes it possible to provide a single number that describes the morbidity of a number of patients.
SAPS III was designed to provide a realistic predicted mortality for a particular patient or a particular group of patients. It does this by calibrating against known mortalities on an existing set of patients, for a specific definition of mortality (like 30-days mortality). This way, it can answer questions like "Did we improve our quality of care from 2004 to 2005?" or "If hospital A's patients had been treated at hospital B, would they have a better or a worse mortality?".
== Children scoring systems ==
PIM2 delivers a predicted mortality value, intended to be used for benchmarking.
== Other scoring systems ==
SOFA was designed to provide a simple daily score, that indicates how the status of the patient evolves over time.
Glasgow Coma Scale (also named GCS) is designed to provide the status for the central nervous system. It is often used as part of other scoring systems.
FOUR score - 17-point scale for the assessment of level of consciousness. Aims to have higher sensitivity and specificity then GCS, applicable in intubated patients.
CMM - Cancer Mortality Model
specific score to predict outcome of critical cancer patients
MPM - Mortality Probability Model
model to assess risk of death at ICU admission
has prediction models for assessment at admittance, 24h, 48h and 72h after
RIFLE - Risk, injury, failure, loss and end-stage kidney classification
has 3 severity levels (risk, injury and failure) and 2 possible outcomes (loss and end-stage)
CP - Child–Pugh score
for patient with liver failure.
used also outside of the ICU.
Ranson score
simple score used specifically for patients with pancreatitis
MODS Multiple Organ Dysfunction Score
with similar objectives as SOFA Score
LODS Logistic Organ Dysfunction System
developed for evaluation at admittance and not as a monitoring tool
APACHE IV
used to predict hospital mortality and ICU LOS
== References == | Wikipedia/ICU_scoring_systems |
Hematologic diseases are disorders which primarily affect the blood and blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease and complications from chemotherapy or transfusions.
== Myeloid ==
Hemoglobinopathies (congenital abnormality of the hemoglobin molecule or of the rate of hemoglobin synthesis)
Sickle cell disease
Thalassemia
Methemoglobinemia
Anemias (lack of red blood cells or hemoglobin)
Iron-deficiency anemia
Megaloblastic anemia
Vitamin B12 deficiency
Pernicious anemia
Folate deficiency
Hemolytic anemias (destruction of red blood cells)
Genetic disorders of RBC membrane
Hereditary spherocytosis
Hereditary elliptocytosis
Congenital dyserythropoietic anemia
Genetic disorders of RBC metabolism
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
Pyruvate kinase deficiency
Immune mediated hemolytic anemia (direct Coombs test is positive)
Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans syndrome (antiplatelet antibodies and hemolytic antibodies)
Cold autoimmune hemolytic anemia
Cold agglutinin disease
Paroxysmal cold hemoglobinuria (rare)
Infectious mononucleosis
Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
Drug induced immune mediated hemolytic anemia
Penicillin (high dose)
Methyldopa
Hemoglobinopathies (where these is an unstable or crystalline hemoglobin)
Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface proteins)
Direct physical damage to RBCs
Microangiopathic hemolytic anemia
Secondary to artificial heart valve(s)
Aplastic anemia
Fanconi anemia
Diamond–Blackfan anemia (inherited pure red cell aplasia)
Acquired pure red cell aplasia
Decreased numbers of cells
Myelodysplastic syndrome
Myelofibrosis
Neutropenia (decrease in the number of neutrophils)
Agranulocytosis
Glanzmann's thrombasthenia
Thrombocytopenia (decrease in the number of platelets)
Idiopathic thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura (TTP)
Heparin-induced thrombocytopenia (HIT)
Myeloproliferative disorders (Increased numbers of cells)
Polycythemia vera (increase in the number of cells in general)
Erythrocytosis (increase in the number of red blood cells)
Leukocytosis (increase in the number of white blood cells)
Thrombocytosis (increase in the number of platelets)
Myeloproliferative disorder
Transient myeloproliferative disease
Coagulopathies (disorders of bleeding and coagulation)
Thrombocytosis
Recurrent thrombosis
Disseminated intravascular coagulation
Disorders of clotting proteins
Hemophilia
Hemophilia A
Hemophilia B (also known as Christmas disease)
Hemophilia C
Von Willebrand disease
Disseminated intravascular coagulation
Protein S deficiency
Antiphospholipid syndrome
Disorders of platelets
Thrombocytopenia
Glanzmann's thrombasthenia
Wiskott–Aldrich syndrome
== Hematological malignancies ==
Hematological malignancies
Lymphomas
Hodgkin's disease
Non-Hodgkin's lymphoma {includes the next five entries}
Burkitt's lymphoma
Anaplastic large cell lymphoma
Splenic marginal zone lymphoma
Hepatosplenic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma (AILT)
Myelomas
Multiple myeloma
Waldenström macroglobulinemia
Plasmacytoma
Leukemias increased WBC
Acute lymphocytic leukemia (ALL)
Chronic lymphocytic leukemia (CLL){now included in theCLL/SCLL type NHL}
Acute myelogenous leukemia (AML)
Acute megakaryoblastic leukemia (AMKL), a sub-type of acute myelogenous leukemia
Chronic Idiopathic Myelofibrosis (MF)
Chronic myelogenous leukemia (CML)
T-cell prolymphocytic leukemia (T-PLL)
B-cell prolymphocytic leukemia (B-PLL)
Chronic neutrophilic leukemia (CNL)
Hairy cell leukemia (HCL)
T-cell large granular lymphocyte leukemia (T-LGL)
Aggressive NK-cell leukemia
== Miscellaneous ==
Hemochromatosis
Asplenia
Hypersplenism
Gaucher's disease
Monoclonal gammopathy of undetermined significance
Hemophagocytic lymphohistiocytosis
Tempi syndrome
== Hematological changes secondary to non-hematological disorders ==
Anemia of chronic disease
Infectious mononucleosis
AIDS
Malaria
Leishmaniasis
== References ==
== External links ==
https://web.archive.org/web/20100527085120/http://hematologic.niddk.nih.gov/info/index.htm | Wikipedia/Hematologic_disease |
Lifestyle diseases can be defined as the diseases linked to the manner in which a person lives their life. These diseases are non-communicable, and can be caused by lack of physical activity, unhealthy eating, alcohol, substance use disorders and smoking tobacco, which can lead to heart disease, stroke, obesity, type II diabetes and lung cancer. The diseases that appear to increase in frequency as countries become more industrialized and people live longer include Alzheimer's disease, arthritis, atherosclerosis, asthma, cancer, chronic liver disease or cirrhosis, chronic obstructive pulmonary disease, colitis, irritable bowel syndrome, type 2 diabetes, heart disease, hypertension, metabolic syndrome, chronic kidney failure, osteoporosis, PCOD, stroke, depression, obesity and vascular dementia.
Concerns were raised in 2011 that lifestyle diseases could soon have an impact on the workforce and the cost of health care. Treating these non-communicable diseases can be expensive. It can be critical for the patient's health to receive primary prevention and identify early symptoms of these non-communicable diseases. These lifestyle diseases are expected to increase throughout the years if people do not improve their lifestyle choices.
Some commenters maintain a distinction between diseases of longevity and diseases of civilization or diseases of affluence. Certain diseases, such as diabetes, dental caries and asthma, appear at greater rates in young populations living in the "western" way; their increased incidence is not related to age, so the terms cannot accurately be used interchangeably for all diseases.
== Causes ==
Diet and lifestyle are major factors thought to influence susceptibility to many diseases. Substance use disorders, such as tobacco smoking, and excessive consumption of alcohol, and a lack of or too much exercise may also increase the risk of developing certain diseases, especially later in life.
In many Western countries, people began to consume more meat, dairy products, vegetable oils, tobacco, sugary foods, sugary beverages, and alcoholic beverages during the latter half of the 20th century. People also developed sedentary lifestyles and greater rates of obesity. Rates of colorectal, breast, prostate, endometrial and lung cancer started increasing after this dietary change. People in developing countries, whose diets still depend largely on low-sugar starchy foods with little meat or fat have lower rates of these cancers. Causes are not just from smoking tobacco and alcohol use. Adults can develop lifestyle diseases through behavioral factors that impact them. Behavioral factors including unemployment, unsafe life, poor social environment, working conditions, stress and home life can increase their risk of developing one of these non-communicable diseases.
== Death statistics in Australia ==
Between 1995 and 2005, 813,000 Australians were hospitalized due to alcohol. In 2014, 11.2 million Australians were overweight or obese.
In 2013, there were 147,678 deaths within Australia mostly from lifestyle diseases. Smoking tobacco, alcohol use and other substances, violence, and unhealthy weight have impacted the Australians' death rate. The leading cause of death of Australian males was heart disease with 11,016 deaths, followed by lung cancer with 4,995 deaths, and chronic pulmonary disease killing 3,572. All these conditions were mainly attributed to smoking, excessive alcohol use or an unhealthy lifestyle. In 2013, coronary heart disease was the leading cause of death in 8,750 women, mainly as a result of their lifestyle. Dementia and Alzheimer's disease came second, affecting 7,277 females and thirdly, cerebrovascular disease, killing 6,368. These top three causes of deaths could be minimized through lifestyle changes within the Australian population.
The table shows the ages of people dying and the top five diseases for which they are dying.
== Death statistics in the United States ==
In 1900, the top three causes of death in the United States were pneumonia/influenza, tuberculosis, and diarrhea/enteritis. Communicable diseases accounted for about 60 percent of all deaths. In 1900, heart disease and cancer were ranked number four and eight, respectively. Since the 1940s, the majority of deaths in the United States have resulted from heart disease, cancer, and other degenerative diseases. By the late 1990s, degenerative diseases accounted for more than 60 percent of all deaths.
Lifestyle diseases have their onset later in an individual's life; they appear to increase in frequency as countries become more industrialized and people live longer. This suggests that the life expectancy at birth of 49.24 years in 1900
was too short for degenerative diseases to occur, compared to a life expectancy at birth of 77.8 years in 2004. Also, survivorship to the age of 50 was 58.5% in 1900, and 93.7% in 2007.
== Death statistics in India ==
According to a report published by the Indian Council of Medical Research in 2017, 3 of the 5 leading individual causes of disease burden in India were non-communicable, with ischemic heart disease and chronic obstructive pulmonary disease as the top two causes and stroke as the fifth leading cause. The range of disease burden or DALY rate among the states in 2016 was 9-fold for ischemic heart disease, 4-fold for chronic obstructive pulmonary disease, 6-fold for stroke, and 4-fold for diabetes across India. Of the total deaths from major disease groups, 62% of all deaths were caused by non-communicable diseases.
== Prevention ==
Prevention of these non-communicable diseases involves remedies or activities that aim to reduce the likelihood of a disease or disorder affecting people. Lifestyle diseases are preventable for children if parents set them on the correct path, as early life decisions and influences can impact people later on in life. Lifestyle diseases can be prevented through reduction in smoking of tobacco. The Australian Government started by introducing plain packaging for all tobacco products and increasing the prices of tobacco production. Obesity can be prevented through a well-balanced lifestyle through healthy eating and exercise. 30 minutes of moderate exercise daily or 150 minutes of moderate intensity exercise a week can be the start of a new lifestyle change. Examples of moderate exercise include a brisk walk, swim, bicycle ride or it can also be everyday life activities like mowing the lawn or house cleaning. In addition, studies have suggested that early life exercise can reduce the risk of developing metabolic diseases in adulthood. All causes of lifestyle disease can be prevented through giving up smoking and other substances, reducing one's intake of alcohol, processed meats (like bacon and sausages), red meats (like pork, beef and lamb), fatty foods and by engaging in daily exercise. However, new studies also show preventive effects on recurrent respiratory tract infections in children through the intake of unprocessed food. Beef, green vegetables, and whole dairy can be beneficial because they are unprocessed compared to processed foods. Beef, unlike other types of red meat, can contribute to the health-promoting effects. Eating an excess amount of these foods can have an impact on one's health. Certain foods and activities such as smoking and drinking should be done in moderation.
== See also ==
Affluenza
Diseases of affluence
Health
Health care in Australia
Healthcare in the United Kingdom
== References ==
== External links ==
Media related to Lifestyle disease at Wikimedia Commons
Hu, Frank; Cheung, Lilian; Otis, Brett; Oliveira, Nancy; Musicus, Aviva, eds. (19 January 2021). "The Nutrition Source – Healthy Living Guide 2020/2021: A Digest on Healthy Eating and Healthy Living". Boston: Department of Nutrition at the Harvard T.H. Chan School of Public Health. Archived from the original on 5 October 2021. Retrieved 11 October 2021. | Wikipedia/Lifestyle_disease |
A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. It differs from a localized disease, which is a disease affecting only part of the body (e.g., a mouth ulcer).
== Examples ==
Mastocytosis, including mast cell activation syndrome and eosinophilic esophagitis
Chronic fatigue syndrome
Systemic vasculitis e.g. SLE, PAN
Sarcoidosis – a disease that mainly affects the lungs, brain, joints and eyes, found most often in young African-American women.
Hypothyroidism – where the thyroid gland produces too little thyroid hormones.
Diabetes mellitus – an imbalance in blood glucose (sugar) levels.
Fibromyalgia
Ehlers-Danlos syndromes - an inherited connective tissue disorder with multiple subcategories
Adrenal insufficiency – where the adrenal glands don't produce enough steroid hormones
Coeliac disease – an autoimmune disease triggered by gluten consumption, which may involve several organs and cause a variety of symptoms, or be completely asymptomatic.
Ulcerative colitis – an inflammatory bowel disease
Crohn's disease – an inflammatory bowel disease
Hypertension (high blood pressure)
Metabolic syndrome
AIDS – a disease caused by a virus that cripples the body's immune defenses.
Graves' disease – a thyroid disorder, most often in women, which can cause a goiter (swelling in the front part of the neck) and protruding eyes.
Systemic lupus erythematosus – a connective tissue disorder involving mainly the skin, joints and kidneys.
Rheumatoid arthritis – an inflammatory disease which mainly attacks the joints. But can also affect a person's skin, eyes, lungs and mouth.
Atherosclerosis – a hardening of the arteries
Sickle cell disease – an inherited blood disorder that can block circulation throughout the body, primarily affecting people of sub-Saharan origin.
Myasthenia gravis
Systemic sclerosis
Sinusitis
Sjogren's Syndrome - an autoimmune disease that primarily attacks the lacrimal and salivary glands, but also impacts other organs such as the lungs, kidneys, liver, and nervous system.
== Detection ==
Getting a regular eye exam may play a role in identifying the signs of some systemic diseases. "The eye is composed of many different types of tissue. This unique feature makes the eye susceptible to a wide variety of diseases as well as provides insights into many body systems. Almost any part of the eye can give important clues to the diagnosis of systemic diseases. Signs of a systemic disease may be evident on the outer surface of the eye (eyelids, conjunctiva and cornea), middle of the eye and at the back of the eye (retina)."
Since 500 B.C., some researchers have believed that the physical condition of the fingernails and toenails can indicate various systemic diseases. Careful examination of the fingernails and toenails may provide clues to underlying systemic diseases , since some diseases have been found to cause disruptions in the nail growth process. The nail plate is the hard keratin cover of the nail. The nail plate is generated by the nail matrix located just under the cuticle. As the nail grows, the area closest to becoming exposed to the outside world (distal) produces the deeper layers of the nail plate, while the part of the nail matrix deeper inside the finger (proximal) makes the superficial layers. Any disruption in this growth process can lead to an alteration in the shape and texture.
For example, pitting looks like depressions in the hard part of the nail. Pitting is to be associated with psoriasis, affecting 10% - 50% of patients with that disorder. Pitting also may be caused by a variety of systemic diseases, including reactive arthritis and other connective tissue disorders, sarcoidosis, pemphigus, alopecia areata, and incontinentia pigmenti. Because pitting is caused by defective layering of the superficial nail plate by the proximal nail matrix, any localized dermatitis (e.g., atopic dermatitis or chemical dermatitis) that disrupts orderly growth in that area also can cause pitting.
== See also ==
== References == | Wikipedia/Systemic_disease |
Disease burden is the impact of a health problem as measured by financial cost, mortality, morbidity, or other indicators. It is often quantified in terms of quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs). Both of these metrics quantify the number of years lost due to disability (YLDs), sometimes also known as years lost due to disease or years lived with disability/disease. One DALY can be thought of as one year of healthy life lost, and the overall disease burden can be thought of as a measure of the gap between current health status and the ideal health status (where the individual lives to old age without disease and disability).
According to an article published in The Lancet in June 2015, low back pain and major depressive disorder were among the top ten causes of YLDs and were the cause of more health loss than diabetes, chronic obstructive pulmonary disease, and asthma combined. The study based on data from 188 countries, considered to be the largest and most detailed analysis to quantify levels, patterns, and trends in ill health and disability, concluded that "the proportion of disability-adjusted life years due to YLDs increased globally from 21.1% in 1990 to 31.2% in 2013."
The environmental burden of disease is defined as the number of DALYs that can be attributed to environmental factors. Similarly, the work-related burden of disease is defined as the number of deaths and DALYs that can be attributed to occupational risk factors to human health. These measures allow for comparison of disease burdens, and have also been used to forecast the possible impacts of health interventions. By 2014, DALYs per head were "40% higher in low-income and middle-income regions."
The World Health Organization (WHO) has provided a set of detailed guidelines for measuring disease burden at the local or national level. In 2004, the health issue leading to the highest YLD for both men and women was unipolar depression; in 2010, it was lower back pain. According to an article in The Lancet published in November 2014, disorders in those aged 60 years and older represent "23% of the total global burden of disease" and leading contributors to disease burden in this group in 2014 were "cardiovascular diseases (30.3%), malignant neoplasms (15.1%), chronic respiratory diseases (9.5%), musculoskeletal diseases (7.5%), and neurological and mental disorders (6.6%).": 549
== Statistics ==
The first study on the global burden of disease, conducted in 1990, quantified the health effects of more than 100 diseases and injuries for eight regions of the world, giving estimates of morbidity and mortality by age, sex, and region. It also introduced the DALY as a new metric to quantify the burden of diseases, injuries, and risk factors. From 2000 to 2002, the 1990 study was updated to include a more extensive analysis using a framework known as comparative risk factor assessment.
In 2004, the World Health Organization calculated that 1.5 billion disability-adjusted life years were lost to disease and injury.
== Modifiable risk factors ==
In 2006, the WHO released a report which addressed the amount of global disease that could be prevented by reducing environmental risk factors. The report found that approximately one-fourth of the global disease burden and more than one-third of the burden among children was due to modifiable environmental factors. The "environmentally-mediated" disease burden is much higher in developing countries, with the exception of certain non-communicable diseases, such as cardiovascular diseases and cancers, where the per capita disease burden is larger in developed countries. Children have the highest death toll, with more than 4 million environmentally-caused deaths yearly, mostly in developing countries. The infant death rate attributed to environmental causes is also 12 times higher in developing countries. 85 out of the 102 major diseases and injuries classified by WHO were due to environmental factors.
To measure the environmental health impact, environment was defined as "all the physical, chemical and biological factors external to a person, and all the related behaviours". The definition of modifiable environment included:
Air, soil, and water pollution with chemicals or biological agents
Ultraviolet and ionizing radiation
Noise and electromagnetic fields
Built environment
Agricultural methods and irrigation schemes
Human-made climate change and ecosystem degradation
Occupational risks, including exposure to long working hours
Individual behaviors, such as hand-washing and food contamination due to unsafe water or dirty hands
Certain environmental factors were excluded from this definition:
Indoor smoke from solid fuel use
Lead
Mercury
Natural climate change (as opposed to human-caused climate change)
Occupational airborne particulates or carcinogens
Outdoor air pollution
Sanitation and hygiene problems
Second-hand smoke
Solar ultraviolet radiation
== Methodology ==
The WHO developed a methodology to quantify the health of a population using summary measures, which combine information on mortality and non-fatal health outcomes. The measures quantify either health gaps or health expectancies; the most commonly used health summary measure is the DALY.
The exposure-based approach, which measures exposure via pollutant levels, is used to calculate the environmental burden of disease. This approach requires knowledge of the outcomes associated with the relevant risk factor, exposure levels and distribution in the study population, and dose-response relationships of the pollutants.
A dose-response relationship is a function of the exposure parameter assessed for the study population. Exposure distribution and dose-response relationships are combined to yield the study population's health impact distribution, usually expressed in terms of incidence. The health impact distribution can then be converted into health summary measures, such as DALYs. Exposure-response relationships for a given risk factor are commonly obtained from epidemiological studies. For example, the disease burden of outdoor air pollution for Santiago, Chile, was calculated by measuring the concentration of atmospheric particulate matter (PM10), estimating the susceptible population, and combining these data with relevant dose-response relationships. A reduction of particulate matter levels in the air to recommended standards would cause a reduction of about 5,200 deaths, 4,700 respiratory hospital admissions, and 13,500,000 days of restricted activity per year, for a total population of 4.7 million.
In 2002, the WHO estimated the global environmental burden of disease by using risk assessment data to develop environmentally attributable fractions (EAFs) of mortality and morbidity for 85 categories of disease. In 2007, they released the first country-by-country analysis of the impact environmental factors had on health for its then 192 member states. These country estimates were the first step to assist governments in carrying out preventive action. The country estimates were divided into three parts:
Environmental burden of disease for selected risk factors
This presents the yearly burden, expressed in deaths and DALYs, attributable to: indoor air pollution from solid fuel use; outdoor air pollution; and unsafe water, sanitation, and hygiene. Results are calculated using the exposure-based approach.
Total environmental burden of disease for the relevant country
The total number of deaths, DALYs per capita, and the percentage of the national burden of disease attributable to the environment represent the disease burden that could be avoided by modifying the environment as a whole.
Environmental burden by disease category
Each country summary was broken down by the disease group, where the annual number of DALYs per capita attributable to environmental factors were calculated for each group.
== Implementation and interpretation ==
The public health impacts of air pollution (annual means of PM10 and ozone), noise pollution, and radiation (radon and UV), can be quantified using DALYs. For each disease, a DALY is calculated as:
DALYs = number of people with the disease × duration of the disease (or loss of life expectancy in the case of mortality) × severity (varying from 0 for perfect health to 1 for death)
Necessary data include prevalence data, exposure-response relationships, and weighting factors that give an indication of the severity of a certain disorder. When information is missing or vague, experts will be consulted in order to decide which alternative data sources to use. An uncertainty analysis is carried out so as to analyze the effects of different assumptions.
=== Uncertainty ===
When estimating the environmental burden of disease, a number of potential sources of error may arise in the measure of exposure and exposure-risk relationship, assumptions made in applying the exposure or exposure-risk relationship to the relevant country, health statistics, and, if used, expert opinions.
Generally, it is not possible to estimate a formal confidence interval, but it is possible to estimate a range of possible values the environmental disease burden may take based on different input parameters and assumptions. When more than one definition has to be made about a certain element in the assessment, multiple analyses can be run, using different sets of definitions. Sensitivity and decision analyses can help determine which sources of uncertainty affect the final results the most.
== Examples ==
=== The Netherlands ===
In the Netherlands, air pollution is associated with respiratory and cardiovascular diseases, and exposure to certain forms of radiation can lead to the development of cancer. Quantification of the health impact of the environment was done by calculating DALYs for air pollution, noise, radon, UV, and indoor dampness for the period 1980 to 2020. In the Netherlands, 2–5% of the total disease burden in 2000 could be attributed to the effects of (short-term) exposure to air pollution, noise, radon, natural UV radiation, and dampness in houses. The percentage can increase to up to 13% due to uncertainty, assuming no threshold.
Among the investigated factors, long-term PM10 exposure have the greatest impact on public health. As levels of PM10 decrease, related disease burden is also expected to decrease. Noise exposure and its associated disease burden is likely to increase to a level where the disease burden is similar to that of traffic accidents. The rough estimates do not provide a complete picture of the environmental health burden, because data are uncertain, not all environmental-health relationships are known, not all environmental factors have been included, and it was not possible to assess all potential health effects. The effects of a number of these assumptions were evaluated in an uncertainty analysis.
=== Canada ===
Exposure to environmental hazards may cause chronic diseases, so the magnitude of their contribution to Canada's total disease burden is not well understood. In order to give an initial estimate of the environmental burden of disease for four major categories of disease, the EAF developed by the WHO, EAFs developed by other researchers, and data from Canadian public health institutions were used. Results showed a total of 10,000–25,000 deaths, with 78,000–194,000 hospitalizations; 600,000–1.5 million days spent in hospital; 1.1–1.8 million restricted activity days for individuals with asthma; 8000–24,000 new cases of cancer; 500–2,500 babies with low birth weights; and C$3.6–9.1 billion in costs each year due to respiratory disease, cardiovascular illness, cancer, and congenital conditions associated with adverse environmental exposures.
=== Burden of disease attributable to lack of water, sanitation, hygiene ===
== Criticism ==
There is no consensus on the best measures of the public's health. This may be due to the fact that measurements are used to accomplish diverse functions, such as population health assessment, evaluation of the effectiveness of interventions, formulation of health policies, and projection of future resource needs. The choice of measures may also depend on individual and societal values. Measures that only consider premature death will omit the burden of living with a disease or disability, and measures that combine both in a single measure (i.e. DALYs) need to make a judgment to the significance of these measures compared to each other. Other metrics such as economic costs will not capture pain and suffering or other broader aspects of burden.
DALYs are a simplification of a complex reality, and therefore only give a crude indication of environmental health impact. Relying on DALYs may make donors take a narrow approach to health care programs. Foreign aid is most often directed at diseases with the highest DALYs, ignoring the fact that other diseases, despite having lower DALYs, are still major contributors to disease burden. Less-publicized diseases thus have little or no funding for health efforts. For example, maternal death (one of the top three killers in most poor countries) and pediatric respiratory and intestinal infections maintain a high disease burden, and safe pregnancy and the prevention of coughs in infants do not receive adequate funding.
== See also ==
Climate change and infectious diseases
Vectorborne diseases
WASH (water, sanitation and hygiene)
Waterborne diseases
== References ==
=== Sources === | Wikipedia/Disease_burden |
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable disease, is an illness resulting from an infection.
Infections can be caused by a wide range of pathogens, most prominently bacteria and viruses. Hosts can fight infections using their immune systems. Mammalian hosts react to infections with an innate response, often involving inflammation, followed by an adaptive response.
Treatment for infections depends on the type of pathogen involved. Common medications include:
Antibiotics for bacterial infections.
Antivirals for viral infections.
Antifungals for fungal infections.
Antiprotozoals for protozoan infections.
Antihelminthics for infections caused by parasitic worms.
Infectious diseases remain a significant global health concern, causing approximately 9.2 million deaths in 2013 (17% of all deaths). The branch of medicine that focuses on infections is referred to as infectious diseases.
== Types ==
Infections are caused by infectious agents (pathogens) including:
Bacteria (e.g. Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Clostridium botulinum, and Salmonella spp.)
Viruses and subviral agents such as viroids and prions. (E.g. HIV, Rhinovirus, Lyssaviruses such as Rabies virus, Ebolavirus and Severe acute respiratory syndrome coronavirus 2)
Fungi, further subclassified into:
Ascomycota, including yeasts such as Candida (the most common fungal infection); filamentous fungi such as Aspergillus; Pneumocystis species; and dermatophytes, a group of organisms causing infection of skin and other superficial structures in humans.
Basidiomycota, including the human-pathogenic genus Cryptococcus.
Parasites, which are usually divided into:
Unicellular organisms (e.g. malaria, Toxoplasma, Babesia)
Macroparasites (worms or helminths) including nematodes such as parasitic roundworms and pinworms, tapeworms (cestodes), and flukes (trematodes, such as schistosomes). Diseases caused by helminths are sometimes termed infestations, but are sometimes called infections.
Arthropods such as ticks, mites, fleas, and lice, can also cause human disease, which conceptually are similar to infections, but invasion of a human or animal body by these macroparasites is usually termed infestation.
== Signs and symptoms ==
The signs and symptoms of an infection depend on the type of disease. Some signs of infection affect the whole body generally, such as fatigue, loss of appetite, weight loss, fevers, night sweats, chills, aches and pains. Others are specific to individual body parts, such as skin rashes, coughing, or a runny nose.
In certain cases, infectious diseases may be asymptomatic for much or even all of their course in a given host. In the latter case, the disease may only be defined as a "disease" (which by definition means an illness) in hosts who secondarily become ill after contact with an asymptomatic carrier. An infection is not synonymous with an infectious disease, as some infections do not cause illness in a host.
=== Bacterial or viral ===
As bacterial and viral infections can both cause the same kinds of symptoms, it can be difficult to distinguish which is the cause of a specific infection. Distinguishing the two is important, since viral infections cannot be cured by antibiotics whereas bacterial infections can.
== Pathophysiology ==
There is a general chain of events that applies to infections, sometimes called the chain of infection or transmission chain. The chain of events involves several steps – which include the infectious agent, reservoir, entering a susceptible host, exit and transmission to new hosts. Each of the links must be present in a chronological order for an infection to develop. Understanding these steps helps health care workers target the infection and prevent it from occurring in the first place.
=== Colonization ===
Infection begins when an organism successfully enters the body, grows and multiplies. This is referred to as colonization. Most humans are not easily infected. Those with compromised or weakened immune systems have an increased susceptibility to chronic or persistent infections. Individuals who have a suppressed immune system are particularly susceptible to opportunistic infections. Entrance to the host at host–pathogen interface, generally occurs through the mucosa in orifices like the oral cavity, nose, eyes, genitalia, anus, or the microbe can enter through open wounds. While a few organisms can grow at the initial site of entry, many migrate and cause systemic infection in different organs. Some pathogens grow within the host cells (intracellular) whereas others grow freely in bodily fluids.
Wound colonization refers to non-replicating microorganisms within the wound, while in infected wounds, replicating organisms exist and tissue is injured. All multicellular organisms are colonized to some degree by extrinsic organisms, and the vast majority of these exist in either a mutualistic or commensal relationship with the host. An example of the former is the anaerobic bacteria species, which colonizes the mammalian colon, and an example of the latter are the various species of staphylococcus that exist on human skin. Neither of these colonizations are considered infections. The difference between an infection and a colonization is often only a matter of circumstance. Non-pathogenic organisms can become pathogenic given specific conditions, and even the most virulent organism requires certain circumstances to cause a compromising infection. Some colonizing bacteria, such as Corynebacteria sp. and Viridans streptococci, prevent the adhesion and colonization of pathogenic bacteria and thus have a symbiotic relationship with the host, preventing infection and speeding wound healing.
The variables involved in the outcome of a host becoming inoculated by a pathogen and the ultimate outcome include:
the route of entry of the pathogen and the access to host regions that it gains
the intrinsic virulence of the particular organism
the quantity or load of the initial inoculant
the immune status of the host being colonized
As an example, several staphylococcal species remain harmless on the skin, but, when present in a normally sterile space, such as in the capsule of a joint or the peritoneum, multiply without resistance and cause harm.
An interesting fact that gas chromatography–mass spectrometry, 16S ribosomal RNA analysis, omics, and other advanced technologies have made more apparent to humans in recent decades is that microbial colonization is very common even in environments that humans think of as being nearly sterile. Because it is normal to have bacterial colonization, it is difficult to know which chronic wounds can be classified as infected and how much risk of progression exists. Despite the huge number of wounds seen in clinical practice, there are limited quality data for evaluated symptoms and signs. A review of chronic wounds in the Journal of the American Medical Association's "Rational Clinical Examination Series" quantified the importance of increased pain as an indicator of infection. The review showed that the most useful finding is an increase in the level of pain [likelihood ratio (LR) range, 11–20] makes infection much more likely, but the absence of pain (negative likelihood ratio range, 0.64–0.88) does not rule out infection (summary LR 0.64–0.88).
=== Disease ===
Disease can arise if the host's protective immune mechanisms are compromised and the organism inflicts damage on the host. Microorganisms can cause tissue damage by releasing a variety of toxins or destructive enzymes. For example, Clostridium tetani releases a toxin that paralyzes muscles, and staphylococcus releases toxins that produce shock and sepsis. Not all infectious agents cause disease in all hosts. For example, less than 5% of individuals infected with polio develop disease. On the other hand, some infectious agents are highly virulent. The prion causing mad cow disease and Creutzfeldt–Jakob disease invariably kills all animals and people that are infected.
Persistent infections occur because the body is unable to clear the organism after the initial infection. Persistent infections are characterized by the continual presence of the infectious organism, often as latent infection with occasional recurrent relapses of active infection. There are some viruses that can maintain a persistent infection by infecting different cells of the body. Some viruses once acquired never leave the body. A typical example is the herpes virus, which tends to hide in nerves and become reactivated when specific circumstances arise.
Persistent infections cause millions of deaths globally each year. Chronic infections by parasites account for a high morbidity and mortality in many underdeveloped countries.
=== Transmission ===
For infecting organisms to survive and repeat the infection cycle in other hosts, they (or their progeny) must leave an existing reservoir and cause infection elsewhere. Infection transmission can take place via many potential routes:
Droplet contact, also known as the respiratory route, and the resultant infection can be termed airborne disease. If an infected person coughs or sneezes on another person the microorganisms, suspended in warm, moist droplets, may enter the body through the nose, mouth or eye surfaces.
Fecal-oral transmission, wherein foodstuffs or water become contaminated (by people not washing their hands before preparing food, or untreated sewage being released into a drinking water supply) and the people who eat and drink them become infected. Common fecal-oral transmitted pathogens include Vibrio cholerae, Giardia species, rotaviruses, Entamoeba histolytica, Escherichia coli, and tape worms. Most of these pathogens cause gastroenteritis.
Sexual transmission, with the result being called sexually transmitted infection.
Oral transmission, diseases that are transmitted primarily by oral means may be caught through direct oral contact such as kissing, or by indirect contact such as by sharing a drinking glass or a cigarette.
Transmission by direct contact, Some diseases that are transmissible by direct contact include athlete's foot, impetigo and warts.
Vehicle transmission, transmission by an inanimate reservoir (food, water, soil).
Vertical transmission, directly from the mother to an embryo, fetus or baby during pregnancy or childbirth. It can occur as a result of a pre-existing infection or one acquired during pregnancy.
Iatrogenic transmission, due to medical procedures such as injection or transplantation of infected material.
Vector-borne transmission, transmitted by a vector, which is an organism that does not cause disease itself but that transmits infection by conveying pathogens from one host to another.
The relationship between virulence versus transmissibility is complex; with studies have shown that there were no clear relationship between the two. There is still a small number of evidence that partially suggests a link between virulence and transmissibility.
== Diagnosis ==
Diagnosis of infectious disease sometimes involves identifying an infectious agent either directly or indirectly. In practice most minor infectious diseases such as warts, cutaneous abscesses, respiratory system infections and diarrheal diseases are diagnosed by their clinical presentation and treated without knowledge of the specific causative agent. Conclusions about the cause of the disease are based upon the likelihood that a patient came in contact with a particular agent, the presence of a microbe in a community, and other epidemiological considerations. Given sufficient effort, all known infectious agents can be specifically identified.
Diagnosis of infectious disease is nearly always initiated by medical history and physical examination. More detailed identification techniques involve the culture of infectious agents isolated from a patient. Culture allows identification of infectious organisms by examining their microscopic features, by detecting the presence of substances produced by pathogens, and by directly identifying an organism by its genotype.
Many infectious organisms are identified without culture and microscopy. This is especially true for viruses, which cannot grow in culture. For some suspected pathogens, doctors may conduct tests that examine a patient's blood or other body fluids for antigens or antibodies that indicate presence of a specific pathogen that the doctor suspects.
Other techniques (such as X-rays, CAT scans, PET scans or NMR) are used to produce images of internal abnormalities resulting from the growth of an infectious agent. The images are useful in detection of, for example, a bone abscess or a spongiform encephalopathy produced by a prion.
The benefits of identification, however, are often greatly outweighed by the cost, as often there is no specific treatment, the cause is obvious, or the outcome of an infection is likely to be benign.
=== Symptomatic diagnostics ===
The diagnosis is aided by the presenting symptoms in any individual with an infectious disease, yet it usually needs additional diagnostic techniques to confirm the suspicion. Some signs are specifically characteristic and indicative of a disease and are called pathognomonic signs; but these are rare. Not all infections are symptomatic.
In children the presence of cyanosis, rapid breathing, poor peripheral perfusion, or a petechial rash increases the risk of a serious infection by greater than 5 fold. Other important indicators include parental concern, clinical instinct, and temperature greater than 40 °C.
=== Microbial culture ===
Many diagnostic approaches depend on microbiological culture to isolate a pathogen from the appropriate clinical specimen. In a microbial culture, a growth medium is provided for a specific agent. A sample taken from potentially diseased tissue or fluid is then tested for the presence of an infectious agent able to grow within that medium. Many pathogenic bacteria are easily grown on nutrient agar, a form of solid medium that supplies carbohydrates and proteins necessary for growth, along with copious amounts of water. A single bacterium will grow into a visible mound on the surface of the plate called a colony, which may be separated from other colonies or melded together into a "lawn". The size, color, shape and form of a colony is characteristic of the bacterial species, its specific genetic makeup (its strain), and the environment that supports its growth. Other ingredients are often added to the plate to aid in identification. Plates may contain substances that permit the growth of some bacteria and not others, or that change color in response to certain bacteria and not others. Bacteriological plates such as these are commonly used in the clinical identification of infectious bacterium. Microbial culture may also be used in the identification of viruses: the medium, in this case, being cells grown in culture that the virus can infect, and then alter or kill. In the case of viral identification, a region of dead cells results from viral growth, and is called a "plaque". Eukaryotic parasites may also be grown in culture as a means of identifying a particular agent.
In the absence of suitable plate culture techniques, some microbes require culture within live animals. Bacteria such as Mycobacterium leprae and Treponema pallidum can be grown in animals, although serological and microscopic techniques make the use of live animals unnecessary. Viruses are also usually identified using alternatives to growth in culture or animals. Some viruses may be grown in embryonated eggs. Another useful identification method is Xenodiagnosis, or the use of a vector to support the growth of an infectious agent. Chagas disease is the most significant example, because it is difficult to directly demonstrate the presence of the causative agent, Trypanosoma cruzi in a patient, which therefore makes it difficult to definitively make a diagnosis. In this case, xenodiagnosis involves the use of the vector of the Chagas agent T. cruzi, an uninfected triatomine bug, which takes a blood meal from a person suspected of having been infected. The bug is later inspected for growth of T. cruzi within its gut.
=== Microscopy ===
Another principal tool in the diagnosis of infectious disease is microscopy. Virtually all of the culture techniques discussed above rely, at some point, on microscopic examination for definitive identification of the infectious agent. Microscopy may be carried out with simple instruments, such as the compound light microscope, or with instruments as complex as an electron microscope. Samples obtained from patients may be viewed directly under the light microscope, and can often rapidly lead to identification. Microscopy is often also used in conjunction with biochemical staining techniques, and can be made exquisitely specific when used in combination with antibody based techniques. For example, the use of antibodies made artificially fluorescent (fluorescently labeled antibodies) can be directed to bind to and identify a specific antigens present on a pathogen. A fluorescence microscope is then used to detect fluorescently labeled antibodies bound to internalized antigens within clinical samples or cultured cells. This technique is especially useful in the diagnosis of viral diseases, where the light microscope is incapable of identifying a virus directly.
Other microscopic procedures may also aid in identifying infectious agents. Almost all cells readily stain with a number of basic dyes due to the electrostatic attraction between negatively charged cellular molecules and the positive charge on the dye. A cell is normally transparent under a microscope, and using a stain increases the contrast of a cell with its background. Staining a cell with a dye such as Giemsa stain or crystal violet allows a microscopist to describe its size, shape, internal and external components and its associations with other cells. The response of bacteria to different staining procedures is used in the taxonomic classification of microbes as well. Two methods, the Gram stain and the acid-fast stain, are the standard approaches used to classify bacteria and to diagnosis of disease. The Gram stain identifies the bacterial groups Bacillota and Actinomycetota, both of which contain many significant human pathogens. The acid-fast staining procedure identifies the Actinomycetota genera Mycobacterium and Nocardia.
=== Biochemical tests ===
Biochemical tests used in the identification of infectious agents include the detection of metabolic or enzymatic products characteristic of a particular infectious agent. Since bacteria ferment carbohydrates in patterns characteristic of their genus and species, the detection of fermentation products is commonly used in bacterial identification. Acids, alcohols and gases are usually detected in these tests when bacteria are grown in selective liquid or solid media.
The isolation of enzymes from infected tissue can also provide the basis of a biochemical diagnosis of an infectious disease. For example, humans can make neither RNA replicases nor reverse transcriptase, and the presence of these enzymes are characteristic., of specific types of viral infections. The ability of the viral protein hemagglutinin to bind red blood cells together into a detectable matrix may also be characterized as a biochemical test for viral infection, although strictly speaking hemagglutinin is not an enzyme and has no metabolic function.
Serological methods are highly sensitive, specific and often extremely rapid tests used to identify microorganisms. These tests are based upon the ability of an antibody to bind specifically to an antigen. The antigen, usually a protein or carbohydrate made by an infectious agent, is bound by the antibody. This binding then sets off a chain of events that can be visibly obvious in various ways, dependent upon the test. For example, "Strep throat" is often diagnosed within minutes, and is based on the appearance of antigens made by the causative agent, S. pyogenes, that is retrieved from a patient's throat with a cotton swab. Serological tests, if available, are usually the preferred route of identification, however the tests are costly to develop and the reagents used in the test often require refrigeration. Some serological methods are extremely costly, although when commonly used, such as with the "strep test", they can be inexpensive.
Complex serological techniques have been developed into what are known as immunoassays. Immunoassays can use the basic antibody – antigen binding as the basis to produce an electro-magnetic or particle radiation signal, which can be detected by some form of instrumentation. Signal of unknowns can be compared to that of standards allowing quantitation of the target antigen. To aid in the diagnosis of infectious diseases, immunoassays can detect or measure antigens from either infectious agents or proteins generated by an infected organism in response to a foreign agent. For example, immunoassay A may detect the presence of a surface protein from a virus particle. Immunoassay B on the other hand may detect or measure antibodies produced by an organism's immune system that are made to neutralize and allow the destruction of the virus.
Instrumentation can be used to read extremely small signals created by secondary reactions linked to the antibody – antigen binding. Instrumentation can control sampling, reagent use, reaction times, signal detection, calculation of results, and data management to yield a cost-effective automated process for diagnosis of infectious disease.
=== PCR-based diagnostics ===
Technologies based upon the polymerase chain reaction (PCR) method will become nearly ubiquitous gold standards of diagnostics of the near future, for several reasons. First, the catalog of infectious agents has grown to the point that virtually all of the significant infectious agents of the human population have been identified. Second, an infectious agent must grow within the human body to cause disease; essentially it must amplify its own nucleic acids to cause a disease. This amplification of nucleic acid in infected tissue offers an opportunity to detect the infectious agent by using PCR. Third, the essential tools for directing PCR, primers, are derived from the genomes of infectious agents, and with time those genomes will be known if they are not already.
Thus, the technological ability to detect any infectious agent rapidly and specifically is currently available. The only remaining blockades to the use of PCR as a standard tool of diagnosis are in its cost and application, neither of which is insurmountable. The diagnosis of a few diseases will not benefit from the development of PCR methods, such as some of the clostridial diseases (tetanus and botulism). These diseases are fundamentally biological poisonings by relatively small numbers of infectious bacteria that produce extremely potent neurotoxins. A significant proliferation of the infectious agent does not occur, this limits the ability of PCR to detect the presence of any bacteria.
=== Metagenomic sequencing ===
Given the wide range of bacterial, viral, fungal, protozoal, and helminthic pathogens that cause debilitating and life-threatening illnesses, the ability to quickly identify the cause of infection is important yet often challenging. For example, more than half of cases of encephalitis, a severe illness affecting the brain, remain undiagnosed, despite extensive testing using the standard of care (microbiological culture) and state-of-the-art clinical laboratory methods. Metagenomic sequencing-based diagnostic tests are currently being developed for clinical use and show promise as a sensitive, specific, and rapid way to diagnose infection using a single all-encompassing test. This test is similar to current PCR tests; however, an untargeted whole genome amplification is used rather than primers for a specific infectious agent. This amplification step is followed by next-generation sequencing or third-generation sequencing, alignment comparisons, and taxonomic classification using large databases of thousands of pathogen and commensal reference genomes. Simultaneously, antimicrobial resistance genes within pathogen and plasmid genomes are sequenced and aligned to the taxonomically classified pathogen genomes to generate an antimicrobial resistance profile – analogous to antibiotic sensitivity testing – to facilitate antimicrobial stewardship and allow for the optimization of treatment using the most effective drugs for a patient's infection.
Metagenomic sequencing could prove especially useful for diagnosis when the patient is immunocompromised. An ever-wider array of infectious agents can cause serious harm to individuals with immunosuppression, so clinical screening must often be broader. Additionally, the expression of symptoms is often atypical, making a clinical diagnosis based on presentation more difficult. Thirdly, diagnostic methods that rely on the detection of antibodies are more likely to fail. A rapid, sensitive, specific, and untargeted test for all known human pathogens that detects the presence of the organism's DNA rather than antibodies is therefore highly desirable.
=== Indication of tests ===
There is usually an indication for a specific identification of an infectious agent only when such identification can aid in the treatment or prevention of the disease, or to advance knowledge of the course of an illness prior to the development of effective therapeutic or preventative measures. For example, in the early 1980s, prior to the appearance of AZT for the treatment of AIDS, the course of the disease was closely followed by monitoring the composition of patient blood samples, even though the outcome would not offer the patient any further treatment options. In part, these studies on the appearance of HIV in specific communities permitted the advancement of hypotheses as to the route of transmission of the virus. By understanding how the disease was transmitted, resources could be targeted to the communities at greatest risk in campaigns aimed at reducing the number of new infections. The specific serological diagnostic identification, and later genotypic or molecular identification, of HIV also enabled the development of hypotheses as to the temporal and geographical origins of the virus, as well as a myriad of other hypothesis. The development of molecular diagnostic tools have enabled physicians and researchers to monitor the efficacy of treatment with anti-retroviral drugs. Molecular diagnostics are now commonly used to identify HIV in healthy people long before the onset of illness and have been used to demonstrate the existence of people who are genetically resistant to HIV infection. Thus, while there still is no cure for AIDS, there is great therapeutic and predictive benefit to identifying the virus and monitoring the virus levels within the blood of infected individuals, both for the patient and for the community at large.
=== Classification ===
==== Subclinical versus clinical (latent versus apparent) ====
Symptomatic infections are apparent and clinical, whereas an infection that is active but does not produce noticeable symptoms may be called inapparent, silent, subclinical, or occult. An infection that is inactive or dormant is called a latent infection. An example of a latent bacterial infection is latent tuberculosis. Some viral infections can also be latent, examples of latent viral infections are any of those from the Herpesviridae family.
The word infection can denote any presence of a particular pathogen at all (no matter how little) but also is often used in a sense implying a clinically apparent infection (in other words, a case of infectious disease). This fact occasionally creates some ambiguity or prompts some usage discussion; to get around this it is common for health professionals to speak of colonization (rather than infection) when they mean that some of the pathogens are present but that no clinically apparent infection (no disease) is present.
==== Course of infection ====
Different terms are used to describe how and where infections present over time. In an acute infection, symptoms develop rapidly; its course can either be rapid or protracted. In chronic infection, symptoms usually develop gradually over weeks or months and are slow to resolve. In subacute infections, symptoms take longer to develop than in acute infections but arise more quickly than those of chronic infections. A focal infection is an initial site of infection from which organisms travel via the bloodstream to another area of the body.
==== Primary versus opportunistic ====
Among the many varieties of microorganisms, relatively few cause disease in otherwise healthy individuals. Infectious disease results from the interplay between those few pathogens and the defenses of the hosts they infect. The appearance and severity of disease resulting from any pathogen depend upon the ability of that pathogen to damage the host as well as the ability of the host to resist the pathogen. However, a host's immune system can also cause damage to the host itself in an attempt to control the infection. Clinicians, therefore, classify infectious microorganisms or microbes according to the status of host defenses – either as primary pathogens or as opportunistic pathogens.
===== Primary pathogens =====
Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence (the severity of the disease they cause) is, in part, a necessary consequence of their need to reproduce and spread. Many of the most common primary pathogens of humans only infect humans, however, many serious diseases are caused by organisms acquired from the environment or that infect non-human hosts.
===== Opportunistic pathogens =====
Opportunistic pathogens can cause an infectious disease in a host with depressed resistance (immunodeficiency) or if they have unusual access to the inside of the body (for example, via trauma). Opportunistic infection may be caused by microbes ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract, and they may also result from (otherwise innocuous) microbes acquired from other hosts (as in Clostridioides difficile colitis) or from the environment as a result of traumatic introduction (as in surgical wound infections or compound fractures). An opportunistic disease requires impairment of host defenses, which may occur as a result of genetic defects (such as chronic granulomatous disease), exposure to antimicrobial drugs or immunosuppressive chemicals (as might occur following poisoning or cancer chemotherapy), exposure to ionizing radiation, or as a result of an infectious disease with immunosuppressive activity (such as with measles, malaria or HIV disease). Primary pathogens may also cause more severe disease in a host with depressed resistance than would normally occur in an immunosufficient host.
===== Secondary infection =====
While a primary infection can practically be viewed as the root cause of an individual's current health problem, a secondary infection is a sequela or complication of that root cause. For example, an infection due to a burn or penetrating trauma (the root cause) is a secondary infection. Primary pathogens often cause primary infection and often cause secondary infection. Usually, opportunistic infections are viewed as secondary infections (because immunodeficiency or injury was the predisposing factor).
===== Other types of infection =====
Other types of infection consist of mixed, iatrogenic, nosocomial, and community-acquired infection. A mixed infection is an infection that is caused by two or more pathogens. An example of this is appendicitis, which is caused by Bacteroides fragilis and Escherichia coli. The second is an iatrogenic infection. This type of infection is one that is transmitted from a health care worker to a patient. A nosocomial infection is also one that occurs in a health care setting. Nosocomial infections are those that are acquired during a hospital stay. Lastly, a community-acquired infection is one in which the infection is acquired from a whole community.
==== Infectious or not ====
One manner of proving that a given disease is infectious, is to satisfy Koch's postulates (first proposed by Robert Koch), which require that first, the infectious agent be identifiable only in patients who have the disease, and not in healthy controls, and second, that patients who contract the infectious agent also develop the disease. These postulates were first used in the discovery that Mycobacteria species cause tuberculosis.
However, Koch's postulates cannot usually be tested in modern practice for ethical reasons. Proving them would require experimental infection of a healthy individual with a pathogen produced as a pure culture. Conversely, even clearly infectious diseases do not always meet the infectious criteria; for example, Treponema pallidum, the causative spirochete of syphilis, cannot be cultured in vitro – however the organism can be cultured in rabbit testes. It is less clear that a pure culture comes from an animal source serving as host than it is when derived from microbes derived from plate culture.
Epidemiology, or the study and analysis of who, why and where disease occurs, and what determines whether various populations have a disease, is another important tool used to understand infectious disease. Epidemiologists may determine differences among groups within a population, such as whether certain age groups have a greater or lesser rate of infection; whether groups living in different neighborhoods are more likely to be infected; and by other factors, such as gender and race. Researchers also may assess whether a disease outbreak is sporadic, or just an occasional occurrence; endemic, with a steady level of regular cases occurring in a region; epidemic, with a fast arising, and unusually high number of cases in a region; or pandemic, which is a global epidemic. If the cause of the infectious disease is unknown, epidemiology can be used to assist with tracking down the sources of infection.
==== Contagiousness ====
Infectious diseases are sometimes called contagious diseases when they are easily transmitted by contact with an ill person or their secretions (e.g., influenza). Thus, a contagious disease is a subset of infectious disease that is especially infective or easily transmitted. All contagious diseases are infectious, but not vice versa. Other types of infectious, transmissible, or communicable diseases with more specialized routes of infection, such as vector transmission or sexual transmission, are usually not regarded as "contagious", and often do not require medical isolation (sometimes loosely called quarantine) of those affected. However, this specialized connotation of the word "contagious" and "contagious disease" (easy transmissibility) is not always respected in popular use.
Infectious diseases are commonly transmitted from person to person through direct contact. The types of direct contact are through person to person and droplet spread. Indirect contact such as airborne transmission, contaminated objects, food and drinking water, animal person contact, animal reservoirs, insect bites, and environmental reservoirs are another way infectious diseases are transmitted. The basic reproduction number of an infectious disease measures how easily it spreads through direct or indirect contact.
==== By anatomic location ====
Infections can be classified by the anatomic location or organ system infected, including:
Urinary tract infection
Skin infection
Respiratory tract infection
Odontogenic infection (an infection that originates within a tooth or in the closely surrounding tissues)
Vaginal infections
Intra-amniotic infection
In addition, locations of inflammation where infection is the most common cause include pneumonia, meningitis and salpingitis.
== Prevention ==
Techniques like hand washing, wearing gowns, and wearing face masks can help prevent infections from being passed from one person to another. Aseptic technique was introduced in medicine and surgery in the late 19th century and greatly reduced the incidence of infections caused by surgery. Frequent hand washing remains the most important defense against the spread of unwanted organisms. There are other forms of prevention such as avoiding the use of illicit drugs, using a condom, wearing gloves, and having a healthy lifestyle with a balanced diet and regular exercise. Cooking foods well and avoiding foods that have been left outside for a long time is also important.
Antimicrobial substances used to prevent transmission of infections include:
antiseptics, which are applied to living tissue/skin
disinfectants, which destroy microorganisms found on non-living objects.
antibiotics, called prophylactic when given as prevention rather as treatment of infection. However, long term use of antibiotics leads to resistance of bacteria. While humans do not become immune to antibiotics, the bacteria does. Thus, avoiding using antibiotics longer than necessary helps preventing bacteria from forming mutations that aide in antibiotic resistance.
One of the ways to prevent or slow down the transmission of infectious diseases is to recognize the different characteristics of various diseases. Some critical disease characteristics that should be evaluated include virulence, distance traveled by those affected, and level of contagiousness. The human strains of Ebola virus, for example, incapacitate those infected extremely quickly and kill them soon after. As a result, those affected by this disease do not have the opportunity to travel very far from the initial infection zone. Also, this virus must spread through skin lesions or permeable membranes such as the eye. Thus, the initial stage of Ebola is not very contagious since its victims experience only internal hemorrhaging. As a result of the above features, the spread of Ebola is very rapid and usually stays within a relatively confined geographical area. In contrast, the human immunodeficiency virus (HIV) kills its victims very slowly by attacking their immune system. As a result, many of its victims transmit the virus to other individuals before even realizing that they are carrying the disease. Also, the relatively low virulence allows its victims to travel long distances, increasing the likelihood of an epidemic.
Another effective way to decrease the transmission rate of infectious diseases is to recognize the effects of small-world networks. In epidemics, there are often extensive interactions within hubs or groups of infected individuals and other interactions within discrete hubs of susceptible individuals. Despite the low interaction between discrete hubs, the disease can jump and spread in a susceptible hub via a single or few interactions with an infected hub. Thus, infection rates in small-world networks can be reduced somewhat if interactions between individuals within infected hubs are eliminated (Figure 1). However, infection rates can be drastically reduced if the main focus is on the prevention of transmission jumps between hubs. The use of needle exchange programs in areas with a high density of drug users with HIV is an example of the successful implementation of this treatment method. Another example is the use of ring culling or vaccination of potentially susceptible livestock in adjacent farms to prevent the spread of the foot-and-mouth virus in 2001.
A general method to prevent transmission of vector-borne pathogens is pest control.
In cases where infection is merely suspected, individuals may be quarantined until the incubation period has passed and the disease manifests itself or the person remains healthy. Groups may undergo quarantine, or in the case of communities, a cordon sanitaire may be imposed to prevent infection from spreading beyond the community, or in the case of protective sequestration, into a community. Public health authorities may implement other forms of social distancing, such as school closings, lockdowns or temporary restrictions (e.g. circuit breakers) to control an epidemic.
=== Immunity ===
Infection with most pathogens does not result in death of the host and the offending organism is ultimately cleared after the symptoms of the disease have waned. This process requires immune mechanisms to kill or inactivate the inoculum of the pathogen. Specific acquired immunity against infectious diseases may be mediated by antibodies and/or T lymphocytes. Immunity mediated by these two factors may be manifested by:
a direct effect upon a pathogen, such as antibody-initiated complement-dependent bacteriolysis, opsonoization, phagocytosis and killing, as occurs for some bacteria,
neutralization of viruses so that these organisms cannot enter cells,
or by T lymphocytes, which will kill a cell parasitized by a microorganism.
The immune system response to a microorganism often causes symptoms such as a high fever and inflammation, and has the potential to be more devastating than direct damage caused by a microbe.
Resistance to infection (immunity) may be acquired following a disease, by asymptomatic carriage of the pathogen, by harboring an organism with a similar structure (crossreacting), or by vaccination. Knowledge of the protective antigens and specific acquired host immune factors is more complete for primary pathogens than for opportunistic pathogens. There is also the phenomenon of herd immunity which offers a measure of protection to those otherwise vulnerable people when a large enough proportion of the population has acquired immunity from certain infections.
Immune resistance to an infectious disease requires a critical level of either antigen-specific antibodies and/or T cells when the host encounters the pathogen. Some individuals develop natural serum antibodies to the surface polysaccharides of some agents although they have had little or no contact with the agent, these natural antibodies confer specific protection to adults and are passively transmitted to newborns.
==== Host genetic factors ====
The organism that is the target of an infecting action of a specific infectious agent is called the host. The host harbouring an agent that is in a mature or sexually active stage phase is called the definitive host. The intermediate host comes in contact during the larvae stage. A host can be anything living and can attain to asexual and sexual reproduction.
The clearance of the pathogens, either treatment-induced or spontaneous, it can be influenced by the genetic variants carried by the individual patients. For instance, for genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in the treatment-induced clearance of the virus. This finding, originally reported in Nature, showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained virological response after the treatment than others. Later report from Nature demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.
== Treatments ==
When infection attacks the body, anti-infective drugs can suppress the infection. Several broad types of anti-infective drugs exist, depending on the type of organism targeted; they include antibacterial (antibiotic; including antitubercular), antiviral, antifungal and antiparasitic (including antiprotozoal and antihelminthic) agents. Depending on the severity and the type of infection, the antibiotic may be given by mouth or by injection, or may be applied topically. Severe infections of the brain are usually treated with intravenous antibiotics. Sometimes, multiple antibiotics are used in case there is resistance to one antibiotic. Antibiotics only work for bacteria and do not affect viruses. Antibiotics work by slowing down the multiplication of bacteria or killing the bacteria. The most common classes of antibiotics used in medicine include penicillin, cephalosporins, aminoglycosides, macrolides, quinolones and tetracyclines.
Not all infections require treatment, and for many self-limiting infections the treatment may cause more side-effects than benefits. Antimicrobial stewardship is the concept that healthcare providers should treat an infection with an antimicrobial that specifically works well for the target pathogen for the shortest amount of time and to only treat when there is a known or highly suspected pathogen that will respond to the medication.
== Susceptibility to infection ==
Pandemics such as COVID-19 show that people dramatically differ in their susceptibility to infection. This may be because of general health, age, or their immune status, e.g. when they have been infected previously. However, it also has become clear that there are genetic factor which determine susceptibility to infection. For instance, up to 40% of SARS-CoV-2 infections may be asymptomatic, suggesting that many people are naturally protected from disease. Large genetic studies have defined risk factors for severe SARS-CoV-2 infections, and genome sequences from 659 patients with severe COVID-19 revealed genetic variants that appear to be associated with life-threatening disease. One gene identified in these studies is type I interferon (IFN). Autoantibodies against type I IFNs were found in up to 13.7% of patients with life-threatening COVID-19, indicating that a complex interaction between genetics and the immune system is important for natural resistance to Covid.
Similarly, mutations in the ERAP2 gene, encoding endoplasmic reticulum aminopeptidase 2, seem to increase the susceptibility to the plague, the disease caused by an infection with the bacteria Yersinia pestis. People who inherited two copies of a complete variant of the gene were twice as likely to have survived the plague as those who inherited two copies of a truncated variant.
Susceptibility also determined the epidemiology of infection, given that different populations have different genetic and environmental conditions that affect infections.
== Epidemiology ==
An estimated 1,680 million people died of infectious diseases in the 20th century and about 10 million in 2010.
The World Health Organization collects information on global deaths by International Classification of Disease (ICD) code categories. The following table lists the top infectious disease by number of deaths in 2002. 1993 data is included for comparison.
The top three single agent/disease killers are HIV/AIDS, TB and malaria. While the number of deaths due to nearly every disease have decreased, deaths due to HIV/AIDS have increased fourfold. Childhood diseases include pertussis, poliomyelitis, diphtheria, measles and tetanus. Children also make up a large percentage of lower respiratory and diarrheal deaths. In 2012, approximately 3.1 million people have died due to lower respiratory infections, making it the number 4 leading cause of death in the world.
=== Historic pandemics ===
With their potential for unpredictable and explosive impacts, infectious diseases have been major actors in human history. A pandemic (or global epidemic) is a disease that affects people over an extensive geographical area. For example:
Plague of Justinian, from 541 to 542, killed between 50% and 60% of Europe's population.
The Black Death of 1347 to 1352 killed 25 million in Europe over five years. The plague reduced the old world population from an estimated 450 million to between 350 and 375 million in the 14th century.
The introduction of smallpox, measles, and typhus to the areas of Central and South America by European explorers during the 15th and 16th centuries caused pandemics among the native inhabitants. Between 1518 and 1568 disease pandemics are said to have caused the population of Mexico to fall from 20 million to 3 million.
The first European influenza epidemic occurred between 1556 and 1560, with an estimated mortality rate of 20%.
Smallpox killed an estimated 60 million Europeans during the 18th century (approximately 400,000 per year). Up to 30% of those infected, including 80% of the children under 5 years of age, died from the disease, and one-third of the survivors went blind.
In the 19th century, tuberculosis killed an estimated one-quarter of the adult population of Europe; by 1918 one in six deaths in France were still caused by TB.
The Influenza Pandemic of 1918 (or the Spanish flu) killed 25–50 million people (about 2% of world population of 1.7 billion). Today Influenza kills about 250,000 to 500,000 worldwide each year.
In 2021, COVID-19 emerged as a major global health crisis, directly causing 8.7 million deaths, making it one of the leading causes of mortality worldwide.
=== Emerging diseases ===
In most cases, microorganisms live in harmony with their hosts via mutual or commensal interactions. Diseases can emerge when existing parasites become pathogenic or when new pathogenic parasites enter a new host.
Coevolution between parasite and host can lead to hosts becoming resistant to the parasites or the parasites may evolve greater virulence, leading to immunopathological disease.
Human activity is involved with many emerging infectious diseases, such as environmental change enabling a parasite to occupy new niches. When that happens, a pathogen that had been confined to a remote habitat has a wider distribution and possibly a new host organism. Parasites jumping from nonhuman to human hosts are known as zoonoses. Under disease invasion, when a parasite invades a new host species, it may become pathogenic in the new host.
Several human activities have led to the emergence of zoonotic human pathogens, including viruses, bacteria, protozoa, and rickettsia, and spread of vector-borne diseases, see also globalization and disease and wildlife disease:
Encroachment on wildlife habitats. The construction of new villages and housing developments in rural areas force animals to live in dense populations, creating opportunities for microbes to mutate and emerge.
Changes in agriculture. The introduction of new crops attracts new crop pests and the microbes they carry to farming communities, exposing people to unfamiliar diseases.
The destruction of rain forests. As countries make use of their rain forests, by building roads through forests and clearing areas for settlement or commercial ventures, people encounter insects and other animals harboring previously unknown microorganisms.
Uncontrolled urbanization. The rapid growth of cities in many developing countries tends to concentrate large numbers of people into crowded areas with poor sanitation. These conditions foster transmission of contagious diseases.
Modern transport. Ships and other cargo carriers often harbor unintended "passengers", that can spread diseases to faraway destinations. While with international jet-airplane travel, people infected with a disease can carry it to distant lands, or home to their families, before their first symptoms appear.
== Germ theory of disease ==
In Antiquity, the Greek historian Thucydides (c. 460 – c. 400 BCE) was the first person to write, in his account of the plague of Athens, that diseases could spread from an infected person to others. In his On the Different Types of Fever (c. 175 AD), the Greco-Roman physician Galen speculated that plagues were spread by "certain seeds of plague", which were present in the air. In the Sushruta Samhita, the ancient Indian physician Sushruta theorized: "Leprosy, fever, consumption, diseases of the eye, and other infectious diseases spread from one person to another by sexual union, physical contact, eating together, sleeping together, sitting together, and the use of same clothes, garlands and pastes." This book has been dated to about the sixth century BC.
A basic form of contagion theory was proposed by Persian physician Ibn Sina (known as Avicenna in Europe) in The Canon of Medicine (1025), which later became the most authoritative medical textbook in Europe up until the 16th century. In Book IV of the Canon, Ibn Sina discussed epidemics, outlining the classical miasma theory and attempting to blend it with his own early contagion theory. He mentioned that people can transmit disease to others by breath, noted contagion with tuberculosis, and discussed the transmission of disease through water and dirt. The concept of invisible contagion was later discussed by several Islamic scholars in the Ayyubid Sultanate who referred to them as najasat ("impure substances"). The fiqh scholar Ibn al-Haj al-Abdari (c. 1250–1336), while discussing Islamic diet and hygiene, gave warnings about how contagion can contaminate water, food, and garments, and could spread through the water supply, and may have implied contagion to be unseen particles.
When the Black Death bubonic plague reached Al-Andalus in the 14th century, the Arab physicians Ibn Khatima (c. 1369) and Ibn al-Khatib (1313–1374) hypothesised that infectious diseases were caused by "minute bodies" and described how they can be transmitted through garments, vessels and earrings. Ideas of contagion became more popular in Europe during the Renaissance, particularly through the writing of the Italian physician Girolamo Fracastoro. Anton van Leeuwenhoek (1632–1723) advanced the science of microscopy by being the first to observe microorganisms, allowing for easy visualization of bacteria.
In the mid-19th century John Snow and William Budd did important work demonstrating the contagiousness of typhoid and cholera through contaminated water. Both are credited with decreasing epidemics of cholera in their towns by implementing measures to prevent contamination of water. Louis Pasteur proved beyond doubt that certain diseases are caused by infectious agents, and developed a vaccine for rabies. Robert Koch provided the study of infectious diseases with a scientific basis known as Koch's postulates. Edward Jenner, Jonas Salk and Albert Sabin developed effective vaccines for smallpox and polio, which would later result in the eradication and near-eradication of these diseases, respectively. Alexander Fleming discovered the world's first antibiotic, penicillin, which Florey and Chain then developed. Gerhard Domagk developed sulphonamides, the first broad spectrum synthetic antibacterial drugs.
=== Medical specialists ===
The medical treatment of infectious diseases falls into the medical field of Infectious Disease and in some cases the study of propagation pertains to the field of Epidemiology. Generally, infections are initially diagnosed by primary care physicians or internal medicine specialists. For example, an "uncomplicated" pneumonia will generally be treated by the internist or the pulmonologist (lung physician). The work of the infectious diseases specialist therefore entails working with both patients and general practitioners, as well as laboratory scientists, immunologists, bacteriologists and other specialists.
An infectious disease team may be alerted when:
The disease has not been definitively diagnosed after an initial workup
The patient is immunocompromised (for example, in AIDS or after chemotherapy);
The infectious agent is of an uncommon nature (e.g. tropical diseases);
The disease has not responded to first line antibiotics;
The disease might be dangerous to other patients, and the patient might have to be isolated
== Society and culture ==
Several studies have reported associations between pathogen load in an area and human behavior. Higher pathogen load is associated with decreased size of ethnic and religious groups in an area. This may be due high pathogen load favoring avoidance of other groups, which may reduce pathogen transmission, or a high pathogen load preventing the creation of large settlements and armies that enforce a common culture. Higher pathogen load is also associated with more restricted sexual behavior, which may reduce pathogen transmission. It also associated with higher preferences for health and attractiveness in mates. Higher fertility rates and shorter or less parental care per child is another association that may be a compensation for the higher mortality rate. There is also an association with polygyny which may be due to higher pathogen load, making selecting males with a high genetic resistance increasingly important. Higher pathogen load is also associated with more collectivism and less individualism, which may limit contacts with outside groups and infections. There are alternative explanations for at least some of the associations although some of these explanations may in turn ultimately be due to pathogen load. Thus, polygyny may also be due to a lower male: female ratio in these areas but this may ultimately be due to male infants having increased mortality from infectious diseases. Another example is that poor socioeconomic factors may ultimately in part be due to high pathogen load preventing economic development.
== Fossil record ==
Evidence of infection in fossil remains is a subject of interest for paleopathologists, scientists who study occurrences of injuries and illness in extinct life forms. Signs of infection have been discovered in the bones of carnivorous dinosaurs. When present, however, these infections seem to tend to be confined to only small regions of the body. A skull attributed to the early carnivorous dinosaur Herrerasaurus ischigualastensis exhibits pit-like wounds surrounded by swollen and porous bone. The unusual texture of the bone around the wounds suggests they were affected by a short-lived, non-lethal infection. Scientists who studied the skull speculated that the bite marks were received in a fight with another Herrerasaurus. Other carnivorous dinosaurs with documented evidence of infection include Acrocanthosaurus, Allosaurus, Tyrannosaurus and a tyrannosaur from the Kirtland Formation. The infections from both tyrannosaurs were received by being bitten during a fight, like the Herrerasaurus specimen.
== Outer space ==
A 2006 Space Shuttle experiment found that Salmonella typhimurium, a bacterium that can cause food poisoning, became more virulent when cultivated in space. On April 29, 2013, scientists in Rensselaer Polytechnic Institute, funded by NASA, reported that, during spaceflight on the International Space Station, microbes seem to adapt to the space environment in ways "not observed on Earth" and in ways that "can lead to increases in growth and virulence". More recently, in 2017, bacteria were found to be more resistant to antibiotics and to thrive in the near-weightlessness of space. Microorganisms have been observed to survive the vacuum of outer space.
== See also ==
== References ==
== External links ==
European Center for Disease Prevention and Control
U.S. Centers for Disease Control and Prevention,
Infectious Disease Society of America (IDSA)
Vaccine Research Center Information concerning vaccine research clinical trials for Emerging and re-Emerging Infectious Diseases.
Microbes & Infection (journal) | Wikipedia/Communicable_disease |
A chronic condition (also known as chronic disease or chronic illness) is a health condition or disease that is persistent or otherwise long-lasting in its effects or a disease that comes with time. The term chronic is often applied when the course of the disease lasts for more than three months.
Common chronic diseases include diabetes, functional gastrointestinal disorder, eczema, arthritis, asthma, chronic obstructive pulmonary disease, autoimmune diseases, genetic disorders and some viral diseases such as hepatitis C and acquired immunodeficiency syndrome.
An illness which is lifelong because it ends in death is a terminal illness. It is possible and not unexpected for an illness to change in definition from terminal to chronic as medicine progresses. Diabetes and HIV for example were once terminal yet are now considered chronic, due to the availability of insulin for diabetics and daily drug treatment for individuals with HIV, which allow these individuals to live while managing symptoms.
In medicine, chronic conditions are distinguished from those that are acute. An acute condition typically affects one portion of the body and responds to treatment. A chronic condition, on the other hand, usually affects multiple areas of the body, is not fully responsive to treatment, and persists for an extended period of time.
Chronic conditions may have periods of remission or relapse where the disease temporarily goes away, or subsequently reappear. Periods of remission and relapse are commonly discussed when referring to substance abuse disorders which some consider to fall under the category of chronic condition.
Chronic conditions are often associated with non-communicable diseases which are distinguished by their non-infectious causes. Some chronic conditions though, are caused by transmissible infections such as HIV/AIDS.
63% of all deaths worldwide are from chronic conditions. Chronic diseases constitute a major cause of mortality, and the World Health Organization (WHO) attributes 38 million deaths a year to non-communicable diseases. In the United States approximately 40% of adults have at least two chronic conditions.
Having more than one chronic condition is referred to as multimorbidity.
== Types ==
Chronic conditions have often been used to describe the various health related states of the human body such as syndromes, physical impairments, disabilities as well as diseases. Epidemiologists have found interest in chronic conditions due to the fact they contribute to disease, disability, and diminished physical and/or mental capacity.
For example, high blood pressure or hypertension is considered to be not only a chronic condition itself but also correlated with diseases such as heart attack or stroke.
Researchers, particularly those studying the United States, utilize the Chronic Condition Indicator (CCI) which maps ICD codes as "chronic" or "non-chronic".
The list below includes these chronic conditions and diseases:
In 2015 the World Health Organization produced a report on non-communicable diseases, citing the four major types as:
Cancers
Cardiovascular diseases, including cerebrovascular disease, heart failure, and ischemic cardiopathy
Chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD)
Diabetes mellitus (type 1, type 2, pre-diabetes)
Other examples of chronic diseases and health conditions include:
Alzheimer's disease
Atrial fibrillation
Attention deficit hyperactivity disorder
Autism Spectrum Disorder
Autoimmune diseases, such as ulcerative colitis, lupus erythematosus, Crohn's disease, coeliac disease, Hashimoto's thyroiditis, and relapsing polychondritis
Blindness
Cerebral palsy (all types)
Chronic graft-versus-host disease
Chronic hepatitis
Chronic pancreatitis
Chronic kidney disease
Chronic osteoarticular diseases, such as osteoarthritis and rheumatoid arthritis
Chronic pain syndromes, such as post-vasectomy pain syndrome and complex regional pain syndrome
Dermatological conditions such as atopic dermatitis and psoriasis
Down Syndrome
Dwarfism
Deafness and hearing impairment
Ehlers–Danlos syndrome (various types)
Endometriosis
Epilepsy
Fetal alcohol spectrum disorder
Fibromyalgia
HIV/AIDS
Hereditary spherocytosis
Huntington's disease
Hypertension
Mental illness
Migraines
Multiple sclerosis
Myalgic encephalomyelitis (a.k.a. chronic fatigue syndrome)
Narcolepsy
Obesity
Osteogenesis Imperfecta
Osteoporosis
Parkinson's disease
Periodontal disease
Polycystic Ovarian Syndrome
Postural orthostatic tachycardia syndrome
Prader-Willi Syndrome
Sickle cell anemia and other hemoglobin disorders
Substance Abuse Disorders
Sleep apnea
Thyroid disease
Tuberculosis
Williams Syndrome
And many more.
== Risk factors ==
While risk factors vary with age and gender, many of the common chronic diseases in the US are caused by dietary, lifestyle and metabolic risk factors. Therefore, these conditions might be prevented by behavioral changes, such as quitting smoking, adopting a healthy diet, and increasing physical activity. Social determinants are important risk factors for chronic diseases. Social factors, e.g., socioeconomic status, education level, and race/ethnicity, are a major cause for the disparities observed in the care of chronic disease. Lack of access and delay in receiving care result in worse outcomes for patients from minorities and underserved populations. Those barriers to medical care complicate patients monitoring and continuity in treatment.
In the US, minorities and low-income populations are less likely to seek, access and receive preventive services necessary to detect conditions at an early stage.
The majority of US health care and economic costs associated with medical conditions are incurred by chronic diseases and conditions and associated health risk behaviors. Eighty-four percent of all health care spending in 2006 was for the 50% of the population who have one or more common chronic medical conditions (CDC, 2014).
There are several psychosocial risk and resistance factors among children with chronic illness and their family members. Adults with chronic illness were significantly more likely to report life dissatisfaction than those without chronic illness. Compared to their healthy peers, children with chronic illness have about a twofold increase in psychiatric disorders. Higher parental depression and other family stressors predicted more problems among patients. In addition, sibling problems along with the burden of illness on the family as a whole led to more psychological strain on the patients and their families.
Africa
African countries are currently grappling with a double health burden—while infectious diseases continue to be a major cause of death, chronic illnesses are increasingly becoming more deadly, particularly in sub-Saharan Africa. This region reports some of the highest chronic disease mortality rates globally, impacting both men and women alike.
The surge in chronic conditions such as diabetes, hypertension, and cardiovascular disease is being driven by poor lifestyle choices like unhealthy diets, physical inactivity, smoking, and obesity. These modifiable behaviors are becoming widespread across both rural and urban areas. In addition to lifestyle factors, genetics also plays a role in the region’s chronic disease profile, particularly for conditions like high blood pressure and diabetes.
Compounding the problem is the state of healthcare systems, which often lack the infrastructure, funding, and public awareness needed to respond effectively to this growing crisis.
Asia
Asia's chronic disease burden is rising sharply, driven by a mix of aging populations, genetic predispositions, and fast-paced urbanization. The transition to more sedentary lifestyles and Westernized diets brought on by industrialization and economic growth—has contributed significantly to the growing number of non-communicable diseases (NCDs). South Asians, in particular, are at greater risk, developing these conditions earlier in life and often at lower body weights compared to global norms, resulting in higher healthcare costs and lower productivity.
Tobacco use remains a critical risk factor across South Asia, with a strong link to chronic illnesses. For instance, the Maldives has reported some of the highest rates of NCD-related deaths among women. Poor diets and smoking rank among the top contributors to early death and disability, made worse by limited access to healthcare and low levels of health awareness in many communities.
Latin America and the Caribbean
In Latin America and the Caribbean, changing lifestyles and environmental conditions are key contributors to the rise in chronic diseases. Many young people, including students, are engaging in habits such as poor nutrition, high consumption of processed foods and sugary drinks, and low levels of physical activity all of which increase their vulnerability to conditions like diabetes and heart disease.
The region’s rapid urban growth and influence from global food and media trends have also shifted daily routines toward more sedentary and unhealthy patterns. Combined with existing social and economic challenges, these changes are putting additional pressure on public health systems, underscoring the urgent need for prevention strategies and stronger public policies.
== Cause ==
Some people suffered from chronic symptoms that developed soon after Covid-19 injections, and this long term condition is known as post-vaccination syndrome (PVS). In February 2025, research from Yale University School of Medicine showed that more frequent Epstein-Barr virus (EBV) reactivation and elevated levels of circulating spike protein were observed in PVS participants, including those who were not infected, compared to healthy controls.
== Prevention ==
A growing body of evidence supports that prevention is effective in reducing the effect of chronic conditions; in particular, early detection results in less severe outcomes. Clinical preventive services include screening for the existence of the disease or predisposition to its development, counseling and immunizations against infectious agents. Despite their effectiveness, the utilization of preventive services is typically lower than for regular medical services. In contrast to their apparent cost in time and money, the benefits of preventive services are not directly perceived by patient because their effects are on the long term or might be greater for society as a whole than at the individual level.
Therefore, public health programs are important in educating the public, and promoting healthy lifestyles and awareness about chronic diseases. While those programs can benefit from funding at different levels (state, federal, private) their implementation is mostly in charge of local agencies and community-based organizations.
Studies have shown that public health programs are effective in reducing mortality rates associated to cardiovascular disease, diabetes and cancer, but the results are somewhat heterogeneous depending on the type of condition and the type of programs involved. For example, results from different approaches in cancer prevention and screening depended highly on the type of cancer.
The rising number of patient with chronic diseases has renewed the interest in prevention and its potential role in helping control costs. In 2008, the Trust for America's Health produced a report that estimated investing $10 per person annually in community-based programs of proven effectiveness and promoting healthy lifestyle (increase in physical activity, healthier diet and preventing tobacco use) could save more than $16 billion annually within a period of just five years.
A 2017 review (updated in 2022) found that it is uncertain whether school-based policies on targeting risk factors on chronic diseases such as healthy eating policies, physical activity policies, and tobacco policies can improve student health behaviours or knowledge of staffs and students. The updated review in 2022 did determine a slight improvement in measures of obesity and physical activity as the use of improved strategies lead to increased implementation interventions but continued to call for additional research to address questions related to alcohol use and risk. Encouraging those with chronic conditions to continue with their outpatient (ambulatory) medical care and attend scheduled medical appointments may help improve outcomes and reduce medical costs due to missed appointments. Finding patient-centered alternatives to doctors or consultants scheduling medical appointments has been suggested as a means of improving the number of people with chronic conditions that miss medical appointments, however there is no strong evidence that these approaches make a difference.
== Nursing ==
Nursing can play an important role in assisting patients with chronic diseases achieve longevity and experience wellness. Scholars point out that the current neoliberal era emphasizes self-care, in both affluent and low-income communities. This self-care focus extends to the nursing of patients with chronic diseases, replacing a more holistic role for nursing with an emphasis on patients managing their own health conditions. Critics note that this is challenging if not impossible for patients with chronic disease in low-income communities where health care systems, and economic and social structures do not fully support this practice.
A study in Ethiopia showcases a nursing-heavy approach to the management of chronic disease. Foregrounding the problem of distance from healthcare facility, the study recommends patients increase their request for care. It uses nurses and health officers to fill, in a cost-efficient way, the large unmet need for chronic disease treatment. They led their health centers staffed by nurses and health officers; so, there are specific training required for involvement in the programmed must be carried out regularly, to ensure that new staff is educated in administering chronic disease care. The program shows that community-based care and education, primarily driven by nurses and health officers, works. It highlights the importance of nurses following up with individuals in the community, and allowing nurses flexibility in meeting their patients' needs and educating them for self-care in their homes.
== Epidemiology ==
The epidemiology of chronic disease is diverse and the epidemiology of some chronic diseases can change in response to new treatments. In the treatment of HIV, the success of anti-retroviral therapies means that many patients will experience this infection as a chronic disease that for many will span several decades of their chronic life.
Some epidemiology of chronic disease can apply to multiple diagnosis. Obesity and body fat distribution for example contribute and are risk factors for many chronic diseases such as diabetes, heart, and kidney disease. Other epidemiological factors, such as social, socioeconomic, and environment do not have a straightforward cause and effect relationship with chronic disease diagnosis. While typically higher socioeconomic status is correlated with lower occurrence of chronic disease, it is not known is there is a direct cause and effect relationship between these two variables.
The epidemiology of communicable chronic diseases such as AIDS is also different from that of noncommunicable chronic disease. While Social factors do play a role in AIDS prevalence, only exposure is truly needed to contract this chronic disease. Communicable chronic diseases are also typically only treatable with medication intervention, rather than lifestyle change as some non-communicable chronic diseases can be treated.
=== United States ===
As of 2003, there are a few programs which aim to gain more knowledge on the epidemiology of chronic disease using data collection. The hope of these programs is to gather epidemiological data on various chronic diseases across the United States and demonstrate how this knowledge can be valuable in addressing chronic disease.
In the United States, as of 2004 nearly one in two Americans (133 million) has at least one chronic medical condition, with most subjects (58%) between the ages of 18 and 64. The number is projected to increase by more than one percent per year by 2030, resulting in an estimated chronically ill population of 171 million. The most common chronic conditions are high blood pressure, arthritis, respiratory diseases like emphysema, and high cholesterol.
Based on data from 2014 Medical Expenditure Panel Survey (MEPS), about 60% of adult Americans were estimated to have one chronic illness, with about 40% having more than one; this rate appears to be mostly unchanged from 2008. MEPS data from 1998 showed 45% of adult Americans had at least one chronic illness, and 21% had more than one.
According to research by the CDC, chronic disease is also especially a concern in the elderly population in America. Chronic diseases like stroke, heart disease, and cancer were among the leading causes of death among Americans aged 65 or older in 2002, accounting for 61% of all deaths among this subset of the population. It is estimated that at least 80% of older Americans are currently living with some form of a chronic condition, with 50% of this population having two or more chronic conditions. The two most common chronic conditions in the elderly are high blood pressure and arthritis, with diabetes, coronary heart disease, and cancer also being reported among the elder population.
In examining the statistics of chronic disease among the living elderly, it is also important to make note of the statistics pertaining to fatalities as a result of chronic disease. Heart disease is the leading cause of death from chronic disease for adults older than 65, followed by cancer, stroke, diabetes, chronic lower respiratory diseases, influenza and pneumonia, and, finally, Alzheimer's disease. Though the rates of chronic disease differ by race for those living with chronic illness, the statistics for leading causes of death among elderly are nearly identical across racial/ethnic groups.
Chronic illnesses cause about 70% of deaths in the US and in 2002 chronic conditions (heart disease, cancers, stroke, chronic respiratory diseases, diabetes, Alzheimer's disease, mental illness and kidney diseases) were six of the top ten causes of mortality in the general US population.
=== Canada ===
The government of Canada put a high emphasis on chronic conditions in the country [1]. At least 45.1% of Canadians will experience one chronic condition in their lifetime. On December 11, 2024, Sun Life, a prominent health insurance provider in Canada, reported an increase in chronic diseases across all age groups. They emphasize that chronic conditions affect both young individuals and the elderly. Sun Life highlights that a growing number of young people are facing chronic issues such as diabetes, asthma, high blood pressure, and elevated cholesterol levels. The report examined drug claims for chronic conditions from over three million Sun Life plan members [2].
It is important to note that diabetes is one of the fastest-growing chronic conditions in Canada, having increased by approximately 30% from 2019 to 2023. Claims for diabetes medications have surged more rapidly among Canadians under the age of 30 [3].
Chronic diseases are prevalent among older Canadians. A report indicates that 73% of individuals aged 65 and older have at least one of ten common chronic conditions. The ten most frequent chronic diseases in Canada include hypertension, affecting 65.7% of the elderly, periodontal disease at 52.0%, osteoarthritis at 38.0%, ischemic heart disease at 27.0%, diabetes at 26.8%, osteoporosis at 25.1%, cancer at 21.5%, COPD at 20.2%, asthma at 10.7%, and mood and anxiety disorders at 10.5%. Additionally, COVID-19 has impacted chronic conditions in seniors, and its effects are currently being studied [4].
== Economic impact ==
=== United States ===
Chronic diseases are a major factor in the continuous growth of medical care spending. In 2002, the U.S. Department of Health and Human Services stated that the health care for chronic diseases cost the most among all health problems in the U.S. Healthy People 2010 reported that more than 75% of the $2 trillion spent annually in U.S. medical care are due to chronic conditions; spending are even higher in proportion for Medicare beneficiaries (aged 65 years and older). Furthermore, in 2017 it was estimated that 90% of the $3.3 billion spent on healthcare in the United States was due to the treatment of chronic diseases and conditions. Spending growth is driven in part by the greater prevalence of chronic illnesses and the longer life expectancy of the population. Also, improvement in treatments has significantly extended the lifespans of patients with chronic diseases but results in additional costs over long period of time. A striking success is the development of combined antiviral therapies that led to remarkable improvement in survival rates and quality of life of HIV-infected patients.
In addition to direct costs in health care, chronic diseases are a significant burden to the economy, through limitations in daily activities, loss in productivity and loss of days of work. A particular concern is the rising rates of overweight and obesity in all segments of the U.S. population. Obesity itself is a medical condition and not a disease, but it constitutes a major risk factor for developing chronic illnesses, such as diabetes, stroke, cardiovascular disease and cancers. Obesity results in significant health care spending and indirect costs, as illustrated by a recent study from the Texas comptroller reporting that obesity alone cost Texas businesses an extra $9.5 billion in 2009, including more than $4 billion for health care, $5 billion for lost productivity and absenteeism, and $321 million for disability.
=== Canada ===
The Public Health Agency of Canada states that chronic disease has a negative impact on the labor force participant of individuals. In particular, people with chronic diseases “are likely to have recurrent sick leave, long-term absences from work, and often face an early retirement from the labour force.”
In 2000, the Public Health Agency of Canada stated that the total economic burden of arthritis totaled 6.4 billion Canadian dollars per year, representing 28.9% of all musculoskeletal disease expenditures. 65% of the total economic cost was incurred by those aged 35-64 years old. It is anticipated that people aged 55 and older will most significantly contribute to the prevalence of arthritis. This is projected to result in reduced labor force participant and a substantial increase in morbidity costs. The Public Health Agency of Canada recommends focusing on prevention strategies, minimizing costs by improving health and reducing disability, and providing support to people with arthritis to remain active in the workforce.
=== Japan ===
As of 2004, the estimated economic burden of Chronic obstructive pulmonary disease (COPD) is 805.5 billion yen per year. Direct costs, which include inpatient care, outpatient care, and home oxygen therapy, account for 645.1 billion yen per year. Meanwhile, indirect costs are estimated to cost 160.4 billion yen per year in lost productivity due to absenteeism from work. The high smoking rate and increasing size of the elderly population are likely to exacerbate the economic impact of COPD in Japan.
Major indirect costs of COPD are a decrease in labor force participation, increased cost of healthcare due to assisted living expenses, increased prevalence of premature death, and care giver support cost. In 1999, a survey demonstrated that patients with chronic bronchitis, COPD, or emphysema missed an average of 42.2 days of work per year due to their condition.
== Social and personal impact ==
There have been recent links between social factors and prevalence as well as outcome of chronic conditions.
=== Mental health ===
The connection between loneliness, overall health, and chronic conditions has recently been highlighted. Some studies have shown that loneliness has detrimental health effects similar to that of smoking and obesity. One study found that feelings of isolation are associated with higher self reporting of health as poor, and feelings of loneliness increased the likelihood of mental health disorders in individuals.
The connection between chronic illness and loneliness is established, yet oftentimes ignored in treatment. One study for example found that a greater number of chronic illnesses per individual were associated with feelings of loneliness. Some of the possible reasons for this listed are an inability to maintain independence as well as the chronic illness being a source of stress for the individual. A study of loneliness in adults over age 65 found that low levels of loneliness as well as high levels of familial support were associated with better outcomes of multiple chronic conditions such as hypertension and diabetes.
There are some recent movements in the medical sphere to address these connections when treating patients with chronic illness. The biopsychosocial approach for example, developed in 2006 focuses on patients "patient's personality, family, culture, and health dynamics." Physicians are leaning more towards a psychosocial approach to chronic illness to aid the increasing number of individuals diagnosed with these conditions. Despite this movement, there is still criticism that chronic conditions are not being treated appropriately, and there is not enough emphasis on the behavioral aspects of chronic conditions or psychological types of support for patients.
The mental health intersectionality on those with chronic conditions is a large aspect often overlooked by doctors. And chronic illness therapists are available for support to help with the mental toll of chronic illness a it is often underestimated in society. Adults with chronic illness that restrict their daily life present with more depression and lower self-esteem than healthy adults and adults with non-restricting chronic illness. The emotional influence of chronic illness also has an effect on the intellectual and educational development of the individual. For example, people living with type 1 diabetes endure a lifetime of monotonous and rigorous health care management usually involving daily blood glucose monitoring, insulin injections, and constant self-care. This type of constant attention that is required by type 1 diabetes and other chronic illness can result in psychological maladjustment. There have been several theories, namely one called diabetes resilience theory, that posit that protective processes buffer the impact of risk factors on the individual's development and functioning.
=== Financial cost ===
People with chronic conditions pay more out-of-pocket; a study found that Americans spent $2,243 more on average. The financial burden can increase medication non-adherence.
In some countries, laws protect patients with chronic conditions from excessive financial responsibility; for example, as of 2008 France limited copayments for those with chronic conditions, and Germany limits cost sharing to 1% of income versus 2% for the general public.
Within the medical-industrial complex, chronic illnesses can impact the relationship between pharmaceutical companies and people with chronic conditions. Life-saving drugs, or life-extending drugs, can be inflated for a profit. There is little regulation on the cost of chronic illness drugs, which suggests that abusing the lack of a drug cap can create a large market for drug revenue. Likewise, certain chronic conditions can last throughout one's lifetime and create pathways for pharmaceutical companies to take advantage of this.
=== Gender ===
Gender influences how chronic disease is viewed and treated in society. Women's chronic health issues are often considered to be most worthy of treatment or most severe when the chronic condition interferes with a woman's fertility. Historically, there is less of a focus on a woman's chronic conditions when it interferes with other aspects of her life or well-being. Many women report feeling less than or even "half of a woman" due to the pressures that society puts on the importance of fertility and health when it comes to typically feminine ideals. These kinds of social barriers interfere with women's ability to perform various other activities in life and fully work toward their aspirations.
=== Socioeconomic class and race ===
Race is also implicated in chronic illness, although there may be many other factors involved. Racial minorities are 1.5-2 times more likely to have most chronic diseases than white individuals. Non-Hispanic blacks are 40% more likely to have high blood pressure that non-Hispanic whites, diagnosed diabetes is 77% higher among non-Hispanic blacks, and American Indians and Alaska Natives are 60% more likely to be obese than non-Hispanic whites. Some of this prevalence has been suggested to be in part from environmental racism. Flint, Michigan, for example, had high levels of lead poisoning in their drinkable water after waste was dumped into low-value housing areas. There are also higher rates of asthma in children who live in lower income areas due to an abundance of pollutants being released on a much larger scale in these areas.
== Advocacy and research organizations ==
In Europe, the European Chronic Disease Alliance was formed in 2011, which represents over 100,000 healthcare workers.
In the United States, there are a number of nonprofits focused on chronic conditions, including entities focused on specific diseases such as the American Diabetes Association, Alzheimer's Association, or Crohn's and Colitis Foundation. There are also broader groups focused on advocacy or research into chronic illness in general, such as the National Association of Chronic Disease Directors, Partnership to Fight Chronic Disease, the Chronic Disease Coalition which arose in Oregon in 2015, and the Chronic Policy Care Alliance.
== See also ==
Chronic care management
Chronic disease in China
Chronic disease in Northern Ontario
Chronic Illness (journal)
Chronic pain
Long COVID
Course (medicine)
Disability studies
Disease management (health)
Dynamic treatment regimes
Medical tattoo
Multimorbidity
Natural history of disease
Virtual Wards (a UK term)
== References ==
== Further reading ==
== External links ==
"List of Chronic Human Diseases Linked to Infectious Pathogens". Archived from the original on 2021-01-18.
Center for Managing Chronic Disease, University of Michigan
CHRODIS: EU Joint Action on Chronic Diseases and Promoting Healthy Ageing Across the Life-Cycle
MEDICC Review theme issue on Confronting Chronic Diseases With longer life expectancies in most countries and the globalization of "Western" diets and sedentarism, the main burden of disease and death from these conditions is falling on already-disadvantaged developing countries and poor communities everywhere.
Public Health Agency of Canada: Chronic Disease
World Health Organization: Chronic Disease and Health Promotion | Wikipedia/Chronic_diseases |
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development (a de novo mutation), or it can be inherited from two parents who are carriers of a faulty gene (autosomal recessive inheritance) or from a parent with the disorder (autosomal dominant inheritance). When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA (due to their size).
There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature. More than 600 genetic disorders are treatable. Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves.
Genetic disorders are present before birth, and some genetic disorders produce birth defects, but birth defects can also be developmental rather than hereditary. The opposite of a hereditary disease is an acquired disease. Most cancers, although they involve genetic mutations to a small proportion of cells in the body, are acquired diseases. Some cancer syndromes, however, such as BRCA mutations, are hereditary genetic disorders.
== Single-gene ==
A single-gene disorder (or monogenic disorder) is the result of a single mutated gene. Single-gene disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparental disomy, however, may affect inheritance patterns. The divisions between recessive and dominant types are not "hard and fast", although the divisions between autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, the common form of dwarfism, achondroplasia, is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe and usually lethal skeletal disorder, one that achondroplasics(ones affected with achondroplasia) could be considered carriers for. Sickle cell anemia is also considered a recessive condition, but heterozygous carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition. When a couple where one partner or both are affected or carriers of a single-gene disorder wish to have a child, they can do so through in vitro fertilization, which enables preimplantation genetic diagnosis to occur to check whether the embryo has the genetic disorder.
Most congenital metabolic disorders known as inborn errors of metabolism result from single-gene defects. Many such single-gene defects can decrease the fitness of affected people and are therefore present in the population in lower frequencies compared to what would be expected based on simple probabilistic calculations.
=== Autosomal dominant ===
Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent.: 57 The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reduced penetrance, which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder are Huntington's disease,: 58 neurofibromatosis type 1, neurofibromatosis type 2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, hereditary multiple exostoses (a highly penetrant autosomal dominant disorder), tuberous sclerosis, Von Willebrand disease, and acute intermittent porphyria. Birth defects are also called congenital anomalies.
=== Autosomal recessive ===
Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene and are referred to as genetic carriers. Each parent with a defective gene normally do not have symptoms. Two unaffected people who each carry one copy of the mutated gene have a 25% risk with each pregnancy of having a child affected by the disorder. Examples of this type of disorder are albinism, medium-chain acyl-CoA dehydrogenase deficiency, cystic fibrosis, sickle cell disease, Tay–Sachs disease, Niemann–Pick disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such as wet versus dry earwax, are also determined in an autosomal recessive fashion. Some autosomal recessive disorders are common because, in the past, carrying one of the faulty genes led to a slight protection against an infectious disease or toxin such as tuberculosis or malaria. Such disorders include cystic fibrosis, sickle cell disease, phenylketonuria and thalassaemia.
=== X-linked dominant ===
X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern, with a prime example being X-linked hypophosphatemic rickets. Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions, such as Rett syndrome, incontinentia pigmenti type 2, and Aicardi syndrome, are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys with Klinefelter syndrome (44+xxy) also inherit an X-linked dominant condition and exhibit symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y chromosome), but his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected foetus with each pregnancy, although in cases such as incontinentia pigmenti, only female offspring are generally viable.
=== X-linked recessive ===
X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. The chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected (since they receive their father's Y chromosome), but his daughters will be carriers of one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers of one copy of the mutated gene. X-linked recessive conditions include the serious diseases hemophilia A, Duchenne muscular dystrophy, and Lesch–Nyhan syndrome, as well as common and less serious conditions such as male pattern baldness and red–green color blindness. X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).
=== Y-linked ===
Y-linked disorders are caused by mutations on the Y chromosome. These conditions may only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders in humans can only be passed from men to their sons; females can never be affected because they do not possess Y-allosomes.
Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions is only possible through the circumvention of infertility by medical intervention.
=== Mitochondrial ===
This type of inheritance, also known as maternal inheritance, is the rarest and applies to the 13 genes encoded by mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only mothers (who are affected) can pass on mitochondrial DNA conditions to their children. An example of this type of disorder is Leber's hereditary optic neuropathy.
It is important to stress that the vast majority of mitochondrial diseases (particularly when symptoms develop in early life) are actually caused by a nuclear gene defect, as the mitochondria are mostly developed by non-mitochondrial DNA. These diseases most often follow autosomal recessive inheritance.
== Multifactorial disorder ==
Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person's risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. Studies that aim to identify the cause of complex disorders can use several methodological approaches to determine genotype–phenotype associations. One method, the genotype-first approach, starts by identifying genetic variants within patients and then determining the associated clinical manifestations. This is opposed to the more traditional phenotype-first approach, and may identify causal factors that have previously been obscured by clinical heterogeneity, penetrance, and expressivity.
On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases. This does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g., blood pressure).
Other such cases include:
asthma
autoimmune diseases such as multiple sclerosis
cancers
ciliopathies
cleft palate
diabetes
heart disease
hypertension
inflammatory bowel disease
intellectual disability
mood disorder
obesity
refractive error
infertility
== Chromosomal disorder ==
A chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes. An example of these disorders is Trisomy 21 (the most common form of Down syndrome), in which there is an extra copy of chromosome 21 in all cells.
== Diagnosis ==
Due to the wide range of genetic disorders that are known, diagnosis is widely varied and dependent of the disorder. Most genetic disorders are diagnosed pre-birth, at birth, or during early childhood however some, such as Huntington's disease, can escape detection until the patient begins exhibiting symptoms well into adulthood.
The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depth family history, it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility of stillbirth, or contemplate termination. Prenatal diagnosis can detect the presence of characteristic abnormalities in fetal development through ultrasound, or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis.
== Prognosis ==
Not all genetic disorders directly result in death; however, there are no known cures for genetic disorders. Many genetic disorders affect stages of development, such as Down syndrome, while others result in purely physical symptoms such as muscular dystrophy. Other disorders, such as Huntington's disease, show no signs until adulthood. During the active time of a genetic disorder, patients mostly rely on maintaining or slowing the degradation of quality of life and maintain patient autonomy. This includes physical therapy and pain management.
== Treatment ==
The treatment of disorder an ongoing battle, with over 1,800 gene therapy clinical trials having been completed, are ongoing, or have been approved worldwide. Despite this, most treatment options revolve around treating the symptoms of the disorders in an attempt to improve patient quality of life.
Gene therapy refers to a form of treatment where a healthy gene is introduced to a patient. This should alleviate the defect caused by a faulty gene or slow the progression of the disease. A major obstacle has been the delivery of genes to the appropriate cell, tissue, and organ affected by the disorder. Researchers have investigated how they can introduce a gene into the potentially trillions of cells that carry the defective copy. Finding an answer to this has been a roadblock between understanding the genetic disorder and correcting the genetic disorder.
== Epidemiology ==
Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves. There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature.
== History ==
The earliest known genetic condition in a hominid was in the fossil species Paranthropus robustus, with over a third of individuals displaying amelogenesis imperfecta.
== See also ==
FINDbase (the Frequency of Inherited Disorders database)
Genetic epidemiology
List of genetic disorders
Population groups in biomedicine
Mendelian error
== References ==
== External links ==
Public Health Genomics at CDC
OMIM — Online Mendelian Inheritance in Man, a catalog of human genes and genetic disorders
Genetic and Rare Diseases Information Center (GARD) Office of Rare Diseases (ORD), National Institutes of Health (NIH)
CDC's National Center on Birth Defects and Developmental Disabilities
Genetic Disease Information from the Human Genome Project
Global Genes Project, Genetic and Rare Diseases Organization
List of Genetic Disorders - Genome.gov | Wikipedia/Hereditary_disease |
Geographic information science (GIScience, GISc) or geoinformation science is a scientific discipline at the crossroads of computational science, social science, and natural science that studies geographic information, including how it represents phenomena in the real world, how it represents the way humans understand the world, and how it can be captured, organized, and analyzed. It is a sub-field of geography, specifically part of technical geography. It has applications to both physical geography and human geography, although its techniques can be applied to many other fields of study as well as many different industries.
As a field of study or profession, it can be contrasted with geographic information systems (GIS), which are the actual repositories of geospatial data, the software tools for carrying out relevant tasks, and the profession of GIS users. That said, one of the major goals of GIScience is to find practical ways to improve GIS data, software, and professional practice; it is more focused on how gis is applied in real life as opposed to being a geographic information system tool in and of itself. The field is also sometimes called geographical information science.
British geographer Michael Goodchild defined this area in the 1990s and summarized its core interests, including spatial analysis, visualization, and the representation of uncertainty. GIScience is conceptually related to geomatics, information science, computer science, and data science, but it claims the status of an independent scientific discipline. Recent developments in the field have expanded its focus to include studies on human dynamics in hybrid physical-virtual worlds, quantum GIScience, the development of smart cities, and the social and environmental impacts of technological innovations. These advancements indicate a growing intersection of GIScience with contemporary societal and technological issues. Overlapping disciplines are: geocomputation, geoinformatics, geomatics and geovisualization. Other related terms are geographic data science (after data science)
and geographic information science and technology (GISci&T), with job titles geospatial information scientists and technologists.
== Definitions ==
Since its inception in the 1990s, the boundaries between GIScience and cognate disciplines are contested, and different communities might disagree on what GIScience is and what it studies. In particular, Goodchild stated that "information science can be defined as the systematic study according to scientific principles of the nature and properties of information. Geographic information science is the subset of/or information science that is about geographic information." Another influential definition is that by geographic information scientist (GIScientist) David Mark, which states:Geographic Information Science (GIScience) is the basic research field that seeks to redefine geographic concepts and their use in the context of geographic information systems. GIScience also examines the impacts of GIS on individuals and society, and the influences of society on GIS. GIScience re-examines some of the most fundamental themes in traditional spatially oriented fields such as geography, cartography, and geodesy, while incorporating more recent developments in cognitive and information science. It also overlaps with and draws from more specialized research fields such as computer science, statistics, mathematics, and psychology, and contributes to progress in those fields. It supports research in political science and anthropology, and draws on those fields in studies of geographic information and society.
In 2009, Goodchild summarized the history of GIScience and its achievements and open challenges.
== See also ==
Category:Geographic information scientists
Geographic Information Science and Technology Body of Knowledge
Geostatistics
Organizations
Association of Geographic Information Laboratories for Europe
National Center for Geographic Information and Analysis
UCSB Center for Spatial Studies
University Consortium for Geographic Information Science
United States Geospatial Intelligence Foundation
Journals
GIScience & Remote Sensing
International Journal of Applied Earth Observation and Geoinformation
International Journal of Geographical Information Science
Journal of Spatial Information Science
== References ==
== External links ==
Official website of GIScience
List of GIScience Conferences Archived 2023-05-30 at the Wayback Machine
Conference on Spatial Information Theory (COSIT) | Wikipedia/Geographic_Information_Science |
Lymphatic disease is a class of disorders which directly affect the components of the lymphatic system.
Examples include Castleman's disease and lymphedema.
== Types ==
Diseases and disorder
Hodgkin's Disease/Hodgkin's Lymphoma
Hodgkin lymphoma This is a type of cancer of the lymphatic system. It can start almost anywhere in the body. It is believed to be caused by HIV, Epstein-Barr Syndrome, age, and family history. Symptoms include weight gain, fever, swollen lymph nodes, night sweats, itchy skin, fatigue, chest pain, coughing, or trouble swallowing.
Non-Hodgkin's Lymphoma
Lymphoma is usually malignant cancer. It is caused by the body producing too many abnormal white blood cells. It is not the same as Hodgkin's Disease. Symptoms usually include painless, enlarged lymph node or nodes in the neck, weakness, fever, weight loss, and anemia.
Lymphadenitis
Lymphadenitis is an infection of the lymph nodes usually caused by a virus, bacteria or fungi. Symptoms include redness or swelling around the lymph node.
Lymphangitis
Lymphangitis is an inflammation of the lymph vessels. Symptoms usually include swelling, redness, warmth, pain or red streaking around the affected area.
Lymphedema
Lymphedema is the chronic pooling of lymph fluid in the tissue. Lymphedema can start anywhere in the lymphatic system of the body. It's also a side-effect of some surgical procedures. Kathy Bates is an advocate and supporter for further research for lymphedema.
Lymphocytosis
Lymphocytosis is a high lymphocyte count. It can be caused by an infection, blood cancer, lymphoma, or autoimmune disorders that are accompanied by chronic swelling.
== References ==
== External links == | Wikipedia/Lymphatic_disease |
Progressive disease or progressive illness is a disease or physical ailment whose course in most cases is the worsening, growth, or spread of the disease. This may happen until death, serious debility, or organ failure occurs. Some progressive diseases can be halted and reversed by treatment (surgical, dietary, or lifestyle interventions). Many can be slowed by medical therapy. Some cannot be altered by current treatments.
Though the time distinctions are imprecise, diseases can be rapidly progressive (typically days to weeks) or slowly progressive (months to years). The time course of a disease affects whether it is considered acute or chronic. By definition, virtually all slowly progressive diseases are also chronic diseases. Biologically, many of these are also referred to as degenerative diseases due to the cellular changes.
Not all chronic diseases are progressive: a chronic, non-progressive disease may be referred to as a static condition.
Progressive disease can also be a clinical endpoint i.e. an endpoint in a clinical trial. A progressive disease should not be confused with a terminal disease, the difference being that a terminal disease invariably leads to death.
== Examples ==
There are examples of slowly and rapidly progressive diseases affecting all organ systems and parts of the body. The following are some examples of rapidly and slowly progressive diseases affecting various organ systems:
Brain: Creutzfeldt–Jakob disease progresses rapidly compared to Alzheimer's disease.
Eyes: Cataracts can be static or slowly progressive. Macular degeneration is slowly progressive, while retinal detachment is rapidly progressive.
Lungs: Emphysema due to alpha-1 antitrypsin deficiency is a slowly progressive pulmonary disease.
Kidneys: Goodpasture's syndrome is a rapidly progressive glomerulonephritis, while diabetic glomerulosclerosis is slowly progressive.
Pancreas: Type 1 diabetes mellitus involves rapidly progressive loss of insulin secretory capacity compared to type 2 diabetes mellitus, in which the loss of insulin secretion is slowly progressive over many years. MODY 2, due to GCK mutation, is a relatively static form of reduced insulin secretion.
Joints: Both osteoarthritis and rheumatoid arthritis are slowly progressive forms of arthritis.
Nerves: Essential tremor is a slowly progressive neurological disorder which is usually genetically passed down.
Cancer: the abnormal growth of body cells
== References == | Wikipedia/Progressive_disease |
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin.
For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause may not be readily apparent or characterized. In these cases, the origin of the condition is said to be idiopathic. With some other medical conditions, the root cause for a large percentage of all cases has not been established—for example, focal segmental glomerulosclerosis or ankylosing spondylitis; the majority of these cases are deemed idiopathic. Certain medical conditions, when idiopathic, notably some forms of epilepsy and stroke, are preferentially described by the synonymous term of cryptogenic.
== Derivation ==
The term 'idiopathic' derives from Greek ἴδιος idios "one's own" and πάθος pathos "suffering", so idiopathy means approximately "a disease of its own kind".
== Examples ==
Diseases where the cause is seen as wholly or partly idiopathic include:
Idiopathic pulmonary fibrosis
Idiopathic pulmonary haemosiderosis
Idiopathic intracranial hypertension
Idiopathic chronic fatigue
Granulomatous prostatitis
== Medical advances and this term ==
Advances in medical science improve the understanding of causes of diseases and the classification of diseases; thus, regarding any particular condition or disease, as more root causes are discovered and as events that seemed spontaneous have their origins revealed, the percentage of cases designated as idiopathic will decrease. Environmental and occupational risk factors are increasingly being associated with diseases classified as idiopathic. Emerging evidence indicates a complex relationship between intrinsic (genetic) and extrinsic (environmental and occupational risk factors) factors in disease physiopathology.
== Usage of synonyms ==
The word essential is sometimes synonymous with idiopathic (as in essential hypertension, essential thrombocythemia, and essential tremor) and the same is true of primary (as in primary biliary cholangitis, or primary amenorrhea), with the latter term being used in such cases to contrast with secondary in the sense of "secondary to [i.e., caused by] some other condition." Another, less common synonym is agnogenic (agno-, "unknown" + -gen, "cause" + -ic).
The word cryptogenic (crypto-, "hidden" + -gen, "cause" + -ic) has a sense that is synonymous with idiopathic and a sense that is contradistinguished from it. Some disease classifications prefer the use of the synonymous term cryptogenic disease as in cryptogenic stroke, and cryptogenic epilepsy. The use of cryptogenic is also sometimes reserved for cases where it is presumed that the cause is simple and will be found in the future.
Some congenital conditions are idiopathic, and sometimes the word congenital is used synonymously with idiopathic; but careful usage prefers to reserve the word congenital for conditions to which the literal sense of the word applies (that is, those whose pathophysiology has existed since the neonatal period).
== Syndrome without a name ==
The term syndrome without a name (SWAN) is used "when a child or young adult is believed to have a genetic condition and testing has failed to identify its genetic cause". It is believed that "about half (50%) of children with learning disabilities and approximately 60% of children with congenital disabilities (disabilities which are apparent from birth) do not have a definitive diagnosis to explain the cause of their difficulties".
== See also ==
Diagnosis of exclusion
Embolic stroke of undetermined source
Functional disorder
Idiosyncratic drug reaction
Fever of unknown origin
== References ==
== External links ==
The dictionary definition of idiopathic disease at Wiktionary | Wikipedia/Idiopathic_disease |
A sexually transmitted infection (STI), also referred to as a sexually transmitted disease (STD) and the older term venereal disease (VD), is an infection that is spread by sexual activity, especially vaginal intercourse, anal sex, oral sex, or sometimes manual sex. STIs often do not initially cause symptoms, which results in a risk of transmitting them to others. The term sexually transmitted infection is generally preferred over sexually transmitted disease or venereal disease, as it includes cases with no symptomatic disease. Symptoms and signs of STIs may include vaginal discharge, penile discharge, ulcers on or around the genitals, and pelvic pain. Some STIs can cause infertility.
Bacterial STIs include chlamydia, gonorrhea, and syphilis. Viral STIs include genital warts, genital herpes, and HIV/AIDS. Parasitic STIs include trichomoniasis. Most STIs are treatable and curable; of the most common infections, syphilis, gonorrhea, chlamydia, and trichomoniasis are curable, while HIV/AIDS and genital herpes are not curable. Some vaccinations may decrease the risk of certain infections including hepatitis B and a few types of HPV. Safe sex practices such as the use of condoms, having smaller number of sexual partners, and being in a relationship in which each person only has sex with the other also decreases STIs risk. Comprehensive sex education may also be useful.
STI diagnostic tests are usually easily available in the developed world, but they are often unavailable in the developing world. There is often shame and stigma associated with STIs. In 2015, STIs other than HIV resulted in 108,000 deaths worldwide. Globally, in 2015, about 1.1 billion people had STIs other than HIV/AIDS. About 500 million have either syphilis, gonorrhea, chlamydia or trichomoniasis. At least an additional 530 million have genital herpes, and 290 million women have human papillomavirus. Historical documentation of STIs in antiquity dates back to at least the Ebers Papyrus (c. 1550 BCE) and the Hebrew Bible/Old Testament (8th/7th C. BCE).
== Signs and symptoms ==
Not all STIs are symptomatic, and symptoms may not appear immediately after infection. In some instances a disease can be carried with no symptoms, which leaves a greater risk of passing the disease on to others. Depending on the disease, some untreated STIs can lead to infertility, chronic pain or death.
The presence of an STI in prepubescent children may indicate sexual abuse.
== Cause ==
=== Transmission ===
A sexually transmitted infection present in a pregnant woman may be passed on to the infant before or after birth.
=== Bacterial ===
Chancroid (Haemophilus ducreyi)
Chlamydia (Chlamydia trachomatis)
Gonorrhea (Neisseria gonorrhoeae)
Granuloma inguinale or (Klebsiella granulomatis)
Mycoplasma genitalium
Mycoplasma hominis
Syphilis (Treponema pallidum)
Ureaplasma infection
=== Viral ===
Viral hepatitis (hepatitis B virus)—saliva, venereal fluids.(Note: hepatitis A and hepatitis E are transmitted via the fecal–oral route; hepatitis C is rarely sexually transmittable, and the route of transmission of hepatitis D (only if infected with B) is uncertain, but may include sexual transmission.)
Herpes simplex (Herpes simplex virus 1, 2) skin and mucosal, transmissible with or without visible blisters
HIV (Human Immunodeficiency Virus)—venereal fluids, semen, breast milk, blood
HPV (Human Papillomavirus)—skin and mucosal contact. 'High risk' types of HPV cause almost all cervical cancers, as well as some anal, penile, and vulvar cancer. Some other types of HPV cause genital warts.
Molluscum contagiosum (molluscum contagiosum virus MCV)—close contact
Zika virus
=== Parasites ===
Crab louse, colloquially known as "crabs" or "pubic lice" (Pthirus pubis). The infestation and accompanying inflammation is Pediculosis pubis
Scabies (Sarcoptes scabiei)
Trichomoniasis (Trichomonas vaginalis), colloquially known as "trich"
=== Main types ===
Sexually transmitted infections include:
Chlamydia is a sexually transmitted infection caused by the bacterium Chlamydia trachomatis. In women, symptoms may include abnormal vaginal discharge, burning during urination, and bleeding in between periods, although most women do not experience any symptoms. Symptoms in men include pain when urinating, and abnormal discharge from their penis. If left untreated in both men and women, chlamydia can infect the urinary tract and potentially lead to pelvic inflammatory disease (PID). PID can cause serious problems during pregnancy and even has the potential to cause infertility. It can cause a woman to have a potentially deadly ectopic pregnancy, in which the egg implants outside of the uterus. However, chlamydia can be cured with antibiotics.
The two most common forms of herpes are caused by infection with herpes simplex virus (HSV). HSV-1 is typically acquired orally and causes cold sores; HSV-2 is usually acquired during sexual contact and affects the genitals; however, either strain may affect either site. Some people are asymptomatic or have very mild symptoms. Those that do experience symptoms usually notice them 2 to 20 days after exposure which lasts 2 to 4 weeks. Symptoms can include small fluid-filled blisters, headaches, backaches, itching or tingling sensations in the genital or anal area, pain during urination, flu like symptoms, swollen glands, or fever. Herpes is spread through skin contact with a person infected with the virus. The virus affects the areas where it entered the body. This can occur through kissing, vaginal intercourse, oral sex or anal sex. The virus is most infectious during times when there are visible symptoms; however, those who are asymptomatic can still spread the virus through skin contact. The initial infection and symptoms are usually the most severe because the body does not have any antibodies built up. After the primary attack, one might have recurring attacks that are milder or might not even have future attacks. There is no cure for the disease but there are antiviral medications that treat its symptoms and lower the risk of transmission (Valtrex). Although HSV-1 is typically the "oral" version of the virus, and HSV-2 is typically the "genital" version of the virus, a person with HSV-1 orally can transmit that virus to their partner genitally. The virus, either type, will settle into a nerve bundle either at the top of the spine, producing the "oral" outbreak, or a second nerve bundle at the base of the spine, producing the genital outbreak.
The human papillomavirus (HPV) is the most common STI in the United States. There are more than 40 different strands of HPV and many do not cause any health problems. In 90% of cases, the body's immune system clears the infection naturally within two years. Some cases may not be cleared and can lead to genital warts (bumps around the genitals that can be small or large, raised or flat, or shaped like cauliflower) or cervical cancer and other HPV related cancers. Symptoms might not show up until advanced stages. It is important for women to get pap smears in order to check for and treat cancers. There are also two vaccines available for women (Cervarix and Gardasil) that protect against the types of HPV that cause cervical cancer. HPV can be passed through genital-to-genital contact as well as during oral sex. The infected partner might not have any symptoms.
Gonorrhea is caused by bacterium that lives on moist mucous membranes in the urethra, vagina, rectum, mouth, throat, and eyes. The infection can spread through contact with the penis, vagina, mouth, or anus. Symptoms of gonorrhea usually appear two to five days after contact with an infected partner; however, some men might not notice symptoms for up to a month. Symptoms in men include burning and pain while urinating, increased urinary frequency, discharge from the penis (white, green, or yellow in color), red or swollen urethra, swollen or tender testicles, or sore throat. Symptoms in women may include vaginal discharge, burning or itching while urinating, painful sexual intercourse, severe pain in lower abdomen (if infection spreads to fallopian tubes), or fever (if infection spreads to fallopian tubes); however, many women do not show any symptoms. Antibiotic resistant strains of Gonorrhea are a significant concern, but most cases can be cured with existing antibiotics.
Syphilis is an STI caused by a bacterium. Untreated, it can lead to complications and death. Clinical manifestations of syphilis include the ulceration of the uro-genital tract, mouth or rectum; if left untreated the symptoms worsen. In recent years, the prevalence of syphilis has declined in Western Europe, but it has increased in Eastern Europe (former Soviet states). A high incidence of syphilis can be found in places such as Cameroon, Cambodia, Papua New Guinea. Syphilis infections are increasing in the United States.
Trichomoniasis is a common STI that is caused by infection with a protozoan parasite called Trichomonas vaginalis. Trichomoniasis affects both women and men, but symptoms are more common in women. Most patients are treated with an antibiotic called metronidazole, which is very effective.
HIV (human immunodeficiency virus) damages the body's immune system, which interferes with its ability to fight off disease-causing agents. The virus kills CD4 cells, which are white blood cells that help fight off various infections. HIV is carried in body fluids and is spread by sexual activity. It can also be spread by contact with infected blood, breastfeeding, childbirth, and from mother to child during pregnancy. When HIV is at its most advanced stage, an individual is said to have AIDS (acquired immunodeficiency syndrome). There are different stages of the progression of and HIV infection. The stages include primary infection, asymptomatic infection, symptomatic infection, and AIDS. In the primary infection stage, an individual will have flu-like symptoms (headache, fatigue, fever, muscle aches) for about two weeks. In the asymptomatic stage, symptoms usually disappear, and the patient can remain asymptomatic for years. When HIV progresses to the symptomatic stage, the immune system is weakened and has a low cell count of CD4+ T cells. When the HIV infection becomes life-threatening, it is called AIDS. People with AIDS fall prey to opportunistic infections and die as a result. When the disease was first discovered in the 1980s, those who had AIDS were not likely to live longer than a few years. There are now antiretroviral drugs (ARVs) available to treat HIV infections. There is no known cure for HIV or AIDS but the drugs help suppress the virus. By suppressing the amount of virus in the body, people can lead longer and healthier lives. Even though their virus levels may be low they can still spread the virus to others.
=== Viruses in semen ===
Twenty-seven different viruses have been identified in semen. Information on whether or not transmission occurs or whether the viruses cause disease is uncertain. Some of these microbes are known to be sexually transmitted.
== Pathophysiology ==
Many STIs are (more easily) transmitted through the mucous membranes of the penis, vulva, rectum, urinary tract and (less often—depending on type of infection) the mouth, throat, respiratory tract and eyes. The visible membrane covering the head of the penis is a mucous membrane, though it produces no mucus (similar to the lips of the mouth). Mucous membranes differ from skin in that they allow certain pathogens into the body. The amount of contact with infective sources which causes infection varies with each pathogen but in all cases, a disease may result from even light contact from fluid carriers like venereal fluids onto a mucous membrane.
Some STIs such as HIV can be transmitted from mother to child either during pregnancy or breastfeeding.
Healthcare professionals suggest safer sex, such as the use of condoms, as a reliable way of decreasing the risk of contracting sexually transmitted infections during sexual activity, but safer sex cannot be considered to provide complete protection from an STI. The transfer of and exposure to bodily fluids, such as blood transfusions and other blood products, sharing injection needles, needle-stick injuries (when medical staff are inadvertently jabbed or pricked with needles during medical procedures), sharing tattoo needles, and childbirth are other avenues of transmission. These different means put certain groups, such as medical workers, and haemophiliacs and drug users, particularly at risk.
It is possible to be an asymptomatic carrier of sexually transmitted infections. In particular, sexually transmitted infections in women often cause the serious condition of pelvic inflammatory disease.
== Diagnosis ==
Testing may be for a single infection, or consist of a number of tests for a range of STIs, including tests for syphilis, trichomonas, gonorrhea, chlamydia, herpes, hepatitis, and HIV. No procedure tests for all infectious agents.
STI tests may be used for a number of reasons:
as a diagnostic test to determine the cause of symptoms or illness
as a screening test to detect asymptomatic or presymptomatic infections
as a check that prospective sexual partners are free of disease before they engage in sex without safer sex precautions (for example, when starting a long term mutually monogamous sexual relationship, in fluid bonding, or for procreation).
as a check prior to or during pregnancy, to prevent harm to the baby
as a check after birth, to check that the baby has not caught an STI from the mother
to prevent the use of infected donated blood or organs
as part of the process of contact tracing from a known infected individual
as part of mass epidemiological surveillance
Early identification and treatment results in less chance to spread disease, and for some conditions may improve the outcomes of treatment. There is often a window period after initial infection during which an STI test will be negative. During this period, the infection may be transmissible. The duration of this period varies depending on the infection and the test. Diagnosis may also be delayed by reluctance of the infected person to seek a medical professional. One report indicated that people turn to the Internet rather than to a medical professional for information on STIs to a higher degree than for other sexual problems.
=== Classification ===
Until the 1990s, STIs were commonly known as venereal diseases, an antiquated euphemism derived from the Latin venereus, being the adjectival form of Venus, the Roman goddess of love. However, in the post-classical education era the euphemistic effect was entirely lost, and the common abbreviation "VD" held only negative connotations. Other former euphemisms for STIs include "blood diseases" and "social diseases". The present euphemism is in the use of the initials "STI" rather than in the words they represent. The World Health Organization (WHO) has recommended the more inclusive term sexually transmitted infection since 1999. Public health officials originally introduced the term sexually transmitted infection, which clinicians are increasingly using alongside the term sexually transmitted disease in order to distinguish it from the former.
== Prevention ==
Strategies for reducing STI risk include: vaccination, mutual monogamy, reducing the number of sexual partners, and abstinence. Also potentially helpful is behavioral counseling for sexually active adolescents and for adults who are at increased risk. Such interactive counseling, which can be resource-intensive, is directed at a person's risk, the situations in which risk occurs, and the use of personalized goal-setting strategies.
The most effective way to prevent sexual transmission of STIs is to avoid contact of body parts or fluids which can lead to transfer with an infected partner. Not all sexual activities involve contact: cybersex, phone sex or masturbation from a distance are methods of avoiding contact. Proper use of condoms reduces contact and risk. Although a condom is effective in limiting exposure, some disease transmission may occur even with a condom.Both partners can get tested for STIs before initiating sexual contact, or before resuming contact if a partner engaged in contact with someone else. Many infections are not detectable immediately after exposure, so enough time must be allowed between possible exposures and testing for the tests to be accurate. Certain STIs, particularly certain persistent viruses like HPV, may be impossible to detect.
Some treatment facilities use in-home test kits and have the person return the test for follow-up. Other facilities strongly encourage that those previously infected return to ensure that the infection has been eliminated. Novel strategies to foster re-testing have been the use of text messaging and email as reminders. These types of reminders are now used in addition to phone calls and letters. After obtaining a sexual history, a healthcare provider can encourage risk reduction by providing prevention counseling. Prevention counseling is most effective if provided in a nonjudgmental and empathetic manner appropriate to the person's culture, language, gender, sexual orientation, age, and developmental level. Prevention counseling for STIs is usually offered to all sexually active adolescents and to all adults who have received a diagnosis, have had an STI in the past year, or have multiple sex partners.
=== Vaccines ===
Vaccines are available that protect against some viral STIs, such as hepatitis A, hepatitis B, and some types of HPV. Vaccination before initiation of sexual contact is advised to assure maximal protection. The development of vaccines to protect against gonorrhea is ongoing.
=== Condoms ===
Condoms and female condoms only provide protection when used properly as a barrier, and only to and from the area that they cover. Uncovered areas are still susceptible to many STIs.
In the case of HIV, sexual transmission routes almost always involve the penis, as HIV cannot spread through unbroken skin; therefore, properly shielding the penis with a properly worn condom from the vagina or anus effectively stops HIV transmission. An infected fluid to broken skin borne direct transmission of HIV would not be considered "sexually transmitted", but can still theoretically occur during sexual contact. This can be avoided simply by not engaging in sexual contact when presenting open, bleeding wounds.
Other STIs, even viral infections, can be prevented with the use of latex, polyurethane or polyisoprene condoms as a barrier. Some microorganisms and viruses are small enough to pass through the pores in natural skin condoms but are still too large to pass through latex or synthetic condoms.
Proper male condom usage entails:
Not putting the condom on too tight at the tip by leaving 1.5 centimetres (0.6 in) room for ejaculation. Putting the condom on too tightly can and often does lead to failure.
Wearing a condom too loose can defeat the barrier
Avoiding inverting or spilling a condom once worn, whether it has ejaculate in it or not
If a user attempts to unroll the condom, but realizes they have it on the wrong side, then this condom may not be effective
Being careful with the condom if handling it with long nails
Avoiding the use of oil-based lubricants (or anything with oil in it) with latex condoms, as oil can eat holes into them
Using flavored condoms for oral sex only, as the sugar in the flavoring can lead to yeast infections if used to penetrate
In order to best protect oneself and the partner from STIs, the old condom and its contents are to be treated as infectious and properly disposed of. A new condom is used for each act of intercourse, as multiple usages increase the chance of breakage, defeating the effectiveness as a barrier.
In the case of female condoms, the device consists of two rings, one in each terminal portion. The larger ring should fit snugly over the cervix and the smaller ring remains outside the vagina, covering the vulva. This system provides some protection of the external genitalia.
=== Other ===
The cap was developed after the cervical diaphragm. Both cover the cervix and the main difference between the diaphragm and the cap is that the latter must be used only once, using a new one in each sexual act. The diaphragm, however, can be used more than once. These two devices partially protect against STIs (they do not protect against HIV).
Researchers had hoped that nonoxynol-9, a vaginal microbicide would help decrease STI risk. Trials, however, have found it ineffective and it may put women at a higher risk of HIV infection. There is evidence that vaginal dapivirine probably reduces HIV in women who have sex with men, other types of vaginal microbicides have not demonstrated effectiveness for HIV or STIs.
There is little evidence that school-based interventions such as sexual and reproductive health education programmes on contraceptive choices and condoms are effective on improving the sexual and reproductive health of adolescents. Incentive-based programmes may reduce adolescent pregnancy but more data is needed to confirm this.
== Screening ==
Specific age groups, persons who participate in risky sexual behavior, or those have certain health conditions may require screening. The CDC recommends that sexually active women under the age of 25 and those over 25 at risk should be screened for chlamydia and gonorrhea yearly. Appropriate times for screening are during regular pelvic examinations and preconception evaluations. Nucleic acid amplification tests are the recommended method of diagnosis for gonorrhea and chlamydia. This can be done on either urine in both men and women, vaginal or cervical swabs in women, or urethral swabs in men. Screening can be performed:
to assess the presence of infection and prevent tubal infertility in women
during the initial evaluation before infertility treatment
to identify HIV infection
for men who have sex with men
for those who may have been exposed to hepatitis C
for HCV
== Management ==
In the case of rape, the person can be treated prophylacticly with antibiotics.
An option for treating partners of patients (index cases) diagnosed with chlamydia or gonorrhea is patient-delivered partner therapy, which is the clinical practice of treating the sex partners of index cases by providing prescriptions or medications to the patient to take to their partner without the health care provider first examining the partner. In term of preventing reinfection in sexually transmitted infection, treatment with both patient and the sexual partner of patient resulted in more successful than treatment of the patient without the sexual partner. There is no difference in reinfection prevention whether the sexual partner treated with medication without medical examination or after notification by patient.
== Epidemiology ==
In 2008, it was estimated that 500 million people were infected with either syphilis, gonorrhea, chlamydia or trichomoniasis. At least an additional 530 million people have genital herpes and 290 million women have human papillomavirus (HPV). STIs other than HIV resulted in 142,000 deaths in 2013. In the United States there were 19 million new cases of sexually transmitted infections in 2010.
In 2010, 19 million new cases of sexually transmitted infections occurred in women in the United States. A 2008 CDC study found that 25–40% of U.S. teenage girls has a sexually transmitted infection. Out of a population of almost 295,270,000 people there were 110 million new and existing cases of eight sexually transmitted infections.
Over 400,000 sexually transmitted infections were reported in England in 2017, about the same as in 2016, but there were more than 20% increases in confirmed cases of gonorrhoea and syphilis. Since 2008 syphilis cases have risen by 148%, from 2,874 to 7,137, mostly among men who have sex with men. The number of first cases of genital warts in 2017 among girls aged 15–17 years was just 441, 90% less than in 2009 – attributed to the national HPV immunisation programme.
AIDS is among the leading causes of death in present-day Sub-Saharan Africa. HIV/AIDS is transmitted primarily via unprotected sexual intercourse. More than 1.1 million persons are living with HIV/AIDS in the United States, and it disproportionately impacts African Americans. Hepatitis B is also considered a sexually transmitted infection because it can be spread through sexual contact. The highest rates are found in Asia and Africa and lower rates are in the Americas and Europe. Approximately two billion people worldwide have been infected with the hepatitis B virus.
== History ==
The first well-recorded European outbreak of what is now known as syphilis occurred in 1494 when it broke out among French troops besieging Naples in the Italian War of 1494–98. The disease may have originated from the Columbian Exchange. From Naples, the disease swept across Europe, killing more than five million people. As Jared Diamond describes it, "[W]hen syphilis was first definitely recorded in Europe in 1495, its pustules often covered the body from the head to the knees, caused flesh to fall from people's faces, and led to death within a few months," rendering it far more fatal than it is today. Diamond concludes, "[B]y 1546, the disease had evolved into the disease with the symptoms so well known to us today." Gonorrhea is recorded at least up to 700 years ago and associated with a district in Paris formerly known as "Le Clapiers". This is where the prostitutes were to be found at that time.
Prior to the invention of modern medicines, sexually transmitted infections were generally incurable, and treatment was limited to treating the symptoms of the infection. The first voluntary hospital for STIs was founded in 1746 at London Lock Hospital. Treatment was not always voluntary: in the second half of the 19th century, the Contagious Diseases Acts were used to arrest suspected prostitutes. In 1924, a number of states concluded the Brussels Agreement, whereby states agreed to provide free or low-cost medical treatment at ports for merchant seamen with STIs. A proponent of these approaches was Nora Wattie, OBE, Venereal Diseases Officer in Glasgow from 1929, encouraged contact tracing and volunteering for treatment, rather than the prevailing more judgemental view and published her own research on improving sex education and maternity care.
The first effective treatment for a sexually transmitted infection was salvarsan, a treatment for syphilis. With the discovery of antibiotics, a large number of sexually transmitted infections became easily curable, and this, combined with effective public health campaigns against STIs, led to a public perception during the 1960s and 1970s that they have ceased to be a serious medical threat.
During this period, the importance of contact tracing in treating STIs was recognized. By tracing the sexual partners of infected individuals, testing them for infection, treating the infected and tracing their contacts, in turn, STI clinics could effectively suppress infections in the general population.
In the 1980s, first genital herpes and then AIDS emerged into the public consciousness as sexually transmitted infections that could not be cured by modern medicine. AIDS, in particular, has a long asymptomatic period—during which time HIV (the human immunodeficiency virus, which causes AIDS) can replicate and the disease can be transmitted to others—followed by a symptomatic period, which leads rapidly to death unless treated. HIV/AIDS entered the United States from Haiti in about 1969. Recognition that AIDS threatened a global pandemic led to public information campaigns and the development of treatments that allow AIDS to be managed by suppressing the replication of HIV for as long as possible. Contact tracing continues to be an important measure, even when diseases are incurable, as it helps to contain infection.
== See also ==
List of sexually transmitted infections by prevalence
== References ==
== Further reading ==
Aral SO (2008). Behavioral Interventions for Prevention and Control of Sexually Transmitted Diseases. Springer Singapore Pte. Limited. ISBN 978-0-387-85768-8.
Faro S (2003). Sexually transmitted diseases in women. Lippincott Williams & Wilkins. ISBN 978-0-397-51303-1.
Ford CA, Bowers ES (2009). Living with Sexually Transmitted Diseases. Facts on File. ISBN 978-0-8160-7672-7. Sexually transmitted disease.
Edmund O (1911). "Venereal Diseases" . In Chisholm H (ed.). Encyclopædia Britannica. Vol. 27 (11th ed.). Cambridge University Press. pp. 983–85. This provides an overview of pre-modern medicine's approach to the diseases.
Sehgal VN (2003). Sexually Transmitted Diseases (4th ed.). Jaypee Bros. Medical Publishers. ISBN 978-81-8061-105-6.
Shoquist J, Stafford D (2003). The encyclopedia of sexually transmitted diseases. Facts on File. ISBN 978-0-8160-4881-6.
Workowski KA, Bachmann LH, Chan PA, Johnston CM, Muzny CA, Park I, et al. (July 2021). "Sexually Transmitted Infections Treatment Guidelines, 2021" (PDF). MMWR Recomm Rep. 70 (4): 1–187. doi:10.15585/mmwr.rr7004a1. PMC 8344968. PMID 34292926.
== External links ==
CDC Sexually Transmitted Diseases Treatment Guidelines, 2010
STD photo library Archived 21 July 2010 at the Wayback Machine at Dermnet
UNFPA: Breaking the Cycle of Sexually Transmitted Infections at UNFPA
STDs In Color: Sexually Transmitted Disease Facts and Photos
CDC: Sexually transmitted diseases in the U.S.
STI Watch: World Health Organization | Wikipedia/Sexually_transmitted_disease |
Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.
Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because mitochondria are so critical to cell function. A subclass of these diseases that have neuromuscular symptoms are known as mitochondrial myopathies.
== Types ==
Mitochondrial disease can manifest in many different ways whether in children or adults. Examples of mitochondrial diseases include:
Mitochondrial myopathy
Maternally inherited diabetes mellitus and deafness (MIDD)
While diabetes mellitus and deafness can be found together for other reasons, at an early age this combination can be due to mitochondrial disease, as may occur in Kearns–Sayre syndrome and Pearson syndrome
Leber's hereditary optic neuropathy (LHON)
LHON is an eye disorder characterized by progressive loss of central vision due to degeneration of the optic nerves and retina (apparently affecting between 1 in 30,000 and 1 in 50,000 people); visual loss typically begins in young adulthood
Leigh syndrome, subacute necrotizing encephalomyelopathy
after normal development the disease usually begins late in the first year of life, although onset may occur in adulthood
a rapid decline in function occurs and is marked by seizures, altered states of consciousness, dementia, ventilatory failure
Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)
progressive symptoms as described in the acronym
dementia
Myoneurogenic gastrointestinal encephalopathy (MNGIE)
gastrointestinal pseudo-obstruction
neuropathy
MERRF syndrome
progressive myoclonic epilepsy
"Ragged Red Fibers" are clumps of diseased mitochondria that accumulate in the subsarcolemmal region of the muscle fiber and appear when muscle is stained with modified Gömöri trichrome stain
short stature
hearing loss
lactic acidosis
exercise intolerance
MELAS syndrome, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
Mitochondrial DNA depletion syndrome
Conditions such as Friedreich's ataxia can affect the mitochondria but are not associated with mitochondrial proteins.
== Presentation ==
=== Associated conditions ===
Acquired conditions in which mitochondrial dysfunction has been involved include:
ALS
Alzheimer's disease,
Bipolar disorder, schizophrenia, aging and senescence, anxiety disorders
Cancer
Cardiovascular disease
Diabetes
Huntington's disease
Long Covid
ME/CFS
Parkinson's disease
Sarcopenia
The body, and each mutation, is modulated by other genome variants; the mutation that in one individual may cause liver disease might in another person cause a brain disorder. The severity of the specific defect may also be great or small. Some defects include exercise intolerance. Defects often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases.
It has also been reported that drug tolerant cancer cells have an increased number and size of mitochondria, which suggested an increase in mitochondrial biogenesis. A recent study in Nature Nanotechnology has reported that cancer cells can hijack the mitochondria from immune cells via physical tunneling nanotubes.
As a rule, mitochondrial diseases are worse when the defective mitochondria are present in the muscles, cerebrum, or nerves, because these cells use more energy than most other cells in the body.
Although mitochondrial diseases vary greatly in presentation from person to person, several major clinical categories of these conditions have been defined, based on the most common phenotypic features, symptoms, and signs associated with the particular mutations that tend to cause them.
An outstanding question and area of research is whether ATP depletion or reactive oxygen species are in fact responsible for the observed phenotypic consequences.
Cerebellar atrophy or hypoplasia has sometimes been reported to be associated.
== Causes ==
Mitochondrial disorders may be caused by mutations (acquired or inherited), in mitochondrial DNA (mtDNA), or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes.
Nuclear DNA has two copies per cell (except for sperm and egg cells), one copy being inherited from the father and the other from the mother. Mitochondrial DNA, however, is inherited from the mother only (with some exceptions) and each mitochondrion typically contains between 2 and 10 mtDNA copies. During cell division the mitochondria segregate randomly between the two new cells. Those mitochondria make more copies, normally reaching 500 mitochondria per cell. As mtDNA is copied when mitochondria proliferate, they can accumulate random mutations, a phenomenon called heteroplasmy. If only a few of the mtDNA copies inherited from the mother are defective, mitochondrial division may cause most of the defective copies to end up in just one of the new mitochondria (for more detailed inheritance patterns, see human mitochondrial genetics). Mitochondrial disease may become clinically apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called "threshold expression".
Mitochondria possess many of the same DNA repair pathways as nuclei do—but not all of them; therefore, mutations occur more frequently in mitochondrial DNA than in nuclear DNA (see Mutation rate). This means that mitochondrial DNA disorders may occur spontaneously and relatively often. Defects in enzymes that control mitochondrial DNA replication (all of which are encoded for by genes in the nuclear DNA) may also cause mitochondrial DNA mutations.
Most mitochondrial function and biogenesis is controlled by nuclear DNA. Human mitochondrial DNA encodes 13 proteins of the respiratory chain, while most of the estimated 1,500 proteins and components targeted to mitochondria are nuclear-encoded. Defects in nuclear-encoded mitochondrial genes are associated with hundreds of clinical disease phenotypes including anemia, dementia, hypertension, lymphoma, retinopathy, seizures, and neurodevelopmental disorders.
A study by Yale University researchers (published in the February 12, 2004, issue of the New England Journal of Medicine) explored the role of mitochondria in insulin resistance among the offspring of patients with type 2 diabetes.
Other studies have shown that the mechanism may involve the interruption of the mitochondrial signaling process in body cells (intramyocellular lipids). A study conducted at the Pennington Biomedical Research Center in Baton Rouge, Louisiana showed that this, in turn, partially disables the genes that produce mitochondria.
== Mechanisms ==
The effective overall energy unit for the available body energy is referred to as the daily glycogen generation capacity, and is used to compare the mitochondrial output of affected or chronically glycogen-depleted individuals to healthy individuals.
The glycogen generation capacity is entirely dependent on, and determined by, the operating levels of the mitochondria in all of the cells of the human body; however, the relation between the energy generated by the mitochondria and the glycogen capacity is very loose and is mediated by many biochemical pathways. The energy output of full healthy mitochondrial function can be predicted exactly by a complicated theoretical argument, but this argument is not straightforward, as most energy is consumed by the brain and is not easily measurable.
== Diagnosis ==
Mitochondrial diseases are usually detected by analysing muscle samples, where the presence of these organelles is higher. The most common tests for the detection of these diseases are:
Southern blot to detect large deletions or duplications
Polymerase chain reaction and specific mutation testing
Sequencing
== Treatments ==
Although research is ongoing, treatment options are currently limited; vitamins are frequently prescribed, though the evidence for their effectiveness is limited.
Pyruvate has been proposed in 2007 as a treatment option. N-acetyl cysteine reverses many models of mitochondrial dysfunction.
=== Mood disorders ===
In the case of mood disorders, specifically bipolar disorder, it is hypothesized that N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin could be potential treatment options.
=== Gene therapy prior to conception ===
Mitochondrial replacement therapy (MRT), where the nuclear DNA is transferred to another healthy egg cell leaving the defective mitochondrial DNA behind, is an IVF treatment procedure. Using a similar pronuclear transfer technique, researchers at Newcastle University led by Douglass Turnbull successfully transplanted healthy DNA in human eggs from women with mitochondrial disease into the eggs of women donors who were unaffected. In such cases, ethical questions have been raised regarding biological motherhood, since the child receives genes and gene regulatory molecules from two different women. Using genetic engineering in attempts to produce babies free of mitochondrial disease is controversial in some circles and raises important ethical issues. A male baby was born in Mexico in 2016 from a mother with Leigh syndrome using MRT.
In September 2012 a public consultation was launched in the UK to explore the ethical issues involved. Human genetic engineering was used on a small scale to allow infertile women with genetic defects in their mitochondria to have children.
In June 2013, the United Kingdom government agreed to develop legislation that would legalize the 'three-person IVF' procedure as a treatment to fix or eliminate mitochondrial diseases that are passed on from mother to child. The procedure could be offered from 29 October 2015 once regulations had been established.
Embryonic mitochondrial transplant and protofection have been proposed as a possible treatment for inherited mitochondrial disease, and allotopic expression of mitochondrial proteins as a radical treatment for mtDNA mutation load.
In June 2018 Australian Senate's Senate Community Affairs References Committee recommended a move towards legalising Mitochondrial replacement therapy (MRT). Research and clinical applications of MRT were overseen by laws made by federal and state governments. State laws were, for the most part, consistent with federal law. In all states, legislation prohibited the use of MRT techniques in the clinic, and except for Western Australia, research on a limited range of MRT was permissible up to day 14 of embryo development, subject to a license being granted. In 2010, the Hon. Mark Butler MP, then Federal Minister for Mental Health and Ageing, had appointed an independent committee to review the two relevant acts: the Prohibition of Human Cloning for Reproduction Act 2002 and the Research Involving Human Embryos Act 2002. The committee's report, released in July 2011, recommended the existing legislation remain unchanged
Currently, human clinical trials are underway at GenSight Biologics (ClinicalTrials.gov # NCT02064569) and the University of Miami (ClinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in Leber's hereditary optic neuropathy.
== Epidemiology ==
About 1 in 4,000 children in the United States will develop mitochondrial disease by the age of 10 years. Up to 4,000 children per year in the US are born with a type of mitochondrial disease. Because mitochondrial disorders contain many variations and subsets, some particular mitochondrial disorders are very rare.
The average number of births per year among women at risk for transmitting mtDNA disease is estimated to approximately 150 in the United Kingdom and 800 in the United States.
== History ==
The first pathogenic mutation in mitochondrial DNA was identified in 1988; from that time to 2016, around 275 other disease-causing mutations were identified.
== Notable cases ==
Notable people with mitochondrial disease include:
Mattie Stepanek, a poet, peace advocate, and motivational speaker who had dysautonomic mitochondrial myopathy, and who died at age 13.
Rocco Baldelli, a coach and former center fielder in Major League Baseball who had to retire from active play at age 29 due to mitochondrial channelopathy.
Charlie Gard, a British boy who had mitochondrial DNA depletion syndrome; decisions about his care were taken to various law courts.
Charles Darwin, a nineteenth century naturalist who suffered from a disabling illness, is speculated to have MELAS syndrome.
== References ==
== External links ==
International Mito Patients (IMP) | Wikipedia/Mitochondrial_disease |
Connective tissue diseases (also termed connective tissue disorders, or collagen vascular diseases), are medical conditions that affect connective tissue.
Connective tissues protect, support, and provide structure for the body's other tissues and structures. They hold the body's structures together. Connective tissues consist of two distinct proteins: elastin and collagen. Tendons, ligaments, skin, cartilage, bone, and blood vessels are all made of collagen. Skin and ligaments also contain elastin. These proteins and the surrounding tissues may suffer damage when the connective tissues become inflamed.
The two main categories of connective tissue diseases are (1) a set of relatively rare genetic disorders affecting the primary structure of connective tissue, and (2) a variety of acquired diseases where the connective tissues are the site of multiple, more or less distinct immunological and inflammatory reactions.
Diseases in which inflammation or weakness of collagen tends to occur are also referred to as collagen diseases. Collagen vascular diseases can be (but are not necessarily) associated with collagen and blood vessel abnormalities that are autoimmune in nature.
Some connective tissue diseases have strong or weak genetic inheritance risks. Others may be due to environmental factors, or a combination of genetic and environmental influences.
== Classification ==
Connective tissue disease is an umbrella term for many different types of diseases. Connective tissue diseases can be classified into two groups:
a group of relatively rare genetic disorders affecting the primary structure of connective tissue;
a number of acquired conditions where the connective tissues are the site of multiple, more or less distinct immune and inflammatory reactions.
=== Heritable connective tissue disorders ===
Hereditary connective tissue disorders are a diverse set of broad, single-gene disorders that impact one or more of the main components of connective tissues, such as ground substance (glycosaminoglycans), collagen, or elastin. Many result in anomalies of the skeleton and joints, which can substantially impair normal growth and development. In contrast to acquired connective tissue diseases, these conditions are uncommon.
Marfan syndrome - inherited as an autosomal dominant characteristic, due to mutations in the FBN1 gene that encodes fibrillin 1.
Homocystinuria - condition of methionine metabolism brought on by a cystathionine β-synthase deficit that causes a build-up of homocysteine and its metabolites in the urine and blood.
Ehlers–Danlos syndrome - diverse collection of disorders distinguished by the fragility of soft connective tissues and widespread symptoms affecting the skin, ligaments, joints, blood vessels, and internal organs.
Osteogenesis imperfecta - hereditary condition marked by reduced bone mass, weakened bones, increased brittleness, and short stature.
Alkaptonuria - inborn error of metabolism caused by mutations in the HGO gene and homogentisate 1,2-dioxygenase deficiency.
Pseudoxanthoma elasticum - rare multisystem disease marked by gradual calcification and fragmentation of elastic fibres.
Mucopolysaccharidosis - a class of hereditary illnesses distinguished by the excretion of mucopolysaccharide in the urine.
Fibrodysplasia ossificans progressiva - rare and debilitating hereditary disorder characterized by progressive heterotopic ossification and congenital skeletal malformations.
Familial osteochondritis dissecans - separation of the subchondral bone and cartilage from the surrounding tissue.
Stickler syndrome - autosomal dominant disorder distinguished by skeletal, ocular, and orofacial abnormalities.
Alport syndrome - hereditary kidney disease is distinguished by structural abnormalities and malfunction in the glomerular basement membrane, as well as basement membranes in other organs such as the eye and ear.
Congenital contractural arachnodactyly - autosomal dominant disorder defined by arachnodactyly, multiple flexion contractures, abnormal pinnae, severe kyphoscoliosis, and muscular hypoplasia.
Epidermolysis bullosa - hereditary, diverse grouping of rare genetic dermatoses that are marked by blisters and mucocutaneous fragility.
Loeys–Dietz syndrome - autosomal dominant condition linked to a wide range of systemic manifestations, such as skeletal, cutaneous, vascular, and craniofacial abnormalities.
Hypermobility spectrum disorder - a variety of connective tissue diseases that are marked by ongoing pain and joint hypermobility.
=== Autoimmune connective tissue disorders ===
Acquired connective tissue diseases share certain clinical features, such as joint inflammation, inflammation of serous membranes, and vasculitis, as well as a high frequency of involvement of various internal organs that are particularly rich in connective tissue.
Rheumatoid arthritis - autoimmune disease with an unclear cause that manifests as symmetric, erosive synovitis and, occasionally, extraarticular involvement.
Systemic lupus erythematosus - chronic, complex autoimmune inflammatory disorder that can affect every organ in the body.
Scleroderma and systemic scleroderma - diverse collection of autoimmune fibrosing conditions.
Dermatomyositis and polymyositis - autoimmune myopathies that are clinically characterized by extramuscular symptoms, muscle inflammation, proximal muscle weakening, and oftentimes the detection of autoantibodies.
Antisynthetase syndrome - multisystematic autoimmune disease associated with inflammatory myositis and interstitial lung disease.
Vasculitis - disease that results in blood vessel inflammation.
Sjögren syndrome - a systemic autoimmune illness that mostly affects the exocrine glands and causes mucosal surfaces, especially those in the mouth and eyes, to become extremely dry.
Rheumatic fever - multisystem inflammatory illness that develops after group A streptococcal pharyngitis.
Amyloidosis - uncommon condition caused by protein mutations or changes in the body that result in twisted clusters of malformed proteins accumulating on organs and tissues.
Osteoarthritis - common articular cartilage degenerative disease linked to hypertrophic bone abnormalities.
Thrombotic thrombocytopenic purpura - uncommon and potentially fatal thrombotic microangiopathy characterized by severe thrombocytopenia, organ ischemia connected to diffuse microvascular platelet rich-thrombi, and microangiopathic hemolytic anemia.
Relapsing polychondritis - uncommon multisystem autoimmune disease with an unclear etiology that is marked by progressive cartilaginous tissue loss and recurring episodes of inflammation.
Mixed connective tissue disease - systemic autoimmune disease that shares characteristics with two or more other systemic autoimmune diseases, such as rheumatoid arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus, and systemic sclerosis. It is an example of overlap syndrome.
Undifferentiated connective tissue disease - unclassifiable systemic autoimmune disorders that do not meet any of the current classification requirements for connective tissue diseases, yet have clinical and serological signs similar to connective tissue diseases.
Psoriatic arthritis - inflammatory musculoskeletal condition linked to psoriasis.
Cryoglobulinemia - condition sometimes associated with systemic lupus erythematosus or rheumatoid arthritis in which there are abnormal proteins in the blood.
IgG4-related disease - chronic inflammatory condition in which there is deposition of connective tissue (fibrosis) in different organs. Potentially life-threatening.
Periaortitis - a group of rare vascular inflammatory diseases in which fibrous inflammatory tissue develops around the aorta or other structures such as the ureters. Sometimes associated with IgG4-related disease.
== References ==
== Further reading ==
Spagnolo, Paolo; Cordier, Jean-François; Cottin, Vincent (2016-02-25). "Connective tissue diseases, multimorbidity and the ageing lung". European Respiratory Journal. 47 (5): 1535–1558. doi:10.1183/13993003.00829-2015. ISSN 0903-1936. PMID 26917611.
Baildam, Eileen (2014). "Rare connective tissue diseases in childhood". Paediatrics and Child Health. 24 (2): 51–57. doi:10.1016/j.paed.2013.12.005.
== External links ==
"Connective Tissue Disorders". National Library of Medicine. 2017-09-15.
Dunkin, Mary Anne (2023-10-10). "Connective Tissue Disease: Types, Symptoms, Causes". WebMD.
"Connective tissue diseases". DermNet®. 2023-10-26. | Wikipedia/Connective_tissue_disease |
Urologic diseases or conditions include urinary tract infections, kidney stones, bladder control problems, and prostate problems, among others. Some urologic conditions do not affect a person for that long and some are lifetime conditions. Kidney diseases are normally investigated and treated by nephrologists, while the specialty of urology deals with problems in the other organs. Gynecologists may deal with problems of incontinence in women.
Diseases of other bodily systems also have a direct effect on urogenital function. For instance, it has been shown that protein released by the kidneys in diabetes mellitus sensitizes the kidney to the damaging effects of hypertension. Diabetes also can have a direct effect on urination due to peripheral neuropathies, which occur in some individuals with poorly controlled diabetics.
== Kidney disease ==
Kidney disease, or renal disease, also known as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.
Chronic kidney disease causes the gradual loss of kidney function over time. Acute kidney disease is now termed acute kidney injury and is marked by the sudden reduction in kidney function over seven days. About one in eight Americans (as of 2007) has chronic kidney disease. Primary renal cell carcinomas as well as metastatic cancers can affect the kidney.
=== Kidney failure ===
Kidney failure is defined by functional impairment of the kidney, whereas the kidneys are functioning at 15% or less than normal capability. It is divided into acute kidney failure (cases that develop rapidly) and chronic kidney failure (those that are long term). Symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications of acute disease may include uremia, high blood potassium, and volume overload. Complications of chronic disease may include heart disease, high blood pressure, and anemia.
Pre-renal kidney failure refers to impairment of supply of blood to the functional nephrons including renal artery stenosis. Intrinsic kidney diseases are the classic diseases of the kidney including drug toxicity and nephritis. Post-renal kidney failure is outlet obstruction after the kidney, such as a kidney stone or prostatic bladder outlet obstruction. Kidney failure may require medication, dietary lifestyle modifications, and dialysis.
== Non-renal urinary tract disease ==
Structural and or traumatic changes in the urinary tract can lead to hemorrhage, functional blockage or inflammation. Colonization by bacteria, protozoa or fungi can cause infection. Uncontrolled cell growth can cause neoplasia. The term "uropathy" refers to a disease of the urinary tract, while "nephropathy" refers to a disease of the kidney. For example:
Urinary tract infections (UTIs) are infections that affect part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney infection (pyelonephritis). Symptoms from a lower urinary tract infection include pain with urination, frequent urination, and feeling the need to urinate despite having an empty bladder. Symptoms of a kidney infection include fever and flank pain usually in addition to the symptoms of a lower UTI. Rarely the urine may appear bloody. In the very old and the very young, symptoms may be vague or non-specific.
Interstitial cystitis (IC), also known as bladder pain syndrome (BPS), is a type of chronic pain that affects the bladder. Symptoms include feeling the need to urinate right away, needing to urinate often, and pain with sex. IC/BPS is associated with depression and lower quality of life. Many of those affected also have irritable bowel syndrome and fibromyalgia.
Incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a large impact on quality of life. It has been identified as an important issue in geriatric health care. The term enuresis is often used to refer to urinary incontinence primarily in children, such as nocturnal enuresis (bed wetting).
Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss of bladder control. Complications can include urinary tract infections, bladder stones, and chronic kidney problems.
Prostatitis is inflammation of the prostate gland. The condition is classified into acute, chronic, asymptomatic inflammatory prostatitis, and chronic pelvic pain syndrome. It may occur as an appropriate physiological response to an infection, or it may occur in the absence of infection. In the United States, prostatitis is diagnosed in 8 percent of all urologist visits and 1 percent of all primary care physician visits.
Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include loss of bladder control, mild lower abdominal pain, and a weak urine stream. Those with long-term problems are at risk of urinary tract infections. Causes include blockage of the urethra, nerve problems, certain medications, and weak bladder muscles. Blockage can be caused by benign prostatic hyperplasia (BPH), urethral strictures, bladder stones, a cystocele, constipation, or tumors. Nerve problems can occur from diabetes, trauma, spinal cord problems, stroke, or heavy metal poisoning. Medications that can cause problems include anticholinergics, antihistamines, tricyclic antidepressants, decongestants, cyclobenzaprine, diazepam, NSAIDs, amphetamines, and opioids. Diagnosis is typically based on measuring the amount of urine in the bladder after urinating. Treatment is typically with a catheter either through the urethra or lower abdomen.
Transitional cell carcinoma or bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms include blood in the urine, pain with urination, and low back pain.
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, responsible for approximately 90–95% of cases.
Prostate cancer is the development of cancer in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, some grow relatively quickly. The cancer cells may spread from the prostate to other areas of the body, particularly the bones and lymph nodes. It may initially cause no symptoms. In later stages, it can lead to difficulty urinating, blood in the urine or pain in the pelvis, back, or when urinating. A disease known as benign prostatic hyperplasia may produce similar symptoms. Other late symptoms may include feeling tired due to low levels of red blood cells.
Urinary tract obstruction is a urologic disease consisting of a decrease in the free passage of urine through one or both ureters and/or the urethra. It is a cause of urinary retention. Complete obstruction of the urinary tract requires prompt treatment for renal preservation. Any sign of infection, such as fever and chills, in the context of obstruction to urine flow constitutes a urologic emergency.
== Testing ==
Biochemical blood tests determine the amount of typical markers of renal function in the blood serum, for instance serum urea, serum uric acid, and serum creatinine. Biochemistry can also be used to determine serum electrolytes. Special biochemical tests (arterial blood gas) can determine the amount of dissolved gases in the blood, indicating if pH imbalances are acute or chronic.
Urinalysis is a test that studies urine for abnormal substances such as protein or signs of infection. A Full Ward Test, also known as dipstick urinalysis, involves the dipping of a biochemically active test strip into the urine specimen to determine levels of tell-tale chemicals in the urine. Urinalysis may also involve MC&S microscopy, culture and sensitivity
Urodynamic tests evaluate the storage of urine in the bladder and the flow of urine from the bladder through the urethra. It may be performed in cases of incontinence or neurological problems affecting the urinary tract. However the American Urogynecologic Society does not recommend that urodynamics are part of initial diagnosis for uncomplicated overactive bladder.
Ultrasound is routinely used in urology. In a pelvic sonogram, organs of the pelvic region are imaged. This includes the uterus and ovaries or urinary bladder. Males are sometimes given a pelvic sonogram to check on the health of their bladder, the prostate, or their testicles (for example to distinguish epididymitis from testicular torsion). In young males, it is used to distinguish more benign masses (varicocele or hydrocele) from testicular cancer, which is highly curable but which must be treated to preserve health and fertility. There are two methods of performing a pelvic sonography – externally or internally. The internal pelvic sonogram is performed either transvaginally (in a woman) or transrectally (in a man). Sonographic imaging of the pelvic floor can produce important diagnostic information regarding the precise relationship of abnormal structures with other pelvic organs and it represents a useful hint to treat patients with symptoms related to pelvic prolapse, double incontinence and obstructed defecation. It is used to diagnose and, at higher frequencies, to treat (break up) kidney stones or kidney crystals (nephrolithiasis).
=== Radiology based testing ===
KUB stands for Kidneys, Ureters, and Bladder. The projection does not necessarily include the diaphragm. The projection includes the entire urinary system, from the pubic symphysis to the superior aspects of the kidneys. The anteroposterior (AP) abdomen projection, in contrast, includes both halves of the diaphragm. Despite its name, a KUB is not typically used to investigate pathology of the kidneys, ureters, or bladder, since these structures are difficult to assess (for example, the kidneys may not be visible due to overlying bowel gas.) In order to assess these structures radiographically, a technique called an intravenous pyelogram was historically utilized, and today at many institutions CT urography is the technique of choice.
An intravenous pyelogram, also called an intravenous urogram (IVU), is a radiological procedure used to visualize abnormalities of the urinary system, including the kidneys, ureters, and bladder. Unlike a kidneys, ureters, and bladder x-ray (KUB), which is a plain (that is, noncontrast) radiograph, an IVP uses contrast to highlight the urinary tract.
CT urography (CTU) is commonly used in the evaluation of hematuria, and specifically tailored to image the renal collecting system, ureters and bladder in addition to the renal parenchyma. Initial imaging includes a noncontrast phase to detect renal calculi as a source of hematuria. Note that dual energy CT may eventually allow the noncontrast phase to be eliminated. Contrast enhancement techniques for CTU vary from institution to institution. A common technique is a double bolus, single phase imaging algorithm. This technique is a hybrid contrast injection strategy that results in opacification of the renal parenchyma and the collecting system, ureters, and bladder. A small contrast bolus is administered initially, followed 10 minutes later with a larger bolus that is imaged in the corticomedullary phase. Excretory phase imaging allows for not only evaluation of the ureteral lumen, but also periureteral abnormalities including external masses and lymphadenopathy.
MRI is the investigation of choice in the preoperative staging of prostate cancer.
A voiding cystogram is a functional study where contrast "dye" is injected through a catheter into the bladder. Under x-ray the radiologist asks the patient to void (usually young children) and will watch the contrast exiting the body on the x-ray monitor. This examines the child's bladder and lower urinary tract. Typically looking for vesicoureteral reflux, involving urine backflow up into the kidneys.
== References ==
== External links == | Wikipedia/Urologic_disease |
Breast diseases make up a number of conditions. The most common symptoms are a breast mass, breast pain, and nipple discharge.
A majority of breast diseases are noncancerous.
Although breast disease may be benign, or non-life threatening there remains an associated risk with potentially a higher risk of developing breast cancer later on.
== Tumor ==
A breast tumor is an abnormal mass of tissue in the breast as a result of neoplasia. A breast neoplasm may be benign, as in fibroadenoma, or it may be malignant, in which case it is termed breast cancer. Either case commonly presents as a breast lump. Approximately 7% of breast lumps are fibroadenomas and 10% are breast cancer, the rest being other benign conditions or no disease.
Phyllodes tumor is a fibroepithelial tumor which can be benign, borderline or malignant.
=== Breast cancer ===
Breast cancer is cancer of the breast tissues, most commonly arising from the milk ducts. Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases. It is most common in women over age 50.
Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, a newly inverted nipple, or a red or scaly patch of skin. Diagnosis may also be made when the cancer is asymptomatic, through breast cancer screening programs, such as mammograms. Outcomes for breast cancer vary depending on the cancer type, extent of disease, and person's age. Survival rates in the developed world are high, with between 80% and 90% of those in England and the United States alive for at least 5 years.
== Fibrocystic breast changes ==
Also called: fibrocystic breast disease, chronic cystic mastitis, diffuse cystic mastopathy, mammary dysplasia
== Infections and inflammations ==
These may be caused among others by trauma, secretory stasis/milk engorgement, hormonal stimulation, infections or autoimmune reactions.
Repeated occurrence unrelated to lactation requires endocrinological examination.
bacterial mastitis
mastitis from milk engorgement or secretory stasis
mastitis
chronic subareolar abscess
tuberculosis of the breast
syphilis of the breast
retromammary abscess
actinomycosis of the breast
duct ectasia syndrome
breast engorgement
== Other breast conditions ==
Mondor's disease
Paget's disease of the breast
nipple discharge, galactorrhea
breast cyst
mastalgia
galactocoele
== See also ==
Mammary gland
== References ==
== Further reading ==
Irshad, A.; Ackerman, S. J.; Pope, T. L.; Moses, C. K.; Rumboldt, T.; Panzegrau, B. (2008). "Rare Breast Lesions: Correlation of Imaging and Histologic Features with WHO Classification1". Radiographics. 28 (5): 1399–1414. doi:10.1148/rg.285075743. PMID 18794315.
== External links == | Wikipedia/Breast_disease |
This is a partial list of human eye diseases and disorders.
The World Health Organization (WHO) publishes a classification of known diseases and injuries, the International Statistical Classification of Diseases and Related Health Problems, or ICD-10. This list uses that classification.
== H00-H06 Disorders of eyelid, lacrimal system and orbit ==
(H02.1) Ectropion
(H02.2) Lagophthalmos
(H02.3) Blepharochalasis
(H02.4) Ptosis
(H02.5) Stye, an acne type infection of the sebaceous glands on or near the eyelid.
(H02.6) Xanthelasma of eyelid
(H03.0*) Parasitic infestation of eyelid in diseases classified elsewhere
Dermatitis of eyelid due to Demodex species ( B88.0+ )
Parasitic infestation of eyelid in:
leishmaniasis ( B55.-+ )
loiasis ( B74.3+ )
onchocerciasis ( B73+ )
phthiriasis ( B85.3+ )
(H03.1*) Involvement of eyelid in other infectious diseases classified elsewhere
Involvement of eyelid in:
herpesviral (herpes simplex) infection ( B00.5+ )
leprosy ( A30.-+ )
molluscum contagiosum ( B08.1+ )
tuberculosis ( A18.4+ )
yaws ( A66.-+ )
zoster ( B02.3+ )
(H03.8*) Involvement of eyelid in other diseases classified elsewhere
Involvement of eyelid in impetigo ( L01.0+ )
(H04.0) Dacryoadenitis
(H04.2) Epiphora
(H06.2*) Dysthyroid exophthalmos it is shown that if your eye comes out that it will shrink because the optic fluids drain out
== H10-H13 Disorders of conjunctiva ==
(H10.0) Conjunctivitis – inflammation of the conjunctiva commonly due to an infection or an allergic reaction
(H11.129) Conjunctival concretion - development of hard deposits under the eyelid
== H15-H22 Disorders of sclera, cornea, iris and ciliary body ==
(H15.0) Scleritis — a painful inflammation of the sclera
(H16) Keratitis — inflammation of the cornea
(H16.0) Corneal ulcer / Corneal abrasion — loss of the surface epithelial layer of the eye's cornea
(H16.1) Snow blindness / Arc eye — a painful condition caused by exposure of unprotected eyes to bright light
(H16.1) Thygeson's superficial punctate keratopathy
(H16.4) Corneal neovascularization
(H18.5) Fuchs' dystrophy — cloudy morning vision
(H18.6) Keratoconus — degenerative disease: the cornea thins and changes shape to be more like a cone than a parabole
(H19.3) Keratoconjunctivitis sicca — dry eyes
(H20.0) Iritis — inflammation of the iris
(H20.0, H44.1) Uveitis — inflammatory process involving the interior of the eye; Sympathetic ophthalmia is a subset.
== H25-H28 Disorders of lens ==
(H25) Cataract — the lens becomes opaque
(H26) Myopia - close object appears clearly, but far ones do not
(H27) Hypermetropia - Nearby objects appears blurry
(H28) Presbyopia - inability to focus on nearby objects
== H30-H36 Disorders of choroid and retina ==
=== H30 Chorioretinal inflammation ===
(H30) Chorioretinal inflammation
(H30.0) Focal chorioretinal inflammation
Focal:
chorioretinitis
choroiditis
retinitis
retinochoroiditis
(H30.1) Disseminated chorioretinal inflammation
Disseminated:
chorioretinitis
choroiditis
retinitis
retinochoroiditis
Excludes: exudative retinopathy (H35.0)
(H30.2) Posterior cyclitis
Pars planitis
(H30.8) Other chorioretinal inflammations
Harada's disease
(H30.9) Chorioretinal inflammation, unspecified
Chorioretinitis
Choroiditis
Retinitis
Retinochoroiditis
=== H31 Other disorders of choroid ===
(H31) Other disorders of choroid
(H31.0) Chorioretinal scars
Macula scars of posterior pole (postinflammatory) (post-traumatic)
Solar retinopathy
(H31.1) Choroidal degeneration
Atrophy
Sclerosis
Excludes: angioid streaks (H35.3)
(H31.2) Hereditary choroidal dystrophy
Choroideremia
Dystrophy, choroidal (central areolar) (generalized) (peripapillary)
Gyrate atrophy, choroid
Excludes: ornithinaemia ( E72.4 )
(H31.3) Choroidal haemorrhage and rupture
Choroidal haemorrhage:
NOS (Not Otherwise Specified)
expulsive
(H31.4) Choroidal detachment
(H31.8) Other specified disordes of choroid
(H31.9) Disorder of choroid, unspecified
=== H32 Chorioretinal disorders in diseases classified elsewhere ===
(H32) Chorioretinal disorders in diseases classified elsewhere
(H32.0) Chorioretinal inflammation in infectious and parasitic diseases classified elsewhere
Chorioretinitis:
syphilitic, late ( A52.7+ )
toxoplasma ( B58.0+ )
tuberculosis ( A18.5+ )
(H32.8) Other chorioretinal disorders in diseases classified elsewhere
=== H33 Retinal detachments and breaks ===
(H33) Retinal detachment with retinal break
Rhegmatogenous retinal detachment
(H33.1) Retinoschisis and retinal cysts — the retina separates into several layers and may detach
Cyst of ora serrata
Parasitic cyst of retina NOS
Pseudocyst of retina
Excludes: congenital retinoschisis (Q14.1)
microcystoid degeneration of retina (H35.4)
(H33.2) Serous retinal detachment
Retinal detachment:
NOS
without retinal break
Excludes: central serous chorioretinopathy (H35.7)
(H33.3) Retinal breaks without detachment
Horseshoe tear of retina, without detachment
Round hole of retina, without detachment
Operculum
Retinal break NOS
Excludes: chorioretinal scars after surgery for detachment (H59.8)
peripheral retinal degeneration without break (H35.4)
(H33.4) Traction detachment of retina
Proliferative vitreo-retinopathy with retinal detachment
(H33.5) Other retinal detachments
=== H34 Retinal vascular occlusions ===
A retinal vessel occlusion is a blockage in the blood vessel at the back of your eye that can result in sight loss.
=== H35 Other retinal disorders ===
(H35.0) Hypertensive retinopathy — burst blood vessels, due to long-term high blood pressure
(H35.0/E10-E14) Diabetic retinopathy — damage to the retina caused by complications of diabetes mellitus, which could eventually lead to blindness
(H35.0-H35.2) Retinopathy — general term referring to non-inflammatory damage to the retina
(H35.1) Retinopathy of prematurity — scarring and retinal detachment in premature babies
(H35.3) Age-related macular degeneration — the photosensitive cells in the macula malfunction and over time cease to work
(H35.3) Macular degeneration — loss of central vision, due to macular degeneration
Bull's Eye Maculopathy
(H35.3) Epiretinal membrane — a transparent layer forms and tightens over the retina
(H35.4) Peripheral retinal degeneration
(H35.5) Hereditary retinal dystrophy
(H35.5) Retinitis pigmentosa — genetic disorder; tunnel vision preceded by night-blindness
(H35.6) Retinal haemorrhage
(H35.7) Separation of retinal layers
Central serous retinopathy
Retinal detachment: Detachment of retinal pigment epithelium
(H35.8) Other specified retinal disorders
(H35.81) Macular edema — distorted central vision, due to a swollen macula
(H35.9) Retinal disorder, unspecified
=== H36 Retinal disorders in diseases classified elsewhere ===
(H36.0) Diabetic retinopathy
== H40-H42 Glaucoma ==
(H40.1) Primary open-angle glaucoma
(H40.2) Primary angle-closure glaucoma
(H40.3) Primary Normal tension glaucoma
== H43-H45 Disorders of vitreous body and globe ==
=== H43 Disorders of vitreous body ===
(H43.0) Vitreous prolapse
Excludes: vitreous syndrome following cataract surgery (H59.0)
(H43.1) Vitreous haemorrhage
(H43.2) Crystalline deposits in vitreous body
(H43.3) Other vitreous opacities
Vitreous membranes and strands
(H43.8) Other disorders of vitreous body
Vitreous:
degeneration
detachment
Excludes: proliferative vitreo-retinopathy with retinal detachment (H33.4)
(H43.9) Disorder of vitreous body, unspecified
=== H44 Disorders of globe ===
Includes: disorders affecting multiple structures of eye
(H44.0) Purulent endophthalmitis
Panophthalmitis
Vitreous abscess
(H44.1) Other endophthalmitis
Parasitic endophthalmitis NOS
Sympathetic uveitis
(H44.2) Degenerative myopia
(H44.3) Other degenerative disorders of globe
Chalcosis
Siderosis of eye
(H44.4) Hypotony of eye
(H44.5) Degenerated conditions of globe
Absolute glaucoma
Atrophy of globe
Phthisis bulbi
(H44.6) Retained (old) intraocular foreign body, magnetic
Retained (old) magnetic foreign body (in):
anterior chamber
ciliary body
iris
lens
posterior wall of globe
vitreous body
(H44.7) Retained (old) intraocular foreign body, nonmagnetic
Retained (nonmagnetic)(old) foreign body (in):
anterior chamber
ciliary body
iris
lens
posterior wall of globe
vitreous body
(H44.8) Other disorders of globe
Haemophthalmos
Luxation of globe
(H44.9) Disorder of globe, unspecified
=== H45 Disorders of vitreous body and globe in diseases classified elsewhere ===
(H45.0) Vitreous haemorrhage in diseases classified elsewhere
(H45.1) Endophthalmitis in diseases classified elsewhere
Endophthalmitis in:
cysticercosis
onchocerciasis
toxocariasis
(H45.8) Other disorders of vitreous body and globe in diseases classified elsewhere
== H46-H48 Disorders of optic nerve and visual pathways ==
(H47.2) Leber's hereditary optic neuropathy — genetic disorder; loss of central vision,.
(H47.3) Optic disc drusen — globules progressively calcify in the optic disc, compressing the vascularization and optic nerve fibers
== H49-H52 Disorders of ocular muscles, binocular movement, accommodation and refraction ==
(H49-H50) Strabismus (Crossed eye/Wandering eye/Walleye) — the eyes do not point in the same direction
(H49.3-4) Ophthalmoparesis — the partial or total paralysis of the eye muscles
(H49.4) Progressive external ophthaloplegia — weakness of the external eye muscles
(H50.0, H50.3) Esotropia — the tendency for eyes to become cross-eyed
(H50.1, H50.3) Exotropia — the tendency for eyes to look outward
H52 Disorders of refraction and accommodation
(H52.0) Hypermetropia (Farsightedness) — the inability to focus on near objects (and in extreme cases, any objects)
(H52.1) Myopia (Nearsightedness) — distant objects appear blurred
(H52.2) Astigmatism — the cornea or the lens of the eye is not perfectly spherical, resulting in different focal points in different planes
(H52.3) Anisometropia — the lenses of the two eyes have different focal lengths
(H52.4) Presbyopia — a condition that occurs with growing age and results in the inability to focus on close objects
(H52.5) Disorders of accommodation
Internal ophthalmoplegia
== H53-H54.9 Visual disturbances and blindness ==
(H53.0) Amblyopia (lazy eye) — poor or blurry vision due to either no transmission or poor transmission of the visual image to the brain
(H53.0) Leber's congenital amaurosis — genetic disorder; appears at birth, characterised by sluggish or no pupillary responses
(H53.1, H53.4) Scotoma (blind spot) — an area impairment of vision surrounded by a field of relatively well-preserved vision. See also Anopsia.
(H53.5) Color blindness — the inability to perceive differences between some or all colors that other people can distinguish
(H53.5) Achromatopsia / Maskun — a low cone count or lack of function in cone cells
(H53.6) Nyctalopia (Night blindness) — a condition making it difficult or impossible to see in the dark
(H54) Blindness — the brain does not receive optical information, through various causes
(H54/B73) River blindness — blindness caused by long-term infection by a parasitic worm (rare in western societies)
(H54.9) Micropthalmia/coloboma — a disconnection between the optic nerve and the brain and/or spinal cord
== H55-H59 Other disorders of eye and adnexa ==
(H57.9) Red eye — conjunctiva appears red typically due to illness or injury
(H58.0) Argyll Robertson pupil — small, unequal, irregularly shaped pupils
== Other codes ==
The following are not classified as diseases of the eye and adnexa (H00-H59) by the World Health Organization:
(B36.1) Keratomycosis — fungal infection of the cornea
(E50.6-E50.7) Xerophthalmia — dry eyes, caused by vitamin A deficiency
(Q13.1) Aniridia — a rare congenital eye condition leading to underdevelopment or even absence of the iris of the eye
== See also ==
== Notes ==
Please see the References section below for the complete listing of information.
== References ==
EyeWiki: The Eye Encyclopedia written by Eye Physicians & Surgeons (American Academy of Ophthalmology)
International Statistical Classification of Diseases (WHO ICD-10) — Diseases of the eye and adnexa (ICD-10 codes H00-H59)
EyeDiseases: Most Common Eye Diseases Explained With Symptoms and Cure | Wikipedia/Eye_disease |
In medicine, describing a disease as acute denotes that it is of recent onset; it occasionally denotes a short duration. The quantification of how much time constitutes "short" and "recent" varies by disease and by context, but the core denotation of "acute" is always qualitatively in contrast with "chronic", which denotes long-lasting disease (for example, in acute leukaemia and chronic leukaemia).
In the context of the mass noun "acute disease", it refers to the acute phase (that is, a short course) of any disease entity. For example, in an article on ulcerative enteritis in poultry, the author says, "in acute disease there may be increased mortality without any obvious signs", referring to the acute form or phase of ulcerative enteritis.
== Meaning variations ==
A mild stubbed toe is an acute injury. Similarly, many acute upper respiratory infections and acute gastroenteritis cases in adults are mild and usually resolve within a few days or weeks.
The term "acute" is also included in the definition of several diseases, such as severe acute respiratory syndrome, acute leukaemia, acute myocardial infarction, and acute hepatitis. This is often to distinguish diseases from their chronic forms, such as chronic leukaemia, or to highlight the sudden onset of the disease, such as acute myocardial infarct.
=== Related terminology ===
Related terms include:
== Acute care ==
Acute care is the early and specialist management of adult patients who have a wide range of medical conditions requiring urgent or emergency care usually within 48 hours of admission or referral from other specialties.
Acute hospitals are those intended for short-term medical and/or surgical treatment and care which is a medical speciality of acute medicine, as often primary care is not positioned to assume this role.
== References == | Wikipedia/Acute_disease |
The Autobots are a fictional faction of sentient robots in the Transformers multimedia franchise. The Autobots are living robots from the planet Cybertron who, like most Transformers, are each imbued with a unique "life force" known as a "spark." Led by Optimus Prime in most stories, the Autobots believe that "freedom is the right of all sentient life" and are often engaged in a civil war with the Decepticons, a faction of Transformers dedicated to military conquest and usually headed by Megatron. In a mirror universe portrayed in Transformers: Shattered Glass, the Autobots are villains opposed by the heroic Decepticons.
The transformation cog ("T-cog") and the living metal of each transformer's body allows them to change from their natural robotic body into an "alternate mode" based on some form of technology or life that they have scanned. When they were first introduced, most Autobots transformed into cars, trucks and other road vehicles. Over time, Autobots have been introduced with alternate modes that include aircraft, weapons, robotic animals, or a variety of devices (such as music equipment or microscopes). In most Transformers media, the Autobots originally transform into alien-style vehicles and technology native to their home planet Cybertron, but they later adopt alternate forms based on human technology after journeying to Earth.
In the live action films series, as well as in the CGI-animated series Transformers: Prime, the title Autobots is explained to be the short version of the title "Autonomous Robotic Organisms." In Japan, the Autobots are called "Cybertrons" (サイバトロン, Saibatoron) but are referred to as Autobots (オートボット, Ōtobotto) in the film series Transformers: Animated and Transformers: Prime. In Italy, they are called "Autorobot." The Autobot insignia is also sometimes referred to as an "Autobrand", a term that first appeared in issue #14 of the Marvel Comics series. The descendants of the Autobots, the Maximals from Transformers: Beast Wars, are also known as Cybertrons in Japan.
== Physical traits ==
Autobots are living beings, sometimes referred to as "bio-mechanical" and often depicted as being forged from the same "living metal" that makes up their home planet Cybertron. This living metal can heal, grow, and regenerate like organic cell structures. Autobots, like all transformers, need to regularly feed on Energon (a form of energy they can produce from certain fuel sources) or they will grow weaker in health and eventually die. Autobots can also age, just much slower than humans, for example Optimus Prime is approximately 9 million years old. Whereas the first homo sapiens evolved 300,000 years ago.
Since the airing of the animated series Transformers: Beast Wars, the franchise has consistently portrayed that what distinguishes a Transformer as "living" is that each of them is imbued with a "spark", a charged mass of positrons that acts as a "life force" (said to be equivalent to a soul) and is unique to each transformer, granting them their basic personality and influencing certain physical traits. If a transformer dies, either from injury or a lack of Energon, their spark fades and might never be recovered again, as their spark typically returns to the source of positronic energy it originally came from. Some media portrays the source of these sparks as a pool of positronic energy located on Cybertron that is called the Well of All Sparks, while other media portrays the source to be an ancient artifact simply called the Allspark. Some stories have shown characters being able to preserve a dead transformer's spark under the right circumstances, allowing that fallen transformer to return in a repaired body (though this possibility involves great risk and becomes more unlikely as more time passes).
When a transformer is first forged, they are in a "Proto-form" state that resembles either a featureless, mannequin-like robot or a being of liquid, shifting metal. As the transformer's consciousness develops, the proto-form takes shape into a robotic form and an alternate mode is soon determined afterward. How long this process takes varies between different Transformers media. In some media, a Transformer can physically revert to a proto-form to make long space travel easier.
Along with their spark, each transformer has a mechanical "brain module" that houses their memories and regulates sensory input, as well as the transformation cog (or "T-cog") which regulates and stabilizes their transformations. A transformer can have several parts of their body replaced or upgraded, but damage to the brain module or T-cog, as well as other more sensitive internal mechanics (such as eyes and voice boxes), are unique, difficult to upgrade, and can permanently affect or disable a transformer, as well as threaten their life, if seriously damaged.
Some transformers, including several Autobots, have traits that make them part of a subset of their species. Transformers who are so massive in size they are able to convert into fortresses or cities are known as Titans, some of whom (such as Metroplex) have allied themselves with the Autobots. "City-speakers" are transformers able to uniquely commune with Titans, such as the Autobot called Windblade. Like the Decepticons, the Autobots include "combiners" in their ranks, transformers who are able to merge with other specific transformers and become a gestalt, super-robot with greater power and its own distinct personality. In some stories, transformers are given the ability to become combiners by an ancient artifact called the Enigma of Combination. In Cybertron's past, the Guardian Robots were large scale Transformers (though not as large as the Titans) who enforced authority and peace on their planet. While most Guardians are gone, one known as Omega Supreme serves alongside the Autobots. Mini-Cons (sometimes spelled Minicons) are small, human-sized transformers and, in some stories, are able to increase the power of larger transformers with whom they merge.
Due to their biological and sentient nature, Autobots are people, although humans constantly fail to acknowledge this due to their metal composition.
== Home planet ==
In all Transformers stories, the Autobots and their adversaries, the Decepticons, originated on the planet Cybertron. The planet is almost always depicted as a metallic sphere covered in multi-level cities and structures. The capital of Cybertron is Iacon. Although there is no animal or plant life on Cybertron, animated cartoons have depicted it as having an atmosphere that human visitors can breathe, and some stories have shown the planet to experience weather, such as rainfall and storms.
Starting with the original series The Transformers, Cybertron is shown to house a seemingly living super-computer called Vector Sigma. At first, Vector Sigma is depicted to be the source of life for new transformers, imbuing the robots with life and personality. Later, media consistently portrays that Vector Sigma harnesses the power of another source known as the Allspark to imbue a transformer with its individual soul or "spark." Different versions of Transformers media have also shown the life-giving energy of the Allspark to be an ancient artifact (either called the Allspark or the Cube) or have shown it to be a pool of positronic energy located on Cybertron known as the Well of AllSpark or Well of AllSparks.
The UK comic books written by Simon Furman established that Cybertron was once a god-like being named Primus. Following a battle with another god-like being known as Unicron, Primus transforms into Cybertron, a planet of "living metal", and eventually uses his energies to grant life to living robots. In some stories, Primus does this in the hopes that these robots will become warriors who will defeat Unicron and similar threats. Following the introduction of Primus, it is said in some media that it is his mind that acts as the will of the super-computer Vector Sigma. Various stories depict the first living creations of Primus to be a group known as the "original thirteen Primes" or simply "the Thirteen." Eventually, each of the thirteen Primes grants a copy of their nature and schematics into the Allspark energy source that will imbue later Cybertronians with life, making all later transformers their "descendants" who each inherit a unique combination of traits from at least some of the original Thirteen.
Although the transformer race originated on Cybertron, different groups of Cybertronians later left the planet and colonized other worlds. This has led to different factions of transformers with their own cultures and beliefs, some of whom become Autobots while others have no desire to involve themselves in Cybertron's civil war.
== The Primes ==
In the original toyline and animated series The Transformers, Optimus Prime (known as Convoy in Japan) is shown as the leader. Formerly named Orion Pax, his label of "Prime" is indicated to simply be part of the name he adopted when he became a soldier. Since the 1986 animated film The Transformers: The Movie however, US and UK Transformers media have depicted "prime" as a title and rank given to the leader of the Autobots and sometimes all government of Cybertron (while Japanese media has portrayed "convoy" as a rank of military leadership in transformer society). Later media depicted earlier leaders of Cybertron to have names such as Nova Prime, Nominus Prime, and Sentinel Prime, along with others.
In several comics and cartoon stories, the Prime is a figurehead of a ruling council that governs Cybertron (or the entire transformer race that is scattered across different planets). Each Prime is chosen by and bonded to a powerful artifact called the Matrix of Leadership. The origin and nature of the Matrix differs across Transformers media, but it is consistently shown to be a powerful object that houses the memories and wisdom of previous Autobot leaders who wielded it. Often, the Matrix is shown to have a direct connection to Primus, a god-like being who became the planet Cybertron itself and created its race of living robots. Some media portray it as a conduit to the energy source of all transformer life and/or an access point to a dimension that acts as an afterlife for transformers. In some stories, being chosen by the Matrix of Leadership causes an immediate power enhancement and physical change in a transformer.
In several branches of the Transformers franchise, the title of "Prime" is a reference to Prima, a heroic warrior of Cybertron's past. In these versions of canon, Prima is one of "the original thirteen Primes (or "the Thirteen") who are ancestors of the transformer race and direct creations of Primus, the god-like being who became Cybertron. Across Transformers media, Prima is the first to wield the Matrix of Leadership and his wisdom and essence are absorbed into it after he dies in battle with another ancient Prime known as Megatronus.
In some media, Optimus Prime eventually gives up his connection to the Matrix of Leadership and it is passed on to a new leader such as the Autobot soldier Ultra Magnus, the young Autobot fighter called Hot Rod (who becomes Rodimus Prime), or eventually Optimus Primal, a Maximal.
== Transformers: Generation 1 ==
== Transformers: Aligned ==
A group of Autobots (referred to as Team Prime) appear in the 2010 animated series Transformers: Prime, led by Optimus Prime. The video game Transformers: War for Cybertron give a backstory to the Autobots days on Cybertron.
=== Transformers: Prime – The Game ===
Set within an alternate timeline that parallels the show's second season, the Autobots (Team Prime) appear in Transformers: Prime – The Game. Optimus Prime, Arcee, Bulkhead, Bumblebee, Ratchet, Jack, Miko and Raf embark on a journey to defeat the villainous Megatron and the Decepticons in his plan to use his secret new weapon. The Decepticons intercept a mysterious meteor approaching the Earth, and the Autobots arrive to try and thwart the Decepticons' plans. A massive eruption of power during the battle on the meteor breaks out, and the Autobots become separated from Jack, Miko and Raf, who are monitoring them at base. Unknown to the Autobots and their human friends, the Decepticons have uncovered Thunderwing, an ancient power that they will use to try to take over the Earth.
=== Transformers: Prime ===
In Transformers: Prime, with Cybertron dead, the Autobots scattered across the universe. A group landed on Earth consisting of Optimus Prime, Ratchet, Bumblebee, and Bulkhead and which Arcee and Cliffjumper join later. This small team of Autobots led by Optimus is rechristened Team Prime. During the final four episodes of the season, the Autobots unwillingly team up with Megatron to battle a legendary threat to Earth's existence, Unicron.
== Transformers: EarthSpark ==
Many years after the end of the war, the Autobots, now working with Megatron and the secret human organization G.H.O.S.T. to protect Earth from the remaining rogue Decepticons, reach out to the Malto family and offer the Terrans the chance to be mentored by Bumblebee. With new threats on the horizon, such as the mad scientist Dr. Meridian (Mandroid) and the various Decepticons still at large, the Autobots and Maltos work together to keep each other safe and find their place in the world while learning what it truly means to be a family.
One year after the successful defeat and death of Mandroid, a group of Decepticons led by Starscream goes rogue sometime after the shattering of the Emberstone. It is up to the Terrans, the Autobots, the humans, and those Decepticons on their side (namely Megatron) to collect the shards before those Decepticons that sided with Starscream do. This leads to the creation of the Chaos Terrans and the discovery of some secrets about Witwicky itself; the secret includes an Earth-born female Titan Terran named Terratronus whose body was covered by mounds of rocks and soil that would later become the site of Witwicky.
The stakes eventually get higher when the Quintessons get involved and threaten the Maltos, the Autobots, and Earth following the Decepticons' departure from Earth on Prowl's ship. Luckily the Autobots, and the Maltos along with the Chaos Terrans readily team up with Terratronus and successfully destroy the Quintessons for good so that the Quintessons would never harm anybody or anything on the planet Earth anymore.
== Transformers One ==
The Autobots were merely a group of Cybertronian miners without transformation cogs who mined Energon for the Quintessons, and they and all Cybertronians are led by their leader Sentinel Prime, having him as their trust. After discovering the truth about Sentinel by Orion Pax, they follow him to help him expose the truth against Sentinel's crimes. Pax's former friend D-16, kills Sentinel after letting Pax fall to his demise into the core of Iacon City, rechristening himself as Megatron. At the city's core, Pax is blessed by the thirteen Primes and bestowed the Matrix of Leadership, becoming reborn as Optimus Prime. Prime returns to the city's surface and successfully defeats Megatron and members of the High Guard who defect to his side, eventually banishing them for attempting to destroy Iacon. The miners are given their transformation cogs by Optimus Prime, who officially reforms them as the Autobots to protect Cybertron against the threat of the Quintessons, and promising they will maintain peace, order and will fight for justice throughout the galaxy.
== See also ==
Decepticon
Predacons
Maximals
== References ==
== External links ==
Autobots at TFWIKI.Net, The Transformers Wiki
Marvel (US) Comics Transformers series, issues 1-80.
Dreamwave Productions Transformers series.
Marvel (UK) Comics Transformers series.
Paramount/DreamWorks 2007 Transformers Film.
Hasbro Transformers toy line, 1984 through present (both toys and packaging). | Wikipedia/Flareup_(Transformers) |
Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The most common presentation of cerebrovascular disease is an ischemic stroke or mini-stroke and sometimes a hemorrhagic stroke. Hypertension (high blood pressure) is the most important contributing risk factor for stroke and cerebrovascular diseases as it can change the structure of blood vessels and result in atherosclerosis. Atherosclerosis narrows blood vessels in the brain, resulting in decreased cerebral perfusion. Other risk factors that contribute to stroke include smoking and diabetes. Narrowed cerebral arteries can lead to ischemic stroke, but continually elevated blood pressure can also cause tearing of vessels, leading to a hemorrhagic stroke.
A stroke usually presents with an abrupt onset of a neurologic deficit – such as hemiplegia (one-sided weakness), numbness, aphasia (language impairment), or ataxia (loss of coordination) – attributable to a focal vascular lesion. The neurologic symptoms manifest within seconds because neurons need a continual supply of nutrients, including glucose and oxygen, that are provided by the blood. Therefore, if blood supply to the brain is impeded, injury and energy failure is rapid.
Besides hypertension, there are also many less common causes of cerebrovascular disease, including those that are congenital or idiopathic and include CADASIL, aneurysms, amyloid angiopathy, arteriovenous malformations, fistulas, and arterial dissections. Many of these diseases can be asymptomatic until an acute event, such as a stroke, occurs. Cerebrovascular diseases can also present less commonly with headache or seizures. Any of these diseases can result in vascular dementia due to ischemic damage to the brain.
== Signs and symptoms ==
The most common presentation of cerebrovascular diseases is an acute stroke, which occurs when blood supply to the brain is compromised. Symptoms of stroke are usually rapid in onset, and may include weakness of one side of the face or body, numbness on one side of the face or body, inability to produce or understand speech, vision changes, and balance difficulties. Hemorrhagic strokes can present with a very severe, sudden headache associated with vomiting, neck stiffness, and decreased consciousness. Symptoms vary depending on the location and the size of the area of involvement of the stroke. Edema, or swelling, of the brain may occur which increases intracranial pressure and may result in brain herniation. A stroke may result in coma or death if it involves key areas of the brain.
Other symptoms of cerebrovascular disease include migraines, seizures, epilepsy, or cognitive decline. However, cerebrovascular disease may go undetected for years until an acute stroke occurs. In addition, patients with some rare congenital cerebrovascular diseases may begin to have these symptoms in childhood.
== Causes ==
=== Congenital ===
Congenital diseases are medical conditions that are present at birth that may be associated with or inherited through genes. Examples of congenital cerebrovascular diseases include arteriovenous malformations, germinal matrix hemorrhage, and CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Arteriovenous malformations are abnormal tangles of blood vessels. Usually, a capillary bed separates arteries from veins, which protects the veins from the higher blood pressures that occur in arteries. In arteriovenous malformations, arteries are directly connected to veins, which increases the risk of venous rupture and hemorrhage. Cerebral arteriovenous malformations in the brain have a 2–4% chance of rupture each year. However, many arteriovenous malformations go unnoticed and are asymptomatic throughout a person's lifetime.
A germinal matrix hemorrhage is bleeding into the brain of premature infants caused by the rupture of fragile blood vessels within the germinal matrix of premature babies. The germinal matrix is a highly vascularized area within an unborn infant's brain from which brain cells, including neurons and glial cells, originate. Infants are at most risk to germinal matrix hemorrhages when they are born prematurely, before 32 weeks. The stresses exposed after birth, along with the fragile blood vessels, increase risk of hemorrhage. Signs and symptoms include flaccid weakness, seizures, abnormal posturing, or irregular respiration.
CADASIL is an inherited disorder caused by mutations in the NOTCH3 gene located on chromosome 19. NOTCH3 codes for a transmembrane protein whose function is not well-known. However, the mutation causes accumulation of this protein within small to medium-sized blood vessels. This disease often presents in early adulthood with migraines, stroke, mood disturbances, and cognitive deterioration. MRI shows white matter changes in the brain and also signs of repeated strokes. The diagnosis can be confirmed by gene testing.
=== Acquired ===
Acquired cerebrovascular diseases are those that are obtained throughout a person's life that may be preventable by controlling risk factors. The incidence of cerebrovascular disease increases as an individual ages. Causes of acquired cerebrovascular disease include atherosclerosis, embolism, aneurysms, and arterial dissections. Atherosclerosis leads to narrowing of blood vessels and less perfusion to the brain, and it also increases the risk of thrombosis, or a blockage of an artery, within the brain. Major modifiable risk factors for atherosclerosis include:
Controlling these risk factors can reduce the incidence of atherosclerosis and stroke. Atrial fibrillation is also a major risk factor for strokes. Atrial fibrillation causes blood clots to form within the heart, which may travel to the arteries within the brain and cause an embolism. The embolism prevents blood flow to the brain, which leads to a stroke.
An aneurysm is an abnormal bulging of small sections of arteries, which increases the risk of artery rupture. Intracranial aneurysms are a leading cause of subarachnoid hemorrhage, or bleeding around the brain within the subarachnoid space. There are various hereditary disorders associated with intracranial aneurysms, such as Ehlers-Danlos syndrome, autosomal dominant polycystic kidney disease, and familial hyperaldosteronism type I. However, individuals without these disorders may also obtain aneurysms. The American Heart Association and American Stroke Association recommend controlling modifiable risk factors including smoking and hypertension.
Arterial dissections are tears of the internal lining of arteries, often associated with trauma. Dissections within the carotid arteries or vertebral arteries may compromise blood flow to the brain due to thrombosis, and dissections increase the risk of vessel rupture.
=== Idiopathic ===
Idiopathic diseases are those that occur spontaneously without a known cause. Moyamoya is an example of an idiopathic cerebrovascular disorder that results in narrowing and occlusion of intracranial blood vessels. The most common presentation is stroke or transient ischemic attack, but cognitive decline within children may also be a presenting symptom. The disease may begin to show symptoms beginning in adolescence, but some may not have symptoms until adulthood.
== Pathophysiology ==
=== Mechanism of brain cell death ===
When a reduction in blood flow lasting seconds occurs, the brain tissue suffers ischemia, or inadequate blood supply. If the interruption of blood flow is not restored in minutes, the tissue suffers infarction followed by tissue death. When the low cerebral blood flow persists for a longer duration, this may develop into an infarction in the border zones (areas of poor blood flow between the major cerebral artery distributions). In more severe instances, global hypoxia-ischemia causes widespread brain injury leading to a severe cognitive sequelae called hypoxic-ischemic encephalopathy.
An ischemic cascade occurs where an energetic molecular problem arises due to lack of oxygen and nutrients. The cascade results in decreased production of adenosine triphosphate (ATP), which is a high-energy molecule needed for cells in the brain to function. Consumption of ATP continues in spite of insufficient production, this causes total levels of ATP to decrease and lactate acidosis to become established (ionic homeostasis in neurons is lost). The downstream mechanisms of the ischemic cascade thus begins. Ion pumps no longer transport Ca2+ out of cell, this triggers release of glutamate, which in turn allows calcium into cell walls. In the end the apoptosis pathway is initiated and cell death occurs.
There are several arteries that supply oxygen to different areas of the brain, and damage or occlusion of any of them can result in stroke. The carotid arteries cover the majority of the cerebrum. The common carotid artery divides into the internal and the external carotid arteries. The internal carotid artery becomes the anterior cerebral artery and the middle central artery. The ACA transmits blood to the frontal parietal. From the basilar artery are two posterior cerebral arteries. Branches of the basilar and PCA supply the occipital lobe, brain stem, and the cerebellum. Ischemia is the loss of blood flow to the focal region of the brain. This produces heterogeneous areas of ischemia at the affected vascular region, furthermore, blood flow is limited to a residual flow. Regions with blood flow of less than 10 mL/100 g of tissue/min are core regions (cells here die within minutes of a stroke). The ischemic penumbra with a blood flow of <25 ml/100g tissue/min, remain usable for more time (hours).
=== Types of stroke ===
There are two main divisions of strokes: ischemic and hemorrhagic. Ischemic stroke involves decreased blood supply to regions of the brain, while hemorrhagic stroke is bleeding into or around the brain.
==== Ischemic ====
Ischemic stroke, the most common is caused by a blockage of a blood vessel in the brain, usually caused by thrombosis or emboli from a proximal arterial source or the heart, that leads to the brain being starved of oxygen. The neurologic signs and symptoms must last longer than 24 hours or the brain infarction is demonstrated, mainly by imaging techniques.
Transient ischemic attack (TIA) also called a mini-stroke. This is a condition in which the blood flow to a region of the brain is blocked, but blood flow is quickly restored and the brain tissue can fully recover. The symptoms are only transient, leaving no sequelae, or long-term deficits. In order to diagnose this entity, all neurologic signs and symptoms must have been resolved within 24 hrs without evidence of brain infarction on brain imaging.
==== Hemorrhagic ====
Subarachnoid haemorrhage occurs when blood leaks out of damaged vessels into the cerebrospinal fluid in the subarachnoid space around the brain. The most common cause of a subarachnoid hemorrhage is an aneurysm rupture due to the weakened blood vessel walls and increased wall stress. The neurologic symptoms are produced by the blood mass effect on neural structures, from the toxic effects of blood on the brain tissue, or by the increasing of intracranial pressure.
Intracerebral haemorrhage is bleeding directly into the brain rather than around the brain. Causes and risk factors include hypertension, blood thinning medications, trauma, and arteriovenous malformations.
== Diagnosis ==
Diagnoses of cerebrovascular disease may include:
medical history
physical exam
neurological examination
acute stroke imaging is generally performed in significant symptoms of new onset
It is important to differentiate the symptoms caused by a stroke from those caused by syncope (fainting) which is also a reduction in cerebral blood flow, almost always generalized, but they are usually caused by systemic hypotension of various origins: cardiac arrhythmias, myocardial infarction, hemorrhagic shock, among others.
== Treatment ==
Treatment for cerebrovascular disease may include medication, lifestyle changes, and surgery, depending on the cause.
Examples of medications are:
antiplatelets (aspirin, clopidogrel)
blood thinners (heparin, warfarin)
antihypertensives:
ACE inhibitors
beta blockers
calcium channel blockers - in particular Nimodipine reduces the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage (SAH)
anti-diabetic medications.
Surgical procedures include:
endovascular surgery and vascular surgery (for future stroke prevention).
== Prognosis ==
Prognostics factors:
Lower Glasgow Coma Scale score, higher pulse rate, higher respiratory rate and lower arterial oxygen saturation level is prognostic features of in-hospital mortality rate in acute ischemic stroke.
== Epidemiology ==
Worldwide, it is estimated there are 31 million stroke survivors, though about 6 million deaths were due to cerebrovascular disease (2nd most common cause of death in the world and 6th most common cause of disability).
Cerebrovascular disease primarily occurs with advanced age; the risk for developing it goes up significantly after 65 years of age. CVD tends to occur earlier than Alzheimer's Disease (which is rare before the age of 80). In some countries such as Japan, CVD is more common than AD.
In 2012, 6.4 million adults from the US had a stroke, which corresponds to 2.7% of the US. This is approximately 129,000 deaths in 2013.
Geographically, a "stroke belt" in the US has long been known, similar to the "diabetes belt" which includes all of Mississippi and parts of Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, North Carolina, Ohio, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, and West Virginia.
== References ==
== Further reading ==
Chan, Pak H. (2002-03-28). Cerebrovascular Disease: 22nd Princeton Conference. Cambridge University Press. ISBN 9781139439657.
Mark, S. D; Wang, W; Fraumeni, J. F; Li, J.-Y; Taylor, P. R; Wang, G.-Q; Guo, W; Dawsey, S. M; Li, B; Blot, W. J (1996). "Lowered Risks of Hypertension and Cerebrovascular Disease after Vitamin/Mineral Supplementation: The Linxian Nutrition Intervention Trial". American Journal of Epidemiology. 143 (7): 658–664. doi:10.1093/oxfordjournals.aje.a008798. PMID 8651227.
Ning, Mingming; Lopez, Mary; Cao, Jing; Buonanno, Ferdinando S; Lo, Eng H (2012). "Application of proteomics to cerebrovascular disease". Electrophoresis. 33 (24): 3582–3597. doi:10.1002/elps.201200481. PMC 3712851. PMID 23161401.
== External links == | Wikipedia/Cerebrovascular_disease |
A contagious disease is an infectious disease that can be spread rapidly in several ways, including direct contact, indirect contact, and droplet contact.
These diseases are caused by organisms such as parasites, bacteria, fungi, and viruses. While many types of organisms live on the human body and are usually harmless, these organisms can sometimes cause disease.
Some common infectious diseases are influenza, COVID-19, ebola, hepatitis, HIV/AIDS, Human papillomavirus infection, Polio, and Zika virus.
A disease is often known to be contagious before medical science discovers its causative agent. Koch's postulates, which were published at the end of the 19th century, were the standard for the next 100 years or more, especially with diseases caused by bacteria. Microbial pathogenesis attempts to account for diseases caused by a virus.
== Historical meaning ==
Originally, the term referred to a contagion or disease transmissible only by direct physical contact. In the modern-day, the term has sometimes been broadened to encompass any communicable or infectious disease. Often the word can only be understood in context, where it is used to emphasize very infectious, easily transmitted, or especially severe communicable diseases.
In 1849, John Snow first proposed that cholera was a contagious disease.
== Effect on public health response ==
Most epidemics are caused by contagious diseases, with occasional exceptions, such as yellow fever. The spread of non-contagious communicable diseases is changed either very little or not at all by medical isolation of ill persons or medical quarantine for exposed persons. Thus, a "contagious disease" is sometimes defined in practical terms, as a disease for which isolation or quarantine are useful public health responses.
Some locations are better suited for the research into the contagious pathogens due to the reduced risk of transmission afforded by a remote or isolated location.
The basic reproduction number of a disease is used to measure how easily the disease spreads through contact with infected individuals.
Negative room pressure is a technique in health care facilities based on aerobiological designs.
== See also ==
Germ theory of disease
Herd immunity
Notifiable disease
== References == | Wikipedia/Contagious_disease |
Otology is a branch of medicine which studies normal, pathological anatomy and physiology of the ear (hearing). Otology also studies vestibular sensory systems, related structures and functions, as well as their diseases, diagnosis and treatment. Otologic surgery generally refers to surgery of the middle ear and mastoid related to chronic otitis media, such as tympanoplasty (ear drum surgery), ossiculoplasty (surgery of the hearing bones) and mastoidectomy. Otology also includes surgical treatment of conductive hearing loss, such as stapedectomy surgery for otosclerosis.
Neurotology (a related field of medicine and subspecialty of otolaryngology) is the study of diseases of the inner ear, which can lead to hearing and balance disorders. Neurotologic surgery generally refers to surgery of the inner ear, or surgery that involves entering the inner ear with risk to the hearing and balance organs, including labyrinthectomy, cochlear implant surgery, and surgery for tumors of the temporal bone, such as intracanalicular acoustic neuromas. Neurotology is expanded to include surgery of the lateral skull base to treat intracranial tumors related to the ear and surrounding nerve and vascular structures, such as large cerebellar pontine angle acoustic neuromas, glomus jugulare tumors and facial nerve tumors.
Some of the concerns of otology include:
identifying the underlying mechanisms of Ménière's disease,
finding the causes of tinnitus and developing treatment methods, and
defining the development and progression of otitis media.
Related concerns of neurotology include:
studying signal processing in the cochlear implant patient,
investigating postural control areas and vestibulo-ocular mechanisms, and
studying the genetics of acoustic neuromas in patients with neurofibromatosis, to better understanding how to treat these tumors and prevent their growth.
== See also ==
Audiology – Branch of science that studies hearing, balance, and related disorders
Ear Research Foundation – Research institute in USAPages displaying wikidata descriptions as a fallback
Neurotology – Head and neck surgery (otorhinolaryngology) subspecialty
Stenvers projection – Radiological technique
TWJ Foundation – UK health charityPages displaying wikidata descriptions as a fallback
== References == | Wikipedia/Ear_disease |
Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is a deficiency, excess, or imbalance of energy, protein and other nutrients which adversely affects the body's tissues and form.
Malnutrition is a category of diseases that includes undernutrition and overnutrition. Undernutrition is a lack of nutrients, which can result in stunted growth, wasting, and being underweight. A surplus of nutrients causes overnutrition, which can result in obesity or toxic levels of micronutrients. In some developing countries, overnutrition in the form of obesity is beginning to appear within the same communities as undernutrition.
Most clinical studies use the term 'malnutrition' to refer to undernutrition. However, the use of 'malnutrition' instead of 'undernutrition' makes it impossible to distinguish between undernutrition and overnutrition, a less acknowledged form of malnutrition. Accordingly, a 2019 report by The Lancet Commission suggested expanding the definition of malnutrition to include "all its forms, including obesity, undernutrition, and other dietary risks." The World Health Organization and The Lancet Commission have also identified "[t]he double burden of malnutrition", which occurs from "the coexistence of overnutrition (overweight and obesity) alongside undernutrition (stunted growth and wasting)."
== Prevalence ==
It was estimated in 2017 that nearly one in three persons globally had at least one form of malnutrition: wasting, stunting, vitamin or mineral deficiency, overweight, obesity, or diet-related noncommunicable diseases. Undernutrition is more common in developing countries. Stunting is more prevalent in urban slums than in rural areas.
Studies on malnutrition have the population categorised into different groups including infants, under-five children, children, adolescents, pregnant women, adults and the elderly population. The use of different growth references in different studies leads to variances in the undernutrition prevalence reported in different studies. Some of the growth references used in studies include the National Center for Health Statistics (NCHS) growth charts, WHO reference 2007, Centers for Disease Control and Prevention (CDC) growth charts, National Health and Nutrition Examination Survey (NHANES), WHO reference 1995, Obesity Task Force (IOTF) criteria and Indian Academy of Pediatrics (IAP) growth charts. In 2023, an estimated 28.9 percent of the global population – 2.33 billion people – were moderately or severely food insecure.
=== In children ===
The prevalence of undernutrition is highest among children under five. In 2021, 148.1 million children under five years old were stunted, 45 million were wasted, and 37 million were overweight or obese. The same year, an estimated 45% of deaths in children were linked to undernutrition. As of 2020, the prevalence of wasting among children under five in South Asia was reported to be 16% moderately or severely wasted. As of 2022, UNICEF reported this prevalence as having slightly improved, but still being at 14.8%. India has one of the highest burdens of wasting in Asia with over 20% wasted children. However, the burden of undernutrition among under-five children in African countries is much higher. A pooled analysis of the prevalence of chronic undernutrition among under-five children in East Africa was identified to be 33.3%. This prevalence of undernutrition among under-five children ranged from 21.9% in Kenya to 53% in Burundi.
In Tanzania, the prevalence of stunting, among children under five varied from 41% in lowland and 64.5% in highland areas. Undernutrition by underweight and wasting was 11.5% and 2.5% in lowland and 22.% and 1.4% in the highland areas of Tanzania respectively. In South Sudan, the prevalence of undernutrition explained by stunting, underweight and wasting in under-five children were 23.8%, 4.8% and 2.3% respectively. In 28 countries, at least 30% of children were still affected by stunting in 2022.
Vitamin A deficiency affects one third of children under age 5 around the world, leading to 670,000 deaths and 250,000–500,000 cases of blindness. Vitamin A supplementation has been shown to reduce all-cause mortality by 12 to 24%.
=== In adults ===
As of June 2021, 1.9 billion adults were overweight or obese, and 462 million adults were underweight. Globally, two billion people had iodine deficiency in 2017. In 2020, 900 million women and children had anemia, which is often caused by iron deficiency. More than 3.1 billion people in the world – 42% – were unable to afford a healthy diet in 2021.
Certain groups have higher rates of undernutrition, including elderly people and women (in particular while pregnant or breastfeeding children under five years of age). Undernutrition is an increasing health problem in people aged over 65 years, even in developed countries, especially among nursing home residents and in acute care hospitals. In the elderly, undernutrition is more commonly due to physical, psychological, and social factors, not a lack of food. Age-related reduced dietary intake due to chewing and swallowing problems, sensory decline, depression, imbalanced gut microbiome, poverty and loneliness are major contributors to undernutrition in the elderly population. Malnutrition is also attributed due to wrong diet plan adopted by people who aim to reduce their weight without medical practitioners or nutritionist advice.
=== Increase in 2020 ===
There has been a global increase in food insecurity and hunger between 2011 and 2020. In 2015, 795 million people (about one in ten people on earth) had undernutrition. It is estimated that between 691 and 783 million people in the world faced hunger in 2022. According to UNICEF, 2.4 billion people were moderately or severely food insecure in 2022, 391 million more than in 2019.
These increases are partially related to the COVID-19 pandemic, which continues to highlight the weaknesses of current food and health systems. It has contributed to food insecurity, increasing hunger worldwide; meanwhile, lower physical activity during lockdowns has contributed to increases in overweight and obesity. In 2020, experts estimated that by the end of the year, the pandemic could have double the number of people at risk of suffering acute hunger, around 130 million more undernourished people. Similarly, experts estimated that the prevalence of moderate and severe wasting could increase by 14% due to COVID-19; coupled with reductions in nutrition and health services coverage, this could result in over 128,000 additional deaths among children under 5 in 2020 alone. Although COVID-19 is less severe in children than in adults, the risk of severe disease increases with undernutrition.
Other major causes of hunger include manmade conflicts, climate changes, and economic downturns.
== Type ==
=== Undernutrition ===
Undernutrition can occur either due to protein-energy wasting or as a result of micronutrient deficiencies. It adversely affects physical and mental functioning, and causes changes in body composition and body cell mass. Undernutrition is a major health problem, causing the highest mortality rate in children, particularly in those under 5 years, and is responsible for long-lasting physiologic effects. It is a barrier to the complete physical and mental development of children.
Undernutrition can manifest as stunting, wasting, and underweight. If undernutrition occurs during pregnancy, or before two years of age, it may result in permanent problems with physical and mental development. Extreme undernutrition can cause starvation, chronic hunger, Severe Acute Malnutrition (SAM), and/or Moderate Acute Malnutrition (MAM).
The signs and symptoms of micronutrient deficiencies depend on which micronutrient is lacking. However, undernourished people are often thin and short, with very poor energy levels; and swelling in the legs and abdomen is also common. People who are undernourished often get infections and frequently feel cold.
==== Micronutrient undernutrition ====
Micronutrient undernutrition results from insufficient intake of vitamins and minerals. Worldwide, deficiencies in iodine, Vitamin A, and iron are the most common. Children and pregnant women in low-income countries are at especially high risk for micronutrient deficiencies.
Anemia is most commonly caused by iron deficiency, but can also result from other micronutrient deficiencies and diseases. This condition can have major health consequences.
It is possible to have overnutrition simultaneously with micronutrient deficiencies; this condition is termed the double burden of malnutrition.
==== Protein-energy malnutrition ====
'Undernutrition' sometimes refers specifically to protein–energy malnutrition (PEM). This condition involves both micronutrient deficiencies and an imbalance of protein intake and energy expenditure. It differs from calorie restriction in that calorie restriction may not result in negative health effects. Hypoalimentation (underfeeding) is one cause of undernutrition.
Two forms of PEM are kwashiorkor and marasmus; both commonly coexist.
Kwashiorkor is primarily caused by inadequate protein intake. Its symptoms include edema, wasting, liver enlargement, hypoalbuminaemia, and steatosis; the condition may also cause depigmentation of skin and hair. The disorder is further identified by a characteristic swelling of the belly, and extremities which disguises the patient's undernourished condition. 'Kwashiorkor' means 'displaced child' and is derived from the Ga language of coastal Ghana in West Africa. It means "the sickness the baby gets when the next baby is born," as it often occurs when the older child is deprived of breastfeeding and weaned to a diet composed largely of carbohydrates.
Marasmus (meaning 'to waste away') can result from a sustained diet that is deficient in both protein and energy. This causes their metabolism to adapt to prolong survival. The primary symptoms are severe wasting, leaving little or no edema; minimal subcutaneous fat; and abnormal serum albumin levels. It is traditionally seen in cases of famine, significant food restriction, or severe anorexia. Conditions are characterized by extreme wasting of the muscles and a gaunt expression.
=== Overnutrition ===
Excessive consumption of energy-dense foods and drinks and limited physical activity causes overnutrition. It causes overweight, defined as a body mass index (BMI) of 25 or more, and can lead to obesity (a BMI of 30 or more). Obesity has become a major health issue worldwide. Overnutrition is linked to chronic non-communicable diseases like diabetes, certain cancers, and cardiovascular diseases. Hence identifying and addressing the immediate risk factors has become a major health priority. The recent evidence on the impact of diet-induced obesity in fathers and mothers around the time of conception is identified to negatively program the health outcomes of multiple generations.
According to UNICEF, at least 1 in every 10 children under five is overweight in 33 countries.
== Classifying malnutrition ==
=== Definition by Gomez and Galvan ===
In 1956, Gómez and Galvan studied factors associated with death in a group of undernourished children in a hospital in Mexico City, Mexico. They defined three categories of malnutrition: first, second, and third degree. The degree of malnutrition is calculated based on a child's body size compared to the median weight for their age. The risk of death increases with increasing degrees of malnutrition.
An adaptation of Gomez's original classification is still used today. While it provides a way to compare malnutrition within and between populations, this classification system has been criticized for being "arbitrary" and for not considering overweight as a form of malnutrition. Also, height alone may not be the best indicator of malnutrition; children who are born prematurely may be considered short for their age even if they have good nutrition.
=== Definition by Waterlow ===
In the 1970s, John Conrad Waterlow established a new classification system for malnutrition. Instead of using just weight for age measurements, Waterlow's system combines weight-for-height (indicating acute episodes of malnutrition) with height-for-age to show the stunting that results from chronic malnutrition. One advantage of the Waterlow classification is that weight for height can be calculated even if a child's age is unknown.
The World Health Organization frequently uses these classifications of malnutrition, with some modifications.
== Effects ==
Undernutrition weakens every part of the immune system. Protein and energy undernutrition increases susceptibility to infection; so do deficiencies of specific micronutrients (including iron, zinc, and vitamins). In communities or areas that lack access to safe drinking water, these additional health risks present a critical problem.
Undernutrition plays a major role in the onset of active tuberculosis. It also raises the risk of HIV transmission from mother to child, and increases replication of the virus. Undernutrition can cause vitamin-deficiency-related diseases like scurvy and rickets. As undernutrition worsens, those affected have less energy and experience impairment in brain functions.
Undernutrition can also cause acute problems, like hypoglycemia (low blood sugar). This condition can cause lethargy, limpness, seizures, and loss of consciousness. Children are particularly at risk and can become hypoglycemic after 4 to 6 hours without food. Dehydration can also occur in malnourished people, and can be life-threatening, especially in babies and small children.
=== Signs ===
There are many different signs of dehydration in undernourished people. These can include sunken eyes; a very dry mouth; decreased urine output and/or dark urine; increased heart rate with decreasing blood pressure; and altered mental status.
=== Cognitive development ===
Protein-calorie malnutrition can cause cognitive impairments. This most commonly occurs in people who were malnourished during a "critical period ... from the final third of gestation to the first 2 years of life". For example, in children under two years of age, iron deficiency anemia is likely to affect brain function acutely, and probably also chronically. Similarly, folate deficiency has been linked to neural tube defects.
Iodine deficiency is "the most common preventable cause of mental impairment worldwide." "Even moderate [iodine] deficiency, especially in pregnant women and infants, lowers intelligence by 10 to 15 I.Q. points, shaving incalculable potential off a nation's development." Among those affected, very few people experience the most visible and severe effects: disabling goiters, cretinism and dwarfism. These effects occur most commonly in mountain villages. However, 16 percent of the world's people have at least mild goiter (a swollen thyroid gland in the neck)."
== Causes and risk factors ==
=== Social and political ===
Social conditions have a significant influence on the health of people. The social determinants of undernutrition mainly include poor education, poverty, disease burden and lack of women's empowerment. Identifying and addressing these determinants can eliminate undernutrition in the long term. Identification of the social conditions that causes malnutrition in children under five has received significant research attention as it is a major public health problem.
Undernutrition most commonly results from a lack of access to high-quality, nutritious food. The household income is a socio-economic variable that influences the access to nutritious food and the probability of under and overnutrition in a community. In the study by Ghattas et al. (2020), the probability of overnutrition is significantly higher in higher-income families than in disadvantaged families. High food prices is a major factor preventing low income households from getting nutritious food For example, Khan and Kraemer (2009) found that in Bangladesh, low socioeconomic status was associated with chronic malnutrition since it inhibited purchase of nutritious foods (like milk, meat, poultry, and fruits).
Food shortages may also contribute to malnutritions in countries which lack technology. However, in the developing world, eighty percent of malnourished children live in countries that produce food surpluses, according to estimates from the Food and Agriculture Organization (FAO). The economist Amartya Sen observes that, in recent decades, famine has always been a problem of food distribution, purchasing power, and/or poverty, since there has always been enough food for everyone in the world.
There are also sociopolitical causes of malnutrition. For example, the population of a community might be at increased risk for malnutrition if government is poor and the area lacks health-related services. On a smaller scale, certain households or individuals may be at an even higher risk due to differences in income levels, access to land, or levels of education. Community plays a crucial role in addressing the social causes of malnutrition. For example, communities with high social support and knowledge sharing about social protection programs can enable better public service demands. Better public service demands and social protection programs minimise the risk of malnutrition in these communities.
It is argued that commodity speculators are increasing the cost of food. As the real-estate bubble in the United States was collapsing, it is said that trillions of dollars moved to invest in food and primary commodities, causing the 2007–2008 food price crisis.
The use of biofuels as a replacement for traditional fuels raises the price of food. The United Nations special rapporteur on the right to food, Jean Ziegler proposes that agricultural waste, such as corn cobs and banana leaves, should be used as fuel instead of crops.
In some developing countries, overnutrition (in the form of obesity) is beginning to appear in the same communities where malnutrition occurs. Overnutrition increases with urbanisation, food commercialisation and technological developments and increases physical inactivity. Variations in the health status of individuals in the same society are associated with the societal structure and an individual's socioeconomic status which leads to income inequality, racism, educational differences and lack of opportunities.
=== Diseases and conditions ===
Infectious diseases which increase nutrient requirements, such as gastroenteritis, pneumonia, malaria, and measles, can cause malnutrition. So can some chronic illnesses, especially HIV/AIDS.
Malnutrition can also result from abnormal nutrient loss due to diarrhea or chronic small bowel illnesses, like Crohn's disease or untreated coeliac disease. "Secondary malnutrition" can result from increased energy expenditure.
In infants, a lack of breastfeeding may contribute to undernourishment. Anorexia nervosa and bariatric surgery can also cause malnutrition.
=== Dietary practices ===
==== Undernutrition ====
Undernutrition due to lack of adequate breastfeeding is associated with the deaths of an estimated one million children annually. Illegal advertising of breast-milk substitutes contributed to malnutrition and continued three decades after its 1981 prohibition under the WHO International Code of Marketing Breast Milk Substitutes.
Maternal malnutrition can also factor into the poor health or death of a baby. Over 800,000 neonatal deaths have occurred because of deficient growth of the fetus in the mother's womb.
Deriving too much of one's diet from a single source, such as eating almost exclusively potato, maize or rice, can cause malnutrition. This may either be from a lack of education about proper nutrition, only having access to a single food source, or from poor healthcare access and unhealthy environments.
It is not just the total amount of calories that matters but specific nutritional deficiencies such as vitamin A deficiency, iron deficiency or zinc deficiency can also increase risk of death.
==== Overnutrition ====
Overnutrition caused by overeating is also a form of malnutrition. In the United States, more than half of all adults are now overweight—a condition that, like hunger, increases susceptibility to disease and disability, reduces worker productivity, and lowers life expectancy. Overeating is much more common in the United States, since most people have adequate access to food. Many parts of the world have access to a surplus of non-nutritious food. Increased sedentary lifestyles also contribute to overnutrition. Yale University psychologist Kelly Brownell calls this a "toxic food environment", where fat- and sugar-laden foods have taken precedence over healthy nutritious foods.
In these developed countries, overnutrition can be prevented by choosing the right kind of food. More fast food is consumed per capita in the United States than in any other country. This mass consumption of fast food results from its affordability and accessibility. Fast food, which is low in cost and nutrition, is high in calories. Due to increasing urbanization and automation, people are living more sedentary lifestyles. These factors combine to make weight gain difficult to avoid.
Overnutrition also occurs in developing countries. It has appeared in parts of developing countries where income is on the rise. It is also a problem in countries where hunger and poverty persist. Economic development, rapid urbanisation and shifting dietary patterns have increased the burden of overnutrition in the cities of low and middle-income countries. In China, consumption of high-fat foods has increased, while consumption of rice and other goods has decreased.
Overeating leads to many diseases, such as heart disease and diabetes, that may be fatal.
=== Agricultural productivity ===
Local food shortages can be caused by a lack of arable land, adverse weather, and/or poorer farming skills (like inadequate crop rotation). They can also occur in areas which lack the technology or resources needed for the higher yields found in modern agriculture. These resources include fertilizers, pesticides, irrigation, machinery, and storage facilities. As a result of widespread poverty, farmers and governments cannot provide enough of these resources to improve local yields.
Additionally, the World Bank and some wealthy donor countries have pressured developing countries to use free market policies. Even as the United States and Europe extensively subsidized their own farmers, they urged developing countries to cut or eliminate subsidized agricultural inputs, like fertilizer. Without subsidies, few (if any) farmers in developing countries can afford fertilizer at market prices. This leads to low agricultural production, low wages, and high, unaffordable food prices. Fertilizer is also increasingly unavailable because Western environmental groups have fought to end its use due to environmental concerns. The Green Revolution pioneers Norman Borlaug and Keith Rosenberg cited as the obstacle to feeding Africa by .
=== Future threats ===
In the future, variety of factors could potentially disrupt global food supply and cause widespread malnutrition. According to UNICEF's projections, it is projected that almost 600 million people will be chronically undernourished in 2030.
Global warming is of importance to food security. Almost all malnourished people (95%) live in the tropics and subtropics, where the climate is relatively stable. According to the Intergovernmental Panel on Climate Change report in 2007, temperature increases in these regions are "very likely." Even small changes in temperatures can make extreme weather conditions occur more frequently. Extreme weather events, like drought, have a major impact on agricultural production, and hence nutrition. For example, the 1998–2001 Central Asian drought killed about 80 percent of livestock in Iran and caused a 50% reduction in wheat and barley crops there. Other central Asian nations experienced similar losses. An increase in extreme weather such as drought in regions such as Sub-Saharan Africa would have even greater consequences in terms of malnutrition. Even without an increase of extreme weather events, a simple increase in temperature reduces the productivity of many crop species, and decreases food security in these regions.
Another threat is colony collapse disorder, a phenomenon where bees die in large numbers. Since many agricultural crops worldwide are pollinated by bees, colony collapse disorder represents a threat to the global food supply.
== Prevention ==
Reducing malnutrition is key part of the United Nations' Sustainable Development Goal 2 (SDG2), "Zero Hunger", which aims to reduce malnutrition, undernutrition, and stunted child growth. Managing severe acute undernutrition in a community setting has received significant research attention.
=== Food security ===
In the 1950s and 1960s, the Green Revolution aimed to bring modern Western agricultural techniques (like nitrogen fertilizers and pesticides) to Asia. Investments in agriculture, such as fund fertilizers and seeds, increased food harvests and thus food production. Consequently, food prices and malnutrition decreased (as they had earlier in Western nations).
The Green Revolution was possible in Asia because of existing infrastructure and institutions, such as a system of roads and public seed companies that made seeds available. These resources were in short supply in Africa, decreasing the Green Revolution's impact on the continent.
For example, almost five million of the 13 million people in Malawi used to need emergency food aid. However, in the early 2000s, the Malawian government changed its agricultural policies, and implemented subsidies for fertilizer and seed introduced against World Bank strictures. By 2007, farmers were producing record-breaking corn harvests. Corn production leaped to 3.4 million in 2007 compared to 1.2 million in 2005, making Malawi a major food exporter. Consequently, food prices lowered and wages for farmworkers rose. Such investments in agriculture are still needed in other African countries like the Democratic Republic of the Congo (DRC). Despite the country's great agricultural potential, the prevalence of malnutrition in the DRC is among the highest in the world. Proponents for investing in agriculture include Jeffrey Sachs, who argues that wealthy countries should invest in fertilizer and seed for Africa's farmers.
Imported Ready to Use Therapeutic Food (RUTF) has been used to treat malnutrition in northern Nigeria. Some Nigerians also use soy kunu, a locally sourced and prepared blend consisting of peanut, millet and soybeans.
New technology in agricultural production has great potential to combat undernutrition. It makes farming easier, thus improving agricultural yields. By increasing farmers' incomes, this could reduce poverty. It would also open up area which farmers could use to diversify crops for household use.
The World Bank claims to be part of the solution to malnutrition, asserting that countries can best break the cycle of poverty and malnutrition by building export-led economies, which give them the financial means to buy foodstuffs on the world market.
=== Economics ===
Many aid groups have found that giving cash assistance (or cash vouchers) is more effective than donating food. Particularly in areas where food is available but unaffordable, giving cash assistance is a cheaper, faster, and more efficient way to deliver help to the hungry. In 2008, the UN's World Food Program, the biggest non-governmental distributor of food, announced that it would begin distributing cash and vouchers instead of food in some areas, which Josette Sheeran, the WFP's executive director, described as a "revolution" in food aid. The aid agency Concern Worldwide piloted a method of giving cash assistance using a mobile phone operator, Safaricom, which runs a money transfer program that allows cash to be sent from one part of a country to another.
However, during a drought, delivering food might be the most appropriate way to help people, especially those who live far from markets and thus have limited access to them. Fred Cuny stated that "the chances of saving lives at the outset of a relief operation are greatly reduced when food is imported. By the time it arrives in the country and gets to people, many will have died." U.S. law requires food aid to be purchased at home rather than in the countries where the hungry live; this is inefficient because approximately half of the money spent goes for transport. Cuny further pointed out that "studies of every recent famine have shown that food was available in-country—though not always in the immediate food deficit area" and "even though by local standards the prices are too high for the poor to purchase it, it would usually be cheaper for a donor to buy the hoarded food at the inflated price than to import it from abroad."
Food banks and soup kitchens address malnutrition in places where people lack money to buy food. A basic income has been proposed as a way to ensure that everyone has enough money to buy food and other basic needs. This is a form of social security in which all citizens or residents of a country regularly receive an unconditional sum of money, either from a government or some other public institution, in addition to any income received from elsewhere.
==== Successful initiatives ====
Ethiopia pioneered a program that later became part of the World Bank's prescribed method for coping with a food crisis. Through the country's main food assistance program, the Productive Safety Net Program, Ethiopia provided rural residents who were chronically short of food a chance to work for food or cash. Foreign aid organizations like the World Food Program were then able to buy food locally from surplus areas to distribute in areas with a shortage of food. Aid organizations now view the Ethiopian program as a model of how to best help hungry nations.
Successful initiatives also include Brazil's recycling program for organic waste, which benefits farmers, the urban poor, and the city in general. City residents separate organic waste from their garbage, bag it, and then exchange it for fresh fruit and vegetables from local farmers. This reduces the country's waste while giving the urban poor a steady supply of nutritious food.
=== World population ===
Restricting population size is a proposed solution to malnutrition. Thomas Malthus argues that population growth can be controlled by natural disasters and by voluntary limits through "moral restraint." Robert Chapman suggests that government policies are a necessary ingredient for curtailing global population growth. The United Nations recognizes that poverty and malnutrition (as well as the environment) are interdependent and complementary with population growth. According to the World Health Organization, "Family planning is key to slowing unsustainable population growth and the resulting negative impacts on the economy, environment, and national and regional development efforts". However, more than 200 million women worldwide lack adequate access to family planning services.
There are different theories about what causes famine. Some theorists, like the Indian economist Amartya Sen, believe that the world has more than enough resources to sustain its population. In this view, malnutrition is caused by unequal distribution of resources and under- or unused arable land. For example, Sen argues that "no matter how a famine is caused, methods of breaking it call for a large supply of food in the Public Distribution System. This applies not only to organizing rationing and control, but also to undertaking work programmes and other methods of increasing purchasing power for those hit by shifts in exchange entitlements in a general inflationary situation."
=== Food sovereignty ===
Food sovereignty is one suggested policy framework to resolve access issues. In this framework, people (rather than international market forces) have the right to define their own food, agricultural, livestock, and fishery systems. Food First is one of the primary think tanks working to build support for food sovereignty. Neoliberals advocate for an increasing role of the free market.
=== Health facilities ===
Another possible long-term solution to malnutrition is to increase access to health facilities in rural parts of the world. These facilities could monitor undernourished children, act as supplemental food distribution centers, and provide education on dietary needs. Similar facilities have already proven very successful in countries such as Peru and Ghana.
=== Breastfeeding ===
In 2016, estimates suggested that more widespread breastfeeding could prevent about 823,000 deaths annually of children under age 5. In addition to reducing infant deaths, breast milk provides an important source of micronutrients - which are clinically proven to bolster children's immune systems – and provides long-term defenses against non-communicable and allergic diseases. Breastfeeding may improve cognitive abilities in children, and correlates strongly with individual educational achievements. As previously noted, lack of proper breastfeeding is a major factor in child mortality rates, and is a primary determinant of disease development for children. The medical community recommends exclusively breastfeeding infants for 6 months, with nutritional whole food supplementation and continued breastfeeding up to 2 years or older for overall optimal health outcomes. Exclusive breastfeeding is defined as giving an infant only breast milk for six months as a source of food and nutrition. This means no other liquids, including water or semi-solid foods.
==== Barriers to breastfeeding ====
Breastfeeding is noted as one of the most cost-effective medical interventions benefiting child health. While there are considerable differences among developed and developing countries, there are universal determinants of whether a mother breastfeeds or uses formula; these include income, employment, social norms, and access to healthcare. Many newly made mothers face financial barriers; community-based healthcare workers have helped to alleviate these barriers, while also providing a viable alternative to traditional and expensive hospital-based medical care. Recent studies, based upon surveys conducted from 1995 to 2010, show that exclusive breastfeeding rates have risen globally, from 33% to 39%. Despite the growth rates, medical professionals acknowledge the need for improvement given the importance of exclusive breastfeeding.
=== 21st century global initiatives ===
Starting around 2009, there was renewed international media and political attention focused on malnutrition. This resulted in part from spikes in food prices and the 2008 financial crisis. Additionally, there was an emerging consensus that combating malnutrition is one of the most cost-effective ways to contribute to development. This led to the 2010 launch of the UN's Scaling up Nutrition movement (SUN).
In April 2012, a number of countries signed the Food Assistance Convention, the world's first legally binding international agreement on food aid. The following month, the Copenhagen Consensus recommended that politicians and private sector philanthropists should prioritize interventions against hunger and malnutrition to maximize the effectiveness of aid spending. The Consensus recommended prioritizing these interventions ahead of any others, including the fights against malaria and AIDS.
In June 2015, the European Union and the Bill & Melinda Gates Foundation launched a partnership to combat undernutrition, especially in children. The program was first implemented in Bangladesh, Burundi, Ethiopia, Kenya, Laos and Niger. It aimed to help these countries improve information and analysis about nutrition, enabling them to develop effective national nutrition policies.
Also in 2015, the UN's Food and Agriculture Organization created a partnership aimed at ending hunger in Africa by 2025. The African Union's Comprehensive Africa Agriculture Development Programme (CAADP) provided the framework for the partnership. It includes a variety of interventions, including support for improved food production, a strengthening of social protection, and integration of the right to food into national legislation.
The EndingHunger campaign is an online communication campaign whose goal is to raise awareness about hunger. The campaign has created viral videos depicting celebrities voicing their anger about the large number of hungry people in the world.
After the Millennium Development Goals expired in 2015, the Sustainable Development Goals became the main global policy focus to reduce hunger and poverty. In particular, Goal 2: Zero Hunger sets globally agreed-upon targets to wipe out hunger, end all forms of malnutrition, and make agriculture sustainable. The partnership Compact2025 develops and disseminates evidence-based advice to politicians and other decision-makers, with the goal of ending hunger and undernutrition by 2025. The International Food Policy Research Institute (IFPRI) led the partnership, with the involvement of UN organisations, non-governmental organizations (NGOs), and private foundations.
== Treatment ==
=== Improving nutrition ===
Efforts such as infant and young child feeding practices to improve nutrition are some of the common forms of development aid. Interventions often promote breastfeeding to reduce rates of malnutrition and death in children. Some of these interventions have been successful. For example, interventions with commodities such as ready to use therapeutic foods, ready to use supplementary foods, micronutrient intervention and vitamin supplementation were identified to significantly improve nutrition, reduce stunting and prevent diseases in communities with severe acute malnutrition. In young children, outcomes improve when children between six months and two years of age receive complementary food (in addition to breast milk). There is also good evidence that supports giving supplemental micronutrients to pregnant women and young children in the developing world.
The United Nations has reported on the importance of nutritional counselling and support, for example in the care of HIV-infected persons, especially in "resource-constrained settings where malnutrition and food insecurity are endemic". UNICEF provides nutritional counselling services for malnourished children in Afghanistan.
Sending food and money is a common form of development aid, aimed at feeding hungry people. Some strategies help people buy food within local markets. Simply feeding students at school is insufficient.
Longer-term measures include improving agricultural practices, reducing poverty, and improving sanitation.
=== Identifying malnourishment ===
Measuring children is crucial to identifying malnourishment. In 2000, the United States Centers for Disease Control and Prevention (CDC) established the International Micronutrient Malnutrition Prevention and Control (IMMPaCt) program. It tested children for malnutrition by conducting a three-dimensional scan, using an iPad or a tablet. Its objective was to help doctors provide more efficient treatments. There may be some chance of error when using this method. The Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMPa) is another method for the identification and evaluation of malnutrition in young children. The assessment tool has fair to medium reliability in the identification of children at risk of malnutrition.
A systematic review of 42 studies found that many approaches to mitigating acute malnutrition are equally effective; thus, intervention decisions can be based on cost-related factors. Overall, evidence for the effectiveness of acute malnutrition interventions is not robust. The limited evidence related to cost indicates that community and outpatient management of children with uncomplicated malnutrition may be the most cost-effective strategy.
Regularly measuring and charting children's growth and including activities to promote health (an intervention called growth monitoring and promotion, also known as GPM) is often considered by policy makers and is recommended by the World Health Organization. This program is often performed at the same time as a child has their regular immunizations. Despite widespread use of this type of program, further studies are needed to understand the impact of these programs on overall child health and how to better address faltering growth in a child and improve practices related to feeding children in lower to middle income countries.
=== Medical management ===
It is often possible to manage severe malnutrition within a person's home, using ready-to-use therapeutic foods. In people with severe malnutrition complicated by other health problems, treatment in a hospital setting is recommended. In-hospital treatment often involves managing low blood sugar, maintaining adequate body temperature, addressing dehydration, and gradual feeding.
Routine antibiotics are usually recommended because malnutrition weakens the immune system, causing a high risk of infection. Additionally, broad spectrum antibiotics are recommended in all severely undernourished children with diarrhea requiring admission to hospital.
A severely malnourished child who appears to have dehydration, but has not had diarrhea, should be treated as if they have an infection.
Among malnourished people who are hospitalized, nutritional support improves protein intake, calorie intake, and weight.
==== Bangladeshi model ====
In response to child malnutrition, the Bangladeshi government recommends ten steps for treating severe malnutrition:
Prevent or treat dehydration
Prevent or treat low blood sugar
Prevent or treat low body temperature
Prevent or treat infection;
Correct electrolyte imbalances
Correct micronutrient deficiencies
Start feeding cautiously
Achieve catch-up growth
Provide psychological support
Prepare for discharge and follow-up after recovery
=== Therapeutic foods ===
Due in part to limited research on supplementary feeding, there is little evidence that this strategy is beneficial. A 2015 systematic review of 32 studies found that there are limited benefits when children under 5 receive supplementary feeding, especially among younger, poorer, and more undernourished children.
However, specially formulated foods do appear to be useful in treating moderate acute malnutrition in the developing world. These foods may have additional benefits in humanitarian emergencies, since they can be stored for years, can be eaten directly from the packet, and do not have to be mixed with clean water or refrigerated. In young children with severe acute malnutrition, it is unclear if ready-to-use therapeutic food differs from a normal diet.
Severely malnourished individuals can experience refeeding syndrome if fed too quickly. Refeeding syndrome can result regardless of whether food is taken orally, enterally or parenterally. It can present several days after eating with potentially fatal heart failure, dysrhythmias, and confusion.
Some manufacturers have fortified everyday foods with micronutrients before selling them to consumers. For example, flour has been fortified with iron, zinc, folic acid, and other B vitamins like thiamine, riboflavin, niacin and vitamin B12. Baladi bread (Egyptian flatbread) is made with fortified wheat flour. Other fortified products include fish sauce in Vietnam and iodized salt.
=== Micronutrient supplementation ===
According to the World Bank, treating malnutrition – mostly by fortifying foods with micronutrients – improves lives more quickly than other forms of aid, and at a lower cost. After reviewing a variety of development proposals, The Copenhagen Consensus, a group of economists who reviewed a variety of development proposals, ranked micronutrient supplementation as its number-one treatment strategy.
In malnourished people with diarrhea, zinc supplementation is recommended following an initial four-hour rehydration period. Daily zinc supplementation can help reduce the severity and duration of the diarrhea. Additionally, continuing daily zinc supplementation for ten to fourteen days makes diarrhea less likely to recur in the next two to three months.
Malnourished children also need both potassium and magnesium. Within two to three hours of starting rehydration, children should be encouraged to take food, particularly foods rich in potassium like bananas, green coconut water, and unsweetened fresh fruit juice. Along with continued eating, many homemade products can also help restore normal electrolyte levels. For example, early during the course of a child's diarrhea, it can be beneficial to provide cereal water (salted or unsalted) or vegetable broth (salted or unsalted). If available, vitamin A, potassium, magnesium, and zinc supplements should be added, along with other vitamins and minerals.
Giving base (as in Ringer's lactate) to treat acidosis without simultaneously supplementing potassium worsens low blood potassium.
=== Treating diarrhea ===
==== Preventing dehydration ====
Food and drink can help prevent dehydration in malnourished people with diarrhea. Eating (or breastfeeding, among infants) should resume as soon as possible. Sugary beverages like soft drinks, fruit juices, and sweetened teas are not recommended as they may worsen diarrhea.
Malnourished people with diarrhea (especially children) should be encouraged to drink fluids; the best choices are fluids with modest amounts of sugar and salt, like vegetable broth or salted rice water. If clean water is available, they should be encouraged to drink that too. Malnourished people should be allowed to drink as much as they want, unless signs of swelling emerge.
Babies can be given small amounts of fluids via an eyedropper or a syringe without the needle. Children under two should receive a teaspoon of fluid every one to two minutes; older children and adults should take frequent sips of fluids directly from a cup. After the first two hours, fluids and foods should be alternated, rehydration should be continued at the same rate or more slowly, depending on how much fluid the child wants and whether they are having ongoing diarrhea.
If vomiting occurs, fluids can be paused for 5–10 minutes and then restarted more slowly. Vomiting rarely prevents rehydration, since fluids are still absorbed and vomiting is usually short-term.
==== Oral rehydration therapy ====
If prevention has failed and dehydration develops, the preferred treatment is rehydration through oral rehydration therapy (ORT). In severely undernourished children with diarrhea, rehydration should be done slowly, according to the World Health Organization.
Oral rehydration solutions consist of clean water mixed with small amounts of sugars and salts. These solutions help restore normal electrolyte levels, provide a source of carbohydrates, and help with fluid replacement.
Reduced-osmolarity ORS is the current standard of care for oral rehydration therapy, with reasonably wide availability. Introduced in 2003 by WHO and UNICEF, reduced-osmolarity solutions contain lower concentrations of sodium and glucose than original ORS preparations. Reduced-osmolarity ORS has the added benefit of reducing stool volume and vomiting while simultaneously preventing dehydration. Packets of reduced-osmolarity ORS include glucose, table salt, potassium chloride, and trisodium citrate. For general use, each packet should be mixed with a liter of water. However, for malnourished children, experts recommend adding a packet of ORS to two liters of water, along with an extra 50 grams of sucrose and some stock potassium solution.
People who have no access to commercially available ORS can make a homemade version using water, sugar, and table salt. Experts agree that homemade ORS preparations should include one liter (34 oz.) of clean water and 6 teaspoons of sugar; however, they disagree about whether they should contain half a teaspoon of table salt or a full teaspoon. Most sources recommend using half a teaspoon of salt per liter of water. However, people with malnutrition have an excess of body sodium. To avoid worsening this symptom, ORS for people with severe undernutrition should contain half the usual amount of sodium and more potassium.
Patients who do not drink may require fluids by nasogastric tube. Intravenous fluids are recommended only in those who have significant dehydration due to their potential complications, including congestive heart failure.
=== Low blood sugar ===
Hypoglycemia, whether known or suspected, can be treated with a mixture of sugar and water. If the patient is conscious, the initial dose of sugar and water can be given by mouth. Otherwise, they should receive glucose by intravenous or nasogastric tube. If seizures occur (and continue after glucose is given), rectal diazepam may be helpful. Blood sugar levels should be re-checked on two-hour intervals.
=== Hypothermia ===
Hypothermia (dangerously low core body temperature) can occur in malnutrition, particularly in children. Mild hypothermia causes confusion, trembling, and clumsiness; more severe cases can be fatal. Keeping malnourished children warm can prevent or treat hypothermia. Covering the child (including their head) in blankets is one method. Another method is to warm the child through direct skin-to-skin contact with their mother or father, then covering both parent and child.
Warming methods are usually most important at night. Prolonged bathing or prolonged medical exams can further lower body temperature and are not recommended for malnourished children at high risk of hypothermia.
== Epidemiology ==
The figures provided in this section on epidemiology all refer to undernutrition even if the term malnutrition is used which, by definition, could also apply to too much nutrition.
The Global Hunger Index (GHI) is a multidimensional statistical tool used to describe the state of countries' hunger situation. The GHI measures progress and failures in the global fight against hunger. The GHI is updated once a year. The data from the 2015 report shows that Hunger levels have dropped 27% since 2000. Fifty two countries remain at serious or alarming levels. In addition to the latest statistics on Hunger and Food Security, the GHI also features different special topics each year. The 2015 report include an article on conflict and food security.
=== People affected ===
The United Nations estimated that there were 821 million undernourished people in the world in 2017. This is using the UN's definition of 'undernourishment', where it refers to insufficient consumption of raw calories, and so does not necessarily include people who lack micro nutrients. The undernourishment occurred despite the world's farmers producing enough food to feed around 12 billion people—almost double the current world population.
Malnutrition, as of 2010, was the cause of 1.4% of all disability adjusted life years.
=== Mortality ===
In 2010 protein-energy malnutrition resulted in 600,000 deaths down from 883,000 deaths in 1990. Other nutritional deficiencies, which include iodine deficiency and iron deficiency anemia, result in another 84,000 deaths. In 2010 malnutrition caused about 1.5 million deaths in women and children.
According to the World Health Organization, malnutrition is the biggest contributor to child mortality, present in half of all cases. Six million children die of hunger every year. Underweight births and intrauterine growth restrictions cause 2.2 million child deaths a year. Poor or non-existent breastfeeding causes another 1.4 million. Other deficiencies, such as lack of vitamin A or zinc, for example, account for 1 million. Malnutrition in the first two years is irreversible. Malnourished children grow up with worse health and lower education achievement. Their own children tend to be smaller. Malnutrition was previously seen as something that exacerbates the problems of diseases such as measles, pneumonia and diarrhea, but malnutrition actually causes diseases, and can be fatal in its own right.
== History ==
Hunger has been a perennial human problem. However, until the early 20th century, there was relatively little awareness of the qualitative aspects of malnutrition.
Throughout history, various peoples have known the importance of eating certain foods to prevent symptoms now associated with malnutrition. Yet such knowledge appears to have been repeatedly lost and then re-discovered. For example, the ancient Egyptians reportedly knew the symptoms of scurvy. Much later, in the 14th century, Crusaders sometimes used anti-scurvy measures – for example, ensuring that citrus fruits were planted on Mediterranean islands, for use on sea journeys. However, for several centuries, Europeans appear to have forgotten the importance of these measures. They rediscovered this knowledge in the 18th century, and by the early 19th century, the Royal Navy was issuing frequent rations of lemon juice to every crewman on their ships. This massively reduced scurvy deaths among British sailors, which in turn gave the British a significant advantage in the Napoleonic Wars. Later on in the 19th century, the Royal Navy replaced lemons with limes (unaware at the time that lemons are far more effective at preventing scurvy).
According to historian Michael Worboys, malnutrition was essentially discovered, and the science of nutrition established, between World War I and World War II. Advances built on prior works like Casimir Funk's 1912 formulisation of the concept of vitamins. Scientific study of malnutrition increased in the 1920s and 1930s, and grew even more common after World War II.
Non-governmental organizations and United Nations agencies began to devote considerable energy to alleviating malnutrition around the world. The exact methods and priorities for doing this tended to fluctuate over the years, with varying levels of focus on different types of malnutrition like Kwashiorkor or Marasmus; varying levels of concern on protein deficiency compared to vitamins, minerals and lack of raw calories; and varying priorities given to the problem of malnutrition in general compared to other health and development concerns. The green Revolution of the 1950s and 1960s saw considerable improvement in capability to prevent malnutrition.
One of the first official global documents addressing Food security and global malnutrition was the 1948 Universal Declaration of Human Rights(UDHR). Within this document it stated that access to food was part of an adequate right to a standard of living. The Right to food was asserted in the International Covenant on Economic, Social and Cultural Rights, a treaty adopted by the United Nations General Assembly on December 16, 1966. The Right to food is a human right for people to feed themselves in dignity, be free from hunger, food insecurity, and malnutrition. As of 2018, the treaty has been signed by 166 countries, by signing states agreed to take steps to the maximum of their available resources to achieve the right to adequate food.
However, after the 1966 International Covenant the global concern for the access to sufficient food only became more present, leading to the first ever World Food Conference that was held in 1974 in Rome, Italy. The Universal Declaration on the Eradication of Hunger and Malnutrition was a UN resolution adopted November 16, 1974 by all 135 countries that attended the 1974 World Food Conference. This non-legally binding document set forth certain aspirations for countries to follow to sufficiently take action on the global food problem. Ultimately this document outline and provided guidance as to how the international community as one could work towards fighting and solving the growing global issue of malnutrition and hunger.
Adoption of the right to food was included in the Additional Protocol to the American Convention on Human Rights in the area of Economic, Social, and Cultural Rights, this 1978 document was adopted by many countries in the Americas, the purpose of the document is, "to consolidate in this hemisphere, within the framework of democratic institutions, a system of personal liberty and social justice based on respect for the essential rights of man."
A later document in the timeline of global initiatives for malnutrition was the 1996 Rome Declaration on World Food Security, organized by the Food and Agriculture Organization. This document reaffirmed the right to have access to safe and nutritious food by everyone, also considering that everyone gets sufficient food, and set the goals for all nations to improve their commitment to food security by halving their number of undernourished people by 2015. In 2004 the Food and Agriculture Organization adopted the Right to Food Guidelines, which offered states a framework of how to increase the right to food on a national basis.
== Special populations ==
Undernutrition is an important determinant of maternal and child health, accounting for more than a third of child deaths and more than 10 percent of the total global disease burden according to 2008 studies.
=== Children ===
Undernutrition adversely affects the cognitive development of children, contributing to poor earning capacity and poverty in adulthood. The development of childhood undernutrition coincides with the introduction of complementary weaning foods which are usually nutrient deficient. The World Health Organization estimated in 2008 that malnutrition accounted for 54 percent of child mortality worldwide, about 1 million children. There is a strong association between undernutrition and child mortality.
Another estimate in 2008 also by WHO stated that childhood underweight was the cause for about 35% of all deaths of children under the age of five years worldwide. Over 90% of the stunted children below five years of age live in sub-Saharan Africa and South Central Asia. Although access to adequate food and improving nutritional intake is an obvious solution to tackling undernutrition in children, the progress in reducing children undernutrition has been disappointing.
=== Women ===
In 2022, more than 1 billion adolescent girls and women suffered from undernutrition, according to UNICEF's 2023 report "Undernourished and Overlooked: A Global Nutrition Crisis in Adolescent Girls and Women". The gender gap in food insecurity more than doubled between 2019 (49 million) and 2021 (126 million). The report shows that globally, 30% of women aged 15–49 years are living with anaemia while 10 per cent of women aged 20–49 years suffer from underweight. South Asia, West and Central Africa and Eastern and Southern Africa are home to 60% of women with anaemia and 65% of women being underweight. In contrast, overweight is affecting more than 35% of women aged 20–49 years, of which 13% are living with obesity.
The Middle East and North Africa has the highest prevalence of overweight with 61% affected. North America closely follows at 60%. Fewer than 1 in 3 adolescent girls and women have diets meeting the minimum dietary diversity in the Sudan (10%), Burundi (12%), Burkina Faso (17%) and Afghanistan (26%). In Niger, the percentage of women accessing a minimally diverse diet fell from 53% to 37% between 2020 and 2022.
Researchers from the Centre for World Food Studies in 2003 found that the gap between levels of undernutrition in men and women is generally small, but that the gap varies from region to region and from country to country. These small-scale studies showed that female undernutrition prevalence rates exceeded male undernutrition prevalence rates in South/Southeast Asia and Latin America and were lower in Sub-Saharan Africa. Datasets for Ethiopia and Zimbabwe reported undernutrition rates between 1.5 and 2 times higher in men than in women; however, in India and Pakistan, datasets rates of undernutrition were 1.5–2 times higher in women than in men. Intra-country variation also occurs, with frequent high gaps between regional undernutrition rates. Gender inequality in nutrition in some countries such as India is present in all stages of life.
Studies on nutrition concerning gender bias within households look at patterns of food allocation, and one study from 2003 suggested that women often receive a lower share of food requirements than men. Gender discrimination, gender roles, and social norms affecting women can lead to early marriage and childbearing, close birth spacing, and undernutrition, all of which contribute to malnourished mothers.
Within the household, there may be differences in levels of malnutrition between men and women, and these differences have been shown to vary significantly from one region to another, with problem areas showing relative deprivation of women. Samples of 1000 women in India in 2008 demonstrated that malnutrition in women is associated with poverty, lack of development and awareness, and illiteracy. The same study showed that gender discrimination in households can prevent a woman's access to sufficient food and healthcare. How socialization affects the health of women in Bangladesh, Najma Rivzi explains in an article about a research program on this topic. In some cases, such as in parts of Kenya in 2006, rates of malnutrition in pregnant women were even higher than rates in children.
Women in some societies are traditionally given less food than men since men are perceived to have heavier workloads. Household chores and agricultural tasks can in fact be very arduous and require additional energy and nutrients; however, physical activity, which largely determines energy requirements, is difficult to estimate.
==== Physiology ====
Women have unique nutritional requirements, and in some cases need more nutrients than men; for example, women need twice as much calcium as men.
==== Pregnancy and breastfeeding ====
During pregnancy and breastfeeding, women must ingest enough nutrients for themselves and their child, so they need significantly more protein and calories during these periods, as well as more vitamins and minerals (especially iron, iodine, calcium, folic acid, and vitamins A, C, and K). In 2001 the FAO of the UN reported that iron deficiency affected 43 percent of women in developing countries and increased the risk of death during childbirth. A 2008 review of interventions estimated that universal supplementation with calcium, iron, and folic acid during pregnancy could prevent 105,000 maternal deaths (23.6 percent of all maternal deaths). Malnutrition has been found to affect three-quarters of UK women aged 16–49 indicated by them having less folic acid than the WHO recommended levels.
Frequent pregnancies with short intervals between them and long periods of breastfeeding add an additional nutritional burden.
==== Educating children ====
"Action for Healthy Kids" has created several methods to teach children about nutrition. They introduce 2 different topics, self-awareness which teaches children about taking care of their own health and social awareness, which is how culinary arts vary from culture to culture. As well as its importance when it comes to nutrition. They include eBooks, tips, cooking clubs. including facts about vegetables and fruits.
Team Nutrition has created "MyPlate eBooks" this includes 8 different eBooks to download for free. These eBooks contain drawings to color, audio narration, and a large number of characters to make nutrition lessons entertaining for children.
According to the FAO, women are often responsible for preparing food and have the chance to educate their children about beneficial food and health habits, giving mothers another chance to improve the nutrition of their children.
=== Elderly ===
Malnutrition and being underweight are more common in the elderly than in adults of other ages. If elderly people are healthy and active, the aging process alone does not usually cause malnutrition. However, changes in body composition, organ functions, adequate energy intake and ability to eat or access food are associated with aging, and may contribute to malnutrition. Sadness or depression can play a role, causing changes in appetite, digestion, energy level, weight, and well-being. A study on the relationship between malnutrition and other conditions in the elderly found that malnutrition in the elderly can result from gastrointestinal and endocrine system disorders, loss of taste and smell, decreased appetite and inadequate dietary intake. Poor dental health, ill-fitting dentures, or chewing and swallowing problems can make eating difficult. As a result of these factors, malnutrition is seen to develop more easily in the elderly.
Rates of malnutrition tend to increase with age with less than 10 percent of the "young" elderly (up to age 75) malnourished, while 30 to 65 percent of the elderly in home care, long-term care facilities, or acute hospitals are malnourished. Many elderly people require assistance in eating, which may contribute to malnutrition. However, the mortality rate due to undernourishment may be reduced. Because of this, one of the main requirements of elderly care is to provide an adequate diet and all essential nutrients. Providing the different nutrients such as protein and energy keeps even small but consistent weight gain. Hospital admissions for malnutrition in the United Kingdom have been related to insufficient social care, where vulnerable people at home or in care homes are not helped to eat.
In Australia malnutrition or risk of malnutrition occurs in 80 percent of elderly people presented to hospitals for admission. Malnutrition and weight loss can contribute to sarcopenia with loss of lean body mass and muscle function. Abdominal obesity or weight loss coupled with sarcopenia lead to immobility, skeletal disorders, insulin resistance, hypertension, atherosclerosis, and metabolic disorders. A paper from the Journal of the American Dietetic Association noted that routine nutrition screenings represent one way to detect and therefore decrease the prevalence of malnutrition in the elderly.
== See also ==
== Sources ==
This article incorporates text from a free content work. Licensed under CC BY-SA 4.0 (license statement/permission). Text taken from The State of Food Security and Nutrition in the World 2024, Food and Agriculture Organization.
== References ==
== External links ==
United Nation 2007 report
World Food Programme | WFP
UN
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List of childhood diseases and disorders
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List of eponymous diseases
List of eye diseases and disorders
List of intestinal diseases
List of infectious diseases
List of human disease case fatality rates
List of notifiable diseases – diseases that should be reported to public health services, e.g., hospitals.
Lists of plant diseases
List of pollution-related diseases
List of skin conditions
List of diseases by year of discovery
Disorders
List of communication disorders
List of genetic disorders
List of heart disorders
List of liver disorders
List of neurological conditions and disorders
List of mental disorders
List of eating disorders
List of mood disorders
List of personality disorders
List of voice disorders
List of vulvovaginal disorders
== See also ==
Category:Diseases and disorders
Category:Lists of diseases
List of disorders
List of syndromes
List of abbreviations for diseases and disorders
List of fictional diseases, diseases found only in works of fiction.
Airborne disease, a disease that spreads through the air.
Contagious disease, a subset of infectious diseases.
Cryptogenic disease, a disease whose cause is currently unknown.
Disseminated disease, a disease that is spread throughout the body.
Environmental disease
Lifestyle disease, a disease caused largely by lifestyle choices.
Localized disease, a disease affecting one body part or area.
Non-communicable disease, a disease that can not be spread between people.
Organic disease
Progressive disease, a disease that gets worse over time.
Rare disease, a disease that affects very few people.
Systemic disease, a disease affecting the whole body.
== External links ==
List of rare diseases from Health On the Net Foundation, available in several languages
Rare Diseases and Related Terms from National Institutes of Health
Search for a rare disease from Orphanet
List of Diseases from Biomedical Entity Network | Wikipedia/Lists_of_diseases |
Diseases of affluence, previously called diseases of rich people, is a term sometimes given to selected diseases and other health conditions which are commonly thought to be a result of increasing wealth in a society. Also referred to as the "Western disease" paradigm, these diseases are in contrast to "diseases of poverty", which largely result from and contribute to human impoverishment. These diseases of affluence have vastly increased in prevalence since the end of World War II.
Examples of diseases of affluence include mostly chronic non-communicable diseases (NCDs) and other physical health conditions for which personal lifestyles and societal conditions associated with economic development are believed to be an important risk factor—such as type 2 diabetes, asthma, coronary heart disease, cerebrovascular disease, peripheral vascular disease, obesity, hypertension, cancer, alcoholism, gout, and some types of allergy. They may also be considered to include depression and other mental health conditions associated with increased social isolation and lower levels of psychological well-being observed in many developed countries. Many of these conditions are interrelated, for example obesity is thought to be a partial cause of many other illnesses.
In contrast, the diseases of poverty have tended to be largely infectious diseases, or the result of poor living conditions. These include tuberculosis, malaria, and intestinal diseases. Increasingly, research is finding that diseases thought to be diseases of affluence also appear in large part in the poor. These diseases include obesity and cardiovascular disease and, coupled with infectious diseases, these further increase global health inequalities.
Diseases of affluence started to become more prevalent in developing countries as diseases of poverty decline, longevity increases, and lifestyles change. In 2008, nearly 80% of deaths due to NCDs—including heart disease, strokes, chronic lung diseases, cancers and diabetes—occurred in low- and middle-income countries.
== Main instances ==
According to the World Health Organization (WHO), the top 10 causes of deaths in 2019 were from:
Ischemic heart diseases
Stroke
Chronic obstructive pulmonary disease
Lower respiratory infections
Neonatal conditions
Trachea, bronchus, lung cancers
Alzheimer's disease and other dementias
Diarrheal diseases
Diabetes
Kidney diseases
Seven of the main causes of death are non-communicable diseases. In 2019, WHO reported 55.4 million deaths worldwide, and more than half (55%) were due to the top causes of death previously mentioned.
== Causes ==
Factors associated with the increase of these conditions and illnesses appear to be things that are a direct result of technological advances. They include:
Less strenuous physical exercise, often through increased use of motor vehicles
Irregular exercise as a result of office jobs involving no physical labor.
Easy accessibility in society to large amounts of low-cost food (relative to the much-lower caloric food availability in a subsistence economy)
More food generally, with much less physical exertion expended to obtain a moderate amount of food
Higher consumption of vegetable oils and high sugar-containing foods
Higher consumption of meat and dairy products
Higher consumption of refined grains and products made of such, like white bread and white rice.
A notable historical example is that of Beriberi, a thiamin deficiency syndrome which was long known as a disease of the wealthy in east Asia: Brown rice and other cereal grains are a good source of thiamin, while white rice is not. Because of the labor and waste involved, white rice was long seen as a luxury, meaning a thiamin-deficient diet was something only the rich could afford. Eventually, however, the development of motorized rice-polishing equipment brought luxury—and disease—to the masses.
More foods which are processed, cooked, and commercially provided (rather than seasonal, fresh foods prepared locally at the time of eating)
Prolonged periods of little activity
Greater use of alcohol and tobacco
Longer lifespans
Reduced exposure to infectious agents throughout life (this can result in a more idle and inexperienced immune system, as compared to an individual who experienced relatively frequent exposure to certain pathogens in their time of life)
Increased cleanliness. The hygiene hypothesis postulates that children of affluent families are now exposed to fewer antigens than has been normal in the past, giving rise to increased prevalence of allergy and autoimmune diseases.
== Diabetes mellitus ==
Diabetes is a chronic metabolic disease characterized by increase blood glucose level. Type 2 diabetes is the most common form of diabetes. It is caused by resistance to insulin or the lack of production of insulin. It is seen most commonly in adults. Type 1 diabetes or juvenile diabetes is diagnosed mostly in children. This condition is due to little or lack of insulin production from the pancreas.
According to WHO the prevalence of diabetes has quadrupled from 1980 to 422 million adults. The global prevalence of diabetes has increased from 4.7% in 1980 to 8.5% in 2014. Diabetes has been a major cause for blindness, kidney failure, heart attack, stroke and lower limb amputation.
=== Prevalence in countries of affluence ===
The Centers of Disease Control and Prevention (CDC) released a report in 2015 indicating that more than 100 million Americans have diabetes or pre-diabetes. Diabetes was the seventh leading cause of death in the United States in 2015. In developed countries like the United States, the risk for diabetes is seen in people with low socioeconomic status (SES). Socioeconomic status is defined by the education and the income level of a person. The prevalence of diabetes varies by education level. Of those diagnosed with diabetes:12.6% of adults had less than a high school education, 9.5% had a high school education and 7.2% had more than high school education.
Differences in diabetes prevalence are seen in the population and ethnic groups in the US. Diabetes is more common in non-Hispanic whites who are less educated and have a lower income. It is also more common in less educated Hispanics. The highest prevalence of diabetes is seen in the southeast, southern and Appalachian portion of the United States. In the United States the prevalence of diabetes is increasing in children and adolescents. In 2015, 25 million people were diagnosed with diabetes, of which 193,000 were children. The total direct and indirect cost of diagnosed diabetes in US in 2012 was $245 billion.
In 2009, the Canadian Diabetes Association (CDA) estimated that diagnosed diabetes will increase from 1.3 million in 2000 to 2.5 million in 2010 and 3.7 million in 2020. Diabetes was the 7th leading cause of death in Canada in 2015. Like United States, diabetes in more prevalent in the low socioeconomic group of people in Canada.
According to the International Diabetes Federation, more than 58 million people are diagnosed with diabetes in the European Union Region (EUR), and this will go up to 66.7 million by 2045. Similar to other affluent countries like America and Canada, diabetes is more prevalent in the poorer parts of Europe like Central and Eastern Europe.
In Australia according to self-reported data, 1 in 7 adults or approximately 1.2 million people had diabetes in 2014–2015. People who were living in remote or socioeconomically disadvantaged areas were 4 times more likely to develop type 2 diabetes as compared to non-indigenous Australians. Australia incurred $20.8 million in direct costs towards hospitalization, medication, and out-patient treatment towards diabetes. In 2015, $1.2 billion were lost in Australia's Gross Domestic Product (GDP) due to diabetes.
In these countries of affluence, diabetes is prevalent in low socioeconomic groups of people as there is abundance of unhealthy food choices, high energy rich food, and decreased physical activity. More affluent people are typically more educated and have tools to counter unhealthy foods, such as access to healthy food, physical trainers, and parks and fitness centers.
=== Risk factors ===
Obesity and being overweight is one of the main risk factors of type 2 diabetes. Other risk factors include lack of physical activity, genetic predisposition, being over 45 years old, tobacco use, high blood pressure and high cholesterol. In United States, the prevalence of obesity was 39.8% in adults and 18.5% in children and adolescents in 2015–2016. In Australia in 2014–2015, 2 out 3 adults or 63% were overweight or obese. Also, 2 out of 3 adults did little or no exercise. According to the World Health Organization, Europe had the 2nd highest proportion of overweight or obese people in 2014 behind the Americas.
=== In developing countries ===
According to WHO the prevalence of diabetes is rising more in the middle and low income countries. Over the next 25 years, the number of people with diabetes in developing countries will increase by over 150%. Diabetes is typically seen in people above the retirement age in developed countries, but in developing countries people in the age of 35–64 are mostly affected. Although, diabetes is considered a disease of affluence affecting the developed countries, there is more loss of life and premature death among people with diabetes in the developing countries. Asia accounts for 60% of the world's diabetic population. In 1980 less than 1% of Chinese adults were affected by diabetes, but by 2008 the prevalence was 10%. It is predicted that by 2030 diabetes may affect 79.4 million people in India, 42.3 million people in China and 30.3 million in United States.
These changes are the result of developing nations having rapid economic development. This rapid economic development has caused a change in the lifestyle and food habits leading to over-nutrition, increased intake of fast food causing increase in weight, and insulin resistance. Compared to the west, obesity in Asia is low. India has very low prevalence of obesity, but a very high prevalence of diabetes suggesting that diabetes may occur at a lower BMI in Indians as compared to the Europeans. Smoking increases the risk for diabetes by 45%. In developing countries around 50–60% adult males are regular smokers, increasing their risk for diabetes. In developing countries, diabetes is more commonly seen in the more urbanized areas. The prevalence of diabetes in rural population is 1/4th that of urban population for countries like India, Bangladesh, Nepal, Bhutan and Sri Lanka.
== Cardiovascular disease ==
Cardiovascular disease refers to a disease of the heart and blood vessels. Conditions and diseases associated with heart disease include: stroke, coronary heart disease, congenital heart disease, heart failure, peripheral vascular disease, and cardiomyopathy. Cardiovascular disease is known as the world's biggest killer. 17.5 million people die from it each year, which equals 31% of all deaths. Heart disease and stroke cause 80% of these deaths.
=== Risk factors ===
High blood pressure is the leading risk factor for cardiovascular disease and has contributed to 12% of the cardiovascular related deaths worldwide. Other significant risk factors for heart disease include high cholesterol and smoking. 47% of all Americans have one of these three risk factors. Lifestyle choices, such as poor diet and physical inactivity, and excessive alcohol use can also contribute to cardiovascular disease. Medical conditions, like diabetes and obesity can also be risk factors.
=== Prevalence in countries of affluence ===
In the United States, 610,000 people die every year from heart disease which is equal to 1 in 4 deaths. The leading cause of death for both men and women in the United States is heart disease. In Canada, heart disease is the second leading cause of death. In 2014, it was the cause of death for 51,000 people. In Australia, heart disease is also the leading cause of death. 29% of deaths in 2015, had an underlying cause of heart disease. Heart disease causes one in four premature deaths in the United Kingdom and in 2015 heart disease caused 26% of all deaths in that country.
People of lower socio-economic status are more likely to have cardiovascular disease than those who have a higher socio-economic status. This inequality gap has occurred in developed countries because people who have a lower socio-economic status often face many of the risk factors of tobacco and alcohol use, obesity as well as having a sedentary lifestyle. Further social and environmental factors such as poverty, pollution, family history, housing and employment contribute to this inequality gap and to risk of having a health condition caused by cardiovascular disease. The increasing inequality gap between the higher and lower income populations continues in countries such as Canada, despite the availability of health care for everyone.
== Alzheimer's disease and other dementias ==
Dementia is a chronic syndrome which is characterized by deterioration in the thought process beyond what is expected from normal aging. It affects the persons memory, thinking, orientation, comprehension, behavior and ability to perform everyday activity. There are many different forms of dementia. Alzheimer is the most common form which contributes to 60–70% of the dementia cases. Different forms of dementia can co-exist. Young onset dementia which occurs in individuals before the age of 65 contributes to 9% of the total cases. It is the major cause of disability and dependency among old people.
Worldwide, there are 50 million people with dementia and every year 10 million new cases are being reported. The total number of people with dementia is projected to reach 82 million by 2030 and 152 million in 2050.
=== Prevalence in countries of affluence ===
According to CDC, Alzheimer is the 6th leading cause of death in U.S. adults and 5th leading cause of death in adults over the age of 65. In 2014, 5 million Americans above the age of 65 were diagnosed with Alzheimer. This number is predicted to triple by the year 2060 and reach up to 14 million. Dementia and Alzheimer has been shown to go unreported on death certificates, leading to under representation of the actual mortality caused by these diseases. Between 2000 and 2015, mortality due to cardiovascular diseases has decreased by 11%, where as death from Alzheimer has increased by 123%. 1 in 3 people over the age of 65 die from Alzheimer or other forms of dementia. Furthermore, 200,000 individuals have been affected by young onset dementia. In United States, Alzheimer affects more women than men. It is twice more common in African-Americans and Hispanics than in whites. As the number of older Americans increases rapidly, the number of new cases of Alzheimer will rise too .
East Asia has the most people living with dementia (9.8 million) followed by Western Europe (7.5 million), South Asia (5.1 million) and North America (4.8 million). In 2016, the prevalence of Alzheimer was 5.05% in Europe. Like in United States, it is more prevalent in women than in men. In the European Union, Finland has the highest mortality among both men and women due to dementia. In Canada, over half a million people are living with dementia. It is projected that by 2031 the number will go up by 66% to 937,000. Every year 25,000 new cases of dementia are diagnosed .
Dementia is the second leading cause of death in Australia. In 2016, it was the leading cause of deaths in females. In Australia 436,366 people are living with dementia in 2018. 3 in 10 people over the age of 85 and 1 in 10 people over the age of 65 have dementia. It is the single greatest cause of disability in older Australians . Rates of dementia are higher for indigenous people. In people from the northern territory and western Australia the prevalence of dementia is 26 times higher in the 45–69 year old group and about 20 times greater in 60–69 year old group.
=== Risk factors in countries of affluence ===
The risk factors for developing dementia or Alzheimer's include age, family history, genetic factors, environmental factors, brain injury, viral infections, neurotoxic chemicals, and various immunological and hormonal disorders.
A new research study has found an association between the affluence of a country, hygiene conditions and the prevalence of Alzheimer in their population. According to the Hygiene Hypothesis, affluent countries with more urbanized and industrialized areas have better hygiene, better sanitation, clean water and improved access to antibiotics. This reduces the exposure to the friendly bacteria, virus and other microorganisms that help stimulate our immune system. Decreased microbial exposure leads to immune system that is poorly developed, which exposes the brain to inflammation as is seen in Alzheimer's disease.
Countries like the UK and France that have access to clean drinking water, improved sanitation facilities and have a high GDP show a 9% increase in Alzheimer's disease as opposed to countries like Kenya and Cambodia. Also countries like UK and Australia, where three quarters of their population lives in urban areas, have a 10% higher Alzheimer's rate than in countries like Bangladesh and Nepal where less than one tenth of their population live in urban areas.
Alzheimer's risk changes with the environment. Individuals from the same ethnic background living in an area of low sanitation will have a lower risk as compared to the same individuals living in an area of high sanitation who will be exposed to a higher risk of developing Alzheimer's. An African-American in U.S. has a higher risk of developing Alzheimer's as compared to one living in Nigeria. Immigrant populations exhibit Alzheimer disease rates intermediate between their home country and adopted country. Moving from a country of high sanitation to a country of low sanitation reduces the risk associated with the disease.
== Mental illness ==
People who face poverty have more risks related to having a mental illness and also do not have as much access to treatment. The stressful events that they face, unsafe living condition and poor physical health lead to cycle of poverty and mental illness that is seen all over the world. According to the World Health Organization 76–85% of people living in lower and middle income countries are not treated for their mental illness. For those in higher-income counties, 35–50% of people with mental illness do not receive treatment. It is estimated that 90% of deaths by suicide are caused by substance use disorders and mental illness in higher income countries. In lower to middle income countries, this number is lower.
=== Prevalence of mental illness ===
One in four people have experienced mental illness at one time in their lives, and approximately 450 million people in the world currently have a mental illness. Those who are impoverished live in conditions associated with a higher risk for mental illness and, to compound the issue, do not have as much access to treatment. Stress, unsafe living conditions, and poor physical health associated with lack of sufficient income lead to a cycle of poverty and mental illness that is observed worldwide. In the U.S., approximately one in five adults has a mental illness, or 44.7 million people. In 2016, it was estimated that 268 million people in the world had depression.
Anxiety disorders, such as generalized anxiety, Obsessive Compulsive Disorder, and Post Traumatic Stress Disorder affected 275 million people worldwide in 2016. The global proportion of people affected by anxiety disorders is between 2.5 and 6.5%. Australia, Brazil, Argentina, Iran, the United States, and a number of countries in Western Europe appear to have a higher prevalence of anxiety disorders.
== Cancer ==
Cancer is a generic term for a large group of diseases characterized by the rapid creation of abnormal cells that grow beyond their usual boundaries. These cells can invade adjoining parts of the body and spread to other organs, which is a major cause of death. According to the WHO, cancer is the second leading cause of death globally. One in six deaths worldwide are caused by cancer, accounting to a total of 9.6 million deaths in 2018. Tracheal, bronchus, and lung cancer are the leading forms of cancer deaths across most high and middle-income countries.
=== Prevalence in countries of affluence ===
In United States, 1,735,350 new cases of cancer will be diagnosed in 2018. Most common forms of cancer are cancer of the breast, lung, bronchus, prostate, colorectal cancer, melanoma of skin, Non-Hodgkin's lymphoma, renal cancer, thyroid cancer and liver cancer. Cancer mortality is higher among men than women. African-Americans have the highest risk of cancer-related mortality. Cancer is also the leading cause of death in Australia. The most common cancers in Australia are prostate, breast, colorectal, melanoma, and lung cancer. These account for 60% of the cancer cases diagnosed in Australia.
Europe contains only 1/8 of the global population, but has around one quarter of the global cancer cases, with 3.7 million new cases each year. Lung, breast, stomach, liver, and colon are the most common cancers in Europe. The overall incidences among different cancers vary across countries.
About one in two Canadians will develop cancer in their lifetime, and one in four will die of the disease. In 2017, 206,200 new cases of cancer were diagnosed. Lung, colorectal, breast, and prostate cancer accounted for about half of all cancer diagnoses and deaths.
=== Risk factors ===
High prevalence of cancer in high-income countries is attributed to lifestyle factors like obesity, smoking, physical inactivity, diet and alcohol intake. Around 40% of the cancers can be prevented by modifying these factors.
== Allergies/autoimmune diseases ==
The rate of allergies around the world has risen in industrialized nations over the past 50 years. A number of public health measures, such as sterilized milk, use of antibiotics and improved food production have contributed to a decrease in infections in developed countries. There is a proposed causal relationship, known as the "hygiene hypothesis" that indicates that there are more autoimmune disorders and allergies in developed countries with fewer infections. In developing countries, it is assumed that the rates of allergies are lower than developed countries. That assumption may not be accurate due to limited data on prevalence. Research has found an increase in asthma by 10% in countries such as Peru, Costa Rica, and Brazil.
== See also ==
Affluenza: "placing a high value on money, possessions, appearances (physical and social) and fame" may increase risk of mental illnesses
Nutrition
Social determinants of health
The China Study: 2005 book on the relationship between the consumption of animal products and selected illnesses
Urbanization
Westernization
== References ==
== Further reading ==
Trowell HC, Burkitt DP. Western Diseases: Their Emergence and Prevention. Harvard University Press. | Wikipedia/Diseases_of_affluence |
Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bronchioles, alveoli, pleurae, pleural cavity, the nerves and muscles of respiration. Respiratory diseases range from mild and self-limiting, such as the common cold, influenza, and pharyngitis to life-threatening diseases such as bacterial pneumonia, pulmonary embolism, tuberculosis, acute asthma, lung cancer, and severe acute respiratory syndromes, such as COVID-19. Respiratory diseases can be classified in many different ways, including by the organ or tissue involved, by the type and pattern of associated signs and symptoms, or by the cause of the disease.
The study of respiratory disease is known as pulmonology. A physician who specializes in respiratory disease is known as a pulmonologist, a chest medicine specialist, a respiratory medicine specialist, a respirologist or a thoracic medicine specialist.
== Obstructive lung disease ==
Asthma, chronic bronchitis, bronchiectasis and chronic obstructive pulmonary disease (COPD) are all obstructive lung diseases characterised by airway obstruction. This limits the amount of air that is able to enter alveoli because of constriction of the bronchial tree, due to inflammation. Obstructive lung diseases are often identified because of symptoms and diagnosed with pulmonary function tests such as spirometry. Many obstructive lung diseases are managed by avoiding triggers (such as dust mites or smoking), with symptom control such as bronchodilators, and with suppression of inflammation (such as through corticosteroids) in severe cases. One common cause of COPD including emphysema, and chronic bronchitis, is tobacco smoking, and common causes of bronchiectasis include severe infections and cystic fibrosis. The definitive cause of asthma is not yet known.
== Restrictive lung diseases ==
Restrictive lung diseases are a category of respiratory diseases characterized by a loss of lung compliance, causing incomplete lung expansion and increased lung stiffness, such as in infants with respiratory distress syndrome. Restrictive lung diseases can be divided into two categories: those caused by intrinsic factors and those caused by extrinsic factors. Restrictive lung diseases yielding from intrinsic factors occur within the lungs themselves, such as tissue death due to inflammation or toxins. Conversely, restrictive lung diseases caused by extrinsic factors result from conditions originating from outside the lungs such as neuromuscular dysfunction and irregular chest wall movements.
== Chronic respiratory disease ==
Chronic respiratory diseases are long-term diseases of the airways and other structures of the lung. They are characterized by a high inflammatory cell recruitment (neutrophil) and/or destructive cycle of infection, (e.g. mediated by Pseudomonas aeruginosa). Some of the most common are asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome. Most chronic respiratory dieseases are not curable; however, various forms of treatment that help dilate major air passages and improve shortness of breath can help control symptoms and increase the quality of life.
=== Telerehabilitation for chronic respiratory disease ===
The latest evidence suggests that primary pulmonary rehabilitation and maintenance rehabilitation delivered through telerehabilitation for people with chronic respiratory disease reaches outcomes similar to centre-based rehabilitation. While there are no safety issues identified, the findings are based on evidence limited by a small number of studies.
== Respiratory tract infections ==
Infections can affect any part of the respiratory system. They are traditionally divided into upper respiratory tract infections and lower respiratory tract infections.
=== Upper respiratory tract infection ===
The upper airway is defined as all the structures connecting the glottis to the mouth and nose. The most common upper respiratory tract infection is the common cold. However, infections of specific organs of the upper respiratory tract such as sinusitis, tonsillitis, otitis media, pharyngitis and laryngitis are also considered upper respiratory tract infections.
Epiglottitis is a bacterial infection of the larynx which causes life-threatening swelling of the epiglottis with a mortality rate of 7% in adults and 1% in children. Haemophilus influenzae is still the primary cause even with vaccinations. Also Streptococcus pyogenes can cause epiglottitis. Symptoms include drooling, stridor, difficulty breathing and swallowing, and a hoarse voice.
Croup (Laryngotracheobronchitis) is a viral infection of the vocal cords typically lasting five to six days. The main symptom is a barking cough and low-grade fever. On an X-ray, croup can be recognized by the "steeple sign", which is a narrowing of the trachea. It most commonly occurs in winter months in children between the ages of 3 months and 5 years. A severe form caused by bacteria is called bacterial tracheitis.
Tonsillitis is swelling of the tonsils by a bacterial or viral infection. This inflammation can lead to airway obstruction. From tonsillitis can come a peritonsillar abscess which is the most common upper airway infection and occurs primarily in young adults. It causes swelling in one of the tonsils, pushing the uvula to the unaffected side. Diagnosis is usually made based on the presentation and examination. Symptoms generally include fever, sore throat, trouble swallowing, and sounding like they have a "hot potato" in their mouth.
=== Lower respiratory tract infection ===
The most common lower respiratory tract infection is pneumonia, an infection of the lungs which is usually caused by bacteria, particularly Streptococcus pneumoniae in Western countries. Worldwide, tuberculosis is an important cause of pneumonia. Other pathogens such as viruses and fungi can cause pneumonia, for example severe acute respiratory syndrome, COVID-19 and pneumocystis pneumonia. Pneumonia may develop complications such as a lung abscess, a round cavity in the lung caused by the infection, or may spread to the pleural cavity.
Poor oral care may be a contributing factor to lower respiratory disease, as bacteria from gum disease may travel through airways and into the lungs. There is also a co-occurrence between acute eosinophilic pneumonia, desquamative interstitial pneumonia and tobacco use.
=== Upper and lower respiratory tract infection ===
Primary ciliary dyskinesia is a genetic disorder causing the cilia to not move in a coordinated manner. This causes chronic respiratory infections, cough, and nasal congestion. This can lead to bronchiectasis, which can cause life-threatening breathing issues.
== Tumors ==
=== Malignant tumors ===
Malignant tumors of the respiratory system, particularly primary carcinomas of the lung, are a major health problem responsible for 15% of all cancer diagnoses and 30% of all cancer deaths. The majority of respiratory system cancers are attributable to smoking tobacco.
The major histological types of respiratory system cancer are:
Small cell lung cancer
Non-small cell lung cancer
Adenocarcinoma of the lung
Squamous cell carcinoma of the lung
Large cell lung carcinoma
Other lung cancers (carcinoid, Kaposi's sarcoma, melanoma)
Lymphoma
Head and neck cancer
Pleural mesothelioma, almost always caused by exposure to asbestos dust.
In addition, since many cancers spread via the bloodstream and the entire cardiac output passes through the lungs, it is common for cancer metastases to occur within the lung. Breast cancer may invade directly through local spread, and through lymph node metastases. After metastasis to the liver, colon cancer frequently metastasizes to the lung. Prostate cancer, germ cell cancer and renal cell carcinoma may also metastasize to the lung.
Treatment of respiratory system cancer depends on the type of cancer. Surgical removal of part of a lung (lobectomy, segmentectomy, or wedge resection) or of an entire lung pneumonectomy), along with chemotherapy and radiotherapy, are all used. The chance of surviving lung cancer depends on the cancer stage at the time the cancer is diagnosed, and to some extent on the histology, and is only about 14–17% overall. In the case of metastases to the lung, treatment can occasionally be curative but only in certain, rare circumstances.
=== Benign tumors ===
Benign tumors are relatively rare causes of respiratory disease. Examples of benign tumors are:
Pulmonary hamartoma
Congenital malformations such as pulmonary sequestration and congenital cystic adenomatoid malformation (CCAM).
== Pleural cavity diseases ==
Pleural cavity diseases include pleural mesothelioma which are mentioned above.
A collection of fluid in the pleural cavity is known as a pleural effusion. This may be due to fluid shifting from the bloodstream into the pleural cavity due to conditions such as congestive heart failure and cirrhosis. It may also be due to inflammation of the pleura itself as can occur with infection, pulmonary embolus, tuberculosis, mesothelioma and other conditions.
A pneumothorax is a hole in the pleura covering the lung allowing air in the lung to escape into the pleural cavity. The affected lung "collapses" like a deflated balloon. A tension pneumothorax is a particularly severe form of this condition where the air in the pleural cavity cannot escape, so the pneumothorax keeps getting bigger until it compresses the heart and blood vessels, leading to a life-threatening situation.
== Pulmonary vascular disease ==
Pulmonary vascular diseases are conditions that affect the pulmonary circulation. Examples are:
Pulmonary embolism, a blood clot that forms in a vein, breaks free, travels through the heart and lodges in the lungs (thromboembolism). Large pulmonary emboli are fatal, causing sudden death. A number of other substances can also embolise (travel through the blood stream) to the lungs but they are much more rare: fat embolism (particularly after bony injury), amniotic fluid embolism (with complications of labour and delivery), air embolism (iatrogenic – caused by invasive medical procedures).
Pulmonary arterial hypertension, elevated pressure in the pulmonary arteries. Most commonly it is idiopathic (i.e. of unknown cause) but it can be due to the effects of another disease, particularly COPD. This can lead to strain on the right side of the heart, a condition known as cor pulmonale.
Pulmonary edema, leakage of fluid from capillaries of the lung into the alveoli (or air spaces). It is usually due to congestive heart failure.
Pulmonary hemorrhage, inflammation and damage to capillaries in the lung resulting in blood leaking into the alveoli. This may cause blood to be coughed up. Pulmonary hemorrhage can be due to auto-immune disorders such as granulomatosis with polyangiitis and Goodpasture's syndrome.
== Neonatal diseases ==
Pulmonary diseases also impact newborns and the disorders are often unique from those that affect adults.
Infant respiratory distress syndrome most commonly occurs in less than six hours after birth in about 1% of all births in the United States. The main risk factor is prematurity with the likelihood of it occurring going up to 71% in infants under 750g. Other risk factors include infant of a diabetic mother (IDM), method of delivery, fetal asphyxia, genetics, prolonged rupture of membranes (PROM), maternal toxemia, chorioamnionitis, and male sex. The widely accepted pathophysiology of respiratory distress syndrome is it caused by insufficient surfactant production and immature lung and vascular development. The lack of surfactant makes the lungs atelectatic causing a ventilation to perfusion mismatch, lowered compliance, and increased air resistance. This causes hypoxia and respiratory acidosis which can lead to pulmonary hypertension. It has a ground glass appearance on an x-ray. Symptoms can include tachypnea, nasal flaring, paradoxical chest movement, grunting, and subcostal retractions.
Bronchopulmonary Dysplasia is a condition that occurs after birth usually from mechanical ventilation and oxygen use. It happens almost exclusively in pre-mature infants and is characterized by the alveoli, and lung vasculature becoming inflamed and damaged. Complications from BPD can follow a patient into adulthood. As a child they may experience learning disabilities, pulmonary hypertension, and hearing problems. As an adult, there is an increased likelihood for asthma and exercise intolerance.
Meconium Aspiration Syndrome occurs in full term or post-term infants who aspirate meconium. Risk factors include a diabetic mother, fetal hypoxia, precipitous delivery, and maternal high blood pressure. Its diagnosis is based on meconium stained amniotic fluid at delivery and staining on the skin, nails, and umbilical cord. Aspiration can cause airway obstruction, air-trapping, pneumonia, lung inflammation, and inactivated surfactant. It presents as patchy atelectasis and hyperinflation on an x-ray with a pneumothorax of pneumomediastinum also possible.
Persistent Pulmonary Hypertension of the Newborn (PPHN) is a syndrome that occurs from an abnormal transition to extra-uterine life. It is marked by an elevated pulmonary vascular resistance and vasoconstriction causing a right-to-left shunt of the blood through the foramen ovale or ductus arteriosus. There are three main causes of PPHN are parenchymal diseases such as meconium aspiration syndrome, idiopathic, and hypoplastic vasculature like in a diaphragmatic hernia. It will eventually resolve in most infants. This is the only syndrome that inhaled nitric oxide is approved for by the FDA.
Transient Tachypnea of the Newborn is caused by the retention of alveolar fluid in the lungs. It commonly occurs in infants who are delivered via caesarean section without the onset of labor because absorption of amniotic fluid in the lungs has not yet commenced. Other risk factors are male sex, macrosomia, multiple gestations, and maternal asthma. It usually presents with tachypnea and increased work of breathing. On an x-ray diffuse infiltrates, interlobar fissures, and sometimes pleural effusions can be seen. It is a diagnosis of exclusion because of its similarity to other diseases and frequently CPAP is used to help push the lung fluid into the pulmonary vasculature.
Pulmonary interstitial emphysema is the condition of air escaping overdistended alveoli into the pulmonary interstitium. It is a rare disease that occurs most often in premature infants, even though it is possible to appear in adults. It often presents as a slow deterioration with the need for increased ventilatory support. Chest x-ray is the standard for diagnosis where it is seen as linear or cystic translucencies extending to the edges of the lungs.
Bronchiolitis is the swelling and buildup of mucus in the bronchioles. It is usually caused by respiratory syncytial virus (RSV), which is spread when an infant touches the nose or throat fluids of someone infected. The virus infects the cells causing ciliary dysfunction and death. The debris, edema, and inflammation eventually leads to the symptoms. It is the most common reason for admission of children under the age of one year. It can present widely from a mild respiratory infection to respiratory failure. Since there is no medication to treat the disease, it is only managed supportively with fluids and oxygen.
== Diagnosis ==
Respiratory diseases may be investigated by performing one or more of the following tests:
Biopsy of the lung or pleura
Blood test
Bronchoscopy
Chest X-ray
CT scan, including high-resolution computed tomography
Culture of microorganisms from secretions such as sputum
Ultrasound scanning can be useful to detect fluid such as pleural effusion
Pulmonary function test
Ventilation–perfusion scan
== Epidemiology ==
Respiratory disease is a common and significant cause of illness and death around the world. In the US, approximately one billion common colds occur each year. A study found that in 2010, there were approximately 6.8 million emergency department visits for respiratory disorders in the U.S. for patients under the age of 18. In 2012, respiratory conditions were the most frequent reasons for hospital stays among children.
In the UK, approximately 1 in 7 individuals are affected by some form of chronic lung disease, most commonly chronic obstructive pulmonary disease, which includes asthma, chronic bronchitis and emphysema.
Respiratory diseases (including lung cancer) are responsible for over 10% of hospitalizations and over 16% of deaths in Canada.
In 2011, respiratory disease with ventilator support accounted for 93.3% of ICU utilization in the United States.
== References ==
== External links == | Wikipedia/Respiratory_disease |
Asymptomatic (or clinically silent) is an adjective categorising the medical conditions (i.e., injuries or diseases) that patients carry but without experiencing their symptoms, despite an explicit diagnosis (e.g., a positive medical test).
Pre-symptomatic is the adjective categorising the time periods during which the medical conditions are asymptomatic.
Subclinical and paucisymptomatic are other adjectives categorising either the asymptomatic infections (i.e., subclinical infections), or the psychosomatic illnesses and mental disorders expressing a subset of symptoms but not the entire set an explicit medical diagnosis requires.
== Examples ==
An example of an asymptomatic disease is cytomegalovirus (CMV) which is a member of the herpes virus family. "It is estimated that 1% of all newborns are infected with CMV, but the majority of infections are asymptomatic." (Knox, 1983; Kumar et al. 1984) In some diseases, the proportion of asymptomatic cases can be important. For example, in multiple sclerosis it is estimated that around 25% of the cases are asymptomatic, with these cases detected postmortem or just by coincidence (as incidental findings) while treating other diseases.
== Importance ==
Knowing that a condition is asymptomatic is important because:
It may be contagious, and the contribution of asymptomatic and pre-symptomatic infections to the transmission level of a disease helps set the required control measures to keep it from spreading.
It is not required that a person undergo treatment. It does not cause later medical problems such as high blood pressure and hyperlipidaemia.
Be alert to possible problems: asymptomatic hypothyroidism makes a person vulnerable to Wernicke–Korsakoff syndrome or beri-beri following intravenous glucose.
For some conditions, treatment during the asymptomatic phase is vital. If one waits until symptoms develop, it is too late for survival or to prevent damage.
== Mental health ==
Subclinical or subthreshold conditions are those for which the full diagnostic criteria are not met and have not been met in the past, although symptoms are present. This can mean that symptoms are not severe enough to merit a diagnosis, or that symptoms are severe but do not meet the criteria of a condition.
== List ==
These are conditions for which there is a sufficient number of documented individuals that are asymptomatic that it is clinically noted. For a complete list of asymptomatic infections see subclinical infection.
Millions of women reported lack of symptoms during pregnancy until the point of childbirth or the beginning of labor; they didn't know they were pregnant. This phenomenon is known as cryptic pregnancies.
== See also ==
Symptomatic
Subclinical infection
== References == | Wikipedia/Subclinical |
Functional disorders are a group of recognisable medical conditions which are due to changes to the functioning of the systems of the body rather than due to a disease affecting the structure of the body.
Functional disorders are common and complex phenomena that pose challenges to medical systems. Traditionally in medicine, the body is thought of as consisting of different organ systems, but it is less well understood how the systems interconnect or communicate. Functional disorders can affect the interplay of several organ systems (for example gastrointestinal, respiratory, musculoskeletal or neurological) leading to multiple and variable symptoms. Less commonly there is a single prominent symptom or organ system affected.
Most symptoms that are caused by structural disease can also be caused by a functional disorder. Because of this, individuals often undergo many medical investigations before the diagnosis is clear. Though research is growing to support explanatory models of functional disorders, structural scans such as MRIs, or laboratory investigation such as blood tests do not usually explain the symptoms or the symptom burden. This difficulty in 'seeing' the processes underlying the symptoms of functional disorders has often resulted in these conditions being misunderstood and sometimes stigmatised within medicine and society.
Despite being associated with high disability, functional symptoms are not a threat to life, and are considered modifiable with appropriate treatment.
== Definition ==
Functional disorders are mostly understood as conditions characterised by:
persistent and troublesome symptoms
associated with impairment or disability
where the pathophysiological basis is related to problems with the functioning and communication of the body systems (as opposed to disease affecting the structure of organs or tissues)
=== Examples ===
There are many different functional disorder diagnoses that might be given depending on the symptom or syndrome that is most troublesome. There are many examples of symptoms that individuals may experience; some of these include persistent or recurrent pain, fatigue, weakness, shortness of breath or bowel problems. Single symptoms may be assigned a diagnostic label, such as "functional chest pain", "functional constipation" or "functional seizures". Characteristic collections of symptoms might be described as one of the functional somatic syndromes. A syndrome is a collection of symptoms. Somatic means 'of the body'. Examples of functional somatic syndromes include: irritable bowel syndrome; cyclic vomiting syndrome; some persistent fatigue and chronic pain syndromes, such as fibromyalgia (chronic widespread pain), or chronic pelvic pain; interstitial cystitis; functional neurologic disorder; and multiple chemical sensitivity.
== Overlap ==
Most medical specialties define their own functional somatic syndrome, and a patient may end up with several of these diagnoses without understanding how they are connected. There is overlap in symptoms between all the functional disorder diagnoses. For example, it is not uncommon to have a diagnosis of irritable bowel syndrome (IBS) and chronic widespread pain/fibromyalgia. All functional disorders share risk factors and factors that contribute to their persistence. Increasingly researchers and clinicians are recognising the relationships between these syndromes.
== Classification ==
The terminology for functional disorders has been fraught with confusion and controversy, with many different terms used to describe them. Sometimes functional disorders are equated or mistakenly confused with diagnoses like category of "somatoform disorders", "medically unexplained symptoms", "psychogenic symptoms" or "conversion disorders". Many historical terms are now no longer thought of as accurate, and are considered by many to be stigmatising.
Psychiatric illnesses have historically also been considered as functional disorders in some classification systems, as they often fulfil the criteria above. Whether a given medical condition is termed a functional disorder depends in part on the state of knowledge. Some diseases, such as epilepsy, were historically categorized as functional disorders but are no longer classified that way.
== Prevalence ==
Functional disorders can affect individuals of all ages, ethnic groups and socioeconomic backgrounds. In clinical populations, functional disorders are common and have been found to present in around one-third of consultations in both specialist practice and primary care. Chronic courses of disorders are common and are associated with high disability, health-care usage and social costs.
Rates differ in the clinical population compared with the general population, and will vary depending on the criteria used to make the diagnosis. For example, irritable bowel syndrome is thought to affect 4.1%, and fibromyalgia 0.2–11.4% of the global population.
A recent large study carried out on population samples in Denmark showed the following: In total, 16.3% of adults reported symptoms fulfilling the criteria for at least one Functional Somatic Syndrome, and 16.1% fulfilled criteria for Bodily Distress Syndrome.
== Diagnosis ==
The diagnosis of functional disorders is usually made in the healthcare setting most often by a doctor — this could be a primary care physician or family doctor, hospital physician or specialist in the area of psychosomatic medicine or a consultant-liaison psychiatrist. The primary care physician or family doctor will generally play an important role in coordinating treatment with a secondary care clinician if necessary.
The diagnosis is essentially clinical, whereby the clinician undertakes a thorough medical and mental health history and physical examination. Diagnosis should be based on the nature of the presenting symptoms, and is a "rule in" as opposed to "rule out" diagnosis — this means it is based on the presence of positive symptoms and signs that follow a characteristic pattern. There is usually a process of clinical reasoning to reach this point and assessment might require several visits, ideally with the same doctor.
In the clinical setting, there are no laboratory or imaging tests that can consistently be used to diagnose the conditions; however, as is the case with all diagnoses, often additional diagnostic tests (such as blood tests, or diagnostic imaging) will be undertaken to consider the presence of underlying disease. There are however diagnostic criteria that can be used to help a doctor assess whether an individual is likely to suffer from a particular functional syndrome. These are usually based on the presence or absence of characteristic clinical signs and symptoms. Self-report questionnaires may also be useful.
There has been a tradition of a separate diagnostic classification systems for "somatic" and "mental" disorder classifications. Currently, the 11th version of the International Classification System of Diseases (ICD-11) has specific diagnostic criteria for certain disorders which would be considered by many clinicians to be functional somatic disorders, such as IBS or chronic widespread pain/fibromyalgia, and dissociative neurological symptom disorder.
In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) the older term somatoform (DSM-IV) has been replaced by somatic symptom disorder, which is a disorder characterised by persistent somatic (physical) symptoms, and associated psychological problems to the degree that it interferes with daily functioning and causes distress. (APA, 2022). Bodily distress disorder is a related term in the ICD-11.
Somatic symptom disorder and bodily distress disorder have significant overlap with functional disorders and are often assigned if someone would benefit from psychological therapies addressing psychological or behavioural factors which contribute to the persistence of symptoms. However, people with symptoms partly explained by structural disease (for example, cancer) may also meet the criteria for diagnosis of functional disorders, somatic symptom disorder and bodily distress disorder.
It is not unusual for a functional disorder to coexist with another diagnosis (for example, functional seizures can coexist with epilepsy, or irritable bowel syndrome with inflammatory bowel disease. This is important to recognise as additional treatment approaches might be indicated in order that the patient achieves adequate relief from their symptoms.
The diagnostic process is considered an important step in order for treatment to move forward successfully. When healthcare professionals are giving a diagnosis and carrying out treatment, it is important to communicate openly and honestly and not to fall into the trap of dualistic concepts – that is "either mental or physical" thinking; or attempt to "reattribute" symptoms to a predominantly psychosocial cause. It often important to recognise the need to cease unnecessary additional diagnostic testing if a clear diagnosis has been established .
== Causes ==
Explanatory models that support our understanding of functional disorders take into account the multiple factors involved in symptom development. A personalised, tailored approach is usually needed in order to consider the factors which relate to that individual's biomedical, psychological, social, and material environment.
More recent functional neuroimaging studies have suggested malfunctioning of neural circuits involved in stress processing, emotional regulation, self-agency, interoception, and sensorimotor integration. A recent article in Scientific American proposed that important brain structures suspected in the pathophysiology of functional neurological disorder include increased activity of the amygdala and decreased activity within the right temporoparietal junction.
Healthcare professionals might find it useful to consider three main categories of factors: predisposing, precipitating, and perpetuating (maintaining) factors.
=== Predisposing factors ===
These are factors that make the person more vulnerable to the onset of a functional disorder; and include biological, psychological and social factors. Like all health conditions, some people are probably predisposed to develop functional disorders due to their genetic make-up. However, no single genes have been identified that are associated with functional disorders. Epigenetic mechanisms (mechanisms that affect interaction of genes with their environment) are likely to be important, and have been studied in relation to the hypothalamic–pituitary–adrenal axis. Other predisposing factors include current or prior somatic/physical illness or injury, and endocrine, immunological or microbial factors.
Functional disorders are diagnosed more frequently in female patients. Medical bias possibly contributes to the sex differences in diagnosis: women are more likely to be diagnosed than men with a functional disorder by doctors.
People with functional disorders also have higher rates of pre-existing mental and physical health conditions, including depression and anxiety disorders, Post-traumatic stress disorder, multiple sclerosis and epilepsy. Personality style has been suggested as a risk factor in the development of functional disorders but the effect of any individual personality trait is variable and weak. Alexithymia (difficulties recognising and naming emotions) has been widely studied in patients with functional disorders and is sometimes addressed as part of treatment. Migration, cultural and family understanding of illness, are also factors that influence the chance of an individual developing a functional disorder. Being exposed to illness in the family while growing up or having parents who are healthcare professionals are sometimes considered risk factors. Adverse childhood experiences and traumatic experiences of all kinds are known important risk factors. Newer hypotheses have suggested minority stressors may play a role in the development of functional disorders in marginalized communities.
=== Precipitating factors ===
These are the factors that for some patients appear to trigger the onset of a functional disorder. Typically, these involve either an acute cause of physical or emotional stress, for example an operation, a viral illness, a car accident, a sudden bereavement, or a period of intense and prolonged overload of chronic stressors (for example relationship difficulties, job or financial stress, or caring responsibilities). Not all affected individuals will be able to identify obvious precipitating factors and some functional disorders develop gradually over time.
=== Perpetuating factors ===
These are the factors that contribute to the development of functional disorder as a persistent condition and maintaining symptoms. These can include the condition of the physiological systems including the immune and neuroimmune systems, the endocrine system, the musculoskeletal system, the sleep-wake cycle, the brain and nervous system, the person's thoughts and experience, their experience of the body, social situation and environment. All these layers interact with each other. Illness mechanisms are important therapeutically as they are seen as potential targets of treatment.
The exact illness mechanisms that are responsible for maintaining an individual's functional disorder should be considered on an individual basis. However, various models have been suggested to account for how symptoms develop and continue. For some people there seems to be a process of central-sensitisation, chronic low grade inflammation or altered stress reactivity mediated through the hypothalamic-pituitary-adrenal (HPA) axis (Fischer et al., 2022). For some people attentional mechanisms are likely to be important. Commonly, illness-perceptions or behaviours and expectations (Henningsen, Van den Bergh et al. 2018 ) contribute to maintaining an impaired physiological condition.
Perpetuating illness mechanisms are often conceptualized as "vicious cycles", which highlights the non-linear patterns of causality characteristic of these disorders. Other people adopt a pattern of trying to achieve a lot on "good days" which results in exhaustion for days following and a flare up of symptoms, which has led to various energy management tools being used in the patient community, such as "Spoon Theory."
Depression, PTSD, sleep disorders, and anxiety disorders can also perpetuate functional disorders and should be identified and treated where they are present. Side effects or withdrawal effects of medication often need to be considered. Iatrogenic factors such as lack of a clear diagnosis, not feeling believed or not taken seriously by a healthcare professional, multiple (invasive) diagnostic procedures, ineffective treatments and not getting an explanation for symptoms can increase worry and unhelpful illness behaviours. Stigmatising medical attitudes and unnecessary medical interventions (tests, surgeries or drugs) can also cause harm and worsen symptoms.
== Treatment ==
Functional disorders can be treated successfully and are considered reversible conditions. Treatment strategies should integrate biological, psychological and social perspectives. The body of research around evidence-based treatment in functional disorders is growing.
With regard to self-management, there are many basic things that can be done to optimise recovery. Learning about and understanding the condition is helpful in itself. Many people are able to use bodily complaints as a signal to slow down and reassess their balance between exertion and recovery. Bodily complaints can be used as a signal to begin incorporating stress reduction and balanced lifestyle measures (routine, regular activity and relaxation, diet, social engagement) that can help reduce symptoms and are central to improving quality of life. Mindfulness practice can be helpful for some people. Family members or friends can also be helpful in supporting recovery.
Most affected people benefit from support and encouragement in this process, ideally through a multi-disciplinary team with expertise in treating functional disorders. Family members or friends may also be helpful in supporting recovery. The aim of treatment overall is to first create the conditions necessary for recovery, and then plan a programme of rehabilitation to re-train mind-body connections making use of the body's ability to change. Particular strategies can be taught to manage bowel symptoms, pain or seizures. Though medication alone should not be considered curative in functional disorders, medication to reduce symptoms might be indicated in some instances, for example where mood or pain is a significant issue, preventing adequate engagement in rehabilitation. It is important to address accompanying factors such as sleep disorders, pain, depression and anxiety, and concentration difficulties.
Physiotherapy may be relevant for exercise and activation programs, or when weakness or pain is a problem. Psychotherapy might be helpful to explore a pattern of thoughts, actions and behaviours that could be driving a negative cycle – for example tackling illness expectations or preoccupations about symptoms. Some existing evidence-based treatments include cognitive behavioural therapy (CBT) for functional neurological disorder; physiotherapy for functional motor symptoms, and dietary modification or gut targeting agents for irritable bowel syndrome.
== Controversies and stigma ==
Despite some progress in the last decade, people with functional disorders continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. Stigma is a common experience for individuals who present with functional symptoms and is often driven by historical narratives and factual inaccuracies. Given that functional disorders do not usually have specific biomarkers or findings on structural imaging that are typically undertaken in routine clinical practice, this leads to potential for symptoms to be misunderstood, invalidated, or dismissed, leading to adverse experiences when individuals are seeking help.
Part of this stigma is also driven by theories around "mind body dualism", which frequently surfaces as an area of importance for patients, researchers and clinicians in the realm of functional disorders. Artificial separation of the mind/brain/body (for example the use of phrases such as; "physical versus psychological" or "organic versus non-organic") furthers misunderstanding and misconceptions around these disorders, and only serves to hinder progress in scientific domain and for patients seeking treatment. Some patient groups have fought to have their illnesses not classified as functional disorders, because in some insurance based health-care systems these have attracted lower insurance payments. Current research is moving away from dualistic theories, and recognising the importance of the whole person, both mind and body, in diagnosis and treatment of these conditions.
People with functional disorders frequently describe experiences of doubt, blame, and of being seen as less 'genuine' than those with other disorders. Some clinicians perceive those individuals with functional disorders are imagining their symptoms, are malingering, or doubt the level of voluntary control they have over their symptoms. As a result, individuals with these disorders often wait long periods of time to be seen by specialists and receive appropriate treatment. Currently, there is a lack of specialised treatment services for functional disorders in many countries. However, research is growing in this area, and it is hoped that the implementation of the increased scientific understanding of functional disorders and their treatment will allow effective clinical services supporting individuals with functional disorders to develop. Patient membership organisations/advocate groups have been instrumental in gaining recognition for individuals with these disorders.
== Research ==
Directions for research involve understanding more about the processes underlying functional disorders, identifying what leads to symptom persistence and improving integrated care/treatment pathways for patients.
Research into the biological mechanisms which underpin functional disorders is ongoing. Understanding how stress effects the body over a lifetime, for example via the immune endocrine and autonomic nervous systems, is important Ying-Chih et.al 2020, Tak et. al. 2011, Nater et al. 2011). Subtle dysfunctions of these systems, for example through low grade chronic inflammation, or dysfunctional breathing patterns, are increasingly thought to underlie functional disorders and their treatment. However, more research is needed before these theoretical mechanisms can be used clinically to guide treatment for an individual patient.
== See also ==
Idiopathic disease
Functional gastrointestinal disorder
Functional neurological symptom disorder
Functional symptom
Psychosomatic medicine
== References == | Wikipedia/Functional_disorder |
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable disease, is an illness resulting from an infection.
Infections can be caused by a wide range of pathogens, most prominently bacteria and viruses. Hosts can fight infections using their immune systems. Mammalian hosts react to infections with an innate response, often involving inflammation, followed by an adaptive response.
Treatment for infections depends on the type of pathogen involved. Common medications include:
Antibiotics for bacterial infections.
Antivirals for viral infections.
Antifungals for fungal infections.
Antiprotozoals for protozoan infections.
Antihelminthics for infections caused by parasitic worms.
Infectious diseases remain a significant global health concern, causing approximately 9.2 million deaths in 2013 (17% of all deaths). The branch of medicine that focuses on infections is referred to as infectious diseases.
== Types ==
Infections are caused by infectious agents (pathogens) including:
Bacteria (e.g. Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Clostridium botulinum, and Salmonella spp.)
Viruses and subviral agents such as viroids and prions. (E.g. HIV, Rhinovirus, Lyssaviruses such as Rabies virus, Ebolavirus and Severe acute respiratory syndrome coronavirus 2)
Fungi, further subclassified into:
Ascomycota, including yeasts such as Candida (the most common fungal infection); filamentous fungi such as Aspergillus; Pneumocystis species; and dermatophytes, a group of organisms causing infection of skin and other superficial structures in humans.
Basidiomycota, including the human-pathogenic genus Cryptococcus.
Parasites, which are usually divided into:
Unicellular organisms (e.g. malaria, Toxoplasma, Babesia)
Macroparasites (worms or helminths) including nematodes such as parasitic roundworms and pinworms, tapeworms (cestodes), and flukes (trematodes, such as schistosomes). Diseases caused by helminths are sometimes termed infestations, but are sometimes called infections.
Arthropods such as ticks, mites, fleas, and lice, can also cause human disease, which conceptually are similar to infections, but invasion of a human or animal body by these macroparasites is usually termed infestation.
== Signs and symptoms ==
The signs and symptoms of an infection depend on the type of disease. Some signs of infection affect the whole body generally, such as fatigue, loss of appetite, weight loss, fevers, night sweats, chills, aches and pains. Others are specific to individual body parts, such as skin rashes, coughing, or a runny nose.
In certain cases, infectious diseases may be asymptomatic for much or even all of their course in a given host. In the latter case, the disease may only be defined as a "disease" (which by definition means an illness) in hosts who secondarily become ill after contact with an asymptomatic carrier. An infection is not synonymous with an infectious disease, as some infections do not cause illness in a host.
=== Bacterial or viral ===
As bacterial and viral infections can both cause the same kinds of symptoms, it can be difficult to distinguish which is the cause of a specific infection. Distinguishing the two is important, since viral infections cannot be cured by antibiotics whereas bacterial infections can.
== Pathophysiology ==
There is a general chain of events that applies to infections, sometimes called the chain of infection or transmission chain. The chain of events involves several steps – which include the infectious agent, reservoir, entering a susceptible host, exit and transmission to new hosts. Each of the links must be present in a chronological order for an infection to develop. Understanding these steps helps health care workers target the infection and prevent it from occurring in the first place.
=== Colonization ===
Infection begins when an organism successfully enters the body, grows and multiplies. This is referred to as colonization. Most humans are not easily infected. Those with compromised or weakened immune systems have an increased susceptibility to chronic or persistent infections. Individuals who have a suppressed immune system are particularly susceptible to opportunistic infections. Entrance to the host at host–pathogen interface, generally occurs through the mucosa in orifices like the oral cavity, nose, eyes, genitalia, anus, or the microbe can enter through open wounds. While a few organisms can grow at the initial site of entry, many migrate and cause systemic infection in different organs. Some pathogens grow within the host cells (intracellular) whereas others grow freely in bodily fluids.
Wound colonization refers to non-replicating microorganisms within the wound, while in infected wounds, replicating organisms exist and tissue is injured. All multicellular organisms are colonized to some degree by extrinsic organisms, and the vast majority of these exist in either a mutualistic or commensal relationship with the host. An example of the former is the anaerobic bacteria species, which colonizes the mammalian colon, and an example of the latter are the various species of staphylococcus that exist on human skin. Neither of these colonizations are considered infections. The difference between an infection and a colonization is often only a matter of circumstance. Non-pathogenic organisms can become pathogenic given specific conditions, and even the most virulent organism requires certain circumstances to cause a compromising infection. Some colonizing bacteria, such as Corynebacteria sp. and Viridans streptococci, prevent the adhesion and colonization of pathogenic bacteria and thus have a symbiotic relationship with the host, preventing infection and speeding wound healing.
The variables involved in the outcome of a host becoming inoculated by a pathogen and the ultimate outcome include:
the route of entry of the pathogen and the access to host regions that it gains
the intrinsic virulence of the particular organism
the quantity or load of the initial inoculant
the immune status of the host being colonized
As an example, several staphylococcal species remain harmless on the skin, but, when present in a normally sterile space, such as in the capsule of a joint or the peritoneum, multiply without resistance and cause harm.
An interesting fact that gas chromatography–mass spectrometry, 16S ribosomal RNA analysis, omics, and other advanced technologies have made more apparent to humans in recent decades is that microbial colonization is very common even in environments that humans think of as being nearly sterile. Because it is normal to have bacterial colonization, it is difficult to know which chronic wounds can be classified as infected and how much risk of progression exists. Despite the huge number of wounds seen in clinical practice, there are limited quality data for evaluated symptoms and signs. A review of chronic wounds in the Journal of the American Medical Association's "Rational Clinical Examination Series" quantified the importance of increased pain as an indicator of infection. The review showed that the most useful finding is an increase in the level of pain [likelihood ratio (LR) range, 11–20] makes infection much more likely, but the absence of pain (negative likelihood ratio range, 0.64–0.88) does not rule out infection (summary LR 0.64–0.88).
=== Disease ===
Disease can arise if the host's protective immune mechanisms are compromised and the organism inflicts damage on the host. Microorganisms can cause tissue damage by releasing a variety of toxins or destructive enzymes. For example, Clostridium tetani releases a toxin that paralyzes muscles, and staphylococcus releases toxins that produce shock and sepsis. Not all infectious agents cause disease in all hosts. For example, less than 5% of individuals infected with polio develop disease. On the other hand, some infectious agents are highly virulent. The prion causing mad cow disease and Creutzfeldt–Jakob disease invariably kills all animals and people that are infected.
Persistent infections occur because the body is unable to clear the organism after the initial infection. Persistent infections are characterized by the continual presence of the infectious organism, often as latent infection with occasional recurrent relapses of active infection. There are some viruses that can maintain a persistent infection by infecting different cells of the body. Some viruses once acquired never leave the body. A typical example is the herpes virus, which tends to hide in nerves and become reactivated when specific circumstances arise.
Persistent infections cause millions of deaths globally each year. Chronic infections by parasites account for a high morbidity and mortality in many underdeveloped countries.
=== Transmission ===
For infecting organisms to survive and repeat the infection cycle in other hosts, they (or their progeny) must leave an existing reservoir and cause infection elsewhere. Infection transmission can take place via many potential routes:
Droplet contact, also known as the respiratory route, and the resultant infection can be termed airborne disease. If an infected person coughs or sneezes on another person the microorganisms, suspended in warm, moist droplets, may enter the body through the nose, mouth or eye surfaces.
Fecal-oral transmission, wherein foodstuffs or water become contaminated (by people not washing their hands before preparing food, or untreated sewage being released into a drinking water supply) and the people who eat and drink them become infected. Common fecal-oral transmitted pathogens include Vibrio cholerae, Giardia species, rotaviruses, Entamoeba histolytica, Escherichia coli, and tape worms. Most of these pathogens cause gastroenteritis.
Sexual transmission, with the result being called sexually transmitted infection.
Oral transmission, diseases that are transmitted primarily by oral means may be caught through direct oral contact such as kissing, or by indirect contact such as by sharing a drinking glass or a cigarette.
Transmission by direct contact, Some diseases that are transmissible by direct contact include athlete's foot, impetigo and warts.
Vehicle transmission, transmission by an inanimate reservoir (food, water, soil).
Vertical transmission, directly from the mother to an embryo, fetus or baby during pregnancy or childbirth. It can occur as a result of a pre-existing infection or one acquired during pregnancy.
Iatrogenic transmission, due to medical procedures such as injection or transplantation of infected material.
Vector-borne transmission, transmitted by a vector, which is an organism that does not cause disease itself but that transmits infection by conveying pathogens from one host to another.
The relationship between virulence versus transmissibility is complex; with studies have shown that there were no clear relationship between the two. There is still a small number of evidence that partially suggests a link between virulence and transmissibility.
== Diagnosis ==
Diagnosis of infectious disease sometimes involves identifying an infectious agent either directly or indirectly. In practice most minor infectious diseases such as warts, cutaneous abscesses, respiratory system infections and diarrheal diseases are diagnosed by their clinical presentation and treated without knowledge of the specific causative agent. Conclusions about the cause of the disease are based upon the likelihood that a patient came in contact with a particular agent, the presence of a microbe in a community, and other epidemiological considerations. Given sufficient effort, all known infectious agents can be specifically identified.
Diagnosis of infectious disease is nearly always initiated by medical history and physical examination. More detailed identification techniques involve the culture of infectious agents isolated from a patient. Culture allows identification of infectious organisms by examining their microscopic features, by detecting the presence of substances produced by pathogens, and by directly identifying an organism by its genotype.
Many infectious organisms are identified without culture and microscopy. This is especially true for viruses, which cannot grow in culture. For some suspected pathogens, doctors may conduct tests that examine a patient's blood or other body fluids for antigens or antibodies that indicate presence of a specific pathogen that the doctor suspects.
Other techniques (such as X-rays, CAT scans, PET scans or NMR) are used to produce images of internal abnormalities resulting from the growth of an infectious agent. The images are useful in detection of, for example, a bone abscess or a spongiform encephalopathy produced by a prion.
The benefits of identification, however, are often greatly outweighed by the cost, as often there is no specific treatment, the cause is obvious, or the outcome of an infection is likely to be benign.
=== Symptomatic diagnostics ===
The diagnosis is aided by the presenting symptoms in any individual with an infectious disease, yet it usually needs additional diagnostic techniques to confirm the suspicion. Some signs are specifically characteristic and indicative of a disease and are called pathognomonic signs; but these are rare. Not all infections are symptomatic.
In children the presence of cyanosis, rapid breathing, poor peripheral perfusion, or a petechial rash increases the risk of a serious infection by greater than 5 fold. Other important indicators include parental concern, clinical instinct, and temperature greater than 40 °C.
=== Microbial culture ===
Many diagnostic approaches depend on microbiological culture to isolate a pathogen from the appropriate clinical specimen. In a microbial culture, a growth medium is provided for a specific agent. A sample taken from potentially diseased tissue or fluid is then tested for the presence of an infectious agent able to grow within that medium. Many pathogenic bacteria are easily grown on nutrient agar, a form of solid medium that supplies carbohydrates and proteins necessary for growth, along with copious amounts of water. A single bacterium will grow into a visible mound on the surface of the plate called a colony, which may be separated from other colonies or melded together into a "lawn". The size, color, shape and form of a colony is characteristic of the bacterial species, its specific genetic makeup (its strain), and the environment that supports its growth. Other ingredients are often added to the plate to aid in identification. Plates may contain substances that permit the growth of some bacteria and not others, or that change color in response to certain bacteria and not others. Bacteriological plates such as these are commonly used in the clinical identification of infectious bacterium. Microbial culture may also be used in the identification of viruses: the medium, in this case, being cells grown in culture that the virus can infect, and then alter or kill. In the case of viral identification, a region of dead cells results from viral growth, and is called a "plaque". Eukaryotic parasites may also be grown in culture as a means of identifying a particular agent.
In the absence of suitable plate culture techniques, some microbes require culture within live animals. Bacteria such as Mycobacterium leprae and Treponema pallidum can be grown in animals, although serological and microscopic techniques make the use of live animals unnecessary. Viruses are also usually identified using alternatives to growth in culture or animals. Some viruses may be grown in embryonated eggs. Another useful identification method is Xenodiagnosis, or the use of a vector to support the growth of an infectious agent. Chagas disease is the most significant example, because it is difficult to directly demonstrate the presence of the causative agent, Trypanosoma cruzi in a patient, which therefore makes it difficult to definitively make a diagnosis. In this case, xenodiagnosis involves the use of the vector of the Chagas agent T. cruzi, an uninfected triatomine bug, which takes a blood meal from a person suspected of having been infected. The bug is later inspected for growth of T. cruzi within its gut.
=== Microscopy ===
Another principal tool in the diagnosis of infectious disease is microscopy. Virtually all of the culture techniques discussed above rely, at some point, on microscopic examination for definitive identification of the infectious agent. Microscopy may be carried out with simple instruments, such as the compound light microscope, or with instruments as complex as an electron microscope. Samples obtained from patients may be viewed directly under the light microscope, and can often rapidly lead to identification. Microscopy is often also used in conjunction with biochemical staining techniques, and can be made exquisitely specific when used in combination with antibody based techniques. For example, the use of antibodies made artificially fluorescent (fluorescently labeled antibodies) can be directed to bind to and identify a specific antigens present on a pathogen. A fluorescence microscope is then used to detect fluorescently labeled antibodies bound to internalized antigens within clinical samples or cultured cells. This technique is especially useful in the diagnosis of viral diseases, where the light microscope is incapable of identifying a virus directly.
Other microscopic procedures may also aid in identifying infectious agents. Almost all cells readily stain with a number of basic dyes due to the electrostatic attraction between negatively charged cellular molecules and the positive charge on the dye. A cell is normally transparent under a microscope, and using a stain increases the contrast of a cell with its background. Staining a cell with a dye such as Giemsa stain or crystal violet allows a microscopist to describe its size, shape, internal and external components and its associations with other cells. The response of bacteria to different staining procedures is used in the taxonomic classification of microbes as well. Two methods, the Gram stain and the acid-fast stain, are the standard approaches used to classify bacteria and to diagnosis of disease. The Gram stain identifies the bacterial groups Bacillota and Actinomycetota, both of which contain many significant human pathogens. The acid-fast staining procedure identifies the Actinomycetota genera Mycobacterium and Nocardia.
=== Biochemical tests ===
Biochemical tests used in the identification of infectious agents include the detection of metabolic or enzymatic products characteristic of a particular infectious agent. Since bacteria ferment carbohydrates in patterns characteristic of their genus and species, the detection of fermentation products is commonly used in bacterial identification. Acids, alcohols and gases are usually detected in these tests when bacteria are grown in selective liquid or solid media.
The isolation of enzymes from infected tissue can also provide the basis of a biochemical diagnosis of an infectious disease. For example, humans can make neither RNA replicases nor reverse transcriptase, and the presence of these enzymes are characteristic., of specific types of viral infections. The ability of the viral protein hemagglutinin to bind red blood cells together into a detectable matrix may also be characterized as a biochemical test for viral infection, although strictly speaking hemagglutinin is not an enzyme and has no metabolic function.
Serological methods are highly sensitive, specific and often extremely rapid tests used to identify microorganisms. These tests are based upon the ability of an antibody to bind specifically to an antigen. The antigen, usually a protein or carbohydrate made by an infectious agent, is bound by the antibody. This binding then sets off a chain of events that can be visibly obvious in various ways, dependent upon the test. For example, "Strep throat" is often diagnosed within minutes, and is based on the appearance of antigens made by the causative agent, S. pyogenes, that is retrieved from a patient's throat with a cotton swab. Serological tests, if available, are usually the preferred route of identification, however the tests are costly to develop and the reagents used in the test often require refrigeration. Some serological methods are extremely costly, although when commonly used, such as with the "strep test", they can be inexpensive.
Complex serological techniques have been developed into what are known as immunoassays. Immunoassays can use the basic antibody – antigen binding as the basis to produce an electro-magnetic or particle radiation signal, which can be detected by some form of instrumentation. Signal of unknowns can be compared to that of standards allowing quantitation of the target antigen. To aid in the diagnosis of infectious diseases, immunoassays can detect or measure antigens from either infectious agents or proteins generated by an infected organism in response to a foreign agent. For example, immunoassay A may detect the presence of a surface protein from a virus particle. Immunoassay B on the other hand may detect or measure antibodies produced by an organism's immune system that are made to neutralize and allow the destruction of the virus.
Instrumentation can be used to read extremely small signals created by secondary reactions linked to the antibody – antigen binding. Instrumentation can control sampling, reagent use, reaction times, signal detection, calculation of results, and data management to yield a cost-effective automated process for diagnosis of infectious disease.
=== PCR-based diagnostics ===
Technologies based upon the polymerase chain reaction (PCR) method will become nearly ubiquitous gold standards of diagnostics of the near future, for several reasons. First, the catalog of infectious agents has grown to the point that virtually all of the significant infectious agents of the human population have been identified. Second, an infectious agent must grow within the human body to cause disease; essentially it must amplify its own nucleic acids to cause a disease. This amplification of nucleic acid in infected tissue offers an opportunity to detect the infectious agent by using PCR. Third, the essential tools for directing PCR, primers, are derived from the genomes of infectious agents, and with time those genomes will be known if they are not already.
Thus, the technological ability to detect any infectious agent rapidly and specifically is currently available. The only remaining blockades to the use of PCR as a standard tool of diagnosis are in its cost and application, neither of which is insurmountable. The diagnosis of a few diseases will not benefit from the development of PCR methods, such as some of the clostridial diseases (tetanus and botulism). These diseases are fundamentally biological poisonings by relatively small numbers of infectious bacteria that produce extremely potent neurotoxins. A significant proliferation of the infectious agent does not occur, this limits the ability of PCR to detect the presence of any bacteria.
=== Metagenomic sequencing ===
Given the wide range of bacterial, viral, fungal, protozoal, and helminthic pathogens that cause debilitating and life-threatening illnesses, the ability to quickly identify the cause of infection is important yet often challenging. For example, more than half of cases of encephalitis, a severe illness affecting the brain, remain undiagnosed, despite extensive testing using the standard of care (microbiological culture) and state-of-the-art clinical laboratory methods. Metagenomic sequencing-based diagnostic tests are currently being developed for clinical use and show promise as a sensitive, specific, and rapid way to diagnose infection using a single all-encompassing test. This test is similar to current PCR tests; however, an untargeted whole genome amplification is used rather than primers for a specific infectious agent. This amplification step is followed by next-generation sequencing or third-generation sequencing, alignment comparisons, and taxonomic classification using large databases of thousands of pathogen and commensal reference genomes. Simultaneously, antimicrobial resistance genes within pathogen and plasmid genomes are sequenced and aligned to the taxonomically classified pathogen genomes to generate an antimicrobial resistance profile – analogous to antibiotic sensitivity testing – to facilitate antimicrobial stewardship and allow for the optimization of treatment using the most effective drugs for a patient's infection.
Metagenomic sequencing could prove especially useful for diagnosis when the patient is immunocompromised. An ever-wider array of infectious agents can cause serious harm to individuals with immunosuppression, so clinical screening must often be broader. Additionally, the expression of symptoms is often atypical, making a clinical diagnosis based on presentation more difficult. Thirdly, diagnostic methods that rely on the detection of antibodies are more likely to fail. A rapid, sensitive, specific, and untargeted test for all known human pathogens that detects the presence of the organism's DNA rather than antibodies is therefore highly desirable.
=== Indication of tests ===
There is usually an indication for a specific identification of an infectious agent only when such identification can aid in the treatment or prevention of the disease, or to advance knowledge of the course of an illness prior to the development of effective therapeutic or preventative measures. For example, in the early 1980s, prior to the appearance of AZT for the treatment of AIDS, the course of the disease was closely followed by monitoring the composition of patient blood samples, even though the outcome would not offer the patient any further treatment options. In part, these studies on the appearance of HIV in specific communities permitted the advancement of hypotheses as to the route of transmission of the virus. By understanding how the disease was transmitted, resources could be targeted to the communities at greatest risk in campaigns aimed at reducing the number of new infections. The specific serological diagnostic identification, and later genotypic or molecular identification, of HIV also enabled the development of hypotheses as to the temporal and geographical origins of the virus, as well as a myriad of other hypothesis. The development of molecular diagnostic tools have enabled physicians and researchers to monitor the efficacy of treatment with anti-retroviral drugs. Molecular diagnostics are now commonly used to identify HIV in healthy people long before the onset of illness and have been used to demonstrate the existence of people who are genetically resistant to HIV infection. Thus, while there still is no cure for AIDS, there is great therapeutic and predictive benefit to identifying the virus and monitoring the virus levels within the blood of infected individuals, both for the patient and for the community at large.
=== Classification ===
==== Subclinical versus clinical (latent versus apparent) ====
Symptomatic infections are apparent and clinical, whereas an infection that is active but does not produce noticeable symptoms may be called inapparent, silent, subclinical, or occult. An infection that is inactive or dormant is called a latent infection. An example of a latent bacterial infection is latent tuberculosis. Some viral infections can also be latent, examples of latent viral infections are any of those from the Herpesviridae family.
The word infection can denote any presence of a particular pathogen at all (no matter how little) but also is often used in a sense implying a clinically apparent infection (in other words, a case of infectious disease). This fact occasionally creates some ambiguity or prompts some usage discussion; to get around this it is common for health professionals to speak of colonization (rather than infection) when they mean that some of the pathogens are present but that no clinically apparent infection (no disease) is present.
==== Course of infection ====
Different terms are used to describe how and where infections present over time. In an acute infection, symptoms develop rapidly; its course can either be rapid or protracted. In chronic infection, symptoms usually develop gradually over weeks or months and are slow to resolve. In subacute infections, symptoms take longer to develop than in acute infections but arise more quickly than those of chronic infections. A focal infection is an initial site of infection from which organisms travel via the bloodstream to another area of the body.
==== Primary versus opportunistic ====
Among the many varieties of microorganisms, relatively few cause disease in otherwise healthy individuals. Infectious disease results from the interplay between those few pathogens and the defenses of the hosts they infect. The appearance and severity of disease resulting from any pathogen depend upon the ability of that pathogen to damage the host as well as the ability of the host to resist the pathogen. However, a host's immune system can also cause damage to the host itself in an attempt to control the infection. Clinicians, therefore, classify infectious microorganisms or microbes according to the status of host defenses – either as primary pathogens or as opportunistic pathogens.
===== Primary pathogens =====
Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence (the severity of the disease they cause) is, in part, a necessary consequence of their need to reproduce and spread. Many of the most common primary pathogens of humans only infect humans, however, many serious diseases are caused by organisms acquired from the environment or that infect non-human hosts.
===== Opportunistic pathogens =====
Opportunistic pathogens can cause an infectious disease in a host with depressed resistance (immunodeficiency) or if they have unusual access to the inside of the body (for example, via trauma). Opportunistic infection may be caused by microbes ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract, and they may also result from (otherwise innocuous) microbes acquired from other hosts (as in Clostridioides difficile colitis) or from the environment as a result of traumatic introduction (as in surgical wound infections or compound fractures). An opportunistic disease requires impairment of host defenses, which may occur as a result of genetic defects (such as chronic granulomatous disease), exposure to antimicrobial drugs or immunosuppressive chemicals (as might occur following poisoning or cancer chemotherapy), exposure to ionizing radiation, or as a result of an infectious disease with immunosuppressive activity (such as with measles, malaria or HIV disease). Primary pathogens may also cause more severe disease in a host with depressed resistance than would normally occur in an immunosufficient host.
===== Secondary infection =====
While a primary infection can practically be viewed as the root cause of an individual's current health problem, a secondary infection is a sequela or complication of that root cause. For example, an infection due to a burn or penetrating trauma (the root cause) is a secondary infection. Primary pathogens often cause primary infection and often cause secondary infection. Usually, opportunistic infections are viewed as secondary infections (because immunodeficiency or injury was the predisposing factor).
===== Other types of infection =====
Other types of infection consist of mixed, iatrogenic, nosocomial, and community-acquired infection. A mixed infection is an infection that is caused by two or more pathogens. An example of this is appendicitis, which is caused by Bacteroides fragilis and Escherichia coli. The second is an iatrogenic infection. This type of infection is one that is transmitted from a health care worker to a patient. A nosocomial infection is also one that occurs in a health care setting. Nosocomial infections are those that are acquired during a hospital stay. Lastly, a community-acquired infection is one in which the infection is acquired from a whole community.
==== Infectious or not ====
One manner of proving that a given disease is infectious, is to satisfy Koch's postulates (first proposed by Robert Koch), which require that first, the infectious agent be identifiable only in patients who have the disease, and not in healthy controls, and second, that patients who contract the infectious agent also develop the disease. These postulates were first used in the discovery that Mycobacteria species cause tuberculosis.
However, Koch's postulates cannot usually be tested in modern practice for ethical reasons. Proving them would require experimental infection of a healthy individual with a pathogen produced as a pure culture. Conversely, even clearly infectious diseases do not always meet the infectious criteria; for example, Treponema pallidum, the causative spirochete of syphilis, cannot be cultured in vitro – however the organism can be cultured in rabbit testes. It is less clear that a pure culture comes from an animal source serving as host than it is when derived from microbes derived from plate culture.
Epidemiology, or the study and analysis of who, why and where disease occurs, and what determines whether various populations have a disease, is another important tool used to understand infectious disease. Epidemiologists may determine differences among groups within a population, such as whether certain age groups have a greater or lesser rate of infection; whether groups living in different neighborhoods are more likely to be infected; and by other factors, such as gender and race. Researchers also may assess whether a disease outbreak is sporadic, or just an occasional occurrence; endemic, with a steady level of regular cases occurring in a region; epidemic, with a fast arising, and unusually high number of cases in a region; or pandemic, which is a global epidemic. If the cause of the infectious disease is unknown, epidemiology can be used to assist with tracking down the sources of infection.
==== Contagiousness ====
Infectious diseases are sometimes called contagious diseases when they are easily transmitted by contact with an ill person or their secretions (e.g., influenza). Thus, a contagious disease is a subset of infectious disease that is especially infective or easily transmitted. All contagious diseases are infectious, but not vice versa. Other types of infectious, transmissible, or communicable diseases with more specialized routes of infection, such as vector transmission or sexual transmission, are usually not regarded as "contagious", and often do not require medical isolation (sometimes loosely called quarantine) of those affected. However, this specialized connotation of the word "contagious" and "contagious disease" (easy transmissibility) is not always respected in popular use.
Infectious diseases are commonly transmitted from person to person through direct contact. The types of direct contact are through person to person and droplet spread. Indirect contact such as airborne transmission, contaminated objects, food and drinking water, animal person contact, animal reservoirs, insect bites, and environmental reservoirs are another way infectious diseases are transmitted. The basic reproduction number of an infectious disease measures how easily it spreads through direct or indirect contact.
==== By anatomic location ====
Infections can be classified by the anatomic location or organ system infected, including:
Urinary tract infection
Skin infection
Respiratory tract infection
Odontogenic infection (an infection that originates within a tooth or in the closely surrounding tissues)
Vaginal infections
Intra-amniotic infection
In addition, locations of inflammation where infection is the most common cause include pneumonia, meningitis and salpingitis.
== Prevention ==
Techniques like hand washing, wearing gowns, and wearing face masks can help prevent infections from being passed from one person to another. Aseptic technique was introduced in medicine and surgery in the late 19th century and greatly reduced the incidence of infections caused by surgery. Frequent hand washing remains the most important defense against the spread of unwanted organisms. There are other forms of prevention such as avoiding the use of illicit drugs, using a condom, wearing gloves, and having a healthy lifestyle with a balanced diet and regular exercise. Cooking foods well and avoiding foods that have been left outside for a long time is also important.
Antimicrobial substances used to prevent transmission of infections include:
antiseptics, which are applied to living tissue/skin
disinfectants, which destroy microorganisms found on non-living objects.
antibiotics, called prophylactic when given as prevention rather as treatment of infection. However, long term use of antibiotics leads to resistance of bacteria. While humans do not become immune to antibiotics, the bacteria does. Thus, avoiding using antibiotics longer than necessary helps preventing bacteria from forming mutations that aide in antibiotic resistance.
One of the ways to prevent or slow down the transmission of infectious diseases is to recognize the different characteristics of various diseases. Some critical disease characteristics that should be evaluated include virulence, distance traveled by those affected, and level of contagiousness. The human strains of Ebola virus, for example, incapacitate those infected extremely quickly and kill them soon after. As a result, those affected by this disease do not have the opportunity to travel very far from the initial infection zone. Also, this virus must spread through skin lesions or permeable membranes such as the eye. Thus, the initial stage of Ebola is not very contagious since its victims experience only internal hemorrhaging. As a result of the above features, the spread of Ebola is very rapid and usually stays within a relatively confined geographical area. In contrast, the human immunodeficiency virus (HIV) kills its victims very slowly by attacking their immune system. As a result, many of its victims transmit the virus to other individuals before even realizing that they are carrying the disease. Also, the relatively low virulence allows its victims to travel long distances, increasing the likelihood of an epidemic.
Another effective way to decrease the transmission rate of infectious diseases is to recognize the effects of small-world networks. In epidemics, there are often extensive interactions within hubs or groups of infected individuals and other interactions within discrete hubs of susceptible individuals. Despite the low interaction between discrete hubs, the disease can jump and spread in a susceptible hub via a single or few interactions with an infected hub. Thus, infection rates in small-world networks can be reduced somewhat if interactions between individuals within infected hubs are eliminated (Figure 1). However, infection rates can be drastically reduced if the main focus is on the prevention of transmission jumps between hubs. The use of needle exchange programs in areas with a high density of drug users with HIV is an example of the successful implementation of this treatment method. Another example is the use of ring culling or vaccination of potentially susceptible livestock in adjacent farms to prevent the spread of the foot-and-mouth virus in 2001.
A general method to prevent transmission of vector-borne pathogens is pest control.
In cases where infection is merely suspected, individuals may be quarantined until the incubation period has passed and the disease manifests itself or the person remains healthy. Groups may undergo quarantine, or in the case of communities, a cordon sanitaire may be imposed to prevent infection from spreading beyond the community, or in the case of protective sequestration, into a community. Public health authorities may implement other forms of social distancing, such as school closings, lockdowns or temporary restrictions (e.g. circuit breakers) to control an epidemic.
=== Immunity ===
Infection with most pathogens does not result in death of the host and the offending organism is ultimately cleared after the symptoms of the disease have waned. This process requires immune mechanisms to kill or inactivate the inoculum of the pathogen. Specific acquired immunity against infectious diseases may be mediated by antibodies and/or T lymphocytes. Immunity mediated by these two factors may be manifested by:
a direct effect upon a pathogen, such as antibody-initiated complement-dependent bacteriolysis, opsonoization, phagocytosis and killing, as occurs for some bacteria,
neutralization of viruses so that these organisms cannot enter cells,
or by T lymphocytes, which will kill a cell parasitized by a microorganism.
The immune system response to a microorganism often causes symptoms such as a high fever and inflammation, and has the potential to be more devastating than direct damage caused by a microbe.
Resistance to infection (immunity) may be acquired following a disease, by asymptomatic carriage of the pathogen, by harboring an organism with a similar structure (crossreacting), or by vaccination. Knowledge of the protective antigens and specific acquired host immune factors is more complete for primary pathogens than for opportunistic pathogens. There is also the phenomenon of herd immunity which offers a measure of protection to those otherwise vulnerable people when a large enough proportion of the population has acquired immunity from certain infections.
Immune resistance to an infectious disease requires a critical level of either antigen-specific antibodies and/or T cells when the host encounters the pathogen. Some individuals develop natural serum antibodies to the surface polysaccharides of some agents although they have had little or no contact with the agent, these natural antibodies confer specific protection to adults and are passively transmitted to newborns.
==== Host genetic factors ====
The organism that is the target of an infecting action of a specific infectious agent is called the host. The host harbouring an agent that is in a mature or sexually active stage phase is called the definitive host. The intermediate host comes in contact during the larvae stage. A host can be anything living and can attain to asexual and sexual reproduction.
The clearance of the pathogens, either treatment-induced or spontaneous, it can be influenced by the genetic variants carried by the individual patients. For instance, for genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in the treatment-induced clearance of the virus. This finding, originally reported in Nature, showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained virological response after the treatment than others. Later report from Nature demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.
== Treatments ==
When infection attacks the body, anti-infective drugs can suppress the infection. Several broad types of anti-infective drugs exist, depending on the type of organism targeted; they include antibacterial (antibiotic; including antitubercular), antiviral, antifungal and antiparasitic (including antiprotozoal and antihelminthic) agents. Depending on the severity and the type of infection, the antibiotic may be given by mouth or by injection, or may be applied topically. Severe infections of the brain are usually treated with intravenous antibiotics. Sometimes, multiple antibiotics are used in case there is resistance to one antibiotic. Antibiotics only work for bacteria and do not affect viruses. Antibiotics work by slowing down the multiplication of bacteria or killing the bacteria. The most common classes of antibiotics used in medicine include penicillin, cephalosporins, aminoglycosides, macrolides, quinolones and tetracyclines.
Not all infections require treatment, and for many self-limiting infections the treatment may cause more side-effects than benefits. Antimicrobial stewardship is the concept that healthcare providers should treat an infection with an antimicrobial that specifically works well for the target pathogen for the shortest amount of time and to only treat when there is a known or highly suspected pathogen that will respond to the medication.
== Susceptibility to infection ==
Pandemics such as COVID-19 show that people dramatically differ in their susceptibility to infection. This may be because of general health, age, or their immune status, e.g. when they have been infected previously. However, it also has become clear that there are genetic factor which determine susceptibility to infection. For instance, up to 40% of SARS-CoV-2 infections may be asymptomatic, suggesting that many people are naturally protected from disease. Large genetic studies have defined risk factors for severe SARS-CoV-2 infections, and genome sequences from 659 patients with severe COVID-19 revealed genetic variants that appear to be associated with life-threatening disease. One gene identified in these studies is type I interferon (IFN). Autoantibodies against type I IFNs were found in up to 13.7% of patients with life-threatening COVID-19, indicating that a complex interaction between genetics and the immune system is important for natural resistance to Covid.
Similarly, mutations in the ERAP2 gene, encoding endoplasmic reticulum aminopeptidase 2, seem to increase the susceptibility to the plague, the disease caused by an infection with the bacteria Yersinia pestis. People who inherited two copies of a complete variant of the gene were twice as likely to have survived the plague as those who inherited two copies of a truncated variant.
Susceptibility also determined the epidemiology of infection, given that different populations have different genetic and environmental conditions that affect infections.
== Epidemiology ==
An estimated 1,680 million people died of infectious diseases in the 20th century and about 10 million in 2010.
The World Health Organization collects information on global deaths by International Classification of Disease (ICD) code categories. The following table lists the top infectious disease by number of deaths in 2002. 1993 data is included for comparison.
The top three single agent/disease killers are HIV/AIDS, TB and malaria. While the number of deaths due to nearly every disease have decreased, deaths due to HIV/AIDS have increased fourfold. Childhood diseases include pertussis, poliomyelitis, diphtheria, measles and tetanus. Children also make up a large percentage of lower respiratory and diarrheal deaths. In 2012, approximately 3.1 million people have died due to lower respiratory infections, making it the number 4 leading cause of death in the world.
=== Historic pandemics ===
With their potential for unpredictable and explosive impacts, infectious diseases have been major actors in human history. A pandemic (or global epidemic) is a disease that affects people over an extensive geographical area. For example:
Plague of Justinian, from 541 to 542, killed between 50% and 60% of Europe's population.
The Black Death of 1347 to 1352 killed 25 million in Europe over five years. The plague reduced the old world population from an estimated 450 million to between 350 and 375 million in the 14th century.
The introduction of smallpox, measles, and typhus to the areas of Central and South America by European explorers during the 15th and 16th centuries caused pandemics among the native inhabitants. Between 1518 and 1568 disease pandemics are said to have caused the population of Mexico to fall from 20 million to 3 million.
The first European influenza epidemic occurred between 1556 and 1560, with an estimated mortality rate of 20%.
Smallpox killed an estimated 60 million Europeans during the 18th century (approximately 400,000 per year). Up to 30% of those infected, including 80% of the children under 5 years of age, died from the disease, and one-third of the survivors went blind.
In the 19th century, tuberculosis killed an estimated one-quarter of the adult population of Europe; by 1918 one in six deaths in France were still caused by TB.
The Influenza Pandemic of 1918 (or the Spanish flu) killed 25–50 million people (about 2% of world population of 1.7 billion). Today Influenza kills about 250,000 to 500,000 worldwide each year.
In 2021, COVID-19 emerged as a major global health crisis, directly causing 8.7 million deaths, making it one of the leading causes of mortality worldwide.
=== Emerging diseases ===
In most cases, microorganisms live in harmony with their hosts via mutual or commensal interactions. Diseases can emerge when existing parasites become pathogenic or when new pathogenic parasites enter a new host.
Coevolution between parasite and host can lead to hosts becoming resistant to the parasites or the parasites may evolve greater virulence, leading to immunopathological disease.
Human activity is involved with many emerging infectious diseases, such as environmental change enabling a parasite to occupy new niches. When that happens, a pathogen that had been confined to a remote habitat has a wider distribution and possibly a new host organism. Parasites jumping from nonhuman to human hosts are known as zoonoses. Under disease invasion, when a parasite invades a new host species, it may become pathogenic in the new host.
Several human activities have led to the emergence of zoonotic human pathogens, including viruses, bacteria, protozoa, and rickettsia, and spread of vector-borne diseases, see also globalization and disease and wildlife disease:
Encroachment on wildlife habitats. The construction of new villages and housing developments in rural areas force animals to live in dense populations, creating opportunities for microbes to mutate and emerge.
Changes in agriculture. The introduction of new crops attracts new crop pests and the microbes they carry to farming communities, exposing people to unfamiliar diseases.
The destruction of rain forests. As countries make use of their rain forests, by building roads through forests and clearing areas for settlement or commercial ventures, people encounter insects and other animals harboring previously unknown microorganisms.
Uncontrolled urbanization. The rapid growth of cities in many developing countries tends to concentrate large numbers of people into crowded areas with poor sanitation. These conditions foster transmission of contagious diseases.
Modern transport. Ships and other cargo carriers often harbor unintended "passengers", that can spread diseases to faraway destinations. While with international jet-airplane travel, people infected with a disease can carry it to distant lands, or home to their families, before their first symptoms appear.
== Germ theory of disease ==
In Antiquity, the Greek historian Thucydides (c. 460 – c. 400 BCE) was the first person to write, in his account of the plague of Athens, that diseases could spread from an infected person to others. In his On the Different Types of Fever (c. 175 AD), the Greco-Roman physician Galen speculated that plagues were spread by "certain seeds of plague", which were present in the air. In the Sushruta Samhita, the ancient Indian physician Sushruta theorized: "Leprosy, fever, consumption, diseases of the eye, and other infectious diseases spread from one person to another by sexual union, physical contact, eating together, sleeping together, sitting together, and the use of same clothes, garlands and pastes." This book has been dated to about the sixth century BC.
A basic form of contagion theory was proposed by Persian physician Ibn Sina (known as Avicenna in Europe) in The Canon of Medicine (1025), which later became the most authoritative medical textbook in Europe up until the 16th century. In Book IV of the Canon, Ibn Sina discussed epidemics, outlining the classical miasma theory and attempting to blend it with his own early contagion theory. He mentioned that people can transmit disease to others by breath, noted contagion with tuberculosis, and discussed the transmission of disease through water and dirt. The concept of invisible contagion was later discussed by several Islamic scholars in the Ayyubid Sultanate who referred to them as najasat ("impure substances"). The fiqh scholar Ibn al-Haj al-Abdari (c. 1250–1336), while discussing Islamic diet and hygiene, gave warnings about how contagion can contaminate water, food, and garments, and could spread through the water supply, and may have implied contagion to be unseen particles.
When the Black Death bubonic plague reached Al-Andalus in the 14th century, the Arab physicians Ibn Khatima (c. 1369) and Ibn al-Khatib (1313–1374) hypothesised that infectious diseases were caused by "minute bodies" and described how they can be transmitted through garments, vessels and earrings. Ideas of contagion became more popular in Europe during the Renaissance, particularly through the writing of the Italian physician Girolamo Fracastoro. Anton van Leeuwenhoek (1632–1723) advanced the science of microscopy by being the first to observe microorganisms, allowing for easy visualization of bacteria.
In the mid-19th century John Snow and William Budd did important work demonstrating the contagiousness of typhoid and cholera through contaminated water. Both are credited with decreasing epidemics of cholera in their towns by implementing measures to prevent contamination of water. Louis Pasteur proved beyond doubt that certain diseases are caused by infectious agents, and developed a vaccine for rabies. Robert Koch provided the study of infectious diseases with a scientific basis known as Koch's postulates. Edward Jenner, Jonas Salk and Albert Sabin developed effective vaccines for smallpox and polio, which would later result in the eradication and near-eradication of these diseases, respectively. Alexander Fleming discovered the world's first antibiotic, penicillin, which Florey and Chain then developed. Gerhard Domagk developed sulphonamides, the first broad spectrum synthetic antibacterial drugs.
=== Medical specialists ===
The medical treatment of infectious diseases falls into the medical field of Infectious Disease and in some cases the study of propagation pertains to the field of Epidemiology. Generally, infections are initially diagnosed by primary care physicians or internal medicine specialists. For example, an "uncomplicated" pneumonia will generally be treated by the internist or the pulmonologist (lung physician). The work of the infectious diseases specialist therefore entails working with both patients and general practitioners, as well as laboratory scientists, immunologists, bacteriologists and other specialists.
An infectious disease team may be alerted when:
The disease has not been definitively diagnosed after an initial workup
The patient is immunocompromised (for example, in AIDS or after chemotherapy);
The infectious agent is of an uncommon nature (e.g. tropical diseases);
The disease has not responded to first line antibiotics;
The disease might be dangerous to other patients, and the patient might have to be isolated
== Society and culture ==
Several studies have reported associations between pathogen load in an area and human behavior. Higher pathogen load is associated with decreased size of ethnic and religious groups in an area. This may be due high pathogen load favoring avoidance of other groups, which may reduce pathogen transmission, or a high pathogen load preventing the creation of large settlements and armies that enforce a common culture. Higher pathogen load is also associated with more restricted sexual behavior, which may reduce pathogen transmission. It also associated with higher preferences for health and attractiveness in mates. Higher fertility rates and shorter or less parental care per child is another association that may be a compensation for the higher mortality rate. There is also an association with polygyny which may be due to higher pathogen load, making selecting males with a high genetic resistance increasingly important. Higher pathogen load is also associated with more collectivism and less individualism, which may limit contacts with outside groups and infections. There are alternative explanations for at least some of the associations although some of these explanations may in turn ultimately be due to pathogen load. Thus, polygyny may also be due to a lower male: female ratio in these areas but this may ultimately be due to male infants having increased mortality from infectious diseases. Another example is that poor socioeconomic factors may ultimately in part be due to high pathogen load preventing economic development.
== Fossil record ==
Evidence of infection in fossil remains is a subject of interest for paleopathologists, scientists who study occurrences of injuries and illness in extinct life forms. Signs of infection have been discovered in the bones of carnivorous dinosaurs. When present, however, these infections seem to tend to be confined to only small regions of the body. A skull attributed to the early carnivorous dinosaur Herrerasaurus ischigualastensis exhibits pit-like wounds surrounded by swollen and porous bone. The unusual texture of the bone around the wounds suggests they were affected by a short-lived, non-lethal infection. Scientists who studied the skull speculated that the bite marks were received in a fight with another Herrerasaurus. Other carnivorous dinosaurs with documented evidence of infection include Acrocanthosaurus, Allosaurus, Tyrannosaurus and a tyrannosaur from the Kirtland Formation. The infections from both tyrannosaurs were received by being bitten during a fight, like the Herrerasaurus specimen.
== Outer space ==
A 2006 Space Shuttle experiment found that Salmonella typhimurium, a bacterium that can cause food poisoning, became more virulent when cultivated in space. On April 29, 2013, scientists in Rensselaer Polytechnic Institute, funded by NASA, reported that, during spaceflight on the International Space Station, microbes seem to adapt to the space environment in ways "not observed on Earth" and in ways that "can lead to increases in growth and virulence". More recently, in 2017, bacteria were found to be more resistant to antibiotics and to thrive in the near-weightlessness of space. Microorganisms have been observed to survive the vacuum of outer space.
== See also ==
== References ==
== External links ==
European Center for Disease Prevention and Control
U.S. Centers for Disease Control and Prevention,
Infectious Disease Society of America (IDSA)
Vaccine Research Center Information concerning vaccine research clinical trials for Emerging and re-Emerging Infectious Diseases.
Microbes & Infection (journal) | Wikipedia/Infectious_disease |
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.
Cancer occurs after cells are genetically altered to proliferate rapidly and indefinitely. This uncontrolled proliferation by mitosis produces a primary heterogeneic tumour. The cells which constitute the tumor eventually undergo metaplasia, followed by dysplasia then anaplasia, resulting in a malignant phenotype. This malignancy allows for invasion into the circulation, followed by invasion to a second site for tumorigenesis.
Some cancer cells, known as circulating tumor cells (CTCs), are able to penetrate the walls of lymphatic or blood vessels, and circulate through the bloodstream to other sites and tissues in the body. This process, known respectively as lymphatic or hematogenous spread, allows not only single cells but also groups of cells, or CTC clusters, to travel. Evidence suggests that CTC clusters may retain their multicellular configuration throughout metastasis, enhancing their ability to establish secondary tumors. This perspective aligns with the cancer exodus hypothesis, which posits that maintaining this cluster structure contributes to a higher metastatic potential. Metastasis is one of the hallmarks of cancer, distinguishing it from benign tumors. Most cancers can metastasize, although in varying degrees. Basal cell carcinoma for example rarely metastasizes.
When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are similar to those in the original or primary tumor. This means that if breast cancer metastasizes to the lungs, the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells. The tumor in the lung is then called metastatic breast cancer, not lung cancer. Metastasis is a key element in cancer staging systems such as the TNM staging system, where it represents the "M". In overall stage grouping, metastasis places a cancer in Stage IV. The possibilities of curative treatment are greatly reduced, or often entirely removed when a cancer has metastasized.
== Signs and symptoms ==
Initially, nearby lymph nodes are struck early. The lungs, liver, brain, and bones are the most common metastasis locations from solid tumors.
In lymph node metastasis, a common symptom is lymphadenopathy
Lung metastasis: cough, hemoptysis and dyspnea (shortness of breath)
Liver metastasis: hepatomegaly (enlarged liver), nausea and jaundice
Bone metastasis: bone pain, fracture of affected bones
Brain metastasis: neurological symptoms such as headaches, seizures, and vertigo
Although advanced cancer may cause pain, it is often not the first symptom.
Some patients, however, do not show any symptoms.
When the organ gets a metastatic disease it begins to shrink until its lymph nodes burst, or undergo lysis.
== Pathophysiology ==
Metastatic tumors are very common in the late stages of cancer. The spread of metastasis may occur via the blood or the lymphatics or through both routes. The most common sites of metastases are the lungs, liver, brain, and the bones
Currently, three main theories have been proposed to explain the metastatic pathway of cancer: the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) hypothesis (1), the cancer stem cell hypothesis (2), and the macrophage–cancer cell fusion hybrid hypothesis (3). Some new hypotheses were suggested as well, i.e., under the effect of particular biochemical and/or physical stressors, cancer cells can undergo nuclear expulsion with subsequent macrophage engulfment and fusion, with the formation of cancer fusion cells (CFCs). Understanding the enigma of cancer cell spread to distant sites, which accounts for over 90% of cancer-related deaths, necessitates comprehensive investigation. Key outstanding questions revolve around the survival and migration of cancer cells, such as the nucleus, as they face challenges in passage through capillary valves and hydrodynamic shear forces in the circulation system, making CTCs an unlikely source of metastasis. Moreover, understanding how cancer cells adapt to the metastatic niche and remain dormant (tumor dormancy) for extended periods presents difficult questions that require further investigation.
=== Factors involved ===
Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream, via the lymphatic system, or by direct extension. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumor from adjoining tissues. By degrading these proteins, cancer cells are able to breach the ECM and escape. The location of the metastases is not always random, with different types of cancer tending to spread to particular organs and tissues at a rate that is higher than expected by statistical chance alone. Breast cancer, for example, tends to metastasize to the bones and lungs. This specificity seems to be mediated by soluble signal molecules such as chemokines and transforming growth factor beta. The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressors, of which about a dozen are known.
Human cells exhibit different kinds of motion: collective motility, mesenchymal-type movement, and amoeboid movement. Cancer cells often opportunistically switch between different kinds of motion. Some cancer researchers hope to find treatments that can stop or at least slow down the spread of cancer by somehow blocking some necessary step in one or more kinds of motion.
All steps of the metastatic cascade involve a number of physical processes. Cell migration requires the generation of forces, and when cancer cells transmigrate through the vasculature, this requires physical gaps in the blood vessels to form. Besides forces, the regulation of various types of cell-cell and cell-matrix adhesions is crucial during metastasis.
The metastatic steps are critically regulated by various cell types, including the blood vessel cells (endothelial cells), immune cells or stromal cells. The growth of a new network of blood vessels, called tumor angiogenesis, is a crucial hallmark of cancer. It has therefore been suggested that angiogenesis inhibitors would prevent the growth of metastases. Endothelial progenitor cells have been shown to have a strong influence on metastasis and angiogenesis. Endothelial progenitor cells are important in tumor growth, angiogenesis and metastasis, and can be marked using the Inhibitor of DNA Binding 1 (ID1). This novel finding meant that investigators gained the ability to track endothelial progenitor cells from the bone marrow to the blood to the tumor-stroma and even incorporated in tumor vasculature. Endothelial progenitor cells incorporated in tumor vasculature suggests that this cell type in blood-vessel development is important in a tumor setting and metastasis. Furthermore, ablation of the endothelial progenitor cells in the bone marrow can lead to a significant decrease in tumor growth and vasculature development. Therefore, endothelial progenitor cells are important in tumor biology and present novel therapeutic targets. The immune system is typically deregulated in cancer and affects many stages of tumor progression, including metastasis.
Epigenetic regulation also plays an important role in the metastatic outgrowth of disseminated tumor cells. Metastases display alterations in histone modifications, such as H3K4-methylation and H3K9-methylation, when compared to matching primary tumors. These epigenetic modifications in metastases may allow the proliferation and survival of disseminated tumor cells in distant organs.
A recent study shows that PKC-iota promotes melanoma cell invasion by activating Vimentin during EMT. PKC-iota inhibition or knockdown resulted in an increase in E-cadherin and RhoA levels while decreasing total Vimentin, phosphorylated Vimentin (S39) and Par6 in metastatic melanoma cells. These results suggested that PKC-ι is involved in signaling pathways which upregulate EMT in melanoma thereby directly stimulates metastasis.
Recently, a series of high-profile experiments suggests that the co-option of intercellular cross-talk mediated by exosome vesicles is a critical factor involved in all steps of the invasion-metastasis cascade.
=== Routes ===
Metastasis occurs by the following four routes:
==== Transcoelomic ====
The spread of a malignancy into body cavities can occur via penetrating the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. For example, ovarian tumors can spread transperitoneally to the surface of the liver.
==== Lymphatic spread ====
Lymphatic spread allows the transport of tumor cells to regional lymph nodes near the primary tumor and ultimately, to other parts of the body. This is called nodal involvement, positive nodes, or regional disease. "Positive nodes" is a term that would be used by medical specialists to describe regional lymph nodes that tested positive for malignancy. It is common medical practice to test by biopsy at least one lymph node near a tumor site when carrying out surgery to examine or remove a tumor. This lymph node is then called a sentinel lymph node.
Lymphatic spread is the most common route of initial metastasis for carcinomas. In contrast, it is uncommon for a sarcoma to metastasize via this route. Localized spread to regional lymph nodes near the primary tumor is not normally counted as a metastasis, although this is a sign of a worse outcome.
The lymphatic system does eventually drain from the thoracic duct and right lymphatic duct into the systemic venous system at the venous angle and into the brachiocephalic veins, and therefore these metastatic cells can also eventually spread through the haematogenous route.
==== Hematogenous spread ====
This is typical route of metastasis for sarcomas, but it is also the favored route for certain types of carcinoma, such as renal cell carcinoma originating in the kidney and follicular carcinomas of the thyroid. Because of their thinner walls, veins are more frequently invaded than are arteries, and metastasis tends to follow the pattern of venous flow. That is, hematogenous spread often follows distinct patterns depending on the location of the primary tumor. For example, colorectal cancer spreads primarily through the portal vein to the liver.
==== Canalicular spread ====
Some tumors, especially carcinomas may metastasize along anatomical canalicular spaces. These spaces include for example the bile ducts, the urinary system, the airways and the subarachnoid space. The process is similar to that of transcoelomic spread. However, often it remains unclear whether simultaneously diagnosed tumors of a canalicular system are one metastatic process or in fact independent tumors caused by the same agent (field cancerization).
=== Organ-specific targets ===
There is a propensity for certain tumors to seed in particular organs. This was first discussed as the seed and soil theory by Stephen Paget in 1889. The propensity for a metastatic cell to spread to a particular organ is termed 'organotropism'. For example, prostate cancer usually metastasizes to the bones. In a similar manner, colon cancer has a tendency to metastasize to the liver. Stomach cancer often metastasises to the ovary in women, when it is called a Krukenberg tumor.
According to the seed and soil theory, it is difficult for cancer cells to survive outside their region of origin, so in order to metastasize they must find a location with similar characteristics. For example, breast tumor cells, which gather calcium ions from breast milk, metastasize to bone tissue, where they can gather calcium ions from bone. Malignant melanoma spreads to the brain, presumably because neural tissue and melanocytes arise from the same cell line in the embryo.
In 1928, James Ewing challenged the seed and soil theory, and proposed that metastasis occurs purely by anatomic and mechanical routes. This hypothesis has been recently utilized to suggest several hypotheses about the life cycle of circulating tumor cells (CTCs) and to postulate that the patterns of spread could be better understood through a 'filter and flow' perspective. However, contemporary evidences indicate that the primary tumour may dictate organotropic metastases by inducing the formation of pre-metastatic niches at distant sites, where incoming metastatic cells may engraft and colonise. Specifically, exosome vesicles secreted by tumours have been shown to home to pre-metastatic sites, where they activate pro-metastatic processes such as angiogenesis and modify the immune contexture, so as to foster a favourable microenvironment for secondary tumour growth.
=== Metastasis and primary cancer ===
It is theorized that metastasis always coincides with a primary cancer, and, as such, is a tumor that started from a cancer cell or cells in another part of the body. However, over 10% of patients presenting to oncology units will have metastases without a primary tumor found. In these cases, doctors refer to the primary tumor as "unknown" or "occult," and the patient is said to have cancer of unknown primary origin (CUP) or unknown primary tumors (UPT). It is estimated that 3% of all cancers are of unknown primary origin. Studies have shown that, if simple questioning does not reveal the cancer's source (coughing up blood—"probably lung", urinating blood—"probably bladder"), complex imaging will not either. In some of these cases a primary tumor may appear later.
The use of immunohistochemistry has permitted pathologists to give an identity to many of these metastases. However, imaging of the indicated area only occasionally reveals a primary. In rare cases (e.g., of melanoma), no primary tumor is found, even on autopsy. It is therefore thought that some primary tumors can regress completely, but leave their metastases behind. In other cases, the tumor might just be too small and/or in an unusual location to be diagnosed.
== Diagnosis ==
The cells in a metastatic tumor resemble those in the primary tumor. Once the cancerous tissue is examined under a microscope to determine the cell type, a doctor can usually tell whether that type of cell is normally found in the part of the body from which the tissue sample was taken.
For instance, breast cancer cells look the same whether they are found in the breast or have spread to another part of the body. So, if a tissue sample taken from a tumor in the lung contains cells that look like breast cells, the doctor determines that the lung tumor is a secondary tumor. Still, the determination of the primary tumor can often be very difficult, and the pathologist may have to use several adjuvant techniques, such as immunohistochemistry, FISH (fluorescent in situ hybridization), and others. Despite the use of techniques, in some cases the primary tumor remains unidentified.
Metastatic cancers may be found at the same time as the primary tumor, or months or years later. When a second tumor is found in a patient that has been treated for cancer in the past, it is more often a metastasis than another primary tumor.
It was previously thought that most cancer cells have a low metastatic potential and that there are rare cells that develop the ability to metastasize through the development of somatic mutations. According to this theory, diagnosis of metastatic cancers is only possible after the event of metastasis. Traditional means of diagnosing cancer (e.g. a biopsy) would only investigate a subpopulation of the cancer cells and would very likely not sample from the subpopulation with metastatic potential.
The somatic mutation theory of metastasis development has not been substantiated in human cancers. Rather, it seems that the genetic state of the primary tumor reflects the ability of that cancer to metastasize. Research comparing gene expression between primary and metastatic adenocarcinomas identified a subset of genes whose expression could distinguish primary tumors from metastatic tumors, dubbed a "metastatic signature." Up-regulated genes in the signature include: SNRPF, HNRPAB, DHPS and securin. Actin, myosin and MHC class II down-regulation was also associated with the signature. Additionally, the metastatic-associated expression of these genes was also observed in some primary tumors, indicating that cells with the potential to metastasize could be identified concurrently with diagnosis of the primary tumor. Recent work identified a form of genetic instability in cancer called chromosome instability (CIN) as a driver of metastasis. In aggressive cancer cells, loose DNA fragments from unstable chromosomes spill in the cytosol leading to the chronic activation of innate immune pathways, which are hijacked by cancer cells to spread to distant organs.
Expression of this metastatic signature has been correlated with a poor prognosis and has been shown to be consistent in several types of cancer. Prognosis was shown to be worse for individuals whose primary tumors expressed the metastatic signature. Additionally, the expression of these metastatic-associated genes was shown to apply to other cancer types in addition to adenocarcinoma. Metastases of breast cancer, medulloblastoma and prostate cancer all had similar expression patterns of these metastasis-associated genes.
The identification of this metastasis-associated signature provides promise for identifying cells with metastatic potential within the primary tumor and hope for improving the prognosis of these metastatic-associated cancers. Additionally, identifying the genes whose expression is changed in metastasis offers potential targets to inhibit metastasis.
== Management ==
Treatment and survival is determined, to a great extent, by whether or not a cancer remains localized or spreads to other locations in the body. If the cancer metastasizes to other tissues or organs it usually dramatically increases a patient's likelihood of death. Some cancers—such as some forms of leukemia, a cancer of the blood, or malignancies in the brain—can kill without spreading at all.
Once a cancer has metastasized it may still be treated with radiosurgery, chemotherapy, radiation therapy, biological therapy, hormone therapy, surgery, or a combination of these interventions ("multimodal therapy"). The choice of treatment depends on many factors, including the type of primary cancer, the size and location of the metastases, the patient's age and general health, and the types of treatments used previously. In patients diagnosed with CUP it is often still possible to treat the disease even when the primary tumor cannot be located.
Current treatments are rarely able to cure metastatic cancer though some tumors, such as testicular cancer and thyroid cancer, are usually curable.
Palliative care, care aimed at improving the quality of life of people with major illness, has been recommended as part of management programs for metastasis. Results from a systematic review of the literature on radiation therapy for brain metastases found that there is little evidence to inform comparative effectiveness and patient-centered outcomes on quality of life, functional status, and cognitive effects.
== Research ==
Although metastasis is widely accepted to be the result of the tumor cells migration, there is a hypothesis saying that some metastases are the result of inflammatory processes by abnormal immune cells. The existence of metastatic cancers in the absence of primary tumors also suggests that metastasis is not always caused by malignant cells that leave primary tumors.
The research done by Sarna's team proved that heavily pigmented melanoma cells have Young's modulus about 4.93, when in non-pigmented ones it was only 0.98. In another experiment they found that elasticity of melanoma cells is important for its metastasis and growth: non-pigmented tumors were bigger than pigmented and it was much easier for them to spread. They showed that there are both pigmented and non-pigmented cells in melanoma tumors, so that they can both be drug-resistant and metastatic.
== History ==
The first physician to report the possibility of local metastasis from a primary cancerous source to nearby tissues was Ibn Sina. He described a case of breast cancer and metastatic condition in The Canon of Medicine. His hypothesis was based on clinical course of the patient.
In March 2014 researchers discovered the oldest complete example of a human with metastatic cancer. The tumors had developed in a 3,000-year-old skeleton found in 2013 in a tomb in Sudan dating back to 1200 BC. The skeleton was analyzed using radiography and a scanning electron microscope. These findings were published in the Public Library of Science journal.
== Etymology ==
Metastasis is an Ancient Greek word (μετάστασις) meaning "displacement", from μετά, meta, "next", and στάσις, stasis, "placement".
== See also ==
Abscopal effect
Brain metastasis
Brown-Séquard syndrome
Collective cell migration
Contact normalization
Disseminated disease
Micrometastasis
Mouse models of breast cancer metastasis
Positron emission tomography (PET)
Urogenital pelvic malignancy
== References ==
== External links ==
"Q&A: Metastatic Cancer". National Cancer Institute. U.S. National Institutes of Health. Archived from the original on 4 January 2012.
Seah I, Jun Y (20 November 2014). "How does cancer spread – the route". TED-Ed – via YouTube. | Wikipedia/Metastatic_disease |
A localized disease is an infectious or neoplastic process that originates in and is confined to one organ system or general area in the body, such as a sprained ankle, a boil on the hand, an abscess of finger.
A localized cancer that has not extended beyond the margins of the organ involved can also be described as localized disease, while cancers that extend into other tissues are described as invasive. Tumors that are non-hematologic in origin but extend into the bloodstream or lymphatic system are known as metastatic.
Localized diseases are contrasted with disseminated diseases and systemic diseases.
Some diseases are capable of changing from local to disseminated diseases. Pneumonia, for example, is generally confined to one or both lungs but can become disseminated through sepsis, in which the microorganism responsible for the pneumonia "seeds" the bloodstream or lymphatic system and is transported to distant sites in the body. When that occurs, the process is no longer described as a localized disease, but rather as a disseminated disease.
== See also ==
Disease
Nosology
== References == | Wikipedia/Localized_disease |
Terminal illness or end-stage disease is a disease that cannot be cured or adequately treated and is expected to result in the death of the patient. This term is more commonly used for progressive diseases such as cancer, rather than fatal injury. In popular use, it indicates a disease that will progress until death with near absolute certainty, regardless of treatment. A patient who has such an illness may be referred to as a terminal patient, terminally ill or simply as being terminal. There is no standardized life expectancy for a patient to be considered terminal, although it is generally months or less. An illness which is lifelong but not fatal is called a chronic condition.
Terminal patients have options for disease management after diagnosis. Examples include caregiving, continued treatment, palliative and hospice care, and physician-assisted suicide. Decisions regarding management are made by the patient and their family, although medical professionals may offer recommendations of services available to terminal patients.
Lifestyle after diagnosis varies depending on management decisions and the nature of the disease, and there may be restrictions depending on the condition of the patient. Terminal patients may experience depression or anxiety associated with impending death, and family and caregivers may struggle with psychological burdens. Psychotherapeutic interventions may alleviate some of these burdens, and is often incorporated into palliative care.
When terminal patients are aware of their impending deaths, they have time to prepare for care, such as advance directives and living wills, which have been shown to improve end-of-life care. While death cannot be avoided, patients can strive to die a death seen as good. However, many healthcare providers are uncomfortable telling people or their families that they are dying. To avoid uncomfortable conversations, they will withhold information and evade questions.
== Definition ==
Accurately identifying the start of terminal status is important because it usually occasions a review of treatment goals. Although there is no single official definition, there are four typical characteristics for determining whether a person has a terminal illness:
The person is expected to die from this illness (i.e., not from old age).
The illness cannot be cured (or it is medically unlikely) and is expected to get worse.
The illness has reached an advanced stage.
The statistically likely remaining lifespan is measured in weeks or months, rather than years or decades. For example, four different US federal laws define the maximum expected lifespan in four different ways: no more than six months, nine months, 12 months, or 24 months.
When the remaining lifespan is expected to be days and the physical process of dying has begun, the term active dying may be used instead.
== Communicating terminal status ==
Most terminally ill people are not distressed by being told that they are likely to die sooner rather than later, and they usually value knowing whether their realistic lifespan is likely to be "weeks", "months", or "years", even if more specific estimates are unavailable. However, many healthcare providers avoid telling them this because the healthcare providers are uncomfortable with death or perceive it as a professional failure. To avoid admitting that the person will inevitably die from an incurable condition, they may withhold information or, if pressed, give overly optimistic answers. For example, if the typical person in that situation usually lives for two to six months, they may say only the larger number. They may rationalize the inflated claim by thinking of hopeful possibilities, such as an unproven treatment (which might shorten the person's life even further) being attempted, or because they know that life expectancy is an imperfect estimate and could be both shorter or longer than expected.
They may feel pressure from family members to give pleasant news or to preserve the false appearance of hope. They often want to avoid the emotional outbursts that are associated with people understanding the medical situation accurately. For example, they will use death-denying language such as "She has a life-limiting diagnosis" – a term that makes the inevitable death seem less inevitable – rather than bluntly saying "No matter what we do, your daughter is almost certainly going to die from this cancer, probably within the next few months."
== Management ==
By definition, there is not a cure or adequate treatment for terminal illnesses. However, some kinds of medical treatments may be appropriate anyway, such as treatment to reduce pain or ease breathing.
Some terminally ill patients stop all debilitating treatments to reduce unwanted side effects. Others continue aggressive treatment in the hope of an unexpected success. Still others reject conventional medical treatment and pursue unproven treatments such as radical dietary modifications. Patients' choices about different treatments may change over time. People who pursue aggressive treatment usually do not understand that their illness has reached a terminal stage, and they are pursuing treatment because they do not understand it to be futile.
Palliative care is normally offered to terminally ill patients, regardless of their overall disease management style, if it seems likely to help manage symptoms such as pain and improve quality of life. Hospice care, which can be provided at home or in a long-term care facility, additionally provides emotional and spiritual support for the patient and loved ones. Some complementary approaches, such as relaxation therapy, massage, and acupuncture may relieve some symptoms and other causes of suffering.
=== Caregiving ===
Terminal patients often need a caregiver, who could be a nurse, licensed practical nurse or a family member. Caregivers can help patients receive medications to reduce pain and control symptoms of nausea or vomiting. They can also assist the individual with daily living activities and movement. Caregivers provide assistance with food and psychological support and ensure that the individual is comfortable.
The patient's family may have questions and most caregivers can provide information to help ease the mind. Doctors generally do not provide estimates for fear of instilling false hopes or obliterate an individual's hope.
In most cases, the caregiver works along with physicians and follows professional instructions. Caregivers may call the physician or a nurse if the individual:
experiences excessive pain.
is in distress or having difficulty breathing.
has difficulty passing urine or is constipated.
has fallen and appears hurt.
is depressed and wants to harm themselves.
refuses to take prescribed medications, raising ethical concerns best addressed by a person with more extensive formal training.
or if the caregiver does not know how to handle the situation.
Most caregivers become the patient's listeners and let the individual express fears and concerns without judgment. Caregivers reassure the patient and honor all advance directives. Caregivers respect the individual's need for privacy and usually hold all information confidential.
=== Palliative care ===
Palliative care focuses on addressing patients' needs after disease diagnosis. While palliative care is not disease treatment, it addresses patients' physical needs, such as pain management, offers emotional support, caring for the patient psychologically and spiritually, and helps patients build support systems that can help them get through difficult times. Palliative care can also help patients make decisions and come to understand what they want regarding their treatment goals and quality of life.
Palliative care is an attempt to improve patients' quality-of-life and comfort, and also provide support for family members and carers. Additionally, it lowers hospital admissions costs. However, needs for palliative care are often unmet whether due to lack of government support and also possible stigma associated with palliative care. For these reasons, the World Health Assembly recommends development of palliative care in health care systems.
Palliative care and hospice care are often confused, and they have similar goals. However, hospice care is specifically for terminal patients while palliative care is more general and offered to patients who are not necessarily terminal.
=== Hospice care ===
While hospitals focus on treating the disease, hospices focus on improving patient quality-of-life until death. Hospice patients are able to live at peace away from a hospital setting; they may live at home with a hospice provider or at an inpatient hospice facility.
A common misconception is that hospice care hastens death because patients "give up" fighting the disease. However, people in hospice care often live the same length of time as patients in the hospital, or longer. Additionally, people receiving hospice care have significantly lower healthcare expenditures.
Hospice care allows patients to spend more time with family and friends. People in institutional (rather than home-care) hospice programs are also in the company of other hospice patients, which provides them with an additional support network.
=== Medications for terminal patients ===
Terminal patients experiencing pain, especially cancer-related pain, are often prescribed opioids to relieve suffering. The specific medication prescribed, however, will differ depending on severity of pain and disease status.
There exist inequities in availability of opioids to terminal patients, especially in countries where opioid access is limited.
A common symptom that many terminal patients experience is dyspnea, or difficulty with breathing. To ease this symptom, doctors may also prescribe opioids to patients. Some studies suggest that oral opioids may help with breathlessness. However, due to lack of consistent reliable evidence, it is currently unclear whether they truly work for this purpose.
Depending on the patient's condition, other medications will be prescribed accordingly. For example, if patients develop depression, antidepressants will be prescribed. Anti-inflammation and anti-nausea medications may also be prescribed.
=== Continued treatment ===
Some terminal patients opt to continue extensive treatments in hope of a miracle cure, whether by participating in experimental treatments and clinical trials or seeking more intense treatment for the disease. Rather than to "give up fighting," patients spend thousands more dollars to try to prolong life by a few more months. What these patients often do give up, however, is quality of life at the end of life by undergoing intense and often uncomfortable treatment. A meta-analysis of 34 studies including 11,326 patients from 11 countries found that less than half of all terminal patients correctly understood their disease prognosis, or the course of their disease and likeliness of survival. This could influence patients to pursue unnecessary treatment for the disease due to unrealistic expectations.
=== Transplant ===
For patients with end stage kidney failure, studies have shown that transplants increase the quality of life and decreases mortality in this population. In order to be placed on the organ transplant list, patients are referred and assessed based on criteria that ranges from current comorbidities to potential for organ rejection post transplant. Initial screening measures include: blood tests, pregnancy tests, serologic tests, urinalysis, drug screening, imaging, and physical exams.
For patients who are interested in liver transplantation, patients with acute liver failure have the highest priority over patients with only cirrhosis. Acute liver failure patients will present with worsening symptoms of somnolence or confusion (hepatic encephalopathy) and thinner blood (increased INR) due to the liver's inability to make clotting factors. Some patients could experience portal hypertension, hemorrhages, and abdominal swelling (ascites). Model for End Stage Liver Disease (MELD) is often used to help providers decide and prioritize candidates for transplant.
=== Physician-assisted suicide ===
Physician-assisted suicide (PAS) is highly controversial, and legal in only a few countries. In PAS, physicians, with voluntary written and verbal consent from the patient, give patients the means to die, usually through lethal drugs. The patient then chooses to "die with dignity," deciding on their own time and place to die. Reasons as to why patients choose PAS differ. Factors that may play into a patient's decision include future disability and suffering, lack of control over death, impact on family, healthcare costs, insurance coverage, personal beliefs, religious beliefs, and much more.
PAS may be referred to in many different ways, such as aid in dying, assisted dying, death with dignity, and many more. These often depend on the organization and the stance they take on the issue. In this section of the article, it will be referred to as PAS for the sake of consistency with the pre-existing Wikipedia page: Assisted Suicide.
In the United States, PAS or medical aid in dying is legal in select states, including Oregon, Washington, Montana, Vermont, and New Mexico, and there are groups both in favor of and against legalization.
Some groups favor PAS because they do not believe they will have control over their pain, because they believe they will be a burden on their family, and because they do not want to lose autonomy and control over their own lives among other reasons. They believe that allowing PAS is an act of compassion.
While some groups believe in personal choice over death, others raise concerns regarding insurance policies and potential for abuse. According to Sulmasy et al., the major non-religious arguments against physician-assisted suicide are quoted as follows:
(1) "it offends me", suicide devalues human life;
(2) slippery slope, the limits on euthanasia gradually erode;
(3) "pain can be alleviated", palliative care and modern therapeutics more and more adequately manage pain;
(4) physician integrity and patient trust, participating in suicide violates the integrity of the physician and undermines the trust patients place in physicians to heal and not to harm"
Again, there are also arguments that there are enough protections in the law that the slippery slope is avoided. For example, the Death with Dignity Act in Oregon includes waiting periods, multiple requests for lethal drugs, a psychiatric evaluation in the case of possible depression influencing decisions, and the patient personally swallowing the pills to ensure voluntary decision.
Physicians and medical professionals also have disagreeing views on PAS. Some groups, such as the American College of Physicians (ACP), the American Medical Association (AMA), the World Health Organization, American Nurses Association, Hospice Nurses Association, American Psychiatric Association, and more have issued position statements against its legalization.
The ACP's argument concerns the nature of the doctor-patient relationship and the tenets of the medical profession. They state that instead of using PAS to control death: "through high-quality care, effective communication, compassionate support, and the right resources, physicians can help patients control many aspects of how they live out life's last chapter."
Other groups such as the American Medical Students Association, the American Public Health Association, the American Medical Women's Association, and more support PAS as an act of compassion for the suffering patient.
In many cases, the argument on PAS is also tied to proper palliative care. The International Association for Hospice and Palliative Care issued a position statement arguing against considering legalizing PAS unless comprehensive palliative care systems in the country were in place. It could be argued that with proper palliative care, the patient would experience fewer intolerable symptoms, physical or emotional, and would not choose death over these symptoms. Palliative care would also ensure that patients receive proper information about their disease prognosis as not to make decisions about PAS without complete and careful consideration.
== Medical care ==
Many aspects of medical care are different for terminal patients compared to patients in the hospital for other reasons.
=== Doctor–patient relationships ===
Doctor–patient relationships are crucial in any medical setting, and especially so for terminal patients. There must be an inherent trust in the doctor to provide the best possible care for the patient. In the case of terminal illness, there is often ambiguity in communication with the patient about their condition. While terminal condition prognosis is often a grave matter, doctors do not wish to quash all hope, for it could unnecessarily harm the patient's mental state and have unintended consequences. However, being overly optimistic about outcomes can leave patients and families devastated when negative results arise, as is often the case with terminal illness.
=== Mortality predictions ===
Often, a patient is considered terminally ill when his or her estimated life expectancy is six months or less, under the assumption that the disease will run its normal course based on previous data from other patients. The six-month standard is arbitrary, and best available estimates of longevity may be incorrect. Though a given patient may properly be considered terminal, this is not a guarantee that the patient will die within six months. Similarly, a patient with a slowly progressing disease, such as AIDS, may not be considered terminally ill if the best estimate of longevity is greater than six months. However, this does not guarantee that the patient will not die unexpectedly early.
In general, physicians slightly overestimate the survival time of terminally ill cancer patients, so that, for example, a person who is expected to live for about six weeks would likely die around four weeks.
A recent systematic review on palliative patients in general, rather than specifically cancer patients, states the following: "Accuracy of categorical estimates in this systematic review ranged from 23% up to 78% and continuous estimates over-predicted actual survival by, potentially, a factor of two." There was no evidence that any specific type of clinician was better at making these predictions.
=== Healthcare spending ===
Healthcare during the last year of life is costly, especially for patients who used hospital services often during end-of-life.
In fact, according to Langton et al., there were "exponential increases in service use and costs as death approached."
Many dying terminal patients are also brought to the emergency department (ED) at the end of life when treatment is no longer beneficial, raising costs and using limited space in the ED.
While there are often claims about "disproportionate" spending of money and resources on end-of-life patients, data have not proven this type of correlation.
The cost of healthcare for end-of-life patients is 13% of annual healthcare spending in the U.S. However, of the group of patients with the highest healthcare spending, end-of-life patients only made up 11% of these people, meaning the most expensive spending is not made up mostly of terminal patients.
Many recent studies have shown that palliative care and hospice options as an alternative are much less expensive for end-of-life patients.
== Psychological impact ==
Coping with impending death is a hard topic to digest universally. Patients may experience grief, fear, loneliness, depression, and anxiety among many other possible responses. Terminal illness can also lend patients to become more prone to psychological illness such as depression and anxiety disorders. Insomnia is a common symptom of these.
It is important for loved ones to show their support for the patient during these times and to listen to his or her concerns.
People who are terminally ill may not always come to accept their impending death. For example, a person who finds strength in denial may never reach a point of acceptance or accommodation and may react negatively to any statement that threatens this defense mechanism.
=== Impact on patient ===
Depression is relatively common among terminal patients, and the prevalence increases as patients become sicker. Depression causes quality of life to go down, and a sizable portion of patients who request assisted suicide are depressed. These negative emotions may be heightened by lack of sleep and pain as well. Depression can be treated with antidepressants, therapy, or both, but doctors often do not realize the extent of terminal patients' depression.
Because depression is common among terminal patients, the American College of Physicians recommends regular assessments for depression for this population and appropriate prescription of antidepressants.
Anxiety disorders are also relatively common for terminal patients as they face their mortality. Patients may feel distressed when thinking about what the future may hold, especially when considering the future of their families as well. It is important to note, however, that some palliative medications may facilitate anxiety.
=== Coping for patients ===
Caregivers may listen to the concerns of terminal patients to help them reflect on their emotions. Different forms of psychotherapy and psychosocial intervention, which can be offered with palliative care, may also help patients think about and overcome their feelings. According to Block, "most terminally ill patients benefit from an approach that combines emotional support, flexibility, appreciation of the patient's strengths, a warm and genuine relationship with the therapist, elements of life-review, and exploration of fears and concerns."
=== Impact on family ===
Terminal patients' families often also suffer psychological consequences. If not well equipped to face the reality of their loved one's illness, family members may develop depressive symptoms and even have increased mortality. Taking care of sick family members may also cause stress, grief, and worry. Additionally, financial burden from medical treatment may be a source of stress. Parents of terminally ill children also face additional challenges in addition to mental health stressors including difficulty balancing caregiving and maintaining employment. Many report feeling as if they have to "do it all" by balancing caring for their chronically ill child, limiting absence from work, and supporting their family members. Children of terminally ill parents often experience a role reversal in which they become the caretakers of their adult parents. In taking on the burden of caring for their sick parent and assuming the responsibilities they can no longer accomplish, many children also experience significant declines in academic performance.
=== Coping for family ===
Discussing the anticipated loss and planning for the future may help family members accept and prepare for the patient's death. Interventions may also be offered for anticipatory grief. In the case of more serious consequences such as depression, a more serious intervention or therapy is recommended. Upon the death of someone who is terminally ill, many family members that served as caregivers are likely to experience declines in their mental health. Grief counseling and grief therapy may also be recommended for family members after a loved one's death.
== Dying ==
When dying, patients often worry about their quality of life towards the end, including emotional and physical suffering.
In order for families and doctors to understand clearly what the patient wants for themselves, it is recommended that patients, doctors, and families all convene and discuss the patient's decisions before the patient becomes unable to decide.
=== Advance directives ===
At the end of life, especially when patients are unable to make decisions on their own regarding treatment, it is often up to family members and doctors to decide what they believe the patients would have wanted regarding their deaths, which is often a heavy burden and hard for family members to predict. An estimated 25% of American adults have an advance directive, meaning the majority of Americans leave these decisions to be made by family, which can lead to conflict and guilt. Although it may be a difficult subject to broach, it is important to discuss the patient's plans for how far to continue treatment should they become unable to decide. This must be done while the patient is still able to make the decisions, and takes the form of an advance directive. The advance directive should be updated regularly as the patient's condition changes so as to reflect the patient's wishes.
Some of the decisions that advance directives may address include receiving fluids and nutrition support, getting blood transfusions, receiving antibiotics, resuscitation (if the heart stops beating), and intubation (if the patient stops breathing).
Having an advance directive can improve end-of-life care.
It is highly recommended by many research studies and meta-analyses for patients to discuss and create an advance directive with their doctors and families.
=== Do-not-resuscitate ===
One of the options of care that patients may discuss with their families and medical providers is the do-not-resuscitate (DNR) order. This means that if the patient's heart stops, CPR and other methods to bring back heartbeat would not be performed. This is the patient's choice to make and can depend on a variety of reasons, whether based on personal beliefs or medical concerns. DNR orders can be medically and legally binding depending on the applicable jurisdiction.
Decisions like these should be indicated in the advance directive so that the patient's wishes can be carried out to improve end-of-life care.
=== Symptoms near death ===
A variety of symptoms become more apparent when a patient is nearing death. Recognizing these symptoms and knowing what will come may help family members prepare.
During the final few weeks, symptoms will vary largely depending on the patient's disease. During the final hours, patients usually will reject food and water and will also sleep more, choosing not to interact with those around them. Their bodies may behave more irregularly, with changes in breathing, sometimes with longer pauses between breaths, irregular heart rate, low blood pressure, and coldness in the extremities. It is important to note, however, that symptoms will vary per patient.
=== Good death ===
Patients, healthcare workers, and recently bereaved family members often describe a "good death" in terms of effective choices made in a few areas:
Assurance of effective pain and symptom management.
Education about death and its aftermath, especially as it relates to decision-making.
Completion of any significant goals, such as resolving past conflicts.
In the last hours of life, palliative sedation may be recommended by a doctor or requested by the patient to ease the symptoms of death until they die. Palliative sedation is not intended to prolong life or hasten death; it is merely meant to relieve symptoms.
== See also ==
Advance healthcare directive
Anticipatory grief
Do not resuscitate
End-of-life care
Euthanasia
Hospice care in the United States
Interventionism (medicine)
Liverpool Care Pathway for the Dying Patient
Palliative care
Assisted suicide
== References ==
== Further reading ==
"Letting Go" by Atul Gawande (link)
"Last Days of Life" for cancer patients provided by the National Cancer Institute (link)
"Living with a terminal illness" by Marie Curie (link) | Wikipedia/Terminal_disease |
Your Disease Risk is a publicly available health risk assessment tool on the Internet. Launched in early 2000 and continually updated, the site offers risk assessments for twelve different cancers and four other important chronic diseases: heart disease, stroke, diabetes, and osteoporosis.
The site began in 1998 as a pen and paper questionnaire called the Harvard Cancer Risk Index. In January 2000, The Harvard Cancer Risk Index developed into an online assessment and was renamed Your Cancer Risk, and offered assessments for four cancers: breast, colon, lung, and prostate. Six months later, eight additional cancers were added.
In 2004, the site was renamed Your Disease Risk to reflect the addition of four further conditions: heart disease, stroke, diabetes, and osteoporosis. Since many common chronic diseases share risk factors, the renaming promoted the importance of a healthy lifestyle to lowering disease risks.
In 2007, the site moved to the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
In 2012, researchers released a related iPad app, called Zuum, that offers customized advice for healthier living based on an individual's diet, exercise and other habits.
In December 2018, the site was re-designed to work across multiple screen sizes - from smartphone to desktop - and a new "Snapshot" tool was added, which provides a quick estimate of 6 diseases from one brief questionnaire.
== User experience ==
Your Disease Risk has a simple, straightforward interface. Questionnaires can be completed in a matter of minutes, and for each disease, the site offers both a visual and verbal risk estimate as well as personalized tips for prevention. The site can also show users what their risk could be should they adopt various healthy behaviors. Tailored screening tips and recommendations for making health changes in communities are also part of site results.
== Methodology ==
The calculations and algorithms used to calculate and display risk estimates in Your Disease Risk are the product of an ongoing process of expert consensus. Epidemiologists, clinicians, and other health specialists regularly review the current scientific evidence for each disease, identifying established and probable risk factors for each. This information is then used to develop or revise calculations that generate a user's risk of disease compared to average risk in the population for someone of the same age and sex.
A validation study found Your Disease Risk to provide well calibrated estimates of cancer risk in the general population. For individual women, the discriminatory accuracy for colon cancer was 0.67, for ovarian cancer 0.59, and for pancreatic cancer was 0.71. For individual men, the discriminatory accuracy for colon cancer was 0.71 and for pancreatic cancer was 0.72. These values exceed the performance of many other cancer risk prediction tools.
The approach used to calculate cancer risks in Your Disease. Risk is also used to calculate the risks of the other diseases. Validation studies for these non-cancer estimates are ongoing.
== Awards and media ==
A winner of the eHealthcare Leadership Award, Your Disease Risk has also been the topic of articles in major media outlets.
== References ==
== External links ==
Your Disease Risk
Zuum on iTunes | Wikipedia/Your_Disease_Risk |
Anti-citrullinated protein antibodies (ACPAs) are autoantibodies (antibodies to an individual's own proteins) that are directed against peptides and proteins that are citrullinated. They are present in the majority of patients with rheumatoid arthritis. Clinically, cyclic citrullinated peptides (CCP) are frequently used to detect these antibodies in patient serum or plasma (then referred to as anti–citrullinated peptide antibodies).
During inflammation, arginine amino acid residues can be enzymatically converted into citrulline residues in proteins such as vimentin, by a process called citrullination. If their shapes are significantly altered, the proteins may be seen as antigens by the immune system, thereby generating an immune response.
ACPAs have proved to be powerful biomarkers that allow the diagnosis of rheumatoid arthritis (RA) to be made at a very early stage.
In July 2010, the 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria were introduced. These new classification criteria include ACPA testing, and overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis.
== History ==
The presence of autoantibodies against citrullinated proteins in rheumatoid arthritis patients was first described in the mid-1970s when the biochemical basis of antibody reactivity against keratin and filaggrin was investigated. Subsequent studies demonstrated that autoantibodies from RA patients react with a series of different citrullinated antigens, including fibrinogen, deiminated Epstein-Barr Virus Nuclear Antigen 1 and vimentin, which is a member of the intermediate filament family of proteins. Several assays for detecting ACPAs were developed in the following years, employing mutated citrullinated Vimentin (MCV-assay), filaggrin-derived peptides (CCP-assay) and viral citrullinated peptides (VCP-assay).
A 2006 clinical study showed that anti viral citrullinated peptide (VCP) antibodies of the IgG and IgA isotypes represent a discriminating specific marker of rheumatoid arthritis from other chronic arthritides and disease controls, suggesting an independent production of each isotype.
In 2010, ACPA testing has become substantial part of The 2010 ACR-EULAR classification criteria for rheumatoid arthritis.
== Clinical significance ==
In a comparative study (in 2007), various detection kits had a sensitivity between 69.6% and 77.5% and a specificity between 87.8% and 96.4%. Despite the excellent performance of these immunoassays, for example CCP-assays, they only provide a sensitivity comparable with that of rheumatoid factor (RF). Moreover, analysis of the correlation of anti-CCP antibody titre with RA disease activity yielded conflicting results.
However, novel test systems utilizing ACPA have been developed. Citrullinated vimentin is a very promising autoantigen in RA, and a suitable tool for studying this systemic autoimmune disease. Vimentin is secreted and citrullinated by macrophages in response to apoptosis, or by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha).
A newly developed ELISA system utilises genetically modified citrullinated vimentin (MCV), a naturally occurring isoform of vimentin to optimize the performance of the test. Noteworthy are the findings of a recently published study that highly valuates anti-MCV test systems for diagnosing rheumatoid arthritis in anti-CCP-negative patients. However, data from all around the world vary substantially. Anti-CCP is also very useful in the early diagnosis of rheumatoid arthritis in high-risk groups, such as relatives of RA patients, although Silman and co-workers found that the concordance rate of developing RA was 15.4% among identical (monozygotic) twins and was 3.6% among fraternal (dizygotic) twins.
Given that ACPA are more specific than rheumatoid factor, they are used to distinguish various causes of arthritis. Novel assays may be useful for monitoring disease activity and effects of RA therapy.
The reference ranges for blood tests of anti–citrullinated protein antibodies are:
Anti-CCP is part of the 2010 ACR/EULAR classification criteria for Rheumatoid Arthritis. Anti-CCP positivity is also a good prognostic marker for future radiographic damage, and possibly a marker to B-cell therapy responses including rituximab.
Combination of anti-CCP with other serological markers like rheumatoid factor, 14-3-3η (YWHAH) not only enhances the diagnostic capture rate but together with acute phase reactants either in early disease or at the time of diagnosis may be useful in predicting future outcomes.
== Other ACPAs and citrullinated targets in RA ==
Vimentin, fibrin, filaggrin, enolase and keratin are common citrullination targets. The list of proteins that undergo citrullination and make up the citrullinome continues to increase. The RA associated citrullinome has been reported to include targets from synovial fluid and tissue that range from proteases, receptors, and carrier proteins. These proteins are components of complement, proteolytic activity, cell recognition, endocytosis, and response to biotic stimuli amongst others. 14-3-3η (YWHAH) is also another synovial derived protein that has been reported as a citrullination target.
== References == | Wikipedia/Anti–citrullinated_protein_antibody |
Anti-glycoprotein-210 antibodies (AGPA, anti-gp210, anti-nup210, anti-np210) are directed at gp210 and are found within primary biliary cirrhosis (PBC) patients in high frequency. AGPA recognize the cytoplasmic-oriented carboxyl terminus (tail) of the protein. While AGPA is found as a prognostic marker in only a minority of PBC patients, those that did had higher mortality and were predicted a poor outcome. In addition, patients that responded to ursodeoxycholic acid (UDCA) therapy and, therefore, had AGPA reductions failed to develop end-stage liver disease relative to untreated cohort with anti-gp210 Ab. PBC patients with potentially destructive
AGPA have increased expression of Nup210 in the bile duct, a potential immune tolerance-escaping factor.
Anti-mitochondrial, anti-centromere and anti-p62 antibodies are also found in (PBC). While patients with AGPA progress toward end-stage liver failure, patients with anti-centromere antibodies often progress toward portal hypertension, further indicating a specific role of the AGPA in PBC.
== Notes ==
The glycoprotein gp210 is commonly used in the literature. The gene, NUP210, encodes the nuclear pore (nuclear porin) glycoprotein-210 that is a major component of the human nuclear pore complex.
== References == | Wikipedia/Anti-glycoprotein-210_antibodies |
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spelt and barley. Classic symptoms include gastrointestinal problems such as chronic diarrhoea, abdominal distention, malabsorption, loss of appetite, and among children failure to grow normally.
Non-classic symptoms are more common, especially in people older than two years. There may be mild or absent gastrointestinal symptoms, a wide number of symptoms involving any part of the body, or no obvious symptoms. Due to the frequency of these symptoms, coeliac disease is often considered a systemic disease, rather than a gastrointestinal condition. Coeliac disease was first described as a disease which initially presents during childhood; however, it may develop at any age. It is associated with other autoimmune diseases, such as Type 1 diabetes mellitus and Hashimoto's thyroiditis, among others.
Coeliac disease is caused by a reaction to gluten, a group of various proteins found in wheat and in other grains such as barley and rye. Moderate quantities of oats, free of contamination with other gluten-containing grains, are usually tolerated. The occurrence of problems may depend on the variety of oat. It occurs more often in people who are genetically predisposed. Upon exposure to gluten, an abnormal immune response may lead to the production of several different autoantibodies that can affect a number of different organs. In the small bowel, this causes an inflammatory reaction and may produce shortening of the villi lining the small intestine (villous atrophy). This affects the absorption of nutrients, frequently leading to anaemia.
Diagnosis is typically made by a combination of blood antibody tests and intestinal biopsies, helped by specific genetic testing. Making the diagnosis is not always straightforward. About 10% of the time, the autoantibodies in the blood are negative, and many people have only minor intestinal changes with normal villi. People may have severe symptoms and they may be investigated for years before a diagnosis is achieved. As a result of screening, the diagnosis is increasingly being made in people who have no symptoms. Evidence regarding the effects of screening, however, is currently insufficient to determine its usefulness. While the disease is caused by a permanent intolerance to gluten proteins, it is distinct from wheat allergy, which is much more rare.
The only known effective treatment is a strict lifelong gluten-free diet, which leads to recovery of the intestinal lining (mucous membrane), improves symptoms, and reduces the risk of developing complications in most people. If untreated, it may result in cancers such as intestinal lymphoma, and a slightly increased risk of early death. Rates vary between different regions of the world, from as few as 1 in 300 to as many as 1 in 40, with an average of between 1 in 100 and 1 in 170 people. It is estimated that 80% of cases remain undiagnosed, usually because of minimal or absent gastrointestinal complaints and lack of knowledge of symptoms and diagnostic criteria. Coeliac disease is slightly more common in women than in men.
== Signs and symptoms ==
The classic symptoms of untreated coeliac disease include diarrhea, steatorrhoea, iron-deficiency anemia, and weight loss or failure to gain weight. Other common symptoms may be subtle or primarily occur in organs other than the bowel itself. It is also possible to have coeliac disease without any of the classic symptoms at all. This has been shown to comprise at least 43% of presentations in children. Further, many adults with subtle disease may only present with fatigue, anaemia or low bone mass. Many undiagnosed individuals who consider themselves asymptomatic are in fact not, but rather have become accustomed to living in a state of chronically compromised health. Indeed, after starting a gluten-free diet and subsequent improvement becomes evident, such individuals are often able to retrospectively recall and recognise prior symptoms of their untreated disease that they had mistakenly ignored.
=== Gastrointestinal ===
Diarrhoea that is characteristic of coeliac disease is chronic, sometimes pale, of large volume, and abnormally foul in odor. Abdominal pain, cramping, bloating with abdominal distension (thought to be the result of fermentative production of bowel gas), and mouth ulcers may be present. As the bowel becomes more damaged, a degree of lactose intolerance may develop. This is because in addition to damage in the intestines, coeliac disease can cause a lactase deficiency, which is the enzyme that is responsible for breaking down lactose. Frequently, the symptoms are ascribed to irritable bowel syndrome (IBS), only later to be recognised as coeliac disease. In populations of people with symptoms of IBS, a diagnosis of coeliac disease can be made in about 3.3% of cases, or four times more likely than in general. Screening them for coeliac disease is recommended by the National Institute for Health and Clinical Excellence (NICE), the British Society of Gastroenterology and the American College of Gastroenterology, but is of unclear benefit in North America.
Coeliac disease leads to an increased risk of both adenocarcinoma and lymphoma of the small bowel (enteropathy-associated T-cell lymphoma (EATL) or other non-Hodgkin lymphomas). This risk is also higher in first-degree relatives such as siblings, parents and children. Whether a gluten-free diet brings this risk back to baseline is not clear. Long-standing and untreated disease may lead to other complications, such as ulcerative jejunitis (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring with obstruction of the bowel).
=== Malabsorption-related ===
The changes in the bowel reduce its ability to absorb nutrients, minerals, and the fat-soluble vitamins A, D, E, and K.
Malabsorption of carbohydrates and fats may cause weight loss (or failure to thrive or stunted growth in children) and fatigue or lack of energy.
Anaemia may develop in several ways: iron malabsorption may cause iron deficiency anaemia, and folic acid and vitamin B12 malabsorption may give rise to megaloblastic anaemia.
Calcium and vitamin D malabsorption (and compensatory secondary hyperparathyroidism) may cause osteopenia (decreased mineral content of the bone) or osteoporosis (bone weakening and risk of fragility fractures).
Selenium malabsorption in coeliac disease, combined with low selenium content in many gluten-free foods, confers a risk of selenium deficiency.
Copper and zinc deficiencies have also been associated with coeliac disease.
A small proportion of people have abnormal coagulation because of vitamin K deficiency and are at a slight risk of abnormal bleeding.
=== Miscellaneous ===
Coeliac disease has been linked with many conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.
IgA deficiency is present in 2.3% of people with coeliac disease, and is itself associated with a tenfold increased risk of coeliac disease. Other features of this condition are an increased risk of infections and autoimmune disease.
Dermatitis herpetiformis, an itchy cutaneous condition that has been linked to a transglutaminase enzyme in the skin, features small-bowel changes identical to those in coeliac disease and may respond to gluten withdrawal even if no gastrointestinal symptoms are present.
Growth failure and/or pubertal delay in later childhood can occur even without obvious bowel symptoms or severe malnutrition. Evaluation of growth failure often includes coeliac screening.
Pregnancy complications can occur if coeliac disease is pre-existing or later acquired, with significant outcomes including miscarriage, intrauterine growth restriction, low birthweight and preterm birth.
Hyposplenism (a small and underactive spleen) occurs in about a third of cases and may predispose to infection given the role of the spleen in protecting against harmful bacteria.
Abnormal liver function tests (randomly detected on blood tests) may be seen.
Depression, anxiety and other mental health disorders
Coeliac disease is associated with several other medical conditions, many of which are autoimmune disorders: diabetes mellitus type 1, hypothyroidism, primary biliary cholangitis, microscopic colitis, gluten ataxia, psoriasis, vitiligo, autoimmune hepatitis, primary sclerosing cholangitis, and more.
== Causes ==
Coeliac disease is caused by an inflammatory reaction to gliadins and glutenins (gluten proteins) found in wheat and to similar proteins found in the crops of the tribe Triticeae (which includes other common grains such as barley and rye) and to the tribe Aveneae (oats). Wheat subspecies (such as spelt, durum, and Kamut) and wheat hybrids (such as triticale) also cause symptoms of coeliac disease.
A small number of people with coeliac disease react to oats. Oat toxicity in coeliac people depends on the oat cultivar consumed because the prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins are different in different oat varieties. Also, oats are frequently cross-contaminated with other grains containing gluten. The term "pure oats" refers to oats uncontaminated with other gluten-containing cereals. The long-term effects of pure oat consumption are still unclear, and further studies identifying the cultivars used are needed before making final recommendations on their inclusion in a gluten-free diet. Coeliac people who choose to consume oats need a more rigorous lifelong follow-up, possibly including periodic intestinal biopsies.
=== Other grains ===
Other cereals such as corn, millet, sorghum, teff, rice, and wild rice are safe for people with coeliac disease to consume, as well as non-cereals such as amaranth, quinoa, and buckwheat. Noncereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.
=== Risk modifiers ===
There are various theories as to what determines whether a genetically susceptible individual will go on to develop coeliac disease. Major theories include surgery, pregnancy, infection and emotional stress.
The eating of gluten early in a baby's life does not appear to increase the risk of coeliac disease but later introduction after six months may increase it. There is uncertainty whether being breastfed reduces risk. Prolonging breastfeeding until the introduction of gluten-containing grains into the diet appears to be associated with a 50% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear. These factors may just influence the timing of onset.
== Mechanism ==
Coeliac disease appears to be multifactorial, both in that more than one genetic factor can cause the disease and in that more than one factor is necessary for the disease to manifest in a person.
Almost all people (95%) with coeliac disease have either the variant HLA-DQ2 allele or (less commonly) the HLA-DQ8 allele. However, about 20–30% of people without coeliac disease have also inherited either of these alleles. This suggests that additional factors are needed for coeliac disease to develop; that is, the predisposing HLA risk allele is necessary but not sufficient to develop coeliac disease. Furthermore, around 5% of those people who do develop coeliac disease do not have typical HLA-DQ2 or HLA-DQ8 alleles (see below).
=== Genetics ===
The vast majority of people with coeliac have one of two types (out of seven) of the HLA-DQ protein. HLA-DQ is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. The two subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and HLA-DQB1 genes, located on the short arm of chromosome 6.
There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of people with coeliac have the isoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process.
Most people with coeliac bear a two-gene HLA-DQ2 haplotype referred to as DQ2.5 haplotype. This haplotype is composed of two adjacent gene alleles, DQA1*0501 and DQB1*0201, which encode the two subunits, DQ α5 and DQ β2. In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents (DQ2.5cis). Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from both parents; the latter are especially at risk for coeliac disease as well as being more susceptible to severe complications.
Some individuals inherit DQ2.5 from one parent and an additional portion of the haplotype (either DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent (DQ2.5trans) (called a trans-haplotype association), and these individuals are at similar risk for coeliac disease as those with a single DQ2.5-bearing chromosome 6, but in this instance, the disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 4% have the DQ2.2 isoform, and the remaining 2% lack DQ2 or DQ8.
The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe (Basque Country and Ireland with highest frequencies) and portions of Africa and is associated with disease in India, but it is not found along portions of the West Pacific rim. DQ8 has a wider global distribution than DQ2.5 and is particularly common in South and Central America; up to 90% of individuals in certain Amerindian populations carry DQ8 and thus may display the coeliac phenotype.
Other genetic factors have been repeatedly reported in coeliac disease; however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population. Many of the loci detected have been found in association with other autoimmune diseases. One locus, the LPP or lipoma-preferred partner gene, is involved in the adhesion of extracellular matrix to the cell surface, and a minor variant (SNP=rs1464510) increases the risk of disease by approximately 30%. This gene strongly associates with coeliac disease (p < 10−39) in samples taken from a broad area of Europe and the US.
The prevalence of coeliac disease genotypes in the modern population is not completely understood. Given the characteristics of the disease and its apparent strong heritability, it would normally be expected that the genotypes would undergo negative selection and to be absent in societies where agriculture has been practised the longest (compare with a similar condition, lactose intolerance, which has been negatively selected so strongly that its prevalence went from ~100% in ancestral populations to less than 5% in some European countries). This expectation was first proposed by Simoons (1981). By now, however, it is apparent that this is not the case; on the contrary, there is evidence of positive selection in coeliac disease genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections.
=== Prolamins ===
The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. These are storage proteins rich in proline (prol-) and glutamine (-amin) that dissolve in alcohols and are resistant to proteases and peptidases of the gut. Prolamins are found in cereal grains with different grains having different but related prolamins: wheat (gliadin), barley (hordein), rye (secalin) and oats (avenin). One region of α-gliadin stimulates membrane cells, enterocytes, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than three amino acids to enter the intestinal lining.
Membrane leaking permits peptides of gliadin that stimulate two levels of the immune response: the innate response, and the adaptive (T-helper cell-mediated) response. One protease-resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. This innate response to gliadin results in immune-system signalling that attracts inflammatory cells and increases the release of inflammatory chemicals. The strongest and most common adaptive response to gliadin is directed toward an α2-gliadin fragment of 33 amino acids in length.
The response to the 33mer occurs in most coeliacs who have a DQ2 isoform. This peptide, when altered by intestinal transglutaminase, has a high density of overlapping T-cell epitopes. This increases the likelihood that the DQ2 isoform will bind, and stay bound to, peptide when recognised by T-cells. Gliadin in wheat is the best-understood member of this family, but other prolamins exist, and hordein (from barley), secalin (from rye), and avenin (from oats) may contribute to coeliac disease. Avenin's toxicity in people with coeliac disease depends on the oat cultivar consumed, as prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins vary among oat varieties.
=== Tissue transglutaminase ===
Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in the blood of the majority of people with classic symptoms and complete villous atrophy, but only in 70% of the cases with partial villous atrophy and 30% of the cases with minor mucosal lesions. Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively. These peptides are modified by tTG in two ways, deamidation or transamidation.
Deamidation is the reaction by which a glutamate residue is formed by cleavage of the epsilon-amino group of a glutamine side chain. Transamidation, which occurs three times more often than deamidation, is the cross-linking of a glutamine residue from the gliadin peptide to a lysine residue of tTg in a reaction that is catalysed by the transglutaminase. Crosslinking may occur either within or outside the active site of the enzyme. The latter case yields a permanently covalently linked complex between the gliadin and the tTg. This results in the formation of new epitopes believed to trigger the primary immune response by which the autoantibodies against tTg develop.
Stored biopsies from people with suspected coeliac disease have revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in people who present with other autoimmune diseases, anaemia, or malabsorption phenomena at a much increased rate over the normal population. Endomysial components of antibodies (EMA) to tTG are believed to be directed toward cell-surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative people with coeliac tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms, including autoimmune disease. In this study, the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with work showing that gliadin has an innate response component, suggest that gliadin may be more responsible for the primary manifestations of coeliac disease, whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases. In a large percentage of people with coeliac, the anti-tTG antibodies also recognise a rotavirus protein called VP7. These antibodies stimulate monocyte proliferation, and rotavirus infection might explain some early steps in the cascade of immune cell proliferation.
Indeed, earlier studies of rotavirus damage in the gut showed this causes villous atrophy. This suggests that viral proteins may take part in the initial flattening and stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin-mediated tTG presentation provides a second source of crossreactive antibodies.
Other intestinal disorders may have biopsy that look like coeliac disease including lesions caused by Candida.
=== Villous atrophy and malabsorption ===
The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel's mucosal lining and causes malabsorption as it impairs the body's ability to absorb nutrients, minerals, and fat-soluble vitamins A, D, E, and K from food. Lactose intolerance may be present due to the decreased bowel surface and reduced production of lactase but typically resolves once the coeliac disease is under control. Rarely, lactose intolerance may be the only noticeable symptom of underlying coeliac disease.
Alternative causes of this tissue damage have been proposed and involve the release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of enterocytes by lymphocytes in the epithelium. The villous atrophy seen on biopsy may also be due to unrelated causes, such as tropical sprue, giardiasis and radiation enteritis. While positive serology and typical biopsy are highly suggestive of coeliac disease, lack of response to the diet may require these alternative diagnoses to be considered.
== Diagnosis ==
Diagnosis is often difficult and as of 2019, there continues to be a lack of awareness among physicians about the variability of presentations of coeliac disease and the diagnostic criteria, such that most cases are diagnosed with great delay. It can take up to 12 years to receive a diagnosis from the onset of symptoms and the majority of those affected in most countries never receive it.
Several tests can be used. The level of symptoms may determine the order of the tests, but all tests lose their usefulness if the person is already eating a gluten-free diet. Intestinal damage begins to heal within weeks of gluten being removed from the diet, and antibody levels decline over months. For those who have already started on a gluten-free diet, it may be necessary to perform a rechallenge with some gluten-containing food in one meal a day over six weeks before repeating the investigations.
=== Blood tests ===
Serological blood tests are the first-line investigation required to make a diagnosis of coeliac disease. Its sensitivity correlates with the degree of histological lesions. People who present with minor damage to the small intestine may have seronegative findings so many patients with coeliac disease often are missed. In patients with villous atrophy, anti-endomysial (EMA) antibodies of the immunoglobulin A (IgA) type can detect coeliac disease with a sensitivity and specificity of 90% and 99%, respectively. Serology for anti-transglutaminase antibodies (anti-tTG) was initially reported to have a higher sensitivity (99%) and specificity (>90%). However, it is now thought to have similar characteristics to anti-endomysial antibodies. Both anti-transglutaminase and anti-endomysial antibodies have high sensitivity to diagnose people with classic symptoms and complete villous atrophy, but they are only found in 30–89% of the cases with partial villous atrophy and in less than 50% of the people who have minor mucosal lesions (duodenal lymphocytosis) with normal villi.
Tissue transglutaminase (abbreviated as tTG or TG2) modifies gluten peptides into a form that may stimulate the immune system more effectively. These peptides are modified by tTG in two ways, deamidation or transamidation. Modern anti-tTG assays rely on a human recombinant protein as an antigen. tTG testing should be done first as it is an easier test to perform. An equivocal result on tTG testing should be followed by anti-endomysial antibodies.
Guidelines recommend that a total serum IgA level is checked in parallel, as people with coeliac with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false negative"). In those people, IgG antibodies against transglutaminase (IgG-tTG) may be diagnostic.
If all these antibodies are negative, then anti-DGP antibodies (antibodies against deamidated gliadin peptides) should be determined. IgG class anti-DGP antibodies may be useful in people with IgA deficiency. In children younger than two years, anti-DGP antibodies perform better than anti-endomysial and anti-transglutaminase antibodies tests.
Because of the major implications of a diagnosis of coeliac disease, professional guidelines recommend that a positive blood test is still followed by an endoscopy/gastroscopy and biopsy. A negative serology test may still be followed by a recommendation for endoscopy and duodenal biopsy if clinical suspicion remains high.
Historically three other antibodies were measured: anti-reticulin (ARA), anti-gliadin (AGA) and anti-endomysial (EMA) antibodies. ARA testing, however, is not accurate enough for routine diagnostic use. Serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five. Serology tests are based on indirect immunofluorescence (reticulin, gliadin and endomysium) or ELISA (gliadin or tissue transglutaminase, tTG).
Other antibodies such as anti–Saccharomyces cerevisiae antibodies occur in some people with coeliac disease but also occur in other autoimmune disorders and about 5% of those who donate blood.
Antibody testing may be combined with HLA testing if the diagnosis is unclear. TGA and EMA testing are the most sensitive serum antibody tests, but as a negative HLA-DQ type excludes the diagnosis of coeliac disease, testing also for HLA-DQ2 or DQ8 maximises sensitivity and negative predictive values. In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) does not (as of 2015) recommend the use of HLA typing to rule out coeliac disease outside of a specialist setting, for example, in children who are not having a biopsy, or in patients who already have limited gluten ingestion and opt not to have a gluten challenge.
=== Endoscopy ===
An upper endoscopy with biopsy of the duodenum (beyond the duodenal bulb) or jejunum is performed to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative. Even in the same bioptic fragment, different degrees of
damage may be present.
Most people with coeliac disease have a small intestine that appears to be normal on endoscopy before the biopsies are examined. However, five findings have been associated with high specificity for coeliac disease: scalloping of the small bowel folds (pictured), paucity in the folds, a mosaic pattern to the mucosa (described as a "cracked-mud" appearance), prominence of the submucosa blood vessels, and a nodular pattern to the mucosa.
European guidelines suggest that in children and adolescents with symptoms compatible with coeliac disease, the diagnosis can be made without the need for intestinal biopsy if anti-tTG antibodies titres are very high (10 times the upper limit of normal).
Until the 1970s, biopsies were obtained using metal capsules attached to a suction device. The capsule was swallowed and allowed to pass into the small intestine. After x-ray verification of its position, suction was applied to collect part of the intestinal wall inside the capsule. Often-utilised capsule systems were the Watson capsule and the Crosby–Kugler capsule. This method has now been largely replaced by fibre-optic endoscopy, which carries a higher sensitivity and a lower frequency of errors.
Capsule endoscopy (CE) allows identification of typical mucosal changes observed in coeliac disease but has a lower sensitivity compared to regular endoscopy and histology. CE is therefore not the primary diagnostic tool for coeliac disease. However, CE can be used for diagnosing T-cell lymphoma, ulcerative jejunoileitis, and adenocarcinoma in refractory or complicated coeliac disease.
=== Pathology ===
The classic pathology changes of coeliac disease in the small bowel are categorised by the "Marsh classification":
Marsh stage 0: normal mucosa
Marsh stage 1: increased number of intra-epithelial lymphocytes (IELs), usually exceeding 20 per 100 enterocytes
Marsh stage 2: a proliferation of the crypts of Lieberkühn
Marsh stage 3: partial or complete villous atrophy and crypt hyperplasia
Marsh stage 4: hypoplasia of the small intestine architecture
Marsh's classification, introduced in 1992, was subsequently modified in 1999 to six stages, where the previous stage 3 was split in three substages. Further studies demonstrated that this system was not always reliable and that the changes observed in coeliac disease could be described in one of three stages:
A representing lymphocytic infiltration with normal villous appearance;
B1 describing partial villous atrophy; and
B2 describing complete villous atrophy.
The changes classically improve or reverse after gluten is removed from the diet. However, most guidelines do not recommend a repeat biopsy unless there is no improvement in the symptoms on diet. In some cases, a deliberate gluten challenge, followed by a biopsy, may be conducted to confirm or refute the diagnosis. A normal biopsy and normal serology after challenge indicates the diagnosis may have been incorrect.
In untreated coeliac disease, villous atrophy is more common in children younger than three years, but in older children and adults, it is common to find minor intestinal lesions (duodenal lymphocytosis) with normal intestinal villi.
=== Other diagnostic tests ===
At the time of diagnosis, further investigations may be performed to identify complications, such as iron deficiency (by full blood count and iron studies), folic acid and vitamin B12 deficiency and hypocalcaemia (low calcium levels, often due to decreased vitamin D levels). Thyroid function tests may be requested during blood tests to identify hypothyroidism, which is more common in people with coeliac disease.
Osteopenia and osteoporosis, mildly and severely reduced bone mineral density, are often present in people with coeliac disease, and investigations to measure bone density may be performed at diagnosis, such as dual-energy X-ray absorptiometry (DXA) scanning, to identify the risk of fracture and need for bone protection medication.
=== Gluten withdrawal ===
Although blood antibody tests, biopsies, and genetic tests usually provide a clear diagnosis, occasionally the response to gluten withdrawal on a gluten-free diet is needed to support the diagnosis. Currently, gluten challenge is no longer required to confirm the diagnosis in patients with intestinal lesions compatible with coeliac disease and a positive response to a gluten-free diet. Nevertheless, in some cases, a gluten challenge with a subsequent biopsy may be useful to support the diagnosis, for example in people with a high suspicion for coeliac disease, without a biopsy confirmation, who have negative blood antibodies and are already on a gluten-free diet. Gluten challenge is discouraged before the age of 5 years and during pubertal growth. The alternative diagnosis of non-coeliac gluten sensitivity may be made where there is only symptomatic evidence of gluten sensitivity. Gastrointestinal and extraintestinal symptoms of people with non-coeliac gluten sensitivity can be similar to those of coeliac disease, and improve when gluten is removed from the diet, after coeliac disease and wheat allergy are reasonably excluded.
Up to 30% of people often continue having or redeveloping symptoms after starting a gluten-free diet. A careful interpretation of the symptomatic response is needed, as a lack of response in a person with coeliac disease may be due to continued ingestion of small amounts of gluten, either voluntary or inadvertent, or be due to other commonly associated conditions such as small intestinal bacterial overgrowth (SIBO), lactose intolerance, fructose, sucrose, and sorbitol malabsorption, exocrine pancreatic insufficiency, and microscopic colitis, among others. In untreated coeliac disease, these are often transient conditions derived from the intestinal damage. They normally revert or improve several months after starting a gluten-free diet, but may need temporary interventions such as supplementation with pancreatic enzymes, dietary restrictions of lactose, fructose, sucrose or sorbitol containing foods, or treatment with oral antibiotics in the case of associated bacterial overgrowth. In addition to gluten withdrawal, some people need to follow a low-FODMAPs diet or avoid consumption of commercial gluten-free products, which are usually rich in preservatives and additives (such as sulfites, glutamates, nitrates and benzoates) and might have a role in triggering functional gastrointestinal symptoms.
== Screening ==
There is debate as to the benefits of screening. As of 2017, the United States Preventive Services Task Force found insufficient evidence to make a recommendation among those without symptoms. In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) recommend testing for coeliac disease in first-degree relatives of those with the disease already confirmed, in people with persistent fatigue, abdominal or gastrointestinal symptoms, faltering growth, unexplained weight loss or iron, vitamin B12 or folate deficiency, severe mouth ulcers, and with diagnoses of type 1 diabetes, autoimmune thyroid disease, and with newly diagnosed chronic fatigue syndrome and irritable bowel syndrome. Dermatitis herpetiformis is included in other recommendations. The NICE also recommend offering serological testing for coeliac disease in people with metabolic bone disease (reduced bone mineral density or osteomalacia), unexplained neurological disorders (such as peripheral neuropathy and ataxia), fertility problems or recurrent miscarriage, persistently raised liver enzymes with unknown cause, dental enamel defects and with diagnose of Down syndrome or Turner syndrome.
Some evidence has found that early detection may decrease the risk of developing health complications, such as osteoporosis, anaemia, and certain types of cancer, neurological disorders, cardiovascular diseases, and reproductive problems. They thus recommend screening in people with certain health problems.
Serology has been proposed as a screening measure, because the presence of antibodies would detect some previously undiagnosed cases of coeliac disease and prevent its complications in those people. However, serologic tests have high sensitivity only in people with total villous atrophy and have a very low ability to detect cases with partial villous atrophy or minor intestinal lesions. Testing for coeliac disease may be offered to those with commonly associated conditions.
== Treatment ==
=== Diet ===
At present, the only effective treatment is a lifelong gluten-free diet. No medication exists that prevents damage or prevents the body from attacking the gut when gluten is present. Strict adherence to the diet helps the intestines heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer and in some cases sterility. Compliance to a strict gluten-free diet is difficult for the patient, but evidence has accumulated that a strict gluten-free diet can result in resolution of diarrhea, weight gain and normalization of nutrient malabsorption, with normalization of biopsies in 6 months to 2 years on a gluten-free diet.
Dietitian input is generally requested to ensure the person is aware which foods contain gluten, which foods are safe, and how to have a balanced diet despite the limitations. In many countries, gluten-free products are available on prescription and may be reimbursed by health insurance plans. Gluten-free products are usually more expensive and harder to find than common gluten-containing foods. Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.
The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence. The exact level at which gluten is harmless is uncertain and controversial. A recent systematic review tentatively concluded that consumption of less than 10 mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done. Regulation of the label "gluten-free" varies. In the European Union, the European Commission issued regulations in 2009 limiting the use of "gluten-free" labels for food products to those with less than 20 mg/kg of gluten, and "very low gluten" labels for those with less than 100 mg/kg. In the United States, the FDA issued regulations in 2013 limiting the use of "gluten-free" labels for food products to those with less than 20 ppm of gluten. The current international Codex Alimentarius standard allows for 20 ppm of gluten in so-called "gluten-free" foods.
Gluten-free diet improves healthcare-related quality of life, and strict adherence to the diet gives more benefit than incomplete adherence. Nevertheless, gluten-free diet does not completely normalise the quality of life.
=== Vaccination ===
Even though it is unclear if coeliac patients have a generally increased risk of infectious diseases, they should generally be encouraged to receive all common vaccines against vaccine preventable diseases (VPDs) as the general population. Moreover, some pathogens could be harmful to coeliac patients. According to the European Society for the Study of Coeliac Disease (ESsCD), coeliac disease can be associated with hyposplenism or functional asplenia, which could result in impaired immunity to encapsulated bacteria, with an increased risk of such infections. For this reason, patients who are known to be hyposplenic should be offered at least the pneumococcal vaccine. However, the ESsCD states that it is not clear whether vaccination with the conjugated vaccine is preferable in this setting and whether additional vaccination against Haemophilus, meningococcus, and influenza should be considered if not previously given. However, Mårild et al. suggested considering additional vaccination against influenza because of an observed increased risk of hospital admission for this infection in coeliac patients.
=== Refractory disease ===
Between 0.3% and 10% of affected people have refractory disease, which means that they have persistent villous atrophy on a gluten-free diet despite the lack of gluten exposure for more than 12 months. Nevertheless, inadvertent exposure to gluten is the main cause of persistent villous atrophy, and must be ruled out before a diagnosis of refractory disease is made. People with poor basic education and understanding of gluten-free diet often believe that they are strictly following the diet, but are making regular errors. Also, a lack of symptoms is not a reliable indicator of intestinal recuperation.
If alternative causes of villous atrophy have been eliminated, steroids or immunosuppressants (such as azathioprine) may be considered in this scenario.
Refractory coeliac disease should not be confused with the persistence of symptoms despite gluten withdrawal caused by transient conditions derived from the intestinal damage, which generally revert or improve several months after starting a gluten-free diet, such as small intestinal bacterial overgrowth, lactose intolerance, fructose, sucrose, and sorbitol malabsorption, exocrine pancreatic insufficiency, and microscopic colitis among others.
Refractory coeliac disease can be divided into types I and II. A recent studied compared patients with type I and II. Refractory coeliac disease type I more frequently exhibits diarrhea, anemia, hypoalbuminemia, parenteral nutrition need, ulcerative jejuno-ileitis, and extended small intestinal atrophy. Among patients with refractory coeliac disease type II is more common to develop lymphoma. Among these patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality.
== Epidemiology ==
Globally coeliac disease affects between 1 in 100 and 1 in 170 people. Rates, however, vary between different regions of the world from as few as 1 in 300 to as many as 1 in 40. In the United States it is thought to affect between 1 in 1,750 (defined as clinical disease including dermatitis herpetiformis with limited digestive tract symptoms) to 1 in 105 (defined by presence of IgA TG in blood donors). Due to variable signs and symptoms it is believed that about 85% of people affected are undiagnosed. The percentage of people with clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, India, South America, Australasia and the USA (using serology and biopsy) indicate that the percentage of people with the disease may be between 0.33 and 1.06% in children (but 5.66% in one study of children of the predisposed Sahrawi people) and 0.18–1.2% in adults. Among those in primary care populations who report gastrointestinal symptoms, the rate of coeliac disease is about 3%. In Australia, approximately 1 in 70 people have the disease. The rate amongst adult blood donors in Iran, Israel, Syria and Turkey is 0.60%, 0.64%, 1.61% and 1.15%, respectively.
People of African, Japanese and Chinese descent are rarely diagnosed; this reflects a much lower prevalence of the genetic risk factors, such as HLA-B8. People of Indian ancestry seem to have a similar risk to those of Western Caucasian ancestry. Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due, in part, to many clinicians being unfamiliar with the condition and also due to the fact it can be asymptomatic. Coeliac disease is slightly more common in women than in men. A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic people, 2.6% in second-degree relatives (like grandparents, aunt or uncle, grandchildren, etc.) of a person with coeliac disease and 4.5% in first-degree relatives (siblings, parents or children). This profile is similar to the prevalence in Europe. Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with Down and Turner syndromes, type 1 diabetes, and autoimmune thyroid disease, including both hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid).
Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%, which is approximately
1
50
{\textstyle {\frac {1}{50}}}
of more recent estimates of prevalence. The reason for the recent increases in the number of reported cases is unclear. It may be at least in part due to changes in diagnostic practice. There also appears to be an approximately 4.5 fold true increase that may be due to less exposure to bacteria and other pathogens in Western environments. In the United States, the median age at diagnosis is 38 years. Roughly 20 percent of individuals with coeliac disease are diagnosed after 60 years of age.
== Immune Therapy ==
In 2025, researchers demonstrated the potential of engineered regulatory T cells (eTregs) as a cell-based therapy for celiac disease. By orthotopically inserting T cell receptors (TCRs) specific to immunodominant gluten epitopes into human Tregs, the team created gluten-reactive eTregs that suppressed pathogenic T cell responses in HLA-DQ2.5 transgenic mouse models. These eTregs showed the ability to exert bystander suppression—not only inhibiting T cells with the same antigen specificity, but also suppressing responses to distinct gluten peptides—thus addressing the polyclonal nature of the autoimmune response in celiac disease. The data support the clinical potential of antigen-specific eTreg therapies for autoimmune diseases beyond current applications.
== History ==
The term coeliac comes from Greek κοιλιακός (koiliakós) 'abdominal' and was introduced in the 19th century in a translation of what is generally regarded as an Ancient Greek description of the disease by Aretaeus of Cappadocia.
Humans first started to cultivate grains in the Neolithic period (beginning about 9500 BCE) in the Fertile Crescent in Western Asia, and, likely, coeliac disease did not occur before this time. Aretaeus of Cappadocia, living in the second century in the same area, recorded a malabsorptive syndrome with chronic diarrhoea, causing a debilitation of the whole body.
A 15th-century medical prescription from Mamluk Cairo, attributed to Shams al-Din ibn al-'Afif, the personal physician to Sultan Barsbay and director of the Qalawun complex hospital, describes a treatment for symptoms consistent with coeliac disease. Found in Fustat and now held in the Museum of Islamic Art in Cairo, the remedy combines herbs and plant waters for patients intolerant to wheat.
Aretaeus of Cappadocia's "Cœliac Affection" gained the attention of Western medicine when Francis Adams presented a translation of Aretaeus's work at the Sydenham Society in 1856. The patient described in Aretaeus' work had stomach pain and was atrophied, pale, feeble, and incapable of work. The diarrhoea manifested as loose stools that were white, malodorous, and flatulent, and the disease was intractable and liable to periodic return. The problem, Aretaeus believed, was a lack of heat in the stomach necessary to digest the food and a reduced ability to distribute the digestive products throughout the body, this incomplete digestion resulting in diarrhoea. He regarded this as an affliction of the old and more commonly affecting women, explicitly excluding children. The cause, according to Aretaeus, was sometimes either another chronic disease or even consuming "a copious draught of cold water."
The paediatrician Samuel Gee gave the first modern-day description of the condition in children in a lecture at Hospital for Sick Children, Great Ormond Street, London, in 1887. Gee acknowledged earlier descriptions and terms for the disease and adopted the same term as Aretaeus (coeliac disease). He perceptively stated: "If the patient can be cured at all, it must be by means of diet." Gee recognised that milk intolerance is a problem with coeliac children and that highly starched foods should be avoided. However, he forbade rice, sago, fruit, and vegetables, which all would have been safe to eat, and he recommended raw meat as well as thin slices of toasted bread. Gee highlighted particular success with a child "who was fed upon a quart of the best Dutch mussels daily." However, the child could not bear this diet for more than one season.
Christian Archibald Herter, an American physician, wrote a book in 1908 on children with coeliac disease, which he called "intestinal infantilism". He noted their growth was retarded and that fat was better tolerated than carbohydrate. The eponym Gee-Herter disease was sometimes used to acknowledge both contributions. Sidney V. Haas, an American paediatrician, reported positive effects of a diet of bananas in 1924. This diet remained in vogue until the actual cause of coeliac disease was determined.
While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatrician Willem Karel Dicke. It is likely that clinical improvement of his patients during the Dutch famine of 1944–1945 (during which flour was scarce) may have contributed to his discovery. Dicke noticed that the shortage of bread led to a significant drop in the death rate among children affected by coeliac disease from greater than 35% to essentially zero. He also reported that once wheat was again available after the conflict, the mortality rate soared to previous levels. The link with the gluten component of wheat was made in 1952 by a team from Birmingham, England. Villous atrophy was described by British physician John W. Paulley in 1954 on samples taken at surgery. This paved the way for biopsy samples taken by endoscopy.
Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965. In 1966, dermatitis herpetiformis was linked to gluten sensitivity.
== Society and culture ==
May has been designated as "Coeliac Awareness Month" by several coeliac organisations.
=== Christian churches and the Eucharist ===
Speaking generally, the various denominations of Christians celebrate a Eucharist in which a wafer or small piece of sacramental bread from wheat bread is blessed and then eaten. A typical wafer weighs about half a gram. Small communion wafers typically contain 2-5 mg of gliadin if they are not a gluten-free variety, and many people with coeliac disease report altering their religious practices because of coeliac symptoms caused by these wafers.
Many Christian churches offer their communicants gluten-free alternatives, usually in the form of a rice-based cracker or gluten-free bread. These include the United Methodist, Christian Reformed, Episcopal, the Anglican Church (Church of England, UK) and Lutheran. Catholics may receive from the chalice alone, or ask for gluten-reduced hosts; gluten-free ones however are not considered still to be wheat bread, and hence are invalid matter.
==== Roman Catholic position ====
Roman Catholic doctrine states that for a valid Eucharist, the bread to be used at Mass must be made from wheat. Low-gluten hosts meet all of the Catholic Church's requirements, but they are not entirely gluten free. Requests to use rice wafers have been denied.
The issue is more complex for priests. As a celebrant, a priest is, for the fullness of the sacrifice of the Mass, absolutely required to receive under both species. On 24 July 2003, the Congregation for the Doctrine of the Faith stated, "Given the centrality of the celebration of the Eucharist in the life of a priest, one must proceed with great caution before admitting to Holy Orders those candidates unable to ingest gluten or alcohol without serious harm."
By January 2004, extremely low-gluten Church-approved hosts had become available in the United States, Italy and Australia. As of July 2017, the Vatican still outlawed the use of gluten-free bread for Holy Communion.
=== Passover ===
The Jewish festival of Pesach (Passover) may present problems with its obligation to eat Matzah, which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye. In addition, many other grains that are normally used as substitutes for people with gluten sensitivity, including rice, are avoided altogether on Passover by Ashkenazi Jews. Many kosher-for-Passover products avoid grains altogether and are therefore gluten-free. Potato starch is the primary starch used to replace the grains.
=== Spelling ===
"Coeliac disease" is the preferred spelling in Commonwealth English, while "celiac disease" is typically used in North American English.
== Research directions ==
The search for environmental factors that could be responsible for genetically susceptible people becoming intolerant to gluten has resulted in increasing research activity looking at gastrointestinal infections. Research published in April 2017 suggests that an often-symptomless infection by a common strain of reovirus can increase sensitivity to foods such as gluten.
Various treatment approaches are being studied, including some that would reduce the need for dieting. All are still under development, and are not expected to be available to the general public for a while.
Three main approaches have been proposed as new therapeutic modalities for coeliac disease: gluten detoxification, modulation of the intestinal permeability, and modulation of the immune response.
Using genetically engineered wheat species, or wheat species that have been selectively bred to be minimally immunogenic, may allow the consumption of wheat. This, however, could interfere with the effects that gliadin has on the quality of dough.
Alternatively, gluten exposure can be minimised by the ingestion of a combination of enzymes (prolyl endopeptidase and a barley glutamine-specific cysteine endopeptidase (EP-B2)) that degrade the putative 33-mer peptide in the duodenum. Latiglutenase (IMGX003) is a biotheraputic digestive enzyme therapy currently being trialled that aims to degrade gluten proteins and aid gluten digestion. It was shown to mitigate intestinal mucosal damage and reduce the severity and frequency of symptoms in phase 2 clinical trials and is scheduled for phase 3 clinical trials.
Other potential approaches to pharmacotherapy include the inhibition of zonulin, an endogenous signalling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system. Other modifiers of other well-understood steps in the pathogenesis of coeliac disease, such as the action of HLA-DQ2 or tissue transglutaminase and the MICA/NKG2D interaction that may be involved in the killing of enterocytes.
Attempts to modulate the immune response concerning coeliac disease are mostly still in phase I of clinical testing; one agent (CCX282-B) has been evaluated in a phase II clinical trial based on small-intestinal biopsies taken from people with coeliac disease before and after gluten exposure.
== References ==
== External links == | Wikipedia/Coeliac_disease |
FORCE11 is an international coalition of researchers, librarians, publishers and research funders working to reform or enhance the research publishing and communication system. Initiated in 2011 as a community of interest on scholarly communication, FORCE11 is a registered 501(c)(3) organization based in the United States but with members and partners around the world. Key activities include an annual conference, the Scholarly Communications Institute and a range of working groups.
== History ==
FORCE11 grew out of the FORC Workshop held in Dagstuhl, Germany in August 2011. This meeting resulted in the collaborative creation of a white paper which summarized the problems of scholarly communication and proposed a vision to address them.
== Activities ==
Through various working groups FORCE11 has undertaken a range of activities to improve the standards, interoperability and functionality of digital research communications and developed various statements on principles and policies for best practice. These include:
FAIR Data Principles: The development of a set of principles based on making data Findable, Accessible, Interoperable, and Reusable (FAIR)
Research Resource Identification Initiative (RRID): supporting new guidelines and identifiers in biomedical publications
Joint Declaration of Data Citation Principles (JDDCP): intended to help achieve widespread, uniform human and machine accessibility of deposited data through data citation
Software citation principles
== See also ==
Australian Open Access Strategy Group Archived 2018-02-10 at the Wayback Machine (AOASG)
Coalition for Networked Information (CNI)
Open Access Scholarly Publishers Association (OASPA)
Scholarly Publishing and Academic Resources Coalition (SPARC)
== References == | Wikipedia/FORCE11 |
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five main types of antibodies) produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur. When the disease is moderate or severe, many erythroblasts (immature red blood cells) are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis (British English: erythroblastosis foetalis
HDFN represents a breach of immune privilege for the fetus or some other form of impairment of the immune tolerance in pregnancy. Various types of HDFN are classified by which alloantigen provokes the response. The types include ABO, anti-RhD, anti-RhE, anti-Rhc, anti-Rhe, anti-RhC, multiantigen combinations, and anti-Kell. Although global prevalence studies of the differential contribution of those types are lacking, regional population studies have shown the anti-RhD type to be the most common cause of HDFN, followed by anti-RhE, anti-RhC, and anti-Rhc.
== Signs and symptoms ==
Signs of hemolytic disease of the newborn include a positive direct Coombs test (also called direct agglutination test), elevated cord bilirubin levels, and hemolytic anemia. It is possible for a newborn with this disease to have neutropenia and neonatal alloimmune thrombocytopenia as well. Hemolysis leads to elevated bilirubin levels. After delivery, bilirubin is no longer cleared (via the placenta) from the neonate's blood and the symptoms of jaundice (yellowish skin and yellow discoloration of the whites of the eyes, or icterus) increase within 24 hours after birth. Like other forms of severe neonatal jaundice, there is the possibility of the neonate developing acute or chronic kernicterus, however the risk of kernicterus in HDN is higher because of the rapid and massive destruction of blood cells. Isoimmunization is a risk factor for neurotoxicity and lowers the level at which kernicterus can occur. Untreated profound anemia can cause high-output heart failure, with pallor, enlarged liver and/or spleen, generalized swelling, and respiratory distress.
HDN can be the cause of hydrops fetalis, an often-severe form of prenatal heart failure that causes fetal edema.
=== Complications ===
Complications of HDN could include kernicterus, hepatosplenomegaly, inspissated (thickened or dried) bile syndrome and/or greenish staining of the teeth, hemolytic anemia and damage to the liver due to excess bilirubin. Conditions that may cause similar symptoms in the newborn period include: acquired hemolytic anemia, congenital toxoplasma, congenital syphilis infection, congenital obstruction of the bile duct, and cytomegalovirus (CMV) infection.
High at birth or rapidly rising bilirubin
Prolonged hyperbilirubinemia
Bilirubin Induced Neurological Dysfunction
Cerebral Palsy
Kernicterus
Neutropenia
Thrombocytopenia
Hemolytic anemia — must not be treated with iron
Late onset anemia — must not be treated with iron. Can persist up to 12 weeks after birth.
== Pathophysiology ==
Antibodies are produced when the body is exposed to an antigen foreign to the make-up of the body. If a mother is exposed to a foreign antigen and produces IgG (as opposed to IgM which does not cross the placenta), the IgG will target the antigen, if present in the fetus, and may affect it in utero and persist after delivery. However, the antibodies of the mother do not go away after the first incompatible pregnancy due to immunological memory. The maternal blood is likely to secrete more antibodies and attack the fetal erythrocytes during subsequent pregnancies because of re-exposure to the antigen. The three most common models in which a woman becomes sensitized toward (i.e., produces IgG antibodies against) a particular antigen are hemorrhage, blood transfusion, and ABO incompatibility.
Fetal-maternal hemorrhage, which is the movement of fetal blood cells across the placenta, can occur during abortion, ectopic pregnancy, childbirth, ruptures in the placenta during pregnancy (often caused by trauma), or medical procedures carried out during pregnancy that breach the uterine wall. In subsequent pregnancies, if there is a similar incompatibility in the fetus, these antibodies are then able to cross the placenta into the fetal bloodstream to attach to the red blood cells and cause their destruction (hemolysis). This is a major cause of HDN, because 75% of pregnancies result in some contact between fetal and maternal blood, and 15–50% of pregnancies have hemorrhages with the potential for immune sensitization. The amount of fetal blood needed to cause maternal sensitization depends on the individual's immune system and ranges from 0.1 mL to 30 mL.
The woman may have received a therapeutic blood transfusion. ABO blood group system and the D antigen of the Rhesus (Rh) blood group system typing are routine prior to transfusion. Suggestions have been made that women of child-bearing age or young girls should not be given a transfusion with Rhc-positive blood or Kell1-positive blood to avoid possible sensitization, but this would strain the resources of blood transfusion services, and it is currently considered uneconomical to screen for these blood groups. HDFN can also be caused by antibodies to a variety of other blood group system antigens, but Kell and Rh are the most frequently encountered.
The third sensitization model can occur in women of blood type O. The immune response to A and B antigens, which are widespread in the environment, usually leads to the production of IgM or IgG anti-A and anti-B antibodies early in life. Women of blood type O are more prone than women of types A and B to making IgG anti-A and anti-B antibodies, and these IgG antibodies are able to cross the placenta. For unknown reasons, the incidence of maternal antibodies against type A and B antigens of the IgG type that could potentially cause hemolytic disease of the newborn is greater than the observed incidence of "ABO disease." About 15% of pregnancies involve a type O mother and a type A or type B child; only 3% of these pregnancies result in hemolytic disease due to A/B/O incompatibility. In contrast to antibodies to A and B antigens, production of Rhesus antibodies upon exposure to environmental antigens seems to vary significantly across individuals. In cases where there is ABO incompatibility and Rh incompatibility, the risk of alloimmunization is decreased because fetal red blood cells are removed from maternal circulation due to anti-ABO antibodies before they can trigger an anti-Rh response.
=== Serological types ===
HDN is classified by the type of antigens involved. The main types are ABO HDN, Rhesus HDN, Kell HDN, and other antibodies. Combinations of antibodies (for example, anti-Rhc and anti-RhE occurring together) can be especially severe.
ABO hemolytic disease of the newborn can range from mild to severe, but generally, it is a mild disease. It can be caused by anti-A and anti-B antibodies.
Rhesus D hemolytic disease of the newborn (often called Rh disease) is the most common and only preventable form of severe HDN. Since the introduction of Rho-D immunoglobulin, (Rhogam, at 1968, which prevents the production of maternal Rho-D antibodies, the incidence of anti-D HDN has decreased dramatically.
Rhesus c HDFN can range from a mild to severe disease and is the third most common form of severe HDN. Rhesus e and rhesus C hemolytic disease of the newborn are rare. Anti-C and anti-c can both show a negative DAT but still have a severely affected infant. An indirect Coombs must also be run.
Anti-Kell hemolytic disease of the newborn is most commonly caused by anti-K1 antibodies, the second most common form of severe HDN. Over half of the cases of anti-K1 related HDN are caused by multiple blood transfusions. Antibodies to the other Kell antigens are rare. Anti-Kell can cause severe anemia regardless of titer. It suppresses the bone marrow by inhibiting the erythroid progenitor cells.
Anti-M also recommends antigen testing to rule out the presence of HDN as the direct coombs can come back negative in a severely affected infant.
Kidd antigens are also present on the endothelial cells of the kidneys.
One study states that it would be unwise to routinely dismiss anti-E as being of little clinical consequence. It also found that the most severe case of anti-E HDFN occurred with titers 1:2, concluding that titers are not reliable for the diagnosis of the anti-E type.
== Diagnosis ==
The diagnosis of HDFN is based on history and laboratory findings. If a newly pregnant woman has red cell antibodies in her serum, the antibody titer should be followed with subsequent blood draws. The titer will rise if the fetus expresses the red cell antigen to which she is alloimmunized. In that case, fetal middle cerebral artery doppler ultrasonography is used to determine the degree of fetal anemia and the need for intrauterine transfusion.
Blood tests done on the newborn baby
Biochemistry tests for jaundice including total and direct bilirubin levels.
Complete blood count (CBC), which may show a decreased hemoglobin and hematocrit due to red blood cell destruction
Reticulocyte count, which will usually be increased as the bone marrow makes new red blood cells to replace the ones that are being destroyed, and a peripheral blood smear to look at cell morphology. In the presence of significant hemolysis the smear will show schistocytes (fragmented red blood cells), reticulocytosis, and in severe cases erythroblasts (also known as nucleated red blood cells).
Positive direct Coombs test (might be negative after fetal interuterine blood transfusion)
Blood tests done on the mother
Positive indirect Coombs test
Cell free fetal DNA (cff-DNA) from maternal plasma may be used early in pregnancy to determine whether the fetus expresses the red cell antigen to which the pregnant mother is alloimmunized
Blood tests done on the father (rarely needed)
Erythrocyte antigen status on the father might be a non-preferred alternative, if maternal cff-DNA testing is not available, in conjunction with monitoring the titer of the maternal plasma
== Prevention ==
In cases of Rho(D) incompatibility, Rho(D) immunoglobulin is given to prevent sensitization. However, there is no comparable immunotherapy available for other blood group incompatibilities.
Early pregnancy
IVIG — IVIG stands for Intravenous Immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. IVIG can be more effective than IUT alone. Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.
Plasmapheresis — Plasmapheresis aims to decrease the maternal titer by direct plasma replacement and physical removal of antibody. Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and fetal losses.
Mid- to late- pregnancy
IUT — Intrauterine Transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT). IVT is preferred over IPT. IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.
Steroids — Steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.
Phenobarbital — Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.
Early Delivery — Delivery can occur anytime after the age of viability. Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.
Rhesus-negative mothers who are pregnant with a rhesus-positive infant are offered Rho(D) immune globulin (RhIG, or RhoGam) at 28 weeks during pregnancy, at 34 weeks, and within 48 hours after delivery to prevent sensitization to the D antigen. It works by binding any fetal red blood cells with the D antigen before the mother is able to produce an immune response and form anti-D IgG. A drawback to pre-partum administration of RhIG is that it causes a positive antibody screen when the mother is tested, which can be difficult to distinguish from natural immunological responses that result in antibody production. Without Rho(D) immunoglobulin, the risk of isoimmunization is approximately 17%; with proper administration, the risk is reduced to less than 0.1–0.2%.
== After birth testing ==
Coombs — in certain instances (when there is concern for blood group incompatibility between mother and baby for example), after birth a baby will have a direct Coombs test run to confirm the antibodies attached to the infant's red blood cells. This test is run on the infant's cord blood.
In some cases, the direct Coombs will be negative but severe, even fatal HDN can occur. An indirect Coombs needs to be run in cases of anti-C, anti-c, and anti-M. Infants with Anti-M are also recommended to receive antigen testing to rule out the presence of HDN. The below tests are often useful in cases of hemolytic disease of the newborn but are not required for treatment of all newborns.
Hgb — the infant's hemoglobin should be tested from cord blood.
Reticulocyte count — Reticulocytes are elevated when the infant is producing more red blood cells in response to anemia. A rise in the retic count can mean that an infant may not need additional transfusions. Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell.
Neutrophils — as neutropenia is one of the complications of HDN, the neutrophil count should be checked.
Thrombocytes — as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.
Bilirubin should be tested from cord blood.
Ferritin — because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.
Newborn Screening Tests — Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.
== Treatment ==
After birth, treatment depends on the severity of the condition, but could include temperature stabilization and monitoring, phototherapy, transfusion with compatible packed red blood, exchange transfusion, sodium bicarbonate for correction of acidosis and/or assisted ventilation.
Phototherapy — Exposure to ultraviolet light (phototherapy) is recommended when the cord bilirubin is 3 or higher. Some doctors use it at lower levels while awaiting lab results. This converts unconjugated bilirubin to a conjugated form that is easier for the infant to clear.
IVIG — IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well. IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy. The AAP recommends "In isoimmune hemolytic disease, administration of intravenousγ-globulin (0.5–1 g/kg over 2 hours) is recommended if the TSB (total serum bilirubin) is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34–51 μmol/L) of the exchange level. If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."
Exchange transfusion — Exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the nonogram provided by the American Academy of Pediatrics (Figure 4). Cord bilirubin >4 is also indicative of the need for exchange transfusion.
== Transfusion reactions ==
Once a woman has antibodies, she is at high risk for a future transfusion reaction if she is in need of a blood transfusion. For this reason, she is advised to carry a medical alert card at all times and inform all doctors and emergency personnel of her antibody status. The absence of antibodies however does not preclude a woman from having a transfusion reaction:
"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A, B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures."
For a summary of transfusion reactions in the US, see reference.
== Epidemiology ==
In 2003, the incidence of Rh(D) sensitization in the United States was 6.8 per 1000 live births; 0.27% of women with an Rh incompatible fetus experience alloimmunization.
== See also ==
Exchange transfusion
Hemolytic disease of the newborn (ABO)
Hemolytic disease of the newborn (anti-Kell)
Hemolytic disease of the newborn (anti-Rhc)
Hemolytic disease of the newborn (anti-RhE)
Neonatal isoerythrolysis
Neonatal red cell transfusion
Rh disease
== References ==
== Further reading ==
== External links == | Wikipedia/Hemolytic_disease_of_the_newborn |
An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen of its own with a specific epitope. After an antigen-antibody reaction, the immune complexes can be subject to any of a number of responses, including complement deposition, opsonization, phagocytosis, or processing by proteases. Red blood cells carrying CR1-receptors on their surface may bind C3b-coated immune complexes and transport them to phagocytes, mostly in liver and spleen, and return to the general circulation.
The ratio of antigen to antibody determines size and shape of immune complex. This, in turn, determines the effect of the immune complex. Many innate immune cells have FcRs, which are membrane-bound receptors that bind the constant regions of antibodies. Most FcRs on innate immune cells have low affinity for a singular antibody, and instead need to bind to an immune complex containing multiple antibodies in order to begin their intracellular signaling pathway and pass along a message from outside to inside of the cell. Additionally, the grouping and binding together of multiple immune complexes allows for an increase in the avidity, or strength of binding, of the FcRs. This allows innate immune cells to get multiple inputs at once and prevents them from being activated early.
Immune complexes may themselves cause illness when they are deposited in organs, for example, in certain forms of vasculitis. This is the third form of hypersensitivity in the Gell-Coombs classification, called type III hypersensitivity. Such hypersensitivity progressing to disease states produces the immune complex diseases.
Immune complex deposition is a prominent feature of several autoimmune diseases, including rheumatoid arthritis, scleroderma and Sjögren's syndrome. An inability to degrade immune complexes in the lysosome and subsequent accumulation on the surface of immune cells has been associated with systemic lupus erythematosus.
== Functions ==
=== Regulation of antibody production ===
Immune complexes can also play a role in the regulation of antibody production. B cells express B-cell receptors (BCRs) on their surfaces and antigen binding to these receptors begins a signaling cascade that leads to activation. B cells also express FcγRIIb, low affinity receptors specific to the constant region of IgG, on their surfaces. IgG immune complexes are the ligand for these receptors and immune complex binding to these receptors induces apoptosis, or cell death. After B cells are activated, they differentiate into plasma cells and cease to express BCR but continue to express FcγRIIb, which allows IgG immune complexes to regulate IgG production via negative feedback and prevent uncontrolled IgG production.
=== Activation of dendritic cells and macrophages ===
Immune complexes, particularly those made of IgG, also play a variety of roles in the activation and regulation of phagocytes, which include dendritic cells (DCs) and macrophages. Immune complexes are better at inducing DC maturation than an antigen on its own. Again, the low affinity of many FcγR for IgG means that only immune complexes, not single antibodies, can induce the FcγR’s signaling cascade. When compared to single antibodies binding to FcγRs, immune complexes binding to FcγRs cause significant changes in internalization and processing of antigen, maturation of the vesicles containing the internalized antigen, and activation in DCs and macrophages. There are multiple classes of macrophages and DCs that express different FcγRs, which have differing affinities for single antibodies and immune complexes. This allows the response of the DC or macrophage to be tuned precisely, subsequently tuning the level of IgG. These diverse FcγRs cause different responses in their DCs or macrophages by initiating different signaling pathways that can either activate or inhibit cellular functions. The binding of the immune complex to the DC’s membrane-bound receptor and internalization of the immune complex and receptor begins the process of antigen presentation, which allows the DC to activate T cells. Via this process, immune complexes cause enhanced T cell activation.
=== Elimination of opsonized immune complexes ===
Type I FcγRs activation begins a cascade of reactions to eliminate the IgG-opsonized target. Type I FcγRs is another type of IgG constant region receptor, which can bind to IgG immune complexes and lead to the elimination of the opsonized complex. Immune complexes bind to multiple type I FcγRs, which cluster on the cell surface and begin the ITAM signaling pathway. Although both activating and inhibitory Type I FcγRs can mediate phagocytosis, but the internalization of IgG-opsonized targets through activating FcγRs is more effective for response. Immune complexes bind to multiple type I FcγRs, which cluster on the cell surface and begin the Immunoreceptor Tyrosine-Based Activation Motif (ITAM) signaling pathway. ITAM is composed of tyrosine which is separated from a leucine or isoleucine by two other amino acids and is located in the cytoplasmic tail of the molecule. Following the clustering by IgG complexes, ITAM is phosphorylated by FcγRs crosslinking. This phosphorylation of the ITAM leads to pro-inflammatory signaling that mediates cellular activation which will induce a signaling cascade and eventually leads to elimination of opsonized immune complex.
== References == | Wikipedia/Antigen-antibody_complex |
Extracellular matrix protein 1 is a protein that in humans is encoded by the ECM1 gene.
This gene encodes an extracellular protein containing motifs with a cysteine pattern characteristic of the cysteine pattern of the ligand-binding "double-loop" domains of the albumin protein family. This gene maps outside the epidermal differentiation complex (EDC), a cluster of three gene families involved in epidermal differentiation. Alternatively spliced transcript variants encoding distinct isoforms have been described.
== Diseases ==
ECM1 is implicated in breast cancer, thyroid cancer, hepatocellular carcinoma, and other cancers, and also in ulcerative colitis Germline mutations in ECM-1 cause the genetic disease lipoid proteinosis. Autoimmune attack on ECM-1 is responsible for lichen sclerosus. (see the Atlas of Genetics and Cytogenetics in Oncology and Haematology).
== See also ==
Lipoid proteinosis
== References ==
== Further reading == | Wikipedia/Extracellular_matrix_protein_1 |
A heavy-chain antibody is an antibody which consists only of two heavy chains and lacks the two light chains usually found in antibodies.
In common antibodies, the antigen binding region consists of the variable domains of the heavy and light chains (VH and VL). Heavy-chain antibodies can bind antigens despite having only VH domains. This observation has led to the development of a new type of antibody fragments with potential use as drugs, so-called single-domain antibodies.
== Discovery ==
In 1989 a group of biologists led by Raymond Hamers at the Free University Brussels investigated the immune system of dromedaries. In addition to the expected four-chain antibodies, they identified simpler antibodies consisting only of two heavy chains. This discovery was published in Nature in 1993. In 1995 a research team at the University of Miami found a different type of heavy-chain antibodies in sharks.
== In cartilaginous fishes ==
The immunoglobulin new antigen receptor (IgNAR) of cartilaginous fishes (for example sharks) is a heavy-chain antibody. IgNAR shows significant structural differences to other antibodies. It has five constant domains (CH) per chain instead of the usual three, several disulfide bonds in unusual positions, and the complementarity-determining region 3 (CDR3) forms an extended loop covering the site which binds to a light chain in other antibodies. These differences, in combination with the phylogenetic age of the cartilaginous fishes, have led to the hypothesis that IgNAR could be more closely related to a primordial antigen-binding protein than the mammalian immunoglobulins. To test this hypothesis, it would be necessary to discover IgNAR or similar antibodies in vertebrates that are phylogenetically still older, like the jawless fish lamprey and hagfish. Non-vertebrates do not have antibodies at all.
Sharks, and possibly other cartilaginous fishes, have immunoglobulin M (IgM) and immunoglobulin W (IgW) as well, both types with two heavy and two light chains.
== In camelids ==
The only mammals with heavy-chain (IgG-like) antibodies are camelids such as dromedaries, camels, llamas and alpacas. This is a secondary development: The heavy chains of these antibodies have lost one of their constant domains (CH1) and undergone modifications in the variable domain (VH), both structural elements necessary for the binding of light chains. In one subgroup, the missing CH1 seems to be replaced by an extended hinge region, as shown in the image. Despite their different overall structure, camelid heavy-chain antibodies share several properties with IgNAR, for example the extended CDR3 loop and the conformation of the CDR1. It has been reasoned that these similarities are caused by functional requirements, or convergent evolution, rather than a genuine relationship.
About 50% of the antibodies in camelids are of the ordinary mammalian heavy/light-chain type. It is not known whether any type of animal has only heavy-chain antibodies and completely lacks the common type with two heavy and two light chains.
Heavy-chain camelid antibodies have been found to be just as specific as a regular antibody and in some cases they are more robust. As well, they are easily isolated using the same phage panning procedure used for traditional antibodies, allowing them to be cultured ex vivo in large concentrations. Phage-displayed dromedary camel VHH libraries have been made for isolating single-domain antibodies against SARS-CoV-2 and other virus infections. The smaller size and single domain make these antibodies easier to transform into bacterial cells for bulk production, making them ideal for research purposes.
== References ==
== External links ==
Wikilite: Biology of immunoglobulin light chains | Wikipedia/Heavy-chain_antibody |
Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies.
Retinol and retinoic acid play crucial roles in the modulation of gene expression and overall development of an embryo. However, deficit or excess of either one of these substances can cause early embryo mortality or developmental malformations. Regulation of transport and metabolism of retinol necessary for a successful pregnancy is accomplished via RBP. Retinol-binding proteins have been identified within the uterus, embryo, and extraembryonic tissue of the bovine, ovine, and porcine, clearly indicating that RBP plays a role in proper retinol exposure to the embryo and successful transport at the maternal-fetal interface. Further research is necessary to determine the exact effects of poor RBP expression on pregnancy and threshold levels for said expression.
== Genes ==
Cellular: RBP1, RBP2, RBP5, RBP7
Interstitial: RBP3
Plasma: RBP4
== RBP in pregnancy ==
Retinol plays a crucial role in the growth and differentiation of various body tissues, and it has been previously characterized that embryos are extremely sensitive to alterations in retinol concentration that can lead to spontaneous abortion and malformations occurring during development. Within a mature animal, retinol is transported from the liver via the circulatory system while bound to RBP to the desired target tissue. RBP is also bound to a carrier protein, transthyretin. The process by which RBP releases retinol for cellular availability is still unknown and not concisely determined.
=== Sites of synthesis ===
Traditionally, RBP is synthesized within the liver with secretion being dependent upon retinol concentrations. However, the concentrations levels do not appear to have an effect upon transcription of RBP messenger RNA (mRNA) which remains constant. Literature reveals that the bovine endometrium has also been identified as a location of RBP synthesis, as well as, the conceptus and extraembryonic tissues of various livestock species.
=== Types ===
Plasma retinol-binding protein, the retinol transport vehicle in serum.
CRBP I/II, cellular-binding proteins involved in transport of retinol and metabolites into retinyl esters for storage or into retinoic acid.
CRABPs, cellular retinoic acid–binding proteins capable of binding retinol and retinoic acid with high affinity. It has also been characterized that CRABPs are involved in many aspects of the retinoic acid signaling pathway such as the regulation and availability of retinoic acid to nuclear receptors.
=== Presence in livestock species during gestation ===
Bovine/Ovine
RBP, identical to that found in plasma has been identified in the placental tissues of both the ovine and the bovine, suggesting that RBP may be highly involved in retinol transport and metabolism during pregnancy. However, exact timing of expression had been yet to be identified. An antiserum specific for bovine conceptus RBP and immunohistochemistry has been utilized to identify the presence of RBP at different stages of early pregnancy. Strong immunostaining and hybridization were observed in the trophectoderm of tubular, but not spherical blastocysts at day 13. RBP mRNA was localized to epithelial cells of the chorion, allantois, and amnion at day 45 of pregnancy. Lastly, RBP mRNA was detected in the cotyledons, the fetal contribution to the placenta and the site of attachment to the uterine epithelium for fetal/maternal exchange. Expression of RBP in developing conceptuses, extraembryonic membranes, and at the fetal-maternal interface indicate that there may be some regulation of retinol transport and metabolism that occurs due to RBP by the extraembryonic membranes.
Within the uterus of pregnant bovines, it has been found that RBP synthesis in the luminal and glandular epithelium is quite similar to that of a cyclic animal's; however upon reaching day 17 of the estrous cycle, levels of RBP remain constant and continue to gradually rise throughout gestation. It has also been suggested that ovarian steroids may play a role in regulating uterine RBP expression.
Porcine
All three previously mentioned types of retinol-binding proteins (RBP, CRBP, CRABP) have been identified within the porcine placenta during pregnancy via immunohistochemistry. As previously mentioned, retinol and retinoic acid are modulators of gene expression and are necessary for the proper development and growth of a conceptus. Porcine exhibit a diffuse type placenta that has areolar-gland subunits which allows for transport of larger molecules between dam and fetus. RBP and CRBP have been identified in the endometrial glands and areolar trophoblasts, suggesting that RBP is crucial in transport of retinol from the gland to the trophectoderm of the conceptus. RBP expression has also been identified within the yolk sac, myometrium, oviduct, and numerous other fetal tissues.
== See also ==
STRA6 (Vitamin A receptor)
== References ==
== Further reading ==
== External links ==
Retinol-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Retinol_binding_protein |
Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other blood proteins act as enzymes, complement, components, protease inhibitors or kinin precursors. Contrary to popular belief, haemoglobin is not a blood protein, as it is carried within red blood cells, rather than in the blood serum.
Serum albumin accounts for 55% of blood proteins, is a major contributor to maintaining the oncotic pressure of plasma and assists, as a carrier, in the transport of lipids and steroid hormones. Globulins make up 38% of blood proteins and transport ions, hormones, and lipids assisting in immune function. Fibrinogen comprises 7% of blood proteins; conversion of fibrinogen to insoluble fibrin is essential for blood clotting. The remainder of the plasma proteins (1%) are regulatory proteins, such as enzymes, proenzymes, and hormones. All blood proteins are synthesized in liver except for the gamma globulins.
== Families of blood proteins ==
Examples of specific blood proteins:
Prealbumin (transthyretin)
Alpha 1 antitrypsin (neutralizes trypsin that has leaked from the digestive system)
Alpha-1-acid glycoprotein
Alpha-1-fetoprotein
alpha2-macroglobulin
Gamma globulins
Beta-2 microglobulin
Haptoglobin
Human Serum Albumin
Ceruloplasmin
Complement component 3
Complement component 4
C-reactive protein (CRP)
Lipoproteins (chylomicrons, VLDL, LDL, HDL)
Transferrin
Prothrombin
MBL or MBP
== Clinical significance ==
Separating serum proteins by electrophoresis is a valuable diagnostic tool, as well as a way to monitor clinical progress. Current research regarding blood plasma proteins is centered on performing proteomics analyses of serum/plasma in the search for biomarkers. These efforts started with two-dimensional gel electrophoresis efforts in the 1970s, and in more recent times this research has been performed using LC-tandem MS based proteomics. The normal laboratory value of serum total protein is around 7 g/dL.
Scientists are able to identify blood proteins using Photo-affinity labeling, a means of using photo-reactive ligands as a labeling agent to identify targeted proteins.
== References == | Wikipedia/Blood_proteins |
Protein A/G is a recombinant fusion protein that combines IgG binding domains of both protein A and protein G. Protein A/G contains four Fc binding domains from protein A and two from protein G, yielding a final mass of 50,460 daltons. The binding of protein A/G is less pH-dependent than protein A, but otherwise has the additive properties of protein A and G.
Protein A/G binds to all subclasses of human IgG, making it useful for purifying polyclonal or monoclonal IgG antibodies whose subclasses have not been determined. In addition, it binds to IgA, IgE, IgM and (to a lesser extent) IgD. Protein A/G also binds to all subclasses of mouse IgG but does not bind mouse IgA, IgM or serum albumin. This allows Protein A/G to be used for purification and detection of mouse monoclonal IgG antibodies, without interference from IgA, IgM and serum albumin. Mouse monoclonal antibodies commonly have a stronger affinity to the chimeric protein A/G than to either protein A or protein G. Protein A/G also has been used for purification of macaque IgG.
== Other antibody binding proteins ==
In addition to protein A/G, other immunoglobulin-binding bacterial proteins such as protein A, protein G and protein L are all commonly used to purify, immobilize or detect immunoglobulins. Each of these immunoglobulin-binding proteins has a different antibody binding profile in terms of the portion of the antibody that is recognized and the species and type of antibodies.
== References == | Wikipedia/Protein_A/G |
Anti-mitochondrial antibodies (AMA) are autoantibodies, consisting of immunoglobulins formed against mitochondria, primarily the mitochondria in cells of the liver.
The presence of AMA in the blood or serum of a person may be indicative of the presence of, or the potential to develop, the autoimmune disease primary biliary cholangitis (PBC; previously known as primary biliary cirrhosis). PBC causes scarring of liver tissue, confined primarily to the bile duct drainage system. AMA is present in about 95% of cases. PBC is seen primarily in middle-aged women, and in those afflicted with other autoimmune diseases.
== Antigens ==
Several of the antigens associated with anti-mitochondrial antibodies have been identified.
M1 – cardiolipin (Anti-cardiolipin antibodies, ACA)
M2 – branched-chain alpha-keto acid dehydrogenase complex
M3 – outer mitochondrial membrane
M4 – sulfite oxidase
M5 – outer mitochondrial membrane
M6 – outer mitochondrial membrane
M7 – sarcosine dehydrogenase
M8 – outer mitochondrial membrane
M9 – glycogen phosphorylase
== Disease associations ==
Antibodies to these specific antigens have been associated with a number of conditions: anti M2, M4, M8, and M9 are associated with primary biliary cholangitis; M2 – autoimmune hepatitis; M1 – syphilis; M3 – drug-induced lupus erythematosus; M6 – drug-induced hepatitis; M7 – cardiomyopathy, myocarditis; M5 – systemic lupus erythematosus and undifferentiated collagenosis, autoimmune haemolytic anaemia. These associations are not completely specific and should not be relied upon solely for diagnosis.
Antimitochondrial antibodies can also be detected in Sjögren's syndrome, systemic sclerosis, asymptomatic recurrent bacteriuria in women, pulmonary tuberculosis, and leprosy.
Anti-cardiolipin antibodies are another type of AMA, and cardiolipin is found on the inner mitochondrial membrane.
== Development ==
A cause of AMA has been postulated to be that xenobiotic-induced and/or oxidative modification of mitochondrial autoantigens is a critical step leading to loss of tolerance. In acute liver failure AMA are found against all major liver antigens.
Pyruvate dehydrogenase, E2 subunits
2-Oxo-glutarate dehydrogenase
Branched-chain 2-oxo-acid dehydrogenase
Around 40.5% of acute liver failure patients were found to have elevated AMA, although a larger proportion (56.9%) had anti-transglutaminase antibodies, usually associated with coeliac disease.
== See also ==
Antibodies
Mitochondrion
== References == | Wikipedia/Anti-mitochondrial_antibody |
Synthetic antibodies are affinity reagents generated entirely in vitro, thus completely eliminating animals from the production process. Synthetic antibodies include recombinant antibodies, nucleic acid aptamers and non-immunoglobulin protein scaffolds. As a consequence of their in vitro manufacturing method the antigen recognition site of synthetic antibodies can be engineered to any desired target and may extend beyond the typical immune repertoire offered by natural antibodies. Synthetic antibodies are being developed for use in research, diagnostic and therapeutic applications. Synthetic antibodies can be used in all applications where traditional monoclonal or polyclonal antibodies are used and offer many inherent advantages over animal-derived antibodies, including comparatively low production costs, reagent reproducibility and increased affinity, specificity and stability across a range of experimental conditions.
== Recombinant antibodies ==
Recombinant antibodies are monoclonal antibodies generated in vitro using synthetic genes. Recombinant antibody technology involves recovering the antibody genes from the source cells, amplifying and cloning the genes into an appropriate vector, introducing the vector into a host, and achieving expression of adequate amounts of functional antibody. Recombinant antibodies can be cloned from any species of antibody-producing animal, if the appropriate oligonucleotide primers or hybridization probes are available. The ability to manipulate the antibody genes make it possible to generate new antibodies and antibody fragments, such as Fab fragments and scFv in vitro. This can be done at the level of the whole combining site by making new combinations of H and L chains. It can also be done by mutating individual CDRs. Display libraries, commonly expressed in phage or yeast, can be analysed to select for desirable characteristics arising from such changes in antibody sequence.
== Non-immunoglobulin derived synthetic antibodies ==
These molecules typically differ in structure to that of an antibody and can be generated either from nucleic acids, as in the case of aptamers, or from non-immunoglobulin protein scaffolds / peptide aptamers, into which hypervariable loops are inserted to form the antigen binding site. Constraining the hypervariable binding loop at both ends within the protein scaffold improves the binding affinity and specificity of the synthetic antibody to levels comparable to or exceeding that of a natural antibody. Common advantages of these molecules compared to use of the typical antibody structure include a smaller size, giving improved tissue penetration, rapid generation times of weeks compared to months for natural and recombinant antibodies and cheaper costs.
== Affimer proteins ==
Affimer proteins are small robust affinity reagents, with a molecular weight of 12–14kDa. They are engineered to bind to their target proteins with high affinity and specificity and as such are a member of the synthetic antibody family.
The Affimer protein scaffold is derived from the cysteine protease inhibitor family of cystatins. Within the protein scaffold there exist two variable peptide loops and a variable N-terminal sequence that provide a high affinity binding surface for the specific target protein. Affimer binders have been produced to a large number of targets including ubiquitin chains, immunoglobulins and C-reactive protein for use in a number of molecular recognition applications.
Affimer technology has been commercialised and developed by Avacta Life Sciences, who are developing Affimer binders as reagents for research, diagnostic and therapeutic applications.
== Applications ==
Synthetic antibodies have shown their utility in a number of applications. Their use within the field of research lies predominantly in the life sciences as reagents for protein capture and as protein inhibitors. Within diagnostics they have been utilised in applications ranging from infection and cancer screening to mycotoxin detection in grain samples. Synthetic antibodies are currently the fastest growing class of therapeutics.
== See also ==
Synthetic biology – Interdisciplinary branch of biology and engineering
Synthetic immunology – Design and construction of synthetic systems that perform complex immunological functions
== References ==
== External links ==
An Introduction to Affimers – video | Wikipedia/Synthetic_antibody |
A trifunctional antibody is a monoclonal antibody with binding sites for two different antigens, typically CD3 and a tumor antigen, making it a type of bispecific monoclonal antibody. In addition, its intact Fc-part can bind to an Fc receptor on accessory cells like conventional monospecific antibodies. The net effect is that this type of drug links T cells (via CD3) and monocytes/macrophages, natural killer cells, dendritic cells or other Fc receptor expressing cells to the tumor cells, leading to their destruction.
At an equivalent dose a trifunctional antibody is more potent (more than 1,000-fold) in eliminating tumor cells than conventional antibodies. These drugs evoke the removal of tumor cells by means of (i) antibody-dependent cell-mediated cytoxicity, a process also described for conventional antibodies and more importantly by (ii) polyclonal cytotoxic T cell responses with emphasis on CD8 T cells. These trifunctional antibodies also elicit individual anti-tumor immune responses in cancer patients treated with e.g. catumaxomab; i.e. autologous antibodies as well as CD4 and CD8 T cells directed against the tumor were detected. Furthermore, putative cancer stem cells from malignant ascites fluid were eliminated due to catumaxomab treatment.
Catumaxomab, was the first to be approved for clinical use (in 2009 for the treatment of malignant ascites in cancer patients).
Examples include catumaxomab (EpCAM / CD3), ertumaxomab (HER2/neu / CD3), FBTA05 (CD20 / CD3, proposed trade name Lymphomun) and TRBS07 (GD2 / CD3, proposed trade name Ektomab), drugs against various types of cancer.
== History ==
Trifunctional antibodies were the first type of bispecific monoclonal antibodies to be produced. The first concepts date back to the mid-1980s. For over twenty years, no such antibody was approved for clinical use, mainly because of manufacturing difficulties. Immunogenicity results from the fact that appropriate parental antibodies are obtained from rat and mice. After application, the patient's immune system usually produces anti-drug antibodies, which represent early indicators for a beneficial clinical outcome.
Furthermore, despite the development of anti-drug antibody responses after the first catumaxomab application cycle a repeated cycle of catumaxomab also leads to a treatment success in recurrent malignant ascites. Cross-linking leads to the release of cytokines, resulting in manageable adverse effects like fever, nausea and vomiting, that were generally reversible and mainly related to the immunological mode of action (e.g. catumaxomab).
Catumaxomab, which was approved in 2009 for the treatment of malignant ascites in cancer patients, satisfies these conditions. It was the first, and as of May 2011 the only approved one of these antibodies in clinical use.
Another way of immunotherapeutic intervention strategies is the exploration of bispecific antibodies with different structures, of which bi-specific T-cell engagers (BiTEs) have been produced since the mid-2000s.
== Production ==
At first, mouse hybridoma cells whose monoclonal antibodies target one of the desired antigens are produced. Independently, rat hybridoma cells targeting the other antigen are produced. These two cell types are hybridised, yielding hybrid-hybridomas or quadromas, which produce hybrid (trifunctional) antibody as well as pure mouse and pure rat antibody. The trifunctional antibody is extracted chromatographically with protein A.
Using two different species (mouse and rat) has the advantage that less mismatched antibodies are produced because rat light chains preferably pair with rat heavy chains, and mouse light chains with mouse heavy chains. Single species (mouse/mouse or rat/rat) quadromas, by contrast, produce up to ten different kinds of antibody, most of which have mismatched heavy or light chains, or both.
== References ==
== Further reading ==
Choi, BD; et, al.; Bigner, DD; Mehta, AI; Kuan, CT; Sampson, JH (2011). "Bispecific antibodies engage T cells for antitumor immunotherapy". Expert Opin Biol Ther. 11 (7): 1–11. doi:10.1517/14712598.2011.572874. PMID 21449821. S2CID 1312336.
Thakur, A; Lum, LG (2010). "Cancer therapy with bispecific antibodies: Clinical experience". Current Opinion in Molecular Therapeutics. 12 (3): 340–349. PMC 3785321. PMID 20521223. | Wikipedia/Trifunctional_antibody |
A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic.
Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.
== Mechanism ==
In order to enter cells, pathogens, such as circulating viral particles or extracellular bacteria, use molecules on their surfaces to interact with the cell surface receptors of their target cell which allows them to enter the cell and start their replication cycle. Neutralizing antibodies can inhibit infectivity by binding to the pathogen and blocking the molecules needed for cell entry. This can be due to the antibodies statically interfering with the pathogens, or toxins attaching to host cell receptors. In case of a viral infection, NAbs can bind to glycoproteins of enveloped viruses or capsid proteins of non-enveloped viruses.
Furthermore, neutralizing antibodies can act by preventing particles from undergoing structural changes often needed for successful cell entry. For example, neutralizing antibodies can prevent conformational changes of viral proteins that mediate the membrane fusion needed for entry into the host cell. In some cases, the virus is unable to infect even after the antibody dissociates. The pathogen-antibody complex is eventually taken up and degraded by macrophages.
Neutralizing antibodies are also important in neutralizing the toxic effects of bacterial toxins. An example of a neutralizing antibody is diphtheria antitoxin, which can neutralize the biological effects of diphtheria toxin. Neutralizing antibodies are not effective against extracellular bacteria, as the binding of antibodies does not prevent bacteria from replicating. Here, the immune system uses other functions of antibodies, like opsonisation and complement activation, to kill the bacteria.
=== Difference between neutralizing antibodies and binding antibodies ===
Not all antibodies that bind to a pathogenic particle are neutralizing. Non-neutralizing antibodies, or binding antibodies, bind specifically to the pathogen, but do not interfere with their infectivity. That might be because they do not bind to the right region. Non-neutralizing antibodies can be important to flag the particle for immune cells, signaling that it has been targeted, after which the particle is processed and consequently destroyed by recruited immune cells. Neutralizing antibodies on the other hand can neutralize the biological effects of the antigen without a need for immune cells.
In some cases, non-neutralizing antibodies, or an insufficient amount of neutralizing antibodies binding to viral particles, can be utilized by some species of virus to facilitate uptake into their host cells. This mechanism is known as antibody-dependent enhancement. It has been observed for Dengue virus and Zika virus.
== Production ==
Antibodies are produced and secreted by B cells.
When B cells are produced in the bone marrow, the genes that encode the antibodies undergo random genetic recombination (V(D)J recombination), which results in every mature B cell producing antibodies that differ in their amino acid sequence in the antigen-binding region. Therefore, every B cell produces antibodies that bind specifically to different antigens. A strong diversity in the antibody repertoire allows the immune system to recognize a plethora of pathogens which can come in all different forms and sizes. During an infection only antibodies that bind to the pathogenic antigen with high affinity are produced. This is achieved by clonal selection of a single B cell clone: B cells are recruited to the site of infection by sensing interferons that are released by the infected cells as part of the innate immune response. B cells display B-cell receptors on their cell surface, which is just the antibody anchored to the cell membrane. When the B-cell receptor binds to its cognate antigen with high affinity, an intracellular signalling cascade is triggered. In addition to binding to an antigen, B cells need to be stimulated by cytokines produced by T helper cells as part of the cellular response of the immune system against the pathogen. Once a B cell is fully activated, it rapidly proliferates and differentiates into plasma cells. Plasma cells then secrete the antigen-specific antibody in large quantities.
After a first encounter of the antigen by vaccination or natural infection, immunological memory allows for a more rapid production of neutralizing antibodies following the next exposure to the virus.
== Virus evasion of neutralizing antibodies ==
Viruses use a variety of mechanisms to evade neutralizing antibodies. Viral genomes mutate at a high rate. Mutations that allow viruses to evade a neutralizing antibody will be selected for, and hence prevail. Conversely, antibodies also simultaneously evolve by affinity maturation during the course of an immune response, thereby improving recognition of viral particles. Conserved parts of viral proteins that play a central role in viral function are less likely to evolve over time, and therefore are more vulnerable to antibody binding. However, viruses have evolved certain mechanisms to hinder steric access of an antibody to these regions, making binding difficult. Viruses with a low density of surface structural proteins are more difficult for antibodies to bind to. Some viral glycoproteins are heavily glycosylated by N- and O- linked glycans, creating a so-called glycan shield, which may decrease antibody binding affinity and facilitate evasion of neutralizing antibodies. HIV-1, the cause of human AIDS, uses both of these mechanisms.
== Medical uses of neutralizing antibodies ==
Neutralizing antibodies are used for passive immunisation, and can be used for patients even if they do not have a healthy immune system.
In the early 20th century, infected patients were injected with antiserum, which is the blood serum of a previously infected and recovered patient containing polyclonal antibodies against the infectious agent. This showed that antibodies could be used as an effective treatment for viral infections and toxins. Antiserum is a very crude therapy, because antibodies in the plasma are not purified or standardized and the blood plasma could be rejected by the donor. As it relies on the donation from recovered patients it cannot be easily scaled up. However, serum therapy is today still used as the first line of defence during an outbreak as it can relatively quickly obtained. Serum therapy was shown to reduce mortality in patients during the 2009 swine flu pandemic and the Western African Ebola virus epidemic. It is also being tested as possible treatment for COVID-19. Immunoglobulin therapy, which uses a mixture of antibodies obtained from healthy people, is given to immunodeficient or immunosuppressed patients to fight off infections.
For a more specific and robust treatment, purified polyclonal or monoclonal antibodies (mAb) can be used. Polyclonal antibodies are collection of antibodies that target the same pathogen but bind to different epitopes. Polyclonal antibodies are obtained from human donors or animals that have been exposed to the antigen. The antigen injected into the animal donors can be designed in such a way to preferably produce neutralizing antibodies. Polyclonal antibodies have been used as treatment for cytomegalovirus (CMV), hepatitis b virus (HBV), rabies virus, measles virus, and respiratory syncytial virus (RSV). Diphtheria antitoxin contains polyclonal antibodies against the diphtheria toxin. By treating with antibodies binding multiple epitopes, the treatment is still effective even if the virus mutates and one of the epitopes changes in structure. However, because of the nature of the production, treatment with polyclonal antibodies has batch to batch variation and low antibody titers. Monoclonal antibodies, on the other hand, all bind the same epitope with high specificity. They can be produced with the Hybridoma technology, which allows the production of mAbs in large quantities. mAbs against infections stop working when virus mutates the epitope that is targeted by the mAbs or multiple strain are circulating. Example of drugs that use monoclonal antibodies include ZMapp against Ebola and Palivizumab against RSV. Many mABs against other infections are in clinical trials.
Neutralizing antibodies also play a role in active immunisation by vaccination. By understanding the binding sites and structure of neutralizing antibodies in a natural immune response a vaccine can be rationally designed such that it stimulates the immune system to produce neutralizing antibodies and not binding antibodies.
Introducing a weakened form of a virus through vaccination allows for the production of neutralizing antibodies by B cells. After a second exposure, the neutralizing antibody response is more rapid due to the existence of memory B cells that produce antibodies specific to the virus.
An effective vaccine induces the production of antibodies that are able to neutralize the majority of variants of a virus, although virus mutation resulting in antibody evasion may require vaccines to be updated in response.
Some viruses evolve faster than others, which can require the need for vaccines to be updated in response. A well known example is the vaccine for the influenza virus, which must be updated annually to account for the recent circulating strains of the virus.
Neutralizing antibodies may also assist the treatment of multiple sclerosis. Although this type of antibody has the ability to fight retroviral infections, in some cases it attacks pharmaceuticals administered to the body which would otherwise treat multiple sclerosis. Recombinant protein drugs, especially those derived from animals, are commonly targeted by neutralizing antibodies. A few examples are Rebif, Betaseron and Avonex.
=== Methods for detection and quantification of neutralizing antibodies ===
Neutralization assays are capable of being performed and measured in different ways, including the use of techniques such as plaque reduction (which compares counts of virus plaques in control wells with those in inoculated cultures), microneutralization (which is performed in microtiter plates filled with small amounts of sera), and colorimetric assays (which depend on biomarkers indicating metabolic inhibition of the virus).
== Broadly neutralizing antibodies ==
Most of the neutralizing antibodies produced by the immune system are very specific for a single virus strain due to affinity maturation by B cells. Some pathogens with high genetic variability, such as HIV, constantly change their surface structure such that neutralizing antibodies with high specificity to the old strain can no longer bind to the new virus strain. This immune evasion strategy prevents the immune system from developing immunological memory against the pathogen. Broadly neutralizing antibodies (bNAbs), on the other hand, have the special ability to bind and neutralize multiple strains of a virus species.
bNAbs have been initially found in HIV patients. However, they are quite rare: an in situ screening study showed that only 1% of all patients develop bNAbs against HIV. bNABs can neutralize a wide range of virus strains by binding to conserved regions of the virus surface proteins that are unable to mutate because they are functionally essential for the virus replication. Most binding sites of bNAbs against HIV are on HIV's exposed surface antigen, the envelope (Env) protein (a trimer composed of gp120 and gp41 subunits). These site include the CD4 binding site or the gp41-gp120 interface. Los Alamos National Laboratory's HIV Databases is a comprehensive resource that has a wealth of information about HIV sequences, bNAbs, and more.
Additionally, bNAbs have been found for other viruses including influenza, hepatitis C, dengue and West Nile virus.
=== Research ===
Preliminary research is conducted to identify and test bNAbs against HIV-1. bNAbs are used in research to rationally design vaccines to stimulate production of bNAbs and immunity against viruses. No antigen that triggers bNAb production in animal models or humans is known.
Bispecific antibodies (bsAb) against HIV-1 are also currently being studied. One example of such an antibody binds bind both HIV-1 Env and the CD4 receptor and this seems to allow it to have enhanced ability to neutralise HIV-1 as well as an enhanced neutralisation breadth .
== See also ==
Blocking antibody
Humoral immunity
== References == | Wikipedia/Neutralizing_antibody |
Antithyroid autoantibodies (or simply antithyroid antibodies) are autoantibodies targeted against one or more components on the thyroid. The most clinically relevant anti-thyroid autoantibodies are anti-thyroid peroxidase antibodies (anti-TPO antibodies, TPOAb), thyrotropin receptor antibodies (TRAb) and thyroglobulin antibodies (TgAb). TRAb's are subdivided into activating, blocking and neutral antibodies, depending on their effect on the TSH receptor. Anti-sodium/iodide (Anti–Na+/I−) symporter antibodies are a more recent discovery and their clinical relevance is still unknown. Graves' disease and Hashimoto's thyroiditis are commonly associated with the presence of anti-thyroid autoantibodies. Although there is overlap, anti-TPO antibodies are most commonly associated with Hashimoto's thyroiditis and activating TRAb's are most commonly associated with Graves' disease. Thyroid microsomal antibodies were a group of anti-thyroid antibodies; they were renamed after the identification of their target antigen (TPO).
== Subtypes ==
Anti-thyroid antibodies can be subdivided into groups according to their target antigen.
=== Anti-TPO antibodies ===
Anti-thyroid peroxidase (anti-TPO) antibodies are specific for the autoantigen TPO, a 105 kDa glycoprotein that catalyses iodine oxidation and thyroglobulin tyrosyl iodination reactions in the thyroid gland. Most antibodies produced are directed to conformational epitopes of the immunogenic carboxyl-terminal region of the TPO protein, although antibodies to linear epitopes have been seen. Anti-TPO antibodies are the most common anti-thyroid autoantibody, present in approximately 90% of Hashimoto's thyroiditis, 75% of Graves' disease and 10–20% of nodular goiter or thyroid carcinoma. Also, 10–15% of normal individuals can have high level anti-TPO antibody titres. High serum antibodies are found in active phase chronic autoimmune thyroiditis. Thus, an antibody titer can be used to assess disease activity in patients that have developed such antibodies. The majority of anti-TPO antibodies are produced by thyroid infiltrating lymphocytes, with minor contributions from lymph nodes and the bone marrow. They cause thyroid cell damage by complement activation and antibody dependent cell cytotoxicity. However, anti-TPO antibodies are not believed to contribute to the destruction of the thyroid.
=== TSH receptor antibodies ===
The thyrotropin receptor (TSH receptor) is the antigen for TSH receptor antibodies (TRAbs). It is a seven transmembrane G protein-coupled receptor that is involved in thyroid hormone signalling. TRAbs are grouped depending on their effects on receptor signalling; activating antibodies (associated with hyperthyroidism), blocking antibodies (associated with thyroiditis) and neutral antibodies (no effect on receptor). Activating and blocking antibodies mostly bind to conformational epitopes, whereas neutral antibodies bind to linear epitopes. Binding of the antibody to the amino terminus of the TSH receptor shows stimulatory activity, whereas binding to residues 261-370 or 388-403 block the activity. TRAbs are present in 70–100% of Graves' disease (85–100% for activating antibodies and 75–96% for blocking antibodies) and 1–2% of normal individuals.
Activating TRAbs are characteristic of Graves' disease (autoimmune hyperthyroidism). TPO antibody is measured more easily than the TSH receptor antibody, and so is often used as a surrogate in the diagnosis of Graves' disease. These antibodies activate adenylate cyclase by binding to the TSH receptor. This causes the production of thyroid hormones and subsequent growth and vascularisation of the thyroid. TRAbs are also useful in the diagnosis of Graves' ophthalmopathy. Although the exact mechanism of how TRAbs induce Graves' ophthalmopathy is unknown, it is likely that the antibodies bind to TSH receptors in retro-orbital tissues, causing infiltration of lymphocytes. This inflammatory response leads to cytokine production that causes fibroblasts to produce glycosaminoglycans, leading to ophthalmopathy.
Blocking TRAbs (also known as thyrotropin binding inhibitory immunoglobulins (TBII)) competitively block the activity of TSH on the receptor. This can cause hypothyroidism by reducing the thyrotropic effects of TSH. They are found in Hashimoto's thyroiditis and Graves' disease and may be cause of fluctuation of thyroid function in the latter. During treatment of Graves' disease they may also become the predominant antibody, which can cause hypothyroidism.
The clinical and physiological relevance of neutral antibodies remains unclear. However, they may be involved in prolonging the TSH receptor half-life.
=== Thyroglobulin (TG) antibodies ===
Thyroglobulin antibodies are specific for thyroglobulin, a 660 kDa matrix protein involved in the process of thyroid hormone production. They are found in 70% of Hashimoto's thyroiditis, 60% of idiopathic hypothyroidism, 30% of Graves' disease, a small proportion of thyroid carcinoma and 3% of normal individuals. Anti-TPO antibodies are present in 99% of cases where thyroglobulin antibodies are present, however only 35% of anti-TPO antibody positive cases also demonstrate thyroglobulin antibodies.
=== Anti–Na+/ I− symporter ===
Anti-Na+/I− symporter antibodies are a more recent discovery of possible thyroid autoantibodies and their role in thyroid disease remains uncertain. They are present in approximately 20% of Graves' disease and 24% of Hashimoto's thyroiditis.
== Pathogenesis ==
The production of antibodies in Graves' disease is thought to arise by activation of CD4+ T-cells, followed by B-cell recruitment into the thyroid. These B-cells produce antibodies specific to the thyroid antigens. In Hashimoto's thyroiditis, activated CD4+ T-cells produce interferon-γ, causing the thyroid cells to display MHC class II molecules. This expands the autoreactive T-cell repertoire and prolongs the inflammatory response.
While anti-thyroid antibodies are used to track the presence of autoimmune thyroiditis, they are generally not considered to contribute directly to the destruction of the thyroid.
== Effect on human reproduction ==
The presence of anti-thyroid antibodies is associated with an increased risk of unexplained subfertility (odds ratio 1.5 and 95% confidence interval 1.1–2.0), miscarriage (odds ratio 3.73, 95% confidence interval 1.8–7.6), recurrent miscarriage (odds ratio 2.3, 95% confidence interval 1.5–3.5), preterm birth (odds ratio 1.9, 95% confidence interval 1.1–3.5) and maternal postpartum thyroiditis (odds ratio 11.5, 95% confidence interval 5.6–24).
== History ==
In 1912 Hakaru Hashimoto described hypothyroidism and goiter associated with thyroid lymphoid infiltration. In 1956 the anti-Tg antibody was detected in similar cases, elucidating the autoimmune cause of these characteristics. Later the same year, activating TSH receptor antibodies were discovered. Thyroid microsomal antibodies were discovered in 1964, which were subsequently renamed anti-TPO antibodies due to the identification of their autoantigen.
== References == | Wikipedia/Anti-thyroid_peroxidase_antibody |
Anti-double stranded DNA (Anti-dsDNA) antibodies are a group of anti-nuclear antibodies (ANA) the target antigen of which is double stranded DNA. Blood tests such as enzyme-linked immunosorbent assay (ELISA) and immunofluorescence are routinely performed to detect anti-dsDNA antibodies in diagnostic laboratories. They are highly diagnostic of systemic lupus erythematosus (SLE) and are implicated in the pathogenesis of lupus nephritis.
== Discovery ==
The first evidence for antinuclear antibodies arose in 1948 when Hargraves, Richmond and Morton discovered the LE cell. These abnormal cells, which are found in the bone marrow of persons who have SLE are categorised as polymorphonuclear leukocytes with phagocytosed whole nuclei. Subsequently, in 1957, antibodies to dsDNA were the first autoantibodies to be identified in patients with SLE.
== Antibody production ==
Although the exact mechanism of the generation of dsDNA antibodies is still unknown, it is likely that extracellular DNA is one cause of an immune response against dsDNA. There is a great deal of evidence supporting the idea that dead or dying cells are one major source of this extracellular DNA. Apoptosis is the highly organised process of programmed cell death in which the cell degrades the nuclear DNA and signals for phagocytosis. In people with SLE and other autoimmune disorders this process is thought to be defective, causing either an increase in cell death and/or a decrease in the rate of dead cell clearance.
There is a higher rate of apoptosis in people with SLE and various changes in genes and proteins have been implicated in the defects in apoptosis. These include increased levels of soluble Fas and bcl-2 and polymorphisms in the programmed cell death 1 and runt-related transcription factor X1.
Blebs on apoptotic cells contain nearly all the autoantigens found in SLE, and phagocytes bind these apoptotic cells and phagocytose them. If this process is defective, these autoantigens can be released into the circulation allowing an immune response. Serum amyloid P component is a protein that is thought to aid in the clearance of chromatin produced by apoptotic cells and deficiencies in this protein have been shown (in mice) to cause spontaneous formation of ANA. Autoantigens present on the blebs of apoptotic cells are also prone to modification, which can increase their immunogenicity.
Upon release of nuclear proteins and chromatin, antigen presenting cells, such as dendritic cells and macrophages, display these antigens to T helper cells. Although the details of this process are still controversial, evidence shows that to produce an immune response, DNA must activate an antigen presenting cell to produce type 1 interferons. This cytokine serves to induce maturation of plasmacytoid dendritic cells (PDCs) so that they can display their antigens to T helper cells. The mechanism in which eukaryotic DNA activates these cells is still as yet unclear; however, immunogenic CpG sequences have been found to either activate PDCs or act as adjuvant in the response to eukaryotic DNA. CpG motif DNA acts via the pattern recognition receptor, toll-like receptor 9, found highly expressed in PDCs and B cells. The T helper cells then activate B cells, which are also in the presence of these antigens, causing the production of autoantibodies.
Anti-dsDNA antibodies can also be produced through infection via a mechanism known as molecular mimicry. Upon exposure to pneumococcal polysaccharides, cross reactive antibodies between dsDNA and pneumococcal polysaccharides are produced in lupus. Epstein–Barr virus is also known to induce dsDNA antibodies, as seen after immunisation of animals with EBNA-1 epitopes.
Anti-dsDNA antibodies might also be created secondary to the production of antibodies to other proteins within the nucleosome. Mice that have T cells directed towards the nucleosome can elicit a response to other antigens such as dsDNA and histone via a mechanism known as antigen spreading. This effect can also occur after an infection causes the production of autoantibodies to other structures within the nucleus.
== Role in disease ==
=== SLE ===
Anti-dsDNA antibodies are incredibly specific for SLE, with studies quoting nearly 100%, and are therefore used in the diagnosis of SLE. Higher titres of anti-dsDNA antibodies are more suggestive of SLE and lower titres can be found in people without the disease. In contrast to the high specificity, estimates of 25–85% have been observed for the sensitivity of anti-dsDNA in SLE. Therefore, presence of anti-dsDNA antibodies are suggestive of SLE, however an absence of the antibodies does not rule out the disease.
The levels of circulating anti-dsDNA antibodies fluctuate with disease activity in SLE. Increases in titres of the antibodies can coincide with, or even precede an increase of disease activity. For this reason titres are serially monitored by clinicians to assess disease progression. Titres are monitored more often in cases of more active lupus than that of less active lupus at intervals of 1–3 months and 6–12 months, respectively.
Anti-dsDNA antibodies are highly associated with glomerulonephritis in SLE, although some patients with high titers of anti-dsDNA antibodies do not develop renal disease. This is most likely due to the fact that anti-dsDNA are a heterogeneous population, some of which have been found not to be pathogenic. Anti-dsDNA antibodies can be present in normal individuals, however these antibodies are usually low avidity IgM isotype. In contrast, pathogenic anti-dsDNA antibodies found in SLE are usually of IgG isotype and show high avidity for dsDNA. One possible mechanism for anti-dsDNA and their role in nephritis is the formation of immune complexes that arise by indirect binding to DNA or nucleosomes that are adhered to the glomerular basement membrane (GBM). Another mechanism is direct binding of antibodies to GBM antigens such as C1q, nucleosomal proteins, heparin sulphate or laminin, which can initiate an inflammatory response by activating complement. They can also be internalised by certain molecules on the GBM cells and cause inflammatory cascades, proliferation and alteration of cellular functions.
=== Rheumatoid arthritis ===
Patients with rheumatoid arthritis can develop anti-dsDNA antibodies, however they are usually treatment related. Anti-TNFα biological therapies, such as adalimumab, infliximab and etanercept, can often induce the production of anti-dsDNA antibodies. They are usually low avidity and are only detectable transiently after treatment. The presence of these antibodies can induce a lupus-like syndrome in some cases.
=== Viral infection ===
Infection with viral pathogens can induce anti-dsDNA antibodies transiently. Human immunodeficiency virus, parvovirus B19 and BK virus are known to induce these antibodies.
=== Other diseases ===
There is little evidence supporting the association between anti-dsDNA antibodies and other diseases. Occasionally the monoclonal proteins produced by myeloma patients can be anti-dsDNA. Also, some patients with type 1 autoimmune hepatitis produce anti-dsDNA antibodies.
== Detection and quantitation ==
A variety of assay formats can be used to detect and quantify anti-dsDNA antibodies but there is no 'gold standard' for diagnostic purposes and the concordance between different assays/methods is low.
=== Farr assay ===
The Farr assay is used to quantify the amount of anti-dsDNA antibodies in serum. Ammonium sulphate is used to precipitate antigen-antibody complexes that form if the sera contains antibodies to dsDNA. The quantity of these antibodies is determined by using radioactively labelled dsDNA. Although this test is very specific, it is of little use in routine diagnostic laboratories due to its laboriousness and use of radioactive materials. The Farr assay is one of the only tests available that detects high avidity antibodies (along with Crithidia luciliae) and also has the ability to detect antibodies of any isotype.
=== PEG ===
The polyethylene glycol (PEG) assay precipitates DNA-antibody complexes, similar to the Farr Assay. However, unlike the Farr Assay it does not dissociate the low avidity antibody complexes, allowing for the detection of both high and low avidity anti-dsDNA antibodies.
=== Immunofluorescence ===
==== Animal Tissue ====
Animal tissue was the first substrate for immunofluorescent detection of antinuclear antibodies and has been in use since the late 1950s. Liver and kidney tissue sections from animals such as rats are used to identify anti-dsDNA antibodies. This substrate has largely been superseded by the use of HEp-2 cells.
==== HEp-2 ====
Hep-2 cells, originally of laryngeal carcinoma origin, are actually a contamination of HeLa cells. They are routinely used in the diagnosis of ANA in diagnostic laboratories. HEp-2 cells provide a greater ability to differentiate patterns of ANA than animal sections, due to the large nuclei and high mitotic rate of the cell line. Upon incubation with serum containing anti-dsDNA antibodies and fluorescent labelled secondary antibodies, homogeneous staining of interphase nuclei and condensed chromosomal staining of mitotic cells can be seen.
==== Crithidia ====
Crithidia luciliae is a haemoflagellate protist with an organelle known as the kinetoplast. This organelle contains a high concentration of circular DNA with no recognisable nuclear antigens, allowing for the reliable detection of anti-dsDNA antibodies. The kinetoplast fluoresces if serum contains high avidity anti-dsDNA antibodies. This test has a higher specificity than EIA because it uses unprocessed DNA. Processed DNA can contain regions of ssDNA, allowing detection of anti-ssDNA antibodies, which can give false positive results.
=== EIA ===
EIA (enzyme immunoassay) detects antibodies using a DNA-coated polystyrene microtitre plate. The DNA used in these assays is often recombinant dsDNA or from calf thymus extract. Upon incubation with serum containing anti-dsDNA antibodies, the antibodies will bind to the DNA and can then be visualised using enzyme-linked secondary antibodies. This assay can be quantitative or semi-quantitative, allowing for estimations of the levels of anti-dsDNA antibodies. This test can produce false positives due to contamination of ssDNA from denatured dsDNA. EIA detects low and high avidity anti-dsDNA antibodies, increasing its sensitivity and reducing its specificity.
=== Flow cytometry ===
Flow cytometry for the detection of ANA uses multiplexed polystyrene beads coated with multiple autoantigens, such as SSA, SSB, Sm,
RNP, Scl-70, Jo-1, dsDNA, centromere B and histone. Serum is incubated with the beads and in the presence of anti-dsDNA antibodies, or any other ANA, the antibodies will bind and fluorescent labelled secondary antibodies will be used for detection. The beads are run through a flow cell which uses a laser to detect fluorescence.
=== Multiplex immunoassay (MIA) ===
Similar to the flow cytometry method of ANA detection, the MIA uses wells containing autoantigens and HEp-2 extract coated beads. The bead sets are coated with specific autoantigens and can be detected individually to allow identification of the particular autoantibody. Automated analysis of the well fluorescence allows for rapid detection of autoantibodies.
=== Microarrays ===
Microarrays are a newly emerging method for the detection of ANA. Individual autoantigens are deposited in an array of dots onto a surface such as polystyrene. A single array could consist of hundreds of autoantigens for screening of multiple autoimmune diseases simultaneously. If anti-dsDNA antibodies are present, incubation of serum and the microarray allow for binding and the dots can then be visualised using a fluorescent labelled anti-IgG antibody.
== Therapeutics ==
As a result of the highly specific nature of antibodies, they can be engineered to target and bind key motifs. These motifs can be key features within the pathogenesis of particular diseases, for example human papillomavirus.
== References == | Wikipedia/Anti-dsDNA |
Antibody mimetics are organic compounds that, like antibodies, can specifically bind antigens, but that are not structurally related to antibodies. They are usually artificial peptides or proteins with a molar mass of about 3 to 20 kDa. (Antibodies are ~150 kDa.)
Nucleic acids and small molecules are sometimes considered antibody mimetics as well, but not artificial antibodies, antibody fragments and fusion proteins composed from these.
Common advantages over antibodies are better solubility, tissue penetration, stability towards heat and enzymes, and comparatively low production costs. Antibody mimetics are being developed as therapeutic and diagnostic agents.
== Examples ==
== See also ==
Protein mimetic
Optimer Ligand
== References == | Wikipedia/Antibody_mimetic |
Alcoholic liver disease (ALD), also called alcohol-related liver disease (ARLD), is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis or cirrhosis.
It is the major cause of liver disease in Western countries, and is the leading cause of death from excessive drinking. Although steatosis (fatty liver disease) will develop in any individual who consumes a large quantity of alcoholic beverages over a long period of time, this process is transient and reversible. More than 90% of all heavy drinkers develop fatty liver whilst about 25% develop the more severe alcoholic hepatitis, and 15% liver cirrhosis.
For patients with chronic hepatitis B, a strict adherence to abstinence from alcohol is highly recommended.
== Presentation ==
== Risk factors ==
As of 2010, known risk factors of ALD are:
Quantity of alcohol taken: Consumption of 60–80 g per day (14 g is considered one standard drink in the US, e.g. 1+1⁄2 US fl oz or 44 mL hard liquor, 5 US fl oz or 150 mL wine, 12 US fl oz or 350 mL beer; drinking a six-pack of 5% ABV beer daily would be 84 g and just over the upper limit) for 20 years or more in men, or 20 g/day for women significantly increases the risk of hepatitis and fibrosis by 6% to 41%.
Pattern of drinking: Drinking outside of meal times increases up to 3 times the risk of alcoholic liver disease.
Sex: Women are twice as susceptible to alcohol-related liver disease, and may develop alcoholic liver disease with shorter durations and doses of chronic consumption. The lesser amount of alcohol dehydrogenase secreted in the gut, higher proportion of body fat in women, and changes in alcohol absorption due to the menstrual cycle may explain this phenomenon.
Ethnicity: Higher rates of alcohol-related liver disease, unrelated to differences in amounts of alcohol consumed, are seen in African-American and Hispanic males compared to Caucasian males.
Hepatitis C infection: A concomitant hepatitis C infection significantly accelerates the process of liver injury.
Genetic factors: Genetic factors predispose both to alcoholism and to alcoholic liver disease. Both monozygotic twins are more likely to be alcoholics and to develop liver cirrhosis than both dizygotic twins. Polymorphisms in the enzymes involved in the metabolism of alcohol, such as ADH, ALDH, CYP4502E1, mitochondrial dysfunction, and cytokine polymorphism may partly explain this genetic component. However, no specific polymorphisms have currently been firmly linked to alcoholic liver disease.
Iron overload (hemochromatosis).
Diet: Malnutrition, particularly vitamin A and E deficiencies, can worsen alcohol-induced liver damage by preventing regeneration of hepatocytes. This is particularly a concern as alcoholics are usually malnourished because of a poor diet, anorexia, and encephalopathy.
== Pathophysiology ==
The mechanism of ALD is not completely understood. 80% of alcohol passes through the liver to be detoxified. Chronic consumption of alcohol results in the secretion of pro-inflammatory cytokines (TNF-alpha, interleukin 6 and interleukin 8), oxidative stress, lipid peroxidation, and acetaldehyde toxicity. These factors cause inflammation, apoptosis and eventually fibrosis of liver cells. Why this occurs in only a few individuals is still unclear. Additionally, the liver has tremendous capacity to regenerate and even when 75% of hepatocytes are dead, it continues to function as normal.
=== Fatty change ===
Fatty change, or steatosis, is the accumulation of fatty acids in liver cells. This can be seen as fatty globules under the microscope. Alcoholism causes development of large fatty globules (macro-vesicular steatosis) throughout the liver and can begin to occur after a few days of heavy drinking. Alcohol is metabolized by alcohol dehydrogenase (ADH) into acetaldehyde, then further metabolized by aldehyde dehydrogenase (ALDH) into acetic acid, which is finally oxidized into carbon dioxide (CO2) and water (H2O). This process generates NADH, and increases the NADH/NAD+ ratio. A higher NADH concentration induces fatty acid synthesis while a decreased NAD level results in decreased fatty acid oxidation. Subsequently, the higher levels of fatty acids signal the liver cells to compound it to glycerol to form triglycerides. These triglycerides accumulate, resulting in fatty liver.
=== Alcoholic hepatitis ===
Alcoholic hepatitis is characterized by the inflammation of hepatocytes. Between 10% and 35% of heavy drinkers develop alcoholic hepatitis (NIAAA, 1993). While development of hepatitis is not directly related to the dose of alcohol, some people seem more prone to this reaction than others. This is called alcoholic steato-necrosis and the inflammation appears to predispose to liver fibrosis. Inflammatory cytokines (TNF-alpha, IL-6 and IL-8) are thought to be essential in the initiation and perpetuation of liver injury and cytotoxic hepatomegaly by inducing apoptosis and severe hepatotoxicity. One possible mechanism for the increased activity of TNF-α is the increased intestinal permeability due to liver disease. This facilitates the absorption of the gut-produced endotoxin into the portal circulation. The Kupffer cells of the liver then phagocytose endotoxin, stimulating the release of TNF-α. TNF-α then triggers apoptotic pathways through the activation of caspases, resulting in cell death.
=== Cirrhosis ===
Cirrhosis is a late stage of serious liver disease marked by inflammation (swelling), fibrosis (cellular hardening) and damaged membranes preventing detoxification of chemicals in the body, ending in scarring and necrosis (cell death). Between 10% and 20% of heavy drinkers will develop cirrhosis of the liver (NIAAA, 1993). Acetaldehyde may be responsible for alcohol-induced fibrosis by stimulating collagen deposition by hepatic stellate cells. The production of oxidants derived from NADPH oxi- dase and/or cytochrome P-450 2E1 and the formation of acetaldehyde-protein adducts damage the cell membrane.
Symptoms include jaundice (yellowing), liver enlargement, and pain and tenderness from the structural changes in damaged liver architecture. Without total abstinence from alcohol use, cirrhosis will eventually lead to liver failure. Late complications of cirrhosis or liver failure include portal hypertension (high blood pressure in the portal vein due to the increased flow resistance through the damaged liver), coagulation disorders (due to impaired production of coagulation factors), ascites (heavy abdominal swelling due to buildup of fluids in the tissues) and other complications, including hepatic encephalopathy and the hepatorenal syndrome.
Cirrhosis can also result from other causes than hazardous alcohol use, such as viral hepatitis and heavy exposure to toxins other than alcohol. The late stages of cirrhosis may look similar medically, regardless of cause. This phenomenon is termed the "final common pathway" for the disease.
Fatty change and alcoholic hepatitis with abstinence can be reversible. The later stages of fibrosis and cirrhosis tend to be irreversible, but can usually be contained with abstinence for long periods of time.
== Diagnosis ==
In the early stages, patients with ALD exhibit subtle and often no abnormal physical findings. It is usually not until development of advanced liver disease that stigmata of chronic liver disease become apparent. Early ALD is usually discovered during routine health examinations when liver enzyme levels are found to be elevated. These usually reflect alcoholic hepatic steatosis. Microvesicular and macrovesicular steatosis with inflammation are seen in liver biopsy specimens. These histologic features of ALD are indistinguishable from those of nonalcoholic fatty liver disease. Steatosis usually resolves after discontinuation of alcohol use. Continuation of alcohol use will result in a higher risk of progression of liver disease and cirrhosis. In patients with acute alcoholic hepatitis, clinical manifestations include fever, jaundice, hepatomegaly, and possible hepatic decompensation with hepatic encephalopathy, variceal bleeding, and ascites accumulation. Tender hepatomegaly may be present, but abdominal pain is unusual. Occasionally, the patient may be asymptomatic.
=== Laboratory findings ===
In people with alcoholic hepatitis, the serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is greater than 2:1. AST and ALT levels are almost always less than 500. The elevated AST to ALT ratio is due to deficiency of pyridoxal phosphate, which is required in the ALT enzyme synthetic pathway. Furthermore, alcohol metabolite–induced injury of hepatic mitochondria results in AST isoenzyme release. Other laboratory findings include red blood cell macrocytosis (mean corpuscular volume > 100) and elevations of serum gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels. Folate level is reduced in alcoholic patients due to decreased intestinal absorption, increased bone marrow requirement for folate in the presence of alcohol, and increased urinary loss. The magnitude of leukocytopenia (white blood cell depletion) reflects severity of liver injury. Histologic features include Mallory bodies, giant mitochondria, hepatocyte necrosis, and neutrophil infiltration in the area around the veins. Mallory bodies, which are also present in other liver diseases, are condensations of cytokeratin components in the hepatocyte cytoplasm and do not contribute to liver injury. Up to 70% of patients with moderate to severe alcoholic hepatitis already have cirrhosis identifiable on biopsy examination at the time of diagnosis.
== Treatment ==
Not drinking further alcohol is the most important part of treatment. People with chronic HCV infection should abstain from any alcohol intake, due to the risk for rapid acceleration of liver disease.
=== Medications ===
A 2006 Cochrane review did not find evidence sufficient for the use of androgenic anabolic steroids. Corticosteroids are sometimes used; however, this is recommended only when severe liver inflammation is present.
Silymarin has been investigated as a possible treatment, with ambiguous results. One review claimed benefit for S-adenosyl methionine in disease models.
The effects of anti-tumor necrosis factor medications such as infliximab and etanercept are unclear and possibly harmful. Evidence is unclear for pentoxifylline. Propylthiouracil may result in harm.
Evidence does not support supplemental nutrition in liver disease.
=== Transplantation ===
Although in rare cases liver cirrhosis is reversible, the disease process remains mostly irreversible. Liver transplantation remains the only definitive therapy. Today, survival after liver transplantation is similar for people with ALD and non-ALD. The requirements for transplant listing are the same as those for other types of liver disease, except for a 6-month sobriety prerequisite along with psychiatric evaluation and rehabilitation assistance. Specific requirements vary among the transplant centers. Relapse to alcohol use after transplant listing results in delisting. Re-listing is possible in many institutions, but only after 3–6 months of sobriety. There are limited data on transplant survival in patients transplanted for acute alcoholic hepatitis, but it is believed to be similar to that in nonacute ALD, non-ALD, and alcoholic hepatitis with MDF less than 32.
== Prognosis ==
The prognosis for people with ALD depends on the liver histology as well as cofactors, such as concomitant chronic viral hepatitis. Among patients with alcoholic hepatitis, progression to liver cirrhosis occurs at 10–20% per year, and 70% will eventually develop cirrhosis. Despite cessation of alcohol use, only 10% will have normalization of histology and serum liver enzyme levels. As previously noted, the MDF has been used to predict short-term mortality (i.e., MDF ≥ 32 associated with spontaneous survival of 50–65% without corticosteroid therapy, and MDF < 32 associated with spontaneous survival of 90%). The Model for End-Stage Liver Disease (MELD) score has also been found to have similar predictive accuracy in 30-day (MELD > 11) and 90-day (MELD > 21) mortality. Liver cirrhosis develops in 6–14% of those who consume more than 60–80 g of alcohol daily for men and more than 20 g daily for women. Even in those who drink more than 120 g daily, only 13.5% will experience a serious alcohol-related liver injury. Nevertheless, alcohol-related mortality was the third leading cause of death in 2003 in the United States. Worldwide mortality is estimated to be 150,000 per year. Alcoholic liver disease can lead to the development of exocrine pancreatic insufficiency.
== References ==
== External links == | Wikipedia/Alcoholic_liver_disease |
In autoimmune disease, anti-apolipoprotein H (AAHA) antibodies, also called anti-β2 glycoprotein I antibodies, comprise a subset of anti-cardiolipin antibodies and lupus anticoagulant. These antibodies are involved in sclerosis and are strongly associated with thrombotic forms of lupus. As a result, AAHA are strongly implicated in autoimmune deep vein thrombosis.
Also, it was proposed that AAHA is responsible for lupus anticoagulant. However, antiphospholipid antibodies bind phospholipids at sites similar to sites bound by anti-coagulants such as PAP1 sites and augment anti-coagulation activity.
This contrasts with the major, specific, activity of AAHA, defining a subset of anti-cardiolipin antibodies that specifically interacts with Apo-H. AHAA only inhibits the anti-coagulation activity in the presence of Apo-H and the AAHA component of ACLA correlates with a history of frequent thrombosis. This can be contrasted with lupus anticoagulant which inhibits agglutination in the presence of thrombin. A subset of AHAA appear to mimic the activity of lupus anticoagulant and increase Apo-H binding to phospholipids. These two activities can be differentiated by the binding to Apo-H domains, whereas binding to the 5th domain promotes that anti-coagulant activity binding to the more N-terminal domains promotes lupus anticoagulant-like activities.
AAHA interferes with factor Xa inhibition by Apo-H increasing factor Xa generation. However, like Apo-H the Lupus anticoagulant inhibits factor Xa generation.
AAHA also inhibited the autoactivation of factor XII while at high AAHA concentrations, factor XIIa activation increases at levels comparable to Apo-H that cause inhibition of factor XIIa activation. A synchronized inhibition of factor XII autoactivation by Apo-H and AHAA has been suggested.
== Genetics ==
The haplotype HLA-DR4-DQ3 appears to play a role in the pathogenic AAHA production. The alleles primarily recognized are HLA-DR53 (DRB4*01), DRB1*0402, DQA1*03, and possibly DQB1*0302. All of these alleles are in linkage disequilibrium in the DRB4*01:DRB1*0402:DQA1*0301:DQB1*0302 haplotype, also called DR4-DQ8 and also the DQA1:0303:DQB1*0301 haplotype, DR4-DQ7.3. However, in European Americans which reflects a broad area of Europe in which the original studies were conducted only DR4(0402)-DQ8 was found, indicating that the entire haplotype is involved.
HLA-DR7 may also be associated with these antibodies and the common haplotype association is the HLA-DR53 serotype.
== References == | Wikipedia/Anti-apolipoprotein_antibodies |
Bence Jones protein is a monoclonal globulin protein or immunoglobulin light chain found in the urine, with a molecular weight of 22–24 kDa. Detection of Bence Jones protein may be suggestive of multiple myeloma, or Waldenström's macroglobulinemia.
Bence Jones proteins are particularly diagnostic of multiple myeloma in the context of target organ manifestations such as kidney failure, lytic (or "punched out") bone lesions, anemia, or large numbers of plasma cells in the bone marrow. Bence Jones proteins are present in 2/3 of multiple myeloma cases.
The proteins are immunoglobulin light chains (paraproteins) and are produced by neoplastic plasma cells. They can be kappa (most of the time) or lambda. The light chains can be immunoglobulin fragments or single homogeneous immunoglobulins. They are found in urine as a result of decreased kidney filtration capabilities due to kidney failure, sometimes induced by hypercalcemia from the calcium released as the bones are destroyed, dehydration due to polyuria, amyloidosis or from the light chains themselves. The light chains were historically detected by heating a urine specimen (which causes the protein to precipitate) and nowadays by electrophoresis of concentrated urine. More recently, serum free light chain assays have been utilised in a number of published studies which have indicated superiority over the urine tests, particularly for patients producing low levels of monoclonal free light chains, as seen in nonsecretory multiple myeloma and amyloid light chain amyloidosis (AL amyloidosis).
== History ==
The Bence Jones protein was described by the English physician Henry Bence Jones in 1847 and published in 1848.
== References == | Wikipedia/Bence-Jones_protein |
Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.
ADCC is independent of the immune complement system that also lyses targets but does not require any other cell. ADCC requires an effector cell which classically is known to be natural killer (NK) cells that typically interact with immunoglobulin G (IgG) antibodies. However, macrophages, neutrophils and eosinophils can also mediate ADCC, such as eosinophils killing certain parasitic worms known as helminths via IgE antibodies.
In general, ADCC has typically been described as the immune response to antibody-coated cells leading ultimately to the lysing of the infected or non-host cell. In recent literature, its importance in regards to treatment of cancerous cells and deeper insight into its deceptively complex pathways have been topics of increasing interest to medical researchers.
== NK cells ==
The typical ADCC involves activation of NK cells by antibodies in a multi-tiered progression of immune control. A NK cell expresses Fcγ receptors. These receptors recognize and bind to the reciprocal portion of an antibody, such as IgG, which binds to the surface of a pathogen-infected target cell. The most common of these Fc receptors on the surface of an NK cell is CD16 or FcγRIII. Once the Fc receptor binds to the Fc region of the antibody, the NK cell releases cytotoxic factors that cause the death of the target cell.
During replication of a virus, some of the viral proteins are expressed on the cell surface membrane of the infected cell. Antibodies can then bind to these viral proteins. Next, the NK cells which have reciprocal Fcγ receptors will bind to that antibody, inducing the NK cell to release proteins such as perforin and proteases known as granzymes, which causes the lysis of the infected cell to hinder the spread of the virus.
== Eosinophils ==
Large parasites like helminths are too big to be engulfed and killed by phagocytosis. They also have an external structure or integument that is resistant to attack by substances released by neutrophils and macrophages. After IgE coat these parasites, the Fc receptor (FcɛRI) of an eosinophil will recognize IgE. Subsequently, interaction between FcεRI and the Fc portion of helminth-bound IgE signals the eosinophil to degranulate.
== In vitro assays ==
Several laboratory methods exist for determining the efficacy of antibodies or effector cells in eliciting ADCC. Usually, a target cell line expressing a certain surface-exposed antigen is incubated with antibody specific for that antigen. After washing, effector cells expressing Fc receptor CD16 are co-incubated with the antibody-labelled target cells. Effector cells are typically PBMCs (peripheral blood mononuclear cell), of which a small percentage are NK cells (natural killer cell); less often they are purified NK cells themselves. Over the course of a few hours a complex forms between the antibody, target cell, and effector cell which leads to lysis of the cell membrane of the target. If the target cell was pre-loaded with a label of some sort, that label is released in proportion to the amount of cell lysis. Cytotoxicity can be quantified by measuring the amount of label in solution compared to the amount of label that remains within healthy, intact cells.
The classical method of detecting this is the chromium-51 [51Cr] release assay; the sulfur-35 [35S] release assay is a little used radioisotope-based alternative. Target cell lysis is determined by measuring the amount of radiolabel released into the cell culture medium by means of a gamma counter or scintillation counter. A variety of non-radioactive methods are now in widespread use. Fluorescence-based methods include such things as direct labelling with a fluorescent dye like calcein or labelling with europium that becomes fluorescent when released Eu3+ binds to a chelator. Fluorescence can be measured by means of multi-well fluorometers or by flow cytometry methods. There are also enzymatic-based assays in which the contents of the lysed cells includes cellular enzymes like GAPDH that remain active; supplying a substrate for that enzyme can catalyze a reaction whose product can be detected by luminescence or by absorbance.
== Medical applications ==
NK cells are involved in killing tumor cells and other cells that may lack MHC I on their surface, indicating a non-self cell. NK cells have been shown to behave similarly to memory cells due to their ability to react to destroy non-host cells only after interacting with a host cell. As NK cells are not themselves specific to certain pathways of immune control, they are utilized a majority of the time in ADCC as a less discriminate cell destroyer than antibody-specific apoptosis mechanisms. The ability of activated ex vivo NK cells has been a topic of interest for the treatment of tumors. After early clinical trials involving activation through cytokines produced poor results and severe toxicological side effects, more recent studies have produced success in regulating metastatic tumors using interleukin proteins to activate the NK cell.
The effects against solid tumors of trastuzumab and rituximab monoclonal antibodies have been shown in experiments with mice to involve ADCC as an important mechanism of therapeutic action. In the clinic, the FcgRIII 158V/F polymorphism interfere with the ability to generate ADCC responses in vitro during trastuzumab treatment.
Multiple myeloma can be treated with daratumumab (Darzalex) monoclonal antibody. Studies with in vitro materials and patient materials indicate that ADCC is an important mechanism, along with CDC (complement-dependent cytotoxicity).
ADCC as used in immune control is typically more useful for viral infections than bacterial infections due to IgG antibodies binding to virus-related antigens over prokaryotic cells. Instead of ADCC removing outside toxins, immunoglobulins neutralize products of infecting bacteria and encase infected host cells that have had bacterial toxins directly inserted through the cell membrane.
ADCC is also important in the use of vaccines, as creation of antibodies and the destruction of antigens introduced to the host body are crucial to building immunity through small exposure to viral and bacterial proteins. Examples of this include vaccines targeting repeats in toxins (RTX) that are structurally crucial to a wide variety of erythrocyte-lysing bacteria, described as hemolysins. These bacteria target the CD18 portion of leukocytes, which has historically been shown to impact ADCC in adhesion-deficient cells.
== See also ==
Afucosylated monoclonal antibodies
== References ==
== Further reading ==
Janeway CA Jr.; et al. (2001). Immunobiology (5th ed.). Garland Publishing. ISBN 0-8153-3642-X. (electronic full text via NCBI Bookshelf).
Pier GB, Lyczak JB, Wetzler LM (2004). Immunology, Infection, and Immunity. ASM Press. ISBN 1-55581-246-5.
== External links ==
University of Leicester, Virus Immunopathology Notes
Antibody-Dependent+Cell+Cytotoxicity at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Antibody-dependent_cell-mediated_cytotoxicity |
Serum protein electrophoresis (SPEP or SPE) is a laboratory test that examines specific proteins in the blood called globulins. The most common indications for a serum protein electrophoresis test are to diagnose or monitor multiple myeloma, a monoclonal gammopathy of uncertain significance (MGUS), or further investigate a discrepancy between a low albumin and a relatively high total protein. Unexplained bone pain, anemia, proteinuria, chronic kidney disease, and hypercalcemia are also signs of multiple myeloma, and indications for SPE. Blood must first be collected, usually into an airtight vial or syringe. Electrophoresis is a laboratory technique in which the blood serum (the fluid portion of the blood after the blood has clotted) is applied to either an acetate membrane soaked in a liquid buffer, or to a buffered agarose gel matrix, or into liquid in a capillary tube, and exposed to an electric current to separate the serum protein components into five major fractions by size and electrical charge: serum albumin, alpha-1 globulins, alpha-2 globulins, beta 1 and 2 globulins, and gamma globulins.
== Acetate or gel electrophoresis ==
Proteins are separated by both electrical forces and electroendoosmostic forces. The net charge on a protein is based on the sum charge of its amino acids, and the pH of the buffer. Proteins are applied to a solid matrix such as an agarose gel, or a cellulose acetate membrane in a liquid buffer, and electric current is applied. Proteins with a negative charge will migrate towards the positively charged anode. Albumin has the most negative charge, and will migrate furthest towards the anode. Endoosmotic flow is the movement of liquid towards the cathode, which causes proteins with a weaker charge to move backwards from the application site. Gamma proteins are primarily separated by endoosmotic forces. The drawing of the electrophoretic bands provided by the laboratory may be difficult to remember, and medical students, residents, nurses, and non-specialized medical practitioners may find visual mnemonics useful to recall the five main bands and the shape of normal serum electrophoresis.
== Capillary electrophoresis ==
In capillary electrophoresis, there is no solid matrix. Proteins are separated primarily by strong electroendosmotic forces. The sample is injected into a capillary with a negative surface charge. A high current is applied, and negatively charged proteins such as albumin try to move towards the anode. Liquid buffer flows towards the cathode, and drags proteins with a weaker charge.
== Serum protein fractions ==
=== Albumin ===
Albumin is the major fraction in a normal SPEP. A fall of 30% is necessary before the decrease shows on electrophoresis. Usually a single band is seen. Heterozygous individuals may produce bisalbuminemia – two equally staining bands, the product of two genes. Some variants give rise to a wide band or two bands of unequal intensity but none of these variants is associated with disease. Increased anodic mobility results from the binding of bilirubin, nonesterified fatty acids, penicillin and acetylsalicylic acid, and occasionally from tryptic digestion in acute pancreatitis.
Absence of albumin, known as analbuminaemia, is rare. A decreased level of albumin, however, is common in many diseases, including liver disease, malnutrition, malabsorption, protein-losing nephropathy and enteropathy.
=== Albumin – alpha-1 interzone ===
Even staining in this zone is due to alpha-1 lipoprotein (high density lipoprotein – HDL). Decrease occurs in severe inflammation, acute hepatitis, and cirrhosis. Also, nephrotic syndrome can lead to decrease in albumin level; due to its loss in the urine through a damaged leaky glomerulus. An increase appears in severe alcoholics and in women during pregnancy and in puberty.
The high levels of AFP that may occur in hepatocellular carcinoma may result in a sharp band between the albumin and the alpha-1 zone.
=== Alpha-1 zone ===
Orosomucoid and antitrypsin migrate together but orosomucoid stains poorly so alpha 1 antitrypsin (AAT) constitutes most of the alpha-1 band. Alpha-1 antitrypsin has an SG group and thiol compounds may be bound to the protein altering their mobility. A decreased band is seen in the deficiency state. It is decreased in the nephrotic syndrome and absence could indicate possible alpha 1-antitrypsin deficiency. This eventually leads to emphysema from unregulated neutrophil elastase activity in the lung tissue. The alpha-1 fraction does not disappear in alpha 1-antitrypsin deficiency, however, because other proteins, including alpha-lipoprotein and orosomucoid, also migrate there. As a positive acute phase reactant, AAT is increased in acute inflammation.
Bence Jones protein may bind to and retard the alpha-1 band.
=== Alpha-1 – alpha-2 interzone ===
Two faint bands may be seen representing alpha 1-antichymotrypsin and vitamin D binding protein. These bands fuse and intensify in early inflammation due to an increase in alpha 1-antichymotrypsin, an acute phase protein.
=== Alpha-2 zone ===
This zone consists principally of alpha-2 macroglobulin (AMG or A2M) and haptoglobin. There are typically low levels in haemolytic anaemia (haptoglobin is a suicide molecule which binds with free haemoglobin released from red blood cells and these complexes are rapidly removed by phagocytes). Haptoglobin is raised as part of the acute phase response, resulting in a typical elevation in the alpha-2 zone during inflammation. A normal alpha-2 and an elevated alpha-1 zone is a typical pattern in hepatic metastasis and cirrhosis.
Haptoglobin/haemoglobin complexes migrate more cathodally than haptoglobin as seen in the alpha-2 – beta interzone. This is typically seen as a broadening of the alpha-2 zone.
Alpha-2 macroglobulin may be elevated in children and the elderly. This is seen as a sharp front to the alpha-2 band. AMG is markedly raised (10-fold increase or greater) in association with glomerular protein loss, as in nephrotic syndrome. Due to its large size, AMG cannot pass through glomeruli, while other lower-molecular weight proteins are lost. Enhanced synthesis of AMG accounts for its absolute increase in nephrotic syndrome. Increased AMG is also noted in rats with no albumin indicating that this is a response to low albumin rather than nephrotic syndrome itself
AMG is mildly elevated early in the course of diabetic nephropathy.
=== Alpha-2 - beta interzone ===
Cold insoluble globulin forms a band here which is not seen in plasma because it is precipitated by heparin. There are low levels in inflammation and high levels in pregnancy.
Beta lipoprotein forms an irregular crenated band in this zone. High levels are seen in type II hypercholesterolaemia, hypertriglyceridemia, and in the nephrotic syndrome.
=== Beta zone ===
Transferrin and beta-lipoprotein (LDL) comprises the beta-1. Increased beta-1 protein due to the increased level of free transferrin is typical of iron deficiency anemia, pregnancy, and oestrogen therapy. Increased beta-1 protein due to LDL elevation occurs in hypercholesterolemia. Decreased beta-1 protein occurs in acute or chronic inflammation.
Beta-2 comprises C3 (complement protein 3). It is raised in the acute phase response. Depression of C3 occurs in autoimmune disorders as the complement system is activated and the C3 becomes bound to immune complexes and removed from serum. Fibrinogen, a beta-2 protein, is found in normal plasma but absent in normal serum. Occasionally, blood drawn from heparinized patients does not fully clot, resulting in a visible fibrinogen band between the beta and gamma globulins.
=== Beta-gamma interzone ===
C-reactive protein is found in between the beta and gamma zones producing beta/gamma fusion. IgA has the most anodal mobility and typically migrates in the region between the beta and gamma zones also causing a beta/gamma fusion in patients with cirrhosis, respiratory infection, skin disease, or rheumatoid arthritis (increased IgA). Fibrinogen from plasma samples will be seen in the beta gamma region. Fibrinogen, a beta-2 protein, is found in normal plasma but absent in normal serum. Occasionally, blood drawn from heparinized patients does not fully clot, resulting in a visible fibrinogen band between the beta and gamma globulins.
=== Gamma zone ===
The immunoglobulins or antibodies are generally the only proteins present in the normal gamma region. Of note, any protein migrating in the gamma region will be stained and appear on the gel, which may include protein contaminants, artifacts, or certain medications. Depending on whether an agarose or capillary method is used, interferences vary. Immunoglobulins consist of heavy chains (μ, δ, γ, α, and ε) and light chains (κ and λ). A normal gamma zone should appear as a smooth 'blush', or smear, with no asymmetry or sharp peaks. The gamma globulins may be elevated (hypergammaglobulinemia), decreased (hypogammaglobulinaemia), or have an abnormal peak or peaks. Note that immunoglobulins may also be found in other zones; IgA typically migrates in the beta-gamma zone, and in particular, pathogenic immunoglobulins may migrate anywhere, including the alpha regions.
Hypogammaglobulinaemia is easily identifiable as a "slump" or decrease in the gamma zone. It is normal in infants. It is found in patients with X-linked agammaglobulinemia. IgA deficiency occurs in 1:500 of the population, as is suggested by a pallor in the gamma zone. Of note, hypogammaglobulinema may be seen in the context of MGUS or multiple myeloma.
If the gamma zone shows an increase the first step in interpretation is to establish if the region is narrow or wide. A broad "swell-like" manner (wide) indicates polyclonal immunoglobulin production. If it is elevated in an asymmetric manner or with one or more peaks or narrow "spikes" it could indicate clonal production of one or more immunoglobulins,
Polyclonal gammopathy is indicated by a "swell-like" elevation in the gamma zone, which typically indicates a non-neoplastic condition (although is not exclusive to non-neoplastic conditions). The most common causes of polyclonal hypergammaglobulinaemia detected by electrophoresis are severe infection, chronic liver disease, rheumatoid arthritis, systemic lupus erythematosus and other connective tissue diseases.
A narrow spike is suggestive of a monoclonal gammopathy, also known as a restricted band, or "M-spike". To confirm that the restricted band is an immunoglobulin, follow up testing with immunofixation, or immunodisplacement/immunosubtraction (capillary methods) is performed. Therapeutic monoclonal antibodies (mAb), also migrate in this region and may be misinterpreted as a monoclonal gammopathy, and may also be identified by immunofixation or immunodisplacement/immunosubtraction as they are structurally comparable to human immunoglobulins. The most common cause of a restricted band is an MGUS (monoclonal gammopathy of uncertain significance), which, although a necessary precursor, only rarely progresses to multiple myeloma. (On average, 1%/year.) Typically, a monoclonal gammopathy is malignant or clonal in origin, Myeloma being the most common cause of IgA and IgG spikes. chronic lymphatic leukaemia and lymphosarcoma are not uncommon and usually give rise to IgM paraproteins. Note that up to 8% of healthy geriatric patients may have a monoclonal spike. Waldenström's macroglobulinaemia (IgM), monoclonal gammopathy of undetermined significance (MGUS), amyloidosis, plasma cell leukemia and solitary plasmacytomas also produce an M-spike.
Oligoclonal gammopathy is indicated by one or more discrete clones.
Lysozyme may be seen as a band cathodal to gamma in myelomonocytic leukaemia in which it is released from tumour cells.
== References ==
== External links ==
Protein electrophoresis at Lab Tests Online
Visual mnemonics for serum protein electrophoresis
[1] | Wikipedia/Serum_protein_electrophoresis |
Rh disease (also known as rhesus isoimmunization, Rh (D) disease, or rhesus incompatibility, and blue baby disease) is a type of hemolytic disease of the fetus and newborn (HDFN). The term "Rh disease" is commonly used to refer to HDFN due to anti-D antibodies (the D antigen being only one of more than 50 in the Rh complex), and prior to the discovery of anti-Rho(D) immune globulin, it was the most common type of HDFN. The disease ranges from mild to severe, and occurs in the second or subsequent pregnancies of Rh-D negative women when the biological father is Rh-D positive.
Due to several advances in modern medicine, HDFN due to anti-D is preventable by treating the mother during pregnancy and soon after delivery with an injection of anti-Rho(D) immune globulin (Rhoclone, Rhogam, AntiD). With successful mitigation of this disease by prevention through the use of anti-Rho(D) immune globulin, other antibodies are more commonly the cause of HDFN today.
== Mechanism ==
During pregnancy, there is normally a barrier between maternal and fetal blood called the placenta, a temporary organ that connects a mother’s uterus to the umbilical cord to provide nutrients and oxygen to the fetus. However, in certain circumstances, small amounts of fetal blood cells may enter the mother’s circulation. Certain types of events where this occurs are during childbirth, miscarriage or abortion, trauma, and invasive procedures such as amniocentesis. Once the fetal Rh-positive red blood cells enter the bloodstream of a Rh-negative mother, they are recognized as foreign. The mother’s immune system reacts to the Rh-positive red blood cells the same way that it would respond to something like a virus or bacteria, activating B cells—a type of white blood cell that is key to the triggering of an immune response. These activated B cells then differentiate into plasma cells, which produce anti-D antibodies. After the primary exposure, some of these B cells become memory cells that remember the original exposure, and produce IgG antibodies, which are smaller and can cross the placental barrier. Once they cross this barrier into the fetal bloodstream, they bind to fetal Rh-positive cells, triggering opsonization, which marks the red blood cells for destruction. The fetal spleen and liver then begin to break down those red blood cells, thinking that they are a foreign invader when in reality they are just mismatched.
== Signs and symptoms ==
Symptoms of Rh disease include yellowish amniotic fluid and enlarged spleen, liver or heart or buildup of fluid in the abdomen of the fetus.
== Pathophysiology ==
During the first pregnancy, the Rh− mother's initial exposure to fetal Rh+ red blood cells (RBCs) is usually not sufficient to activate her Rh-recognizing B cells. However, during delivery, the placenta separates from the uterine wall, causing umbilical cord blood to enter the maternal circulation, which results in the mother's proliferation of IgM-secreting plasma B cells to eliminate the fetal Rh+ cells from her blood stream. IgM antibodies do not cross the placental barrier, which is why no effects to the fetus are seen in first pregnancies for Rh-D mediated disease. However, in subsequent pregnancies with Rh+ fetuses, the IgG memory B cells mount an immune response when re-exposed, and these IgG anti-Rh(D) antibodies do cross the placenta and enter fetal circulation. These antibodies are directed against the Rhesus (Rh) factor, a protein found on the surface of the fetal RBCs. The antibody-coated RBCs are destroyed by IgG antibodies binding and activating complement pathways.
The resulting anemia has multiple sequelae:
The immature haematopoietic system of the fetus is taxed as the liver and spleen attempt to put immature RBCs into circulation (erythroblasts, thus the previous name for this disease erythroblastosis fetalis).
As the liver and spleen enlarge under this unexpected demand for RBCs, a condition called portal hypertension develops, and this taxes the immature heart and circulatory system.
Liver enlargement and the prolonged need for RBC production results in decreased ability to make other proteins, such as albumin, and this decreases the plasma colloid osmotic pressure (the fluid-retaining ability of blood plasma) leading to leakage of fluid into tissues and body cavities, termed hydrops fetalis.
The severe anemia taxes the heart to compensate by increasing output in an effort to deliver oxygen to the tissues and results in a condition called high output cardiac failure.
If left untreated, the result may be fetal death.
The destruction of RBCs leads to elevated bilirubin levels (hyperbilirubinemia) as a byproduct. This is not generally a problem during pregnancy, as the maternal circulation can compensate. However, once the infant is delivered, the immature system is not able to handle this amount of bilirubin alone and jaundice or kernicterus (bilirubin deposition in the brain) can develop which may lead to brain damage or death. Sensitizing events during pregnancy include c-section, miscarriage, therapeutic abortion, amniocentesis, ectopic pregnancy, abdominal trauma and external cephalic version. However, in many cases there was no apparent sensitizing event. Approximately 50% of Rh-D positive infants with circulating anti-D are either unaffected or only mildly affected requiring no treatment at all and only monitoring. An additional 20% are severely affected and require transfusions while still in the uterus. This pattern is similar to other types of HDFN due to other commonly encountered antibodies (anti-c, anti-K, and Fy(a)).
== Diagnosis ==
=== Maternal blood ===
In the United States, it is a standard of care to test all expecting mothers for the presence or absence of the RhD protein on their RBCs. However, when medical care is unavailable or prenatal care not given for any other reason, the window to prevent the disease may be missed. In addition, there is more widespread use of molecular techniques to avoid missing women who appear to be Rh-D positive but are actually missing portions of the protein or have hybrid genes creating altered expression of the protein and still at risk of HDFN due to Anti-D.
At the first prenatal visit, the mother is typed for ABO blood type and the presence or absence of RhD using a method sensitive enough to detect weaker versions of this antigen (known as weak-D) and a screen for antibodies is performed.
If she is negative for RhD protein expression and has not formed anti-D already, she is a candidate for RhoGam prophylaxis to prevent alloimmunization.
If she is positive for anti-D antibodies, the pregnancy will be followed with monthly titers (levels) of the antibody to determine if any further intervention is needed.
A screening test to detect for the presence or absence of fetal cells can help determine if a quantitative test (Kleihauer-Betke or flow cytometry) is needed. This is done when exposure is suspected due to a potential sensitizing event (such as a car accident or miscarriage).
If the screening test is positive or the appropriate dose of RhoGam needs to be determined, a quantitative test is performed to determine a more precise amount of fetal blood to which the mother has been exposed.
The Kleihauer–Betke test or Flow Cytometry on a maternal blood sample are the most common ways to determine this, and the appropriate dose of RhoGam is calculated based on this information.
There are also emerging tests using Cell-free DNA. Blood is taken from the mother, and using PCR, can detect fetal DNA. This blood test is non-invasive to the fetus and can help determine the risk of HDFN. Testing has proven very accurate and is routinely done in the UK at the International Blood Group Reference Laboratory in Bristol.
=== Paternal blood ===
Blood is generally drawn from the biological father to help determine fetal antigen status. If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDFN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen.
== Prevention ==
The protection that is offered today against Rh incompatibility involved preventive measures that primarily utilize Rh immunoglobulin, also known as RhoGAM. The aim of these treatments are to prevent the mother's immune system from becoming sensitized to the Rh antigen, which reduces the risk of hemolytic disease in future pregnancies. RhoGAM, Rh immunoglobulin administration, is a product that contains antibodies to the Rh(D) antigen; it is used to prevent the mother from developing an immune response to fetal red blood cells. RhIg 'coats' any Rh-positive fetal red blood cells that enter the mother’s bloodstream, effectively 'hiding' them from the mother's immune system. RhoGAM is typically administered at around 28 weeks of pregnancy, then again within 72 hours after childbirth. It is also given during other events that happen during pregnancy like miscarriages, ectopic pregnancies, amniocentesis, and abdominal trauma.
In Arar, Saudi Arabia, results of a study showed that women had a low level of knowledge regarding maternal–fetal blood incompatibility (about 38% of the studied mothers during the research had knowledge about Rh incompatibility). Regarding their knowledge about anti-D, researchers found that 68.5% of the mothers had knowledge about it, while only 51% of the mothers had knowledge about the administration of prophylactic anti D after delivery.
== Management ==
As medical management advances in this field, it is important that these patients be followed by high risk obstetricians/maternal-fetal medicine, and skilled neonatologists postpartum to ensure the most up to date and appropriate standard of care.
=== Antenatal ===
Routine prenatal labs drawn at the beginning of every pregnancy include a blood type and an antibody screen. Mothers who are Rh negative (A−, B−, AB−, or O− blood types) and have anti-D antibodies (found on the antibody screen) need to determine the fetus's Rh antigen. If the fetus is also Rh negative (A−, B−, AB−, or O− blood types) then the pregnancy can be managed like any other pregnancy. The anti-D antibodies are only dangerous to Rh positive fetuses (A+, B+, AB+, or O+ blood types).
The fetal Rh can be screened using non-invasive prenatal testing (NIPT). This test can screen for the fetus's Rh antigen (positive or negative) at the 10th week of gestation using a blood sample drawn from the mother. The Unity test uses NGS technology to look for Rh alleles (genes) in the cell free fetal DNA in the maternal bloodstream. In healthy pregnancies, at least 5% (fetal fraction) of the cell free DNA in the maternal bloodstream comes from the fetus (placenta cells shed DNA into the maternal bloodstream). This small fraction of cell free DNA from the fetus is enough to determine the fetus's Rh antigen.
Once a woman has been found to have made anti-D (or any clinically significant antibody against fetal red cells), she is followed as a high risk pregnancy with serial blood draws to determine the next steps.
Once the titer of anti-D reaches a certain threshold (normally 8 to 16), serial Doppler ultrasound examinations are performed to detect signs of fetal anemia.
Detection of increased blood flow velocities in the fetus are a surrogate marker for fetal anemia that may require more invasive intervention.
If the flow velocity is found to be elevated a determination of the severity of anemia needs to ensue to determine if an intrauterine transfusion is necessary.
This is normally done with a procedure called percutaneous umbilical cord blood sampling (PUBS or cordocentesis).
Intrauterine blood transfusion
Intraperitoneal transfusion—blood transfused into fetal abdomen
Intravascular transfusion—blood transfused into fetal umbilical vein—This is the method of choice since the late 1980s, and more effective than intraperitoneal transfusion. A sample of fetal blood can be taken from the umbilical vein prior to the transfusion.
Often, this is all done at the same PUBS procedure to avoid the needs for multiple invasive procedures with each transfusion.
=== Postnatal ===
Phototherapy for neonatal jaundice in mild disease
Exchange transfusion if the neonate has moderate or severe disease
Intravenous immunoglobulin (IVIG) can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy.
== History ==
In 1939 Philip Levine and Rufus E. Stetson published their findings about a 25-year-old mother who had a stillborn baby that died of hemolytic disease of the newborn. Both parents were blood group O, so the husband's blood was used to give his wife a blood transfusion due to blood loss during delivery. However, she had a severe transfusion reaction. Since both parents were blood group O, which was believed to be compatible for transfusion, they concluded that there must be a previously undiscovered blood group antigen that was present on the husband's red blood cells (RBCs) but not present on his wife's. This suggested for the first time that a mother could make blood group antibodies because of immune sensitization to her fetus's RBCs as her only previous exposure would be the earlier pregnancy. They did not name this blood group antigen at the time, which is why the discovery of the rhesus blood type is credited to Karl Landsteiner and Alexander S. Wiener with their first publication of their tables for blood-typing and cross-matching in 1940, which was the culmination of years of work. However, there were multiple participants in this scientific race and almost simultaneous publications on this topic. Levine published his theory that the disease known as erythroblastosis fetalis was due to Rh alloimmunization in 1941 while Landsteiner and Wiener published their method to type patients for an antibody causing transfusion reactions, known as "Rh".
The first treatment for Rh disease was an exchange transfusion invented by Wiener and later refined by Harry Wallerstein. Approximately 50,000 infants received this treatment. However, this could only treat the disease after it took root and did not do anything to prevent the disease. In 1960, Ronald Finn, in Liverpool, England, proposed that the disease might be prevented by injecting the at-risk mother with an antibody against fetal red blood cells (anti-RhD). Nearly simultaneously, William Pollack, (an immunologist and protein chemist at Ortho Pharmaceutical Corporation) and John Gorman (blood bank director at Columbia-Presbyterian) with Vincent Freda (an obstetrician at Columbia-Presbyterian Medical Center) came to the same realization in New York City. The three of them set out to prove it by injecting a group of male prisoners at Sing Sing Correctional Facility with antibody provided by Ortho, obtained by a fractionation technique developed by Pollack.
Animal studies had previously been conducted by Pollack using a rabbit model of Rh. This model, named the rabbit HgA-F system, was an animal model of human Rh, and enabled Pollack's team to gain experience in preventing hemolytic disease in rabbits by giving specific HgA antibody, as was later done with Rh-negative mothers. One of the needs was a dosing experiment that could be used to determine the level of circulating Rh-positive cells in an Rh-negative pregnant female derived from her Rh-positive fetus. This was first done in the rabbit system, but subsequent human tests at the University of Manitoba conducted under Pollack's direction confirmed that anti-Rho(D) immune globulin could prevent alloimmunization during pregnancy.
Marianne Cummins was the first at-risk woman to receive a prophylactic injection of anti-Rho(D) immune globulin (RhIG) after its regulatory approval. Clinical trials were set up in 42 centers in the US, Great Britain, Germany, Sweden, Italy, and Australia. RHIG was finally approved in the United Kingdom and the United States in 1968. The FDA approved the drug under the brand name RhoGAM, with a fixed dose of 300 μg, to be given within three days (72 hours) postpartum. Subsequently, a broader peripartum period was approved for dosing which included prophylaxis during pregnancy. Within a year, the antibody had been injected with great success into more than 500,000 women. Time magazine picked it as one of the top ten medical achievements of the 1960s. By 1973, it was estimated that in the US alone, over 50,000 babies' lives had been saved. The use of Rh immune globulin to prevent the disease in babies of Rh negative mothers has become standard practice, and the disease, which used to claim the lives of 10,000 babies each year in the US alone, has been virtually eradicated in the developed world. In 1980, Cyril Clarke, Ronald Finn, John G. Gorman, Vincent Freda, and William Pollack each received an Albert Lasker Award for Clinical Medical Research for their work on rhesus blood types and the prevention of Rh disease.
== See also ==
James Harrison (blood donor) – Australian who donated blood over 1150 times to save babies with Rh disease
== References ==
== Further reading ==
== External links ==
National institute of Clinical Excellence (NICE) Guidelines for anti-D prophylaxis
Summary of transfusion reactions in the US | Wikipedia/Rh_disease |
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
== Production ==
Antibodies are produced by B cells in two ways: (i) randomly, and (ii) in response to a foreign protein or substance within the body. Initially, one B cell produces one specific kind of antibody. In either case, the B cell is allowed to proliferate or is killed off through a process called clonal deletion. Normally, the immune system is able to recognize and ignore the body's own healthy proteins, cells, and tissues, and to not overreact to non-threatening substances in the environment, such as foods. Sometimes, the immune system ceases to recognize one or more of the body's normal constituents as "self", leading to production of pathological autoantibodies. Autoantibodies may also play a nonpathological role; for instance they may help the body to destroy cancers and to eliminate waste products. The role of autoantibodies in normal immune function is also a subject of scientific research.
== Cause ==
The causes of autoantibody production are varied and not well understood. It is thought that some autoantibody production is due to a genetic predisposition combined with an environmental trigger, such as a viral illness or a prolonged exposure to certain toxic chemicals. There is generally not a direct genetic link however.
While families may be susceptible to autoimmune conditions, individual family members may have different autoimmune disorders, or may never develop an autoimmune condition. Researchers believe that there may also be a hormonal component as many of the autoimmune conditions are much more prevalent in women of childbearing age. While the initial event that leads to the production of autoantibodies is still unknown, there is a body of evidence that autoantibodies may have the capacity to maintain their production.
== Diseases ==
The type of autoimmune disorder or disease that occurs and the amount of destruction done to the body depends on which systems or organs are targeted by the autoantibodies, and how strongly. Disorders caused by organ specific autoantibodies, those that primarily target a single organ, (such as the thyroid in Graves' disease and Hashimoto's thyroiditis), are often the easiest to diagnose as they frequently present with organ related symptoms. Disorders due to systemic autoantibodies can be much more elusive. Although the associated autoimmune disorders are rare, the signs and symptoms they cause are relatively common. Symptoms may include: arthritis-type joint pain, fatigue, fever, rashes, cold or allergy-type symptoms, weight loss, and muscular weakness. Associated conditions include vasculitis which are inflammation of blood vessels and anemia. Even if they are due to a particular systemic autoimmune condition, the symptoms will vary from person to person, vary over time, vary with organ involvement, and they may taper off or flare unexpectedly. Add to this the fact that a person may have more than one autoantibody, and thus have more than one autoimmune disorder, and/or have an autoimmune disorder without a detectable level of an autoantibody, complicating making a diagnosis.
The diagnosis of disorders associated with systemic autoantibodies starts with a complete medical history and a thorough physical exam. Based on the patient's signs and symptoms, the doctor may request one or more diagnostic studies that will help to identify a specific disease. As a rule, information is required from multiple sources, rather than a single laboratory test to accurately diagnose disorders associated with systemic autoantibodies. Tests may include:
blood tests to detect inflammation, autoantibodies, and organ involvement
x-rays and other imaging scans to detect changes in bones, joints, and organs
biopsies to look for pathologic changes in tissue specimens
== Indications for autoantibody tests ==
Autoantibody tests may be ordered as part of an investigation of chronic progressive arthritis type symptoms and/or unexplained fevers, fatigue, muscle weakness and rashes. The antinuclear antibody (ANA) test is often ordered first. ANA is a marker of the autoimmune process – it is positive with a variety of different autoimmune diseases but not specific. Consequently, if an ANA test is positive, it is often followed up with other tests associated with arthritis and inflammation, such as a rheumatoid factor (RF), an erythrocyte sedimentation rate (ESR), a c-reactive protein (CRP), and/or complement protein|complement levels.
A single autoantibody test is not diagnostic, but may give clues as to whether a particular disorder is likely or unlikely to be present. Each autoantibody result should be considered individually and as part of the group. Some disorders, such as systemic lupus erythematosus (SLE) may be more likely if several autoantibodies are present, while others, such as mixed connective tissue disease (MCTD) may be more likely if a single autoantibody, ribonucleic protein (RNP), is the only one present. Those who have more than one autoimmune disorder may have several detectable autoantibodies.
Whether a particular autoantibody will be present is both very individual and a matter of statistics. Each will be present in a certain percentage of people who have a particular autoimmune disorder. For instance, up to 80% of those with SLE will have a positive double strand anti-double stranded DNA (anti-dsDNA) autoantibody test, but only about 25–30% will have a positive RNP. Some individuals who do have an autoimmune disorder will have negative autoantibody test results, but at a later date – as the disorder progresses - the autoantibodies may develop.
Systemic autoantibody tests are used to:
Help diagnose systemic autoimmune disorders.
Help determine the degree of organ or system involvement and damage (Along with other tests such as a complete blood count or comprehensive metabolic panel)
Monitor the course of the disorder and the effectiveness of treatments. There is no prevention or cure for autoimmune disorders at this time. Treatment is used to alleviate symptoms and to help maintain body function.
Monitor remissions, flares, and relapses
== Antibody profiling ==
Antibody profiling is used for identifying persons from forensic samples. The technology can uniquely identify a person by analyzing the antibodies in body fluids. A unique, individual set of antibodies, called individual specific autoantibodies (ISA), is found in blood, serum, saliva, urine, semen, perspiration, tears, and body tissues, and the antibodies are not affected by illness, medication, or food/drug intake. An unskilled technician using inexpensive equipment can complete a test in a couple of hours.
== List of some autoantibodies and commonly associated diseases ==
Note: the sensitivity and specificity of various autoantibodies for a particular disease is different for different diseases.
== See also ==
Anti-glutamate receptor antibodies
Reference ranges for blood tests#Autoantibodies
Paraneoplastic syndrome
== References ==
== External links ==
Autoimmunity – an Introduction Industrial Learning Unit on Chemgaroo
Autoimmunityblog - summaries of research articles + glossary terms
Autoantibodies at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Detection of autoantibodies with self-assembling radiolabeled antigen tetramers (a protocol)
Antibody Sensors | Wikipedia/Autoantibody |
The side-chain theory (German, Seitenkettentheorie) is a theory proposed by Paul Ehrlich (1854–1915) to explain the immune response in living cells. Ehrlich theorized from very early in his career that chemical structure could be used to explain why the immune response occurred in reaction to infection. He believed that toxins and antitoxins were chemical substances at a time when very little was known about their nature. The theory explains the interaction of antibodies and antigens in the blood, and how antibodies are produced.
== History ==
In 1891, Paul Ehrlich joined the newly established Robert Koch Institute in Berlin upon the invitation of Robert Koch himself. By 1896 a new branch, the Institute for Serum Research and Testing (Institut für Serumforschung und Serumprüfung), was established in Frankfurt with Ehrlich as its founding director. He worked on antitoxins for diphtheria and their binding to antibodies in the blood. He hypothesised that antibodies bind to antigens through special chemical structures that he called "side chains" (which he later named "receptors"). Borrowing a concept used by Emil Fischer in 1894 to explain the interaction between an enzyme and its substrate, Ehrlich proposed that binding of the receptor to an infectious agent was like the fit between a lock and key. He published the first part of his side-chain theory in 1897, and its full form in 1900 in a lecture he delivered to the Royal Society in London.
== Postulate ==
Ehrlich's theory can be summarised with the following tenets:
Antibodies are produced by white blood cells normally and they act as side chains (receptors) on the cell membrane.
Antibody specificity exists for specific interaction with a given antigen.
Antigen–antibody interaction occurs by precise binding through the side chains.
== Concept ==
Ehrlich supposed that living cells have side chains in the same way dyes have side chains which are related to their coloring properties. These side chains can link with a particular toxin (or any antigen), just as Emil Fischer said enzymes must bind to their receptors "as lock and key."
Ehrlich theorised that a cell under threat grew additional side chains to bind the toxin, and that these additional side chains broke off to become the antibodies that are circulated through the body. According to this theory, the surface of white blood cells is covered with many side chains that form chemical links with the antigens. For any given antigen, at least one of these side chains would bind, stimulating the cell to produce more of the same type, which would then be liberated into the blood stream as antibodies. According to Ehrlich, an antibody could be considered an irregularly shaped, microscopic, three-dimensional label that would bind to a specific antigen but not to the other cells of the organism. It was these antibodies that Ehrlich first described as "magic bullets", agents that specifically target toxins or pathogens without harming the body.
Ehrlich suggested that interaction between an infectious agent and a cell-bound receptor would induce the cell to produce and release more receptors with the same specificity. According to Ehrlich’s theory, the specificity of the receptor was determined before its exposure to antigen, and the antigen selected the appropriate receptor. Ultimately all aspects of Ehrlich's theory would be proven correct with the minor exception that the "receptor" exists as both a soluble antibody molecule and as a cell-bound receptor; it is the soluble form that is secreted rather than the bound form released.
== See also ==
Dr. Ehrlich's Magic Bullet, a 1940 film
Diphtheria
Syphilis
== References ==
== Further reading ==
Silverstein, Arthur M. (2001). Paul Ehrlich's Receptor Immunology the Magnificent Obsession. Burlington: Elsevier. p. 202. ISBN 978-0-080538518.
Günther, O (1966). "Changes in Ehrlich's side-chain theory". Deutsche Medizinische Wochenschrift (in German). 91 (26): 1197–1201. doi:10.1055/s-0028-1110731. PMID 5328273.
Anonymous (1980). "Membranes, receptors, and the immune response. 80 years after Ehrlich's side chain theory". Progress in Clinical and Biological Research. 42 (1): 1–387. PMID 7393927.
Doerr, HW (1996). "Paul Ehrlich's concept of immune defense". Deutsche Medizinische Wochenschrift (in German). 121 (30): 958–961. doi:10.1055/s-0029-1233819. PMID 8765706.
Silverstein, AM (1999). "Paul Ehrlich's passion: the origins of his receptor immunology". Cellular Immunology. 194 (2): 213–221. doi:10.1006/cimm.1999.1505. PMID 10383824.
Prüll, CR (2003). "Part of a scientific master plan? Paul Ehrlich and the origins of his receptor concept". Medical History. 47 (3): 332–356. doi:10.1017/S0025727300057045. PMC 1044632. PMID 12905918. | Wikipedia/Side-chain_theory |
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies are identical and can thus have monovalent affinity, binding only to a particular epitope (the part of an antigen that is recognized by the antibody). In contrast, polyclonal antibodies are mixtures of antibodies derived from multiple plasma cell lineages which each bind to their particular target epitope. Artificial antibodies known as bispecific monoclonal antibodies can also be engineered which include two different antigen binding sites (FABs) on the same antibody.
It is possible to produce monoclonal antibodies that specifically bind to almost any suitable substance; they can then serve to detect or purify it. This capability has become an investigative tool in biochemistry, molecular biology, and medicine. Monoclonal antibodies are used in the diagnosis of illnesses such as cancer and infections and are used therapeutically in the treatment of e.g. cancer and inflammatory diseases.
== History ==
In the early 1900s, immunologist Paul Ehrlich proposed the idea of a Zauberkugel – "magic bullet", conceived of as a compound which selectively targeted a disease-causing organism, and could deliver a toxin for that organism. This underpinned the concept of monoclonal antibodies and monoclonal drug conjugates. Ehrlich and Élie Metchnikoff received the 1908 Nobel Prize for Physiology or Medicine for providing the theoretical basis for immunology.
By the 1970s, lymphocytes producing a single antibody were known, in the form of multiple myeloma – a cancer affecting B-cells. These abnormal antibodies or paraproteins were used to study the structure of antibodies, but it was not yet possible to produce identical antibodies specific to a given antigen.: 324 In 1973, Jerrold Schwaber described the production of monoclonal antibodies using human–mouse hybrid cells. This work remains widely cited among those using human-derived hybridomas. In 1975, Georges Köhler and César Milstein succeeded in making fusions of myeloma cell lines with B cells to create hybridomas that could produce antibodies, specific to known antigens and that were immortalized. They and Niels Kaj Jerne shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery.
In 1988, Gregory Winter and his team pioneered the techniques to humanize monoclonal antibodies, eliminating the reactions that many monoclonal antibodies caused in some patients. By the 1990s research was making progress in using monoclonal antibodies therapeutically, and in 2018, James P. Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation, using monoclonal antibodies that prevent inhibitory linkages.
The translational work needed to implement these ideas is credited to Lee Nadler. As explained in an NIH article, "He was the first to discover monoclonal antibodies directed against human B-cell–specific antigens and, in fact, all the known human B-cell–specific antigens were discovered in his laboratory. He is a true translational investigator, since he used these monoclonal antibodies to classify human B-cell leukemia and lymphomas as well as to create therapeutic agents for patients. . . More importantly, he was the first in the world to administer a monoclonal antibody to a human (a patient with B-cell lymphoma)."
== Production ==
=== Hybridoma development ===
Much of the work behind production of monoclonal antibodies is rooted in the production of hybridomas, which involves identifying antigen-specific plasma/plasmablast cells that produce antibodies specific to an antigen of interest and fusing these cells with myeloma cells. Rabbit B-cells can be used to form a rabbit hybridoma. Polyethylene glycol is used to fuse adjacent plasma membranes, but the success rate is low, so a selective medium in which only fused cells can grow is used. This is possible because myeloma cells have lost the ability to synthesize hypoxanthine-guanine-phosphoribosyl transferase (HGPRT), an enzyme necessary for the salvage synthesis of nucleic acids. The absence of HGPRT is not a problem for these cells unless the de novo purine synthesis pathway is also disrupted. Exposing cells to aminopterin (a folic acid analogue which inhibits dihydrofolate reductase) makes them unable to use the de novo pathway and become fully auxotrophic for nucleic acids, thus requiring supplementation to survive.
The selective culture medium is called HAT medium because it contains hypoxanthine, aminopterin and thymidine. This medium is selective for fused (hybridoma) cells. Unfused myeloma cells cannot grow because they lack HGPRT and thus cannot replicate their DNA. Unfused spleen cells cannot grow indefinitely because of their limited life span. Only fused hybrid cells referred to as hybridomas, are able to grow indefinitely in the medium because the spleen cell partner supplies HGPRT and the myeloma partner has traits that make it immortal (similar to a cancer cell).
This mixture of cells is then diluted and clones are grown from single parent cells on microtitre wells. The antibodies secreted by the different clones are then assayed for their ability to bind to the antigen (with a test such as ELISA or antigen microarray assay) or immuno-dot blot. The most productive and stable clone is then selected for future use.
The hybridomas can be grown indefinitely in a suitable cell culture medium. They can also be injected into mice (in the peritoneal cavity, surrounding the gut). There, they produce tumors secreting an antibody-rich fluid called ascites fluid.
The medium must be enriched during in vitro selection to further favour hybridoma growth. This can be achieved by the use of a layer of feeder fibrocyte cells or supplement medium such as briclone. Culture-media conditioned by macrophages can be used. Production in cell culture is usually preferred as the ascites technique is painful to the animal. Where alternate techniques exist, ascites is considered unethical.
=== Novel mAb development technology ===
Several monoclonal antibody technologies have been developed recently, such as phage display, single B cell culture, single cell amplification from various B cell populations and single plasma cell interrogation technologies. Different from traditional hybridoma technology, the newer technologies use molecular biology techniques to amplify the heavy and light chains of the antibody genes by PCR and produce in either bacterial or mammalian systems with recombinant technology. One of the advantages of the new technologies is applicable to multiple animals, such as rabbit, llama, chicken and other common experimental animals in the laboratory.
=== Purification ===
After obtaining either a media sample of cultured hybridomas or a sample of ascites fluid, the desired antibodies must be extracted. Cell culture sample contaminants consist primarily of media components such as growth factors, hormones and transferrins. In contrast, the in vivo sample is likely to have host antibodies, proteases, nucleases, nucleic acids and viruses. In both cases, other secretions by the hybridomas such as cytokines may be present. There may also be bacterial contamination and, as a result, endotoxins that are secreted by the bacteria. Depending on the complexity of the media required in cell culture and thus the contaminants, one or the other method (in vivo or in vitro) may be preferable.
The sample is first conditioned, or prepared for purification. Cells, cell debris, lipids, and clotted material are first removed, typically by centrifugation followed by filtration with a 0.45 μm filter. These large particles can cause a phenomenon called membrane fouling in later purification steps. In addition, the concentration of product in the sample may not be sufficient, especially in cases where the desired antibody is produced by a low-secreting cell line. The sample is therefore concentrated by ultrafiltration or dialysis.
Most of the charged impurities are usually anions such as nucleic acids and endotoxins. These can be separated by ion exchange chromatography. Either cation exchange chromatography is used at a low enough pH that the desired antibody binds to the column while anions flow through, or anion exchange chromatography is used at a high enough pH that the desired antibody flows through the column while anions bind to it. Various proteins can also be separated along with the anions based on their isoelectric point (pI). In proteins, the isoelectric point (pI) is defined as the pH at which a protein has no net charge. When the pH > pI, a protein has a net negative charge, and when the pH < pI, a protein has a net positive charge. For example, albumin has a pI of 4.8, which is significantly lower than that of most monoclonal antibodies, which have a pI of 6.1. Thus, at a pH between 4.8 and 6.1, the average charge of albumin molecules is likely to be more negative, while mAbs molecules are positively charged and hence it is possible to separate them. Transferrin, on the other hand, has a pI of 5.9, so it cannot be easily separated by this method. A difference in pI of at least 1 is necessary for a good separation.
Transferrin can instead be removed by size exclusion chromatography. This method is one of the more reliable chromatography techniques. Since we are dealing with proteins, properties such as charge and affinity are not consistent and vary with pH as molecules are protonated and deprotonated, while size stays relatively constant. Nonetheless, it has drawbacks such as low resolution, low capacity and low elution times.
A much quicker, single-step method of separation is protein A/G affinity chromatography. The antibody selectively binds to protein A/G, so a high level of purity (generally >80%) is obtained. The generally harsh conditions of this method may damage easily damaged antibodies. A low pH can break the bonds to remove the antibody from the column. In addition to possibly affecting the product, low pH can cause protein A/G itself to leak off the column and appear in the eluted sample. Gentle elution buffer systems that employ high salt concentrations are available to avoid exposing sensitive antibodies to low pH. Cost is also an important consideration with this method because immobilized protein A/G is a more expensive resin.
To achieve maximum purity in a single step, affinity purification can be performed, using the antigen to provide specificity for the antibody. In this method, the antigen used to generate the antibody is covalently attached to an agarose support. If the antigen is a peptide, it is commonly synthesized with a terminal cysteine, which allows selective attachment to a carrier protein, such as KLH during development and to support purification. The antibody-containing medium is then incubated with the immobilized antigen, either in batch or as the antibody is passed through a column, where it selectively binds and can be retained while impurities are washed away. An elution with a low pH buffer or a more gentle, high salt elution buffer is then used to recover purified antibody from the support.
=== Antibody heterogeneity ===
Product heterogeneity is common in monoclonal antibodies and other recombinant biological products and is typically introduced either upstream during expression or downstream during manufacturing.
These variants are typically aggregates, deamidation products, glycosylation variants, oxidized amino acid side chains, as well as amino and carboxyl terminal amino acid additions. These seemingly minute structural changes can affect preclinical stability and process optimization as well as therapeutic product potency, bioavailability and immunogenicity. The generally accepted purification method of process streams for monoclonal antibodies includes capture of the product target with protein A, elution, acidification to inactivate potential mammalian viruses, followed by ion chromatography, first with anion beads and then with cation beads.
Displacement chromatography has been used to identify and characterize these often unseen variants in quantities that are suitable for subsequent preclinical evaluation regimens such as animal pharmacokinetic studies. Knowledge gained during the preclinical development phase is critical for enhanced product quality understanding and provides a basis for risk management and increased regulatory flexibility. The recent Food and Drug Administration's Quality by Design initiative attempts to provide guidance on development and to facilitate design of products and processes that maximizes efficacy and safety profile while enhancing product manufacturability.
=== Recombinant ===
The production of recombinant monoclonal antibodies involves repertoire cloning, CRISPR/Cas9, or phage display/yeast display technologies. Recombinant antibody engineering involves antibody production by the use of viruses or yeast, rather than mice. These techniques rely on rapid cloning of immunoglobulin gene segments to create libraries of antibodies with slightly different amino acid sequences from which antibodies with desired specificities can be selected. The phage antibody libraries are a variant of phage antigen libraries. These techniques can be used to enhance the specificity with which antibodies recognize antigens, their stability in various environmental conditions, their therapeutic efficacy and their detectability in diagnostic applications. Fermentation chambers have been used for large scale antibody production.
=== Chimeric antibodies ===
While mouse and human antibodies are structurally similar, the differences between them were sufficient to invoke an immune response when murine monoclonal antibodies were injected into humans, resulting in their rapid removal from the blood, as well as systemic inflammatory effects and the production of human anti-mouse antibodies (HAMA).
Recombinant DNA has been explored since the late 1980s to increase residence times. In one approach called "CDR grafting", mouse DNA encoding the binding portion of a monoclonal antibody was merged with human antibody-producing DNA in living cells. The expression of this "chimeric" or "humanised" DNA through cell culture yielded part-mouse, part-human antibodies.
=== Human antibodies ===
Ever since the discovery that monoclonal antibodies could be generated, scientists have targeted the creation of fully human products to reduce the side effects of humanised or chimeric antibodies. Several successful approaches have been proposed: transgenic mice, phage display and single B cell cloning.
== Cost ==
Monoclonal antibodies are more expensive to manufacture than small molecules due to the complex processes involved and the general size of the molecules, all in addition to the enormous research and development costs involved in bringing a new chemical entity to patients. They are priced to enable manufacturers to recoup the typically large investment costs, and where there are no price controls, such as the United States, prices can be higher if they provide great value. Seven University of Pittsburgh researchers concluded, "The annual price of mAb therapies is about $100,000 higher in oncology and hematology than in other disease states", comparing them on a per patient basis, to those for cardiovascular or metabolic disorders, immunology, infectious diseases, allergy, and ophthalmology.
== Applications ==
=== Diagnostic tests ===
Once monoclonal antibodies for a given substance have been produced, they can be used to detect the presence of this substance. Proteins can be detected using the Western blot and immuno dot blot tests. In immunohistochemistry, monoclonal antibodies can be used to detect antigens in fixed tissue sections, and similarly, immunofluorescence can be used to detect a substance in either frozen tissue section or live cells.
=== Analytic and chemical uses ===
Antibodies can also be used to purify their target compounds from mixtures, using the method of immunoprecipitation.
=== Therapeutic uses ===
Therapeutic monoclonal antibodies act through multiple mechanisms, such as blocking of targeted molecule functions, inducing apoptosis in cells which express the target, or by modulating signalling pathways.
==== Cancer treatment ====
One possible treatment for cancer involves monoclonal antibodies that bind only to cancer-cell-specific antigens and induce an immune response against the target cancer cell. Such mAbs can be modified for delivery of a toxin, radioisotope, cytokine or other active conjugate or to design bispecific antibodies that can bind with their Fab regions both to target antigen and to a conjugate or effector cell. Every intact antibody can bind to cell receptors or other proteins with its Fc region.
MAbs approved by the FDA for cancer include:
==== Autoimmune diseases ====
Monoclonal antibodies used for autoimmune diseases include infliximab and adalimumab, which are effective in rheumatoid arthritis, Crohn's disease, ulcerative colitis and ankylosing spondylitis by their ability to bind to and inhibit TNF-α. Basiliximab and daclizumab inhibit IL-2 on activated T cells and thereby help prevent acute rejection of kidney transplants. Omalizumab inhibits human immunoglobulin E (IgE) and is useful in treating moderate-to-severe allergic asthma.
==== Examples of therapeutic monoclonal antibodies ====
Monoclonal antibodies for research applications can be found directly from antibody suppliers, or through use of a specialist search engine like CiteAb. Below are examples of clinically important monoclonal antibodies.
=== COVID-19 ===
In 2020, the monoclonal antibody therapies bamlanivimab/etesevimab and casirivimab/imdevimab were given emergency use authorizations by the US Food and Drug Administration to reduce the number of hospitalizations, emergency room visits, and deaths because of COVID-19. In September 2021, the Biden administration purchased US$2.9 billion worth of Regeneron monoclonal antibodies at $2,100 per dose to curb the shortage.
As of December 2021, in vitro neutralization tests indicate monoclonal antibody therapies (with the exception of sotrovimab and tixagevimab/cilgavimab) were not likely to be active against the Omicron variant.
Over 2021–22, two Cochrane reviews found insufficient evidence for using neutralizing monoclonal antibodies to treat COVID-19 infections. The reviews applied only to people who were unvaccinated against COVID‐19, and only to the COVID-19 variants existing during the studies, not to newer variants, such as Omicron.
In March 2024, pemivibart, a monoclonal antibody drug, received an emergency use authorization from the US FDA for use as pre-exposure prophylaxis to protect certain moderately to severely immunocompromised individuals against COVID-19.
== Side effects ==
Several monoclonal antibodies, such as bevacizumab and cetuximab, can cause different kinds of side effects. These side effects can be categorized into common and serious side effects.
Some common side effects include:
Among the possible serious side effects are:
== See also ==
List of monoclonal antibodies
== References ==
== Further reading ==
== External links ==
Monoclonal+antibodies at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Antibodypedia, open-access virtual repository publishing data and commentary on any antibodies available to the scientific community.
Antibody Purification Handbook Archived 5 December 2008 at the Wayback Machine | Wikipedia/Monoclonal_antibody |
Immunology is a branch of biology and medicine that covers the study of immune systems in all organisms.
Immunology charts, measures, and contextualizes the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders (such as autoimmune diseases, hypersensitivities, immune deficiency, and transplant rejection); and the physical, chemical, and physiological characteristics of the components of the immune system in vitro, in situ, and in vivo. Immunology has applications in numerous disciplines of medicine, particularly in the fields of organ transplantation, oncology, rheumatology, virology, bacteriology, parasitology, psychiatry, and dermatology.
The term was coined by Russian biologist Ilya Ilyich Mechnikov, who advanced studies on immunology and received the Nobel Prize for his work in 1908 with Paul Ehrlich "in recognition of their work on immunity". He pinned small thorns into starfish larvae and noticed unusual cells surrounding the thorns. This was the active response of the body trying to maintain its integrity. It was Mechnikov who first observed the phenomenon of phagocytosis, in which the body defends itself against a foreign body. Ehrlich accustomed mice to the poisonous ricin and abrin. After feeding them with small but increasing dosages of ricin he ascertained that they had become "ricin-proof". Ehrlich interpreted this as immunization and observed that it was abruptly initiated after a few days and was still in existence after several months.
Prior to the designation of immunity, from the etymological root immunis, which is Latin for 'exempt', early physicians characterized organs that would later be proven as essential components of the immune system. The important lymphoid organs of the immune system are the thymus, bone marrow, and chief lymphatic tissues such as spleen, tonsils, lymph vessels, lymph nodes, adenoids, and liver. However, many components of the immune system are cellular in nature, and not associated with specific organs, but rather embedded or circulating in various tissues located throughout the body.
== Classical immunology ==
Classical immunology ties in with the fields of epidemiology and medicine. It studies the relationship between the body systems, pathogens, and immunity. The earliest written mention of immunity can be traced back to the plague of Athens in 430 BCE. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. Many other ancient societies have references to this phenomenon, but it was not until the 19th and 20th centuries before the concept developed into scientific theory.
The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science of immunology. The immune system has been divided into a more primitive innate immune system and, in vertebrates, an acquired or adaptive immune system. The latter is further divided into humoral (or antibody) and cell-mediated components.
The immune system has the capability of self and non-self-recognition. An antigen is a substance that ignites the immune response. The cells involved in recognizing the antigen are Lymphocytes. Once they recognize, they secrete antibodies. Antibodies are proteins that neutralize the disease-causing microorganisms. Antibodies do not directly kill pathogens, but instead, identify antigens as targets for destruction by other immune cells such as phagocytes or NK cells.
The (antibody) response is defined as the interaction between antibodies and antigens. Antibodies are specific proteins released from a certain class of immune cells known as B lymphocytes, while antigens are defined as anything that elicits the generation of antibodies (antibody generators). Immunology rests on an understanding of the properties of these two biological entities and the cellular response to both.
It is now getting clear that the immune responses contribute to the development of many common disorders not traditionally viewed as immunologic, including metabolic, cardiovascular, cancer, and neurodegenerative conditions like Alzheimer's disease. Besides, there are direct implications of the immune system in the infectious diseases (tuberculosis, malaria, hepatitis, pneumonia, dysentery, and helminth infestations) as well. Hence, research in the field of immunology is of prime importance for the advancements in the fields of modern medicine, biomedical research, and biotechnology.
== Diagnostic immunology ==
The specificity of the bond between antibody and antigen has made the antibody an excellent tool for the detection of substances by a variety of diagnostic techniques. Antibodies specific for a desired antigen can be conjugated with an isotopic (radio) or fluorescent label or with a color-forming enzyme in order to detect it. However, the similarity between some antigens can lead to false positives and other errors in such tests by antibodies cross-reacting with antigens that are not exact matches.
== Immunotherapy ==
The use of immune system components or antigens to treat a disease or disorder is known as immunotherapy. Immunotherapy is most commonly used to treat allergies, autoimmune disorders such as Crohn's disease, Hashimoto's thyroiditis and rheumatoid arthritis, and certain cancers. Immunotherapy is also often used for patients who are immunosuppressed (such as those with HIV) and people with other immune deficiencies.
This includes regulating factors such as IL-2, IL-10, GM-CSF B, IFN-α.
== Clinical immunology ==
Clinical immunology is the study of diseases caused by disorders of the immune system (failure, aberrant action, and malignant growth of the cellular elements of the system). It also involves diseases of other systems, where immune reactions play a part in the pathology and clinical features.
The diseases caused by disorders of the immune system fall into two broad categories:
immunodeficiency, in which parts of the immune system fail to provide an adequate response (examples include chronic granulomatous disease and primary immune diseases);
autoimmunity, in which the immune system attacks its own host's body (examples include systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's disease and myasthenia gravis).
Other immune system disorders include various hypersensitivities (such as in asthma and other allergies) that respond inappropriately to otherwise harmless compounds.
The most well-known disease that affects the immune system itself is AIDS, an immunodeficiency characterized by the suppression of CD4+ ("helper") T cells, dendritic cells and macrophages by the human immunodeficiency virus (HIV).
Clinical immunologists also study ways to prevent the immune system's attempts to destroy allografts (transplant rejection).
Clinical immunology and allergy is usually a subspecialty of internal medicine or pediatrics. Fellows in Clinical Immunology are typically exposed to many of the different aspects of the specialty and treat allergic conditions, primary immunodeficiencies and systemic autoimmune and autoinflammatory conditions. As part of their training fellows may do additional rotations in rheumatology, pulmonology, otorhinolaryngology, dermatology and the immunologic lab.
=== Clinical and pathology immunology ===
When health conditions worsen to emergency status, portions of immune system organs, including the thymus, spleen, bone marrow, lymph nodes, and other lymphatic tissues, can be surgically excised for examination while patients are still alive.
== Theoretical immunology ==
Immunology is strongly experimental in everyday practice but is also characterized by an ongoing theoretical attitude. Many theories have been suggested in immunology from the end of the nineteenth century up to the present time. The end of the 19th century and the beginning of the 20th century saw a battle between "cellular" and "humoral" theories of immunity. According to the cellular theory of immunity, represented in particular by Elie Metchnikoff, it was cells – more precisely, phagocytes – that were responsible for immune responses. In contrast, the humoral theory of immunity, held by Robert Koch and Emil von Behring, among others, stated that the active immune agents were soluble components (molecules) found in the organism's "humors" rather than its cells.
In the mid-1950s, Macfarlane Burnet, inspired by a suggestion made by Niels Jerne, formulated the clonal selection theory (CST) of immunity. On the basis of CST, Burnet developed a theory of how an immune response is triggered according to the self/nonself distinction: "self" constituents (constituents of the body) do not trigger destructive immune responses, while "nonself" entities (e.g., pathogens, an allograft) trigger a destructive immune response. The theory was later modified to reflect new discoveries regarding histocompatibility or the complex "two-signal" activation of T cells. The self/nonself theory of immunity and the self/nonself vocabulary have been criticized, but remain very influential.
More recently, several theoretical frameworks have been suggested in immunology, including "autopoietic" views, "cognitive immune" views, the "danger model" (or "danger theory"), and the "discontinuity" theory. The danger model, suggested by Polly Matzinger and colleagues, has been very influential, arousing many comments and discussions.
== Developmental immunology ==
The body's capability to react to antigens depends on a person's age, antigen type, maternal factors and the area where the antigen is presented. Neonates are said to be in a state of physiological immunodeficiency, because both their innate and adaptive immunological responses are greatly suppressed. Once born, a child's immune system responds favorably to protein antigens while not as well to glycoproteins and polysaccharides. In fact, many of the infections acquired by neonates are caused by low virulence organisms like Staphylococcus and Pseudomonas. In neonates, opsonic activity and the ability to activate the complement cascade is very limited. For example, the mean level of C3 in a newborn is approximately 65% of that found in the adult. Phagocytic activity is also greatly impaired in newborns. This is due to lower opsonic activity, as well as diminished up-regulation of integrin and selectin receptors, which limit the ability of neutrophils to interact with adhesion molecules in the endothelium. Their monocytes are slow and have a reduced ATP production, which also limits the newborn's phagocytic activity. Although, the number of total lymphocytes is significantly higher than in adults, the cellular and humoral immunity is also impaired. Antigen-presenting cells in newborns have a reduced capability to activate T cells. Also, T cells of a newborn proliferate poorly and produce very small amounts of cytokines like IL-2, IL-4, IL-5, IL-12, and IFN-g which limits their capacity to activate the humoral response as well as the phagocitic activity of macrophage. B cells develop early during gestation but are not fully active.
Maternal factors also play a role in the body's immune response. At birth, most of the immunoglobulin present is maternal IgG. These antibodies are transferred from the placenta to the fetus using the FcRn (neonatal Fc receptor). Because IgM, IgD, IgE and IgA do not cross the placenta, they are almost undetectable at birth. Some IgA is provided by breast milk. These passively-acquired antibodies can protect the newborn for up to 18 months, but their response is usually short-lived and of low affinity. These antibodies can also produce a negative response. If a child is exposed to the antibody for a particular antigen before being exposed to the antigen itself then the child will produce a dampened response. Passively acquired maternal antibodies can suppress the antibody response to active immunization. Similarly, the response of T-cells to vaccination differs in children compared to adults, and vaccines that induce Th1 responses in adults do not readily elicit these same responses in neonates. Between six and nine months after birth, a child's immune system begins to respond more strongly to glycoproteins, but there is usually no marked improvement in their response to polysaccharides until they are at least one year old. This can be the reason for distinct time frames found in vaccination schedules.
During adolescence, the human body undergoes various physical, physiological and immunological changes triggered and mediated by hormones, of which the most significant in females is 17-β-estradiol (an estrogen) and, in males, is testosterone. Estradiol usually begins to act around the age of 10 and testosterone some months later. There is evidence that these steroids not only act directly on the primary and secondary sexual characteristics but also have an effect on the development and regulation of the immune system, including an increased risk in developing pubescent and post-pubescent autoimmunity. There is also some evidence that cell surface receptors on B cells and macrophages may detect sex hormones in the system.
The female sex hormone 17-β-estradiol has been shown to regulate the level of immunological response, while some male androgens such as testosterone seem to suppress the stress response to infection. Other androgens, however, such as DHEA, increase immune response. As in females, the male sex hormones seem to have more control of the immune system during puberty and post-puberty than during the rest of a male's adult life.
Physical changes during puberty such as thymic involution also affect immunological response.
== Ecoimmunology and behavioural immunity ==
Ecoimmunology, or ecological immunology, explores the relationship between the immune system of an organism and its social, biotic and abiotic environment.
More recent ecoimmunological research has focused on host pathogen defences traditionally considered "non-immunological", such as pathogen avoidance, self-medication, symbiont-mediated defenses, and fecundity trade-offs. Behavioural immunity, a phrase coined by Mark Schaller, specifically refers to psychological pathogen avoidance drivers, such as disgust aroused by stimuli encountered around pathogen-infected individuals, such as the smell of vomit. More broadly, "behavioural" ecological immunity has been demonstrated in multiple species. For example, the Monarch butterfly often lays its eggs on certain toxic milkweed species when infected with parasites. These toxins reduce parasite growth in the offspring of the infected Monarch. However, when uninfected Monarch butterflies are forced to feed only on these toxic plants, they suffer a fitness cost as reduced lifespan relative to other uninfected Monarch butterflies. This indicates that laying eggs on toxic plants is a costly behaviour in Monarchs which has probably evolved to reduce the severity of parasite infection.
Symbiont-mediated defenses are also heritable across host generations, despite a non-genetic direct basis for the transmission. Aphids, for example, rely on several different symbionts for defense from key parasites, and can vertically transmit their symbionts from parent to offspring. Therefore, a symbiont that successfully confers protection from a parasite is more likely to be passed to the host offspring, allowing coevolution with parasites attacking the host in a way similar to traditional immunity.
The preserved immune tissues of extinct species, such as the thylacine (Thylacine cynocephalus), can also provide insights into their biology.
== Cancer immunology ==
The study of the interaction of the immune system with cancer cells can lead to diagnostic tests and therapies with which to find and fight cancer. The immunology concerned with physiological reaction characteristic of the immune state. Inflammation is an immune response that has been observed in many types of cancers.
== Reproductive immunology ==
This area of the immunology is devoted to the study of immunological aspects of the reproductive process including fetus acceptance. The term has also been used by fertility clinics to address fertility problems, recurrent miscarriages, premature deliveries and dangerous complications such as pre-eclampsia.
== See also ==
List of immunologists
Immunomics
International Reviews of Immunology
Outline of immunology
History of immunology
Osteoimmunology
== References ==
== External links ==
Media related to Immunology at Wikimedia Commons
American Association of Immunologists
British Society for Immunology
Federation of Clinical Immunology Societies | Wikipedia/Clinical_immunology |
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthesis is most commonly performed by ribosomes in cells. Peptides can also be synthesized in the laboratory. Protein primary structures can be directly sequenced, or inferred from DNA sequences.
== Formation ==
=== Biological ===
Amino acids are polymerised via peptide bonds to form a long backbone, with the different amino acid side chains protruding along it. In biological systems, proteins are produced during translation by a cell's ribosomes. Some organisms can also make short peptides by non-ribosomal peptide synthesis, which often use amino acids other than the encoded 22, and may be cyclised, modified and cross-linked.
=== Chemical ===
Peptides can be synthesised chemically via a range of laboratory methods. Chemical methods typically synthesise peptides in the opposite order (starting at the C-terminus) to biological protein synthesis (starting at the N-terminus).
== Notation ==
Protein sequence is typically notated as a string of letters, listing the amino acids starting at the amino-terminal end through to the carboxyl-terminal end. Either a three letter code or single letter code can be used to represent the 22 naturally encoded amino acids, as well as mixtures or ambiguous amino acids (similar to nucleic acid notation).
Peptides can be directly sequenced, or inferred from DNA sequences. Large sequence databases now exist that collate known protein sequences.
== Modification ==
In general, polypeptides are unbranched polymers, so their primary structure can often be specified by the sequence of amino acids along their backbone. However, proteins can become cross-linked, most commonly by disulfide bonds, and the primary structure also requires specifying the cross-linking atoms, e.g., specifying the cysteines involved in the protein's disulfide bonds. Other crosslinks include desmosine.
=== Isomerisation ===
The chiral centers of a polypeptide chain can undergo racemization. Although it does not change the sequence, it does affect the chemical properties of the sequence. In particular, the L-amino acids normally found in proteins can spontaneously isomerize at the
C
α
{\displaystyle \mathrm {C^{\alpha }} }
atom to form D-amino acids, which cannot be cleaved by most proteases. Additionally, proline can form stable trans-isomers at the peptide bond.
=== Post-translational modification ===
Additionally, the protein can undergo a variety of post-translational modifications, which are briefly summarized here.
The N-terminal amino group of a polypeptide can be modified covalently, e.g.,
acetylation
−
C
(
=
O
)
−
C
H
3
{\displaystyle \mathrm {-C(=O)-CH_{3}} }
The positive charge on the N-terminal amino group may be eliminated by changing it to an acetyl group (N-terminal blocking).
formylation
−
C
(
=
O
)
H
{\displaystyle \mathrm {-C(=O)H} }
The N-terminal methionine usually found after translation has an N-terminus blocked with a formyl group. This formyl group (and sometimes the methionine residue itself, if followed by Gly or Ser) is removed by the enzyme deformylase.
pyroglutamate
An N-terminal glutamine can attack itself, forming a cyclic pyroglutamate group.
myristoylation
−
C
(
=
O
)
−
(
C
H
2
)
12
−
C
H
3
{\displaystyle \mathrm {-C(=O)-\left(CH_{2}\right)_{12}-CH_{3}} }
Similar to acetylation. Instead of a simple methyl group, the myristoyl group has a tail of 14 hydrophobic carbons, which make it ideal for anchoring proteins to cellular membranes.
The C-terminal carboxylate group of a polypeptide can also be modified, e.g.,
amination (see Figure)
The C-terminus can also be blocked (thus, neutralizing its negative charge) by amination.
glycosyl phosphatidylinositol (GPI) attachment
Glycosyl phosphatidylinositol(GPI) is a large, hydrophobic phospholipid prosthetic group that anchors proteins to cellular membranes. It is attached to the polypeptide C-terminus through an amide linkage that then connects to ethanolamine, thence to sundry sugars and finally to the phosphatidylinositol lipid moiety.
Finally, the peptide side chains can also be modified covalently, e.g.,
phosphorylation
Aside from cleavage, phosphorylation is perhaps the most important chemical modification of proteins. A phosphate group can be attached to the sidechain hydroxyl group of serine, threonine and tyrosine residues, adding a negative charge at that site and producing an unnatural amino acid. Such reactions are catalyzed by kinases and the reverse reaction is catalyzed by phosphatases. The phosphorylated tyrosines are often used as "handles" by which proteins can bind to one another, whereas phosphorylation of Ser/Thr often induces conformational changes, presumably because of the introduced negative charge. The effects of phosphorylating Ser/Thr can sometimes be simulated by mutating the Ser/Thr residue to glutamate.
glycosylation
A catch-all name for a set of very common and very heterogeneous chemical modifications. Sugar moieties can be attached to the sidechain hydroxyl groups of Ser/Thr or to the sidechain amide groups of Asn. Such attachments can serve many functions, ranging from increasing solubility to complex recognition. All glycosylation can be blocked with certain inhibitors, such as tunicamycin.
deamidation (succinimide formation)
In this modification, an asparagine or aspartate side chain attacks the following peptide bond, forming a symmetrical succinimide intermediate. Hydrolysis of the intermediate produces either aspartate or the β-amino acid, iso(Asp). For asparagine, either product results in the loss of the amide group, hence "deamidation".
hydroxylation
Proline residues may be hydroxylated at either of two atoms, as can lysine (at one atom). Hydroxyproline is a critical component of collagen, which becomes unstable upon its loss. The hydroxylation reaction is catalyzed by an enzyme that requires ascorbic acid (vitamin C), deficiencies in which lead to many connective-tissue diseases such as scurvy.
methylation
Several protein residues can be methylated, most notably the positive groups of lysine and arginine. Arginine residues interact with the nucleic acid phosphate backbone and commonly form hydrogen bonds with the base residues, particularly guanine, in protein–DNA complexes. Lysine residues can be singly, doubly and even triply methylated. Methylation does not alter the positive charge on the side chain, however.
acetylation
Acetylation of the lysine amino groups is chemically analogous to the acetylation of the N-terminus. Functionally, however, the acetylation of lysine residues is used to regulate the binding of proteins to nucleic acids. The cancellation of the positive charge on the lysine weakens the electrostatic attraction for the (negatively charged) nucleic acids.
sulfation
Tyrosines may become sulfated on their
O
η
{\displaystyle \mathrm {O^{\eta }} }
atom. Somewhat unusually, this modification occurs in the Golgi apparatus, not in the endoplasmic reticulum. Similar to phosphorylated tyrosines, sulfated tyrosines are used for specific recognition, e.g., in chemokine receptors on the cell surface. As with phosphorylation, sulfation adds a negative charge to a previously neutral site.
prenylation and palmitoylation
−
C
(
=
O
)
−
(
C
H
2
)
14
−
C
H
3
{\displaystyle \mathrm {-C(=O)-\left(CH_{2}\right)_{14}-CH_{3}} }
The hydrophobic isoprene (e.g., farnesyl, geranyl, and geranylgeranyl groups) and palmitoyl groups may be added to the
S
γ
{\displaystyle \mathrm {S^{\gamma }} }
atom of cysteine residues to anchor proteins to cellular membranes. Unlike the GPI and myritoyl anchors, these groups are not necessarily added at the termini.
carboxylation
A relatively rare modification that adds an extra carboxylate group (and, hence, a double negative charge) to a glutamate side chain, producing a Gla residue. This is used to strengthen the binding to "hard" metal ions such as calcium.
ADP-ribosylation
The large ADP-ribosyl group can be transferred to several types of side chains within proteins, with heterogeneous effects. This modification is a target for the powerful toxins of disparate bacteria, e.g., Vibrio cholerae, Corynebacterium diphtheriae and Bordetella pertussis.
ubiquitination and SUMOylation
Various full-length, folded proteins can be attached at their C-termini to the sidechain ammonium groups of lysines of other proteins. Ubiquitin is the most common of these, and usually signals that the ubiquitin-tagged protein should be degraded.
Most of the polypeptide modifications listed above occur post-translationally, i.e., after the protein has been synthesized on the ribosome, typically occurring in the endoplasmic reticulum, a subcellular organelle of the eukaryotic cell.
Many other chemical reactions (e.g., cyanylation) have been applied to proteins by chemists, although they are not found in biological systems.
=== Cleavage and ligation ===
In addition to those listed above, the most important modification of primary structure is peptide cleavage (by chemical hydrolysis or by proteases). Proteins are often synthesized in an inactive precursor form; typically, an N-terminal or C-terminal segment blocks the active site of the protein, inhibiting its function. The protein is activated by cleaving off the inhibitory peptide.
Some proteins even have the power to cleave themselves. Typically, the hydroxyl group of a serine (rarely, threonine) or the thiol group of a cysteine residue will attack the carbonyl carbon of the preceding peptide bond, forming a tetrahedrally bonded intermediate [classified as a hydroxyoxazolidine (Ser/Thr) or hydroxythiazolidine (Cys) intermediate]. This intermediate tends to revert to the amide form, expelling the attacking group, since the amide form is usually favored by free energy, (presumably due to the strong resonance stabilization of the peptide group). However, additional molecular interactions may render the amide form less stable; the amino group is expelled instead, resulting in an ester (Ser/Thr) or thioester (Cys) bond in place of the peptide bond. This chemical reaction is called an N-O acyl shift.
The ester/thioester bond can be resolved in several ways:
Simple hydrolysis will split the polypeptide chain, where the displaced amino group becomes the new N-terminus. This is seen in the maturation of glycosylasparaginase.
A β-elimination reaction also splits the chain, but results in a pyruvoyl group at the new N-terminus. This pyruvoyl group may be used as a covalently attached catalytic cofactor in some enzymes, especially decarboxylases such as S-adenosylmethionine decarboxylase (SAMDC) that exploit the electron-withdrawing power of the pyruvoyl group.
Intramolecular transesterification, resulting in a branched polypeptide. In inteins, the new ester bond is broken by an intramolecular attack by the soon-to-be C-terminal asparagine.
Intermolecular transesterification can transfer a whole segment from one polypeptide to another, as is seen in the Hedgehog protein autoprocessing.
== Sequence compression ==
The compression of amino acid sequences is a comparatively challenging task. The existing specialized amino acid sequence compressors are low compared with that of DNA sequence compressors, mainly because of the characteristics of the data. For example, modeling inversions is harder because of the reverse information loss (from amino acids to DNA sequence). The current lossless data compressor that provides higher compression is AC2. AC2 mixes various context models using Neural Networks and encodes the data using arithmetic encoding.
== History ==
The proposal that proteins were linear chains of α-amino acids was made nearly simultaneously by two scientists at the same conference in 1902, the 74th meeting of the Society of German Scientists and Physicians, held in Karlsbad. Franz Hofmeister made the proposal in the morning, based on his observations of the biuret reaction in proteins. Hofmeister was followed a few hours later by Emil Fischer, who had amassed a wealth of chemical details supporting the peptide-bond model. For completeness, the proposal that proteins contained amide linkages was made as early as 1882 by the French chemist E. Grimaux.
Despite these data and later evidence that proteolytically digested proteins yielded only oligopeptides, the idea that proteins were linear, unbranched polymers of amino acids was not accepted immediately. Some scientists such as William Astbury doubted that covalent bonds were strong enough to hold such long molecules together; they feared that thermal agitations would shake such long molecules asunder. Hermann Staudinger faced similar prejudices in the 1920s when he argued that rubber was composed of macromolecules.
Thus, several alternative hypotheses arose. The colloidal protein hypothesis stated that proteins were colloidal assemblies of smaller molecules. This hypothesis was disproved in the 1920s by ultracentrifugation measurements by Theodor Svedberg that showed that proteins had a well-defined, reproducible molecular weight and by electrophoretic measurements by Arne Tiselius that indicated that proteins were single molecules. A second hypothesis, the cyclol hypothesis advanced by Dorothy Wrinch, proposed that the linear polypeptide underwent a chemical cyclol rearrangement C=O + HN
→
{\displaystyle \rightarrow }
C(OH)-N that crosslinked its backbone amide groups, forming a two-dimensional fabric. Other primary structures of proteins were proposed by various researchers, such as the diketopiperazine model of Emil Abderhalden and the pyrrol/piperidine model of Troensegaard in 1942. Although never given much credence, these alternative models were finally disproved when Frederick Sanger successfully sequenced insulin and by the crystallographic determination of myoglobin and hemoglobin by Max Perutz and John Kendrew.
== Primary structure in other molecules ==
Any linear-chain heteropolymer can be said to have a "primary structure" by analogy to the usage of the term for proteins, but this usage is rare compared to the extremely common usage in reference to proteins. In RNA, which also has extensive secondary structure, the linear chain of bases is generally just referred to as the "sequence" as it is in DNA (which usually forms a linear double helix with little secondary structure). Other biological polymers such as polysaccharides can also be considered to have a primary structure, although the usage is not standard.
== Relation to secondary and tertiary structure ==
The primary structure of a biological polymer to a large extent determines the three-dimensional shape (tertiary structure). Protein sequence can be used to predict local features, such as segments of secondary structure, or trans-membrane regions. However, the complexity of protein folding currently prohibits predicting the tertiary structure of a protein from its sequence alone. Knowing the structure of a similar homologous sequence (for example a member of the same protein family) allows highly accurate prediction of the tertiary structure by homology modeling. If the full-length protein sequence is available, it is possible to estimate its general biophysical properties, such as its isoelectric point.
Sequence families are often determined by sequence clustering, and structural genomics projects aim to produce a set of representative structures to cover the sequence space of possible non-redundant sequences.
== See also ==
Protein sequencing
Nucleic acid primary structure
Translation
Pseudo amino acid composition
== Notes and references == | Wikipedia/Protein_sequences |
In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals.
The main goals of preclinical studies are to determine a starting, safe dose for first-in-human study and assess potential toxicity of the product, which typically include new medical devices, prescription drugs, and diagnostics.
Companies use stylized statistics to illustrate the risks in preclinical research, such as that on average, only one in every 5,000 compounds that enters drug discovery to the stage of preclinical development becomes an approved drug.
== Types ==
Each class of product may undergo different types of preclinical research. For instance, drugs may undergo pharmacodynamics (what the drug does to the body) (PD), pharmacokinetics (what the body does to the drug) (PK), ADME, and toxicology testing. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans. Medical devices that do not have drug attached will not undergo these additional tests and may go directly to good laboratory practices (GLP) testing for safety of the device and its components. Some medical devices will also undergo biocompatibility testing which helps to show whether a component of the device or all components are sustainable in a living model. Most preclinical studies must adhere to GLPs in ICH Guidelines to be acceptable for submission to regulatory agencies such as the Food & Drug Administration in the United States.
Typically, both in vitro and in vivo tests will be performed. Studies of drug toxicity include which organs are targeted by that drug, as well as if there are any long-term carcinogenic effects or toxic effects causing illness.
== Animal testing ==
The information collected from these studies is vital so that safe human testing can begin. Typically, in drug development studies animal testing involves two species. The most commonly used models are murine and canine, although primate and porcine are also used.
=== Choice of species ===
The choice of species is based on which will give the best correlation to human trials. Differences in the gut, enzyme activity, circulatory system, or other considerations make certain models more appropriate based on the dosage form, site of activity, or noxious metabolites. For example, canines may not be good models for solid oral dosage forms because the characteristic carnivore intestine is underdeveloped compared to the omnivore's, and gastric emptying rates are increased. Also, rodents can not act as models for antibiotic drugs because the resulting alteration to their intestinal flora causes significant adverse effects. Depending on a drug's functional groups, it may be metabolized in similar or different ways between species, which will affect both efficacy and toxicology.
Medical device studies also use this basic premise. Most studies are performed in larger species such as dogs, pigs and sheep which allow for testing in a similar sized model as that of a human. In addition, some species are used for similarity in specific organs or organ system physiology (swine for dermatological and coronary stent studies; goats for mammary implant studies; dogs for gastric and cancer studies; etc.).
Importantly, the regulatory guidelines of FDA, EMA, and other similar international and regional authorities usually require safety testing in at least two mammalian species, including one non-rodent species, prior to human trials authorization.
=== Ethical issues ===
Animal testing in the research-based pharmaceutical industry has been reduced in recent years both for ethical and cost reasons. However, most research will still involve animal based testing for the need of similarity in anatomy and physiology that is required for diverse product development.
== No observable effect levels ==
Based on preclinical trials, no-observed-adverse-effect levels (NOAELs) on drugs are established, which are used to determine initial phase 1 clinical trial dosage levels on a mass API per mass patient basis. Generally a 1/100 uncertainty factor or "safety margin" is included to account for interspecies (1/10) and inter-individual (1/10) differences.
== See also ==
Drug development
Preclinical imaging
Phases of clinical research
== References == | Wikipedia/Preclinical |
A single-domain antibody (sdAb), also known as a Nanobody, is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, it is able to bind selectively to a specific antigen. With a molecular weight of only 12–15 kDa, single-domain antibodies (sdAbs) are much smaller than common antibodies (150–160 kDa) which are composed of two heavy protein chains and two light chains, and even smaller than Fab fragments (~50 kDa, one light chain and half a heavy chain) and single-chain variable fragments (~25 kDa, two variable domains, one from a light and one from a heavy chain).
The first single-domain antibodies were engineered from heavy-chain antibodies found in camelids at the Université Libre de Bruxelles; these are called VHH fragments. Cartilaginous fishes also have heavy-chain antibodies (IgNAR, 'immunoglobulin new antigen receptor'), from which single-domain antibodies called VNAR fragments can be obtained. An alternative approach is to split the dimeric variable domains from common immunoglobulin G (IgG) from humans or mice into monomers. Although most research into single-domain antibodies is currently based on heavy chain variable domains, Nanobodies derived from light chains have also been shown to bind specifically to target epitopes.
Camelid Nanobodies have been shown to be just as specific as antibodies, and in some cases they are more robust. They are easily isolated using the same phage panning procedure used for antibodies, allowing them to be cultured in vitro in large concentrations. The smaller size and single domain make these antibodies easier to transform into bacterial cells for bulk production, making them ideal for research purposes.
Single-domain antibodies are being researched for multiple pharmaceutical applications, and have potential for use in the treatment of acute coronary syndrome, cancer, Alzheimer's disease, and Covid-19.
== Properties ==
A single-domain antibody is a peptide chain of about 110 amino acids long, comprising one variable domain (VH) of a heavy-chain antibody, or of a common IgG. These peptides have similar affinity to antigens as whole antibodies, but are more heat-resistant and stable towards detergents and high concentrations of urea. Those derived from camelid and fish antibodies are less lipophilic and more soluble in water, owing to their complementarity-determining region 3 (CDR3), which forms an extended loop (coloured orange in the ribbon diagram above) covering the lipophilic site that normally binds to a light chain. In contrast to common antibodies, two out of six single-domain antibodies survived a temperature of 90 °C (194 °F) without losing their ability to bind antigens in a 1999 study. Stability towards gastric acid and proteases depends on the amino acid sequence. Some species have been shown to be active in the intestine after oral application, but their low absorption from the gut impedes the development of systemically active orally administered single-domain antibodies.
The comparatively low molecular mass leads to a better permeability in tissues, and to a short plasma half-life since they are eliminated renally. Unlike whole antibodies, they do not show complement system triggered cytotoxicity because they lack an Fc region. Camelid and fish derived sdAbs are able to bind to hidden antigens that are not accessible to whole antibodies, for example to the active sites of enzymes. This property has been shown to result from their extended CDR3 loop, which is able to penetrate such buried sites.
== Production ==
=== From heavy-chain antibodies ===
A single-domain antibody can be obtained by immunization of dromedaries, camels, llamas, alpacas or sharks with the desired antigen and subsequent isolation of the mRNA coding for the variable region (VNAR and VHH) of heavy-chain antibodies. Large phage displayed VNAR and VHH single domain libraries were established from nurse sharks and dromedary camels. Screening techniques like phage display and ribosome display help to identify the clones binding the antigen. The single domain antibodies including VNARs can be humanized for clinical applications.
=== From conventional antibodies ===
Alternatively, single-domain antibodies can be made from common murine, rabbit or human IgG with four chains. The process is similar, comprising gene libraries from immunized or naïve donors and display techniques for identification of the most specific antigens. A problem with this approach is that the binding region of common IgG consists of two domains (VH and VL), which tend to dimerize or aggregate because of their lipophilicity. Monomerization is usually accomplished by replacing lipophilic by hydrophilic amino acids, but often results in a loss of affinity to the antigen. If affinity can be retained, the single-domain antibodies can likewise be produced in E. coli, S. cerevisiae or other organisms.
=== From human single-domain antibodies ===
Humans occasionally produce single domain antibodies by the random creation of a stop codon in the light chain. Human single-domain antibodies targeting various tumor antigens including mesothelin, GPC2 and GPC3 were isolated by phage display. The HN3 human single-domain antibodies have been used to create immunotoxins and chimeric antigen receptor (CAR) T cells for treating liver cancer. Blocking the Wnt binding domain of GPC3 by the HN3 human single-domain antibody inhibits Wnt activation in liver cancer cells.
== Potential applications ==
Single-domain antibodies allow a broad range of applications in biotechnical as well as therapeutic use due to their small size, simple production and high affinity.
=== Biotechnological and diagnostic ===
The fusion of a fluorescent protein to a Nanobody generates a so-called chromobody. Chromobodies can be used to recognize and trace targets in different compartments of living cells. They can therefore increase the possibilities of live cell microscopy and will enable novel functional studies. The coupling of an anti-GFP Nanobody to a monovalent matrix, called GFP-nanotrap, allows the isolation of GFP-fusion proteins and their interacting partners for further biochemical analyses. Single molecule localization with super-resolution imaging techniques requires the specific delivery of fluorophores into close proximity with a target protein. Due to their large size the use of antibodies coupled to organic dyes can often lead to a misleading signal owing to the distance between the fluorophore and the target protein. The fusion of organic dyes to anti-GFP Nanobodies targeting GFP-tagged proteins allows nanometer spatial resolution and minimal linkage error because of the small size and high affinity. The size dividend of Nanobodies also benefits the correlative light-electron microscopy study. Without any permeabilization agent, the cytoplasm of the chemically fixed cells are readily accessible to the fluorophore tagged Nanobodies. Their small size also allows them to penetrate deeper into volumetric samples than regular antibodies. High ultrastructural quality is preserved in the tissue that is imaged by fluorescence microscope and then electron microscope. This is especially useful for the neuroscience research that requires both molecular labeling and electron microscopic imaging.
In diagnostic biosensor applications Nanobodies may be used prospectively as a tool. Due to their small size, they can be coupled more densely on biosensor surfaces. In addition to their advantage in targeting less accessible epitopes, their conformational stability also leads to higher resistance to surface regeneration conditions. After immobilizing single-domain antibodies on sensor surfaces sensing human prostate-specific antigen (hPSA) were tested. The Nanobodies outperformed the classical antibodies in detecting clinical significant concentrations of hPSA.
To increase the crystallization probability of a target molecule, Nanobodies can be used as crystallization chaperones. As auxiliary proteins, they can reduce the conformational heterogeneity by binding and stabilizing just a subset of conformational states. They also can mask surfaces interfering with the crystallization while extending regions that form crystal contacts.
=== Therapeutic ===
Single-domain antibodies have been tested as a new therapeutic tool against multiple targets. In mice infected with influenza A virus subtype H5N1, Nanobodies directed against hemaglutinin suppressed replication of the H5N1 virus in vivo and reduced morbidity and mortality. Nanobodies targeting the cell receptor binding domain of the virulence factors toxin A and toxin B of Clostridioides difficile were shown to neutralize cytopathic effects in fibroblasts in vitro. Nanobody conjugates recognizing antigen presenting cells have been successfully used for tumor detection or targeted antigen delivery to generate strong immune response.
Orally available single-domain antibodies against E. coli-induced diarrhoea in piglets have been developed and successfully tested. Other diseases of the gastrointestinal tract, such as inflammatory bowel disease and colon cancer, are also possible targets for orally available single-domain antibodies.
Detergent-stable species targeting a surface protein of Malassezia furfur have been engineered for use in anti-dandruff shampoos.
As an approach for photothermal therapy Nanobodies binding to the HER2 antigen, which is overexpressed in breast and ovarian cancer cells, were conjugated to branched gold nanoparticles (see figure). Tumor cells were destroyed photothermally using a laser in a test environment.
Caplacizumab, a single-domain antibody targeting von Willebrand factor is in clinical trials for the prevention of thrombosis in patients with acute coronary syndrome. A Phase II study examining ALX-0081 in high risk percutaneous coronary intervention has started in September 2009.
Ablynx expects that their Nanobodies might cross the blood–brain barrier and permeate into large solid tumours more easily than whole antibodies, which would allow for the development of drugs against brain cancers.
Nanobodies that tightly bind to the RBD domain of the spike protein of betacoronaviruses (including SARS-CoV-2 which causes COVID-19) and blocks interactions of spike with the cell receptor ACE2, has been recently identified
Application of various single domain antibodies (Nanobodies) for the prevention and treatment of infection by various highly pathogenic human coronaviruses (HPhCoVs) has been reported. The prospects, potency and challenges of deploying Nanobodies to bind and neutralize SARS-CoV-2 and akin have been recently highlighted.
One of the most common causes of nagana – Trypanosoma brucei brucei – can be targeted by sdAbs. Stijlemans et al. 2004 succeeded in inducing effective sdAbs from rabbit and Camelus dromedarius by displaying a variable surface glycoprotein antigen to the vertebrates' immune systems using a phage. In the future, these therapies will surpass natural antibodies by reaching locations currently unreachable due to natural antibodies' larger size.
== References ==
== External links ==
Molecule of the Month: Nanobodies, from the Protein Data Bank | Wikipedia/Single-domain_antibody |
A microantibody is an artificial short chain of amino acids copied from a fully functional natural antibody. Microantibodies can stop viruses such as HIV from infecting cells in vitro.
Antibodies are produced naturally by the body and play a key role in fighting infections caused by bacteria and viruses. They can also be used to treat infections by use of injections with blood plasma that contain large amounts of them. The use of whole, natural antibodies as medicines presents many problems: they can only be produced by live cells and this process is difficult to control on an industrial scale, they are large molecules and following administration by injection, they do not diffuse easily from the blood to the tissues and other sites of infections where they are needed.
The use of microantibodies potentially solves these problems. They can be chemically synthesized and their small size allows them to leave the blood circulation quickly and reach the sites of infections in the tissues. They are also poorly immunogenic and do not stimulate an immune response in the host. Production problems remain, but microantibodies have the potential to become an important weapon in the arsenal used to treat infections and other diseases.
== Background ==
Vaccines are used to prevent infections by stimulating the body's own immunity, which includes the production of antibodies that destroy infectious agents such as bacteria and viruses. Some infections can be prevented or treated by antibodies derived from others sources such as blood donations or monoclonal antibodies made in laboratories. This is called passive immunotherapy. However, these treatments have inherent problems; passive antibody exposes the body to foreign protein and although monoclonal antibodies can be humanized they can still invoke an immune response. However, only relatively small regions on antibody molecules are involved in the recognition and inactivation of pathogens. Microantibodies are smaller, synthetic molecules that mimic these regions but do not have the larger regions on antibodies that induce an immune response.
== Prototype ==
A microantibody has been made from a monoclonal antibody produced in mouse cells. This antibody inactivates HIV in vitro.
== See also ==
Single-domain antibody
== References == | Wikipedia/Microantibody |
Anti-neutrophil cytoplasmic antibodies (ANCAs) are a group of autoantibodies, mainly of the IgG type, against antigens in the cytoplasm of neutrophils (the most common type of white blood cell) and monocytes. They are detected as a blood test in a number of autoimmune disorders, but are particularly associated with systemic vasculitis, so called ANCA-associated vasculitides (AAV).
== ANCA IF patterns ==
Immunofluorescence (IF) on ethanol-fixed neutrophils is used to detect ANCA, although formalin-fixed neutrophils may be used to help differentiate ANCA patterns. ANCA can be divided into four patterns when visualised by IF; cytoplasmic ANCA (c-ANCA), C-ANCA (atypical), perinuclear ANCA (p-ANCA) and atypical ANCA (a-ANCA), also known as x-ANCA. c-ANCA shows cytoplasmic granular fluorescence with central interlobular accentuation. C-ANCA (atypical) shows cytoplasmic staining that is usually uniform and has no interlobular accentuation. p-ANCA has three subtypes, classical p-ANCA, p-ANCA without nuclear extension and granulocyte specific-antinuclear antibody (GS-ANA). Classical p-ANCA shows perinuclear staining with nuclear extension, p-ANCA without nuclear extension has perinuclear staining without nuclear extension and GS-ANA shows nuclear staining on granulocytes only. a-ANCA often shows combinations of both cytoplasmic and perinuclear staining.
== ANCA antigens ==
The c-ANCA antigen is specifically proteinase 3 (PR3). p-ANCA antigens include myeloperoxidase (MPO) and bacterial permeability increasing factor Bactericidal/permeability-increasing protein (BPI). Other antigens exist for c-ANCA (atypical), however many are as yet unknown. Classical p-ANCA occurs with antibodies directed to MPO. p-ANCA without nuclear extension occurs with antibodies to BPI, cathepsin G, elastase, lactoferrin and lysozyme. GS-ANA are antibodies directed to granulocyte specific nuclear antigens. Atypical ANCA are thought to be antigens similar to that of the p-ANCAs, however may occur due to differences in neutrophil processing.
Other less common antigens include HMG1 (p-ANCA pattern), HMG2 (p-ANCA pattern), alpha enolase (p and c-ANCA pattern), catalase (p and c-ANCA pattern), beta glucuronidase (p-ANCA pattern), azurocidin (p and c-ANCA pattern), actin (p and a-ANCA) and h-lamp-2 (c-ANCA).
== ELISA ==
Enzyme-linked immunosorbent assay (ELISA) is used in diagnostic laboratories to detect ANCAs. Although IF can be used to screen for many ANCAs, ELISA is used to detect antibodies to individual antigens. The most common antigens used on an ELISA microtitre plate are MPO and PR3, which are usually tested for after a positive IF test.
== Development ==
It is poorly understood how ANCA are developed, although several hypotheses have been suggested. There is probably a genetic contribution, particularly in genes controlling the level of immune response – although genetic susceptibility is likely to be linked to an environmental factor, some possible factors including vaccination or exposure to silicates. Two possible mechanisms of ANCA development are postulated, although neither of these theories answers the question of how the different ANCA specificities are developed, and there is much research still being undertaken on the development of ANCA.
=== Theory of molecular mimicry ===
Microbial superantigens are molecules expressed by bacteria and other microorganisms that have the power to stimulate a strong immune response by activation of T-cells. These molecules generally have regions that resemble self-antigens that promote a residual autoimmune response – this is the theory of molecular mimicry. Staphylococcal and streptococcal superantigens have been characterized in autoimmune diseases – the classical example in post group A streptococcal rheumatic heart disease, where there is similarity between M proteins of Streptococcus pyogenes to cardiac myosin and laminin. It has also been shown that up to 70% of patients with granulomatosis with polyangiitis are chronic nasal carriers of Staphylococcus aureus, with carriers having an eight times increased risk of relapse. This would therefore be considered a type II hypersensitivity reaction.
=== Theory of defective apoptosis ===
Neutrophil apoptosis, or programmed cell death, is vital in controlling the duration of the early inflammatory response, thus restricting damage to tissues by the neutrophils. ANCA may be developed either via ineffective apoptosis or ineffective removal of apoptotic cell fragments, leading to the exposure of the immune system to molecules normally sequestered inside the cells. This theory solves the paradox of how it could be possible for antibodies to be raised against the intracellular antigenic targets of ANCA.
== Role in disease ==
=== Disease associations ===
ANCAs are associated with small vessel vasculitides including granulomatosis with polyangiitis, microscopic polyangiitis, primary pauci-immune necrotizing crescentic glomerulonephritis (a type of renal-limited microscopic polyangiitis), eosinophilic granulomatosis with polyangiitis and drug induced vasculitides. ANCA-associated vasculitides (AAV) have new classification criteria, updated in 2022.
PR3 directed c-ANCA is present in 80-90% of granulomatosis with polyangiitis, 20-40% of microscopic polyangiitis, 20-40% of pauci-immune crescentic glomerulonephritis and 35% of eosinophilic granulomatosis with polyangiitis. c-ANCA (atypical) is present in 80% of cystic fibrosis (with BPI as the target antigen) and also in inflammatory bowel disease, primary sclerosing cholangitis and rheumatoid arthritis (with antibodies to multiple antigenic targets). p-ANCA with MPO specificity is found in 50% of microscopic polyangiitis, 50% of primary pauci-immune necrotizing crescentic glomerulonephritis and 35% of eosinophilic granulomatosis with polyangiitis. p-ANCA with specificity to other antigens are associated with inflammatory bowel disease, rheumatoid arthritis, drug-induced vasculitis, autoimmune liver disease, drug induced syndromes and parasitic infections. Atypical ANCA is associated with drug-induced systemic vasculitis, inflammatory bowel disease and rheumatoid arthritis. The ANCA-positive rate is much higher in patients with type 1 diabetes mellitus than in healthy individuals.
Levamisole, which is a common adulterant of cocaine, can cause an ANCA positive vasculitis.
The presence or absence of ANCA cannot indicate presence or absence of disease and results are correlated with clinical features. The association of ANCA and disease activity remains controversial; however, the reappearance of ANCA after treatment can indicate a relapse.
=== Pathogenesis ===
Although the pathogenic role of ANCA is still controversial, in vitro and animal models support the idea that the antibodies have a direct pathological role in the formation of small vessel vasculitides. MPO and PR3 specific ANCA can activate neutrophils and monocytes through their Fc and Fab'2 receptors, which can be enhanced by cytokines which cause neutrophils to display MPO and PR3 on their surface. Aberrant glycosylation of the MPO and PR3 specific ANCA enhances their ability to interact with activating Fc receptors on neutrophils. The activated neutrophils can then adhere to endothelial cells where degranulation occurs. This releases free oxygen radicals and lytic enzymes, resulting in damage to the endothelium via the induction of necrosis and apoptosis. Furthermore, neutrophils release chemoattractive signalling molecules that recruit more neutrophils to the endothelium, acting as a positive feedback loop. Animal models have shown that MPO antibodies can induce necrotizing crescentic glomerulonephritis and systemic small vessel vasculitis. In these animal models the formation of glomerulonephritis and vasculitis can occur in the absence of T-cells, however neutrophils must be present. Although ANCA titres have been noted to have limited correlation with disease activity, except for kidney disease, and with risk of relapse, this is explained by differences in the epitopes and affinity of ANCAs. ANCAs induce excess activation of neutrophils, resulting in the production of neutrophil extracellular traps (NETs), which cause damage to small blood vessels. In addition, in patients with active disease, treated with Rituximab, an anti-CD20 antibody which remove circulating B-cells, clinical remission correlates more to the decreasing number of circulating B-cells than decrease in ANCA titre, which in some patient does not change during treatment. The same study found that clinical relapse in some patients were in association with the return of circulating B-cells. Based on the above observations and that ANCA reactive B-cells can be found in circulation in patients with AAV, an alternative hypothesis have been proposed assigning a direct pathogenic role of these cells, whereby activated neutrophils and ANCA-reactive B-cells engage in intercellular cross-talk, which leads not only to neutrophil degranulation and inflammation but also to the proliferation and differentiation of ANCA-reactive B-cells. However, this hypothesis remains to be tested.
=== Treatment ===
Avacopan was approved for medical use in the United States to treat anti-neutrophil cytoplasmic autoantibody-associated vasculitis in October 2021.
== History ==
ANCAs were originally described in Davies et al. in 1982 in segmental necrotising glomerulonephritis. The Second International ANCA Workshop, held in The Netherlands in May 1989, fixed the nomenclature on perinuclear vs. cytoplasmic patterns, and the antigens MPO and PR3 were discovered in 1988 and 1989, respectively. International ANCA Workshops have been carried out every two years.
== References ==
== External links ==
images of pANCA and cANCA Archived 2012-09-27 at the Wayback Machine
fluorescence images of ANCA Archived 2007-03-26 at the Wayback Machine
Anti-Neutrophil+Cytoplasmic+Antibody at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Anti-neutrophil_cytoplasmic_antibody |
Antinuclear antibodies (ANAs, also known as antinuclear factor or ANF) are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human proteins (autoantigens). In some cases, antibodies to human antigens are produced; these are known as autoantibodies.
There are many subtypes of ANAs such as anti-Ro antibodies, anti-La antibodies, anti-Sm antibodies, anti-nRNP antibodies, anti-Scl-70 antibodies, anti-dsDNA antibodies, anti-histone antibodies, antibodies to nuclear pore complexes, anti-centromere antibodies and anti-sp100 antibodies. Each of these antibody subtypes binds to different proteins or protein complexes within the nucleus. They are found in many disorders including autoimmunity, cancer and infection, with different prevalences of antibodies depending on the condition. This allows the use of ANAs in the diagnosis of some autoimmune disorders, including systemic lupus erythematosus, Sjögren syndrome, scleroderma, mixed connective tissue disease, polymyositis, dermatomyositis, autoimmune hepatitis and drug-induced lupus.
The ANA test detects the autoantibodies present in an individual's blood serum. The common tests used for detecting and quantifying ANAs are indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA). In immunofluorescence, the level of autoantibodies is reported as a titre. This is the highest dilution of the serum at which autoantibodies are still detectable. Positive autoantibody titres at a dilution equal to or greater than 1:160 are usually considered as clinically significant. Positive titres of less than 1:160 are present in up to 20% of the healthy population, especially the elderly. Although positive titres of 1:160 or higher are strongly associated with autoimmune disorders, they are also found in 5% of healthy individuals. Autoantibody screening is useful in the diagnosis of autoimmune disorders and monitoring levels helps to predict the progression of disease. A positive ANA test is seldom useful if other clinical or laboratory data supporting a diagnosis are not present.
== Immunity and autoimmunity ==
The human body has many defense mechanisms against pathogens, one of which is humoral immunity. This defence mechanism produces antibodies (large glycoproteins) in response to an immune stimulus. Many cells of the immune system are required for this process, including lymphocytes (T-cells and B-cells) and antigen presenting cells. These cells coordinate an immune response upon the detection of foreign proteins (antigens), producing antibodies that bind to these antigens. In normal physiology, lymphocytes that recognise human proteins (autoantigens) either undergo programmed cell death (apoptosis) or become non-functional. This self-tolerance means that lymphocytes should not incite an immune response against human cellular antigens. Sometimes, however, this process malfunctions and antibodies are produced against human antigens, which may lead to autoimmune disease.
== ANA subtypes ==
ANAs are found in many disorders, as well as some healthy individuals. These disorders include: systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren syndrome, scleroderma, polymyositis, dermatomyositis, primary biliary cirrhosis, drug induced lupus, autoimmune hepatitis, multiple sclerosis, discoid lupus, thyroid disease, antiphospholipid syndrome, juvenile idiopathic arthritis, psoriatic arthritis, juvenile dermatomyositis, idiopathic thrombocytopaenic purpura, infection and cancer. These antibodies can be subdivided according to their specificity, and each subset has different propensities for specific disorders.
=== Extractable nuclear antigens ===
Extractable nuclear antigens (ENA) are a group of autoantigens that were originally identified as antibody targets in people with autoimmune disorders. They are termed ENA because they can be extracted from the cell nucleus with saline. The ENAs consist of ribonucleoproteins and non-histone proteins, named by either the name of the donor who provided the prototype serum (Sm, Ro, La, Jo), or the name of the disease setting in which the antibodies were found (SS-A, SS-B, Scl-70).
==== Anti-Ro/SS-A and anti-La/SS-B ====
Anti-Ro and anti-La antibodies, also known as SS-A and SS-B, respectively, are commonly found in primary Sjögren's syndrome, an autoimmune disorder that affects the exocrine glands. The presence of both antibodies is found in 30–60% of Sjögren's syndrome, anti-Ro antibodies alone are found in 50–70% of Sjögren's syndrome and 30% of SLE with cutaneous involvement, and anti-La antibodies are rarely found in isolation. Anti-La antibodies are also found in SLE; however, Sjögren's syndrome is normally also present. Anti-Ro antibodies are also found less frequently in other disorders including autoimmune liver diseases, coeliac disease, autoimmune rheumatic diseases, cardiac neonatal lupus erythematosus and polymyositis. During pregnancy, anti-Ro antibodies can cross the placenta and cause heart block and neonatal lupus in babies. In Sjögren's syndrome, anti-Ro and anti-La antibodies correlate with early onset, increased disease duration, parotid gland enlargement, disease outside the glands and infiltration of glands by lymphocytes. Anti-Ro antibodies are specific to components of the Ro-RNP complex, comprising 45kDa, 52kDa, 54kDa and 60kDa proteins and RNA. The 60kDa DNA/RNA binding protein and 52kDa T-cell regulatory protein are the best characterised antigens of anti-Ro antibodies. Collectively, these proteins are part of a ribonucleoprotein (RNP) complex that associate with the human Y RNAs, hY1-hY5. The La antigen is a 48kDa transcription termination factor of RNA polymerase III, which associates with the Ro-RNP complex.
The mechanism of antibody production in Sjögren's syndrome is not fully understood, but apoptosis (programmed cell death) and molecular mimicry may play a role. The Ro and La antigens are expressed on the surface of cells undergoing apoptosis and may cause the inflammation within the salivary gland by interaction with cells of the immune system. The antibodies may also be produced through molecular mimicry, where cross reactive antibodies bind to both virus and human proteins. This may occur with one of the antigens, Ro or La, and may subsequently produce antibodies to other proteins through a process known as epitope spreading. The retroviral gag protein shows similarity to the La protein and is proposed as a possible example for molecular mimicry in Sjögren's syndrome.
==== Anti-Sm ====
Anti-Smith (Anti-Sm) antibodies are a very specific marker for SLE. Approximately 99% of individuals without SLE lack anti-Sm antibodies, but only 20% of people with SLE have the antibodies. They are associated with central nervous system involvement, kidney disease, lung fibrosis and pericarditis in SLE, but they are not associated with disease activity. The antigens of the anti-Sm antibodies are the core units of the small nuclear ribonucleoproteins (snRNPs), termed A to G, and will bind to the U1, U2, U4, U5 and U6 snRNPs. Most commonly, the antibodies are specific for the B, B' and D units. Molecular and epidemiological studies suggest that anti-Sm antibodies may be induced by molecular mimicry because the protein shows some similarity to Epstein-Barr virus proteins.
==== Anti-nRNP/anti-U1-RNP ====
Anti-nuclear ribonucleoprotein (anti-nRNP) antibodies, also known as anti-U1-RNP antibodies, are found in 30–40% of SLE. They are often found with anti-Sm antibodies, but they may be associated with different clinical associations. In addition to SLE, these antibodies are highly associated with mixed connective tissue disease. Anti-nRNP antibodies recognise the A and C core units of the snRNPs and because of this they primarily bind to the U1-snRNP. The immune response to RNP may be caused by the presentation of the nuclear components on the cell membrane in apoptotic blebs. Molecular mimicry has also been suggested as a possible mechanism for the production of antibodies to these proteins because of similarity between U1-RNP polypeptides and Epstein-Barr virus polypeptides.
==== Anti-Scl-70/anti-topoisomerase I ====
Anti-Scl-70 antibodies are linked to scleroderma. The sensitivity of the antibodies for scleroderma is approximately 34%, but is higher for cases with diffuse cutaneous involvement (40%), and lower for limited cutaneous involvement (10%). The specificity of the antibodies is 98% and 99.6% in other rheumatic diseases and normal individuals, respectively. In addition to scleroderma, these antibodies are found in approximately 5% of individuals with SLE. The antigenic target of anti-Scl-70 antibodies is topoisomerase I.
==== Anti-Jo-1 ====
Although anti-Jo-1 antibodies are often included with ANAs, they are actually antibodies to the cytoplasmic protein, Histidyl-tRNA synthetase – an aminoacyl-tRNA synthetase essential for the synthesis of histidine loaded tRNA. They are highly associated with polymyositis and dermatomyositis, and are rarely found in other connective tissue diseases. Around 20–40% of polymyositis is positive for Jo-1 antibodies and most will have interstitial lung disease, HLA-DR3 and HLA-DRw52 human leukocyte antigen (HLA) markers; collectively known as Jo-1 syndrome.
=== Anti-dsDNA ===
Anti-double stranded DNA (anti-dsDNA) antibodies are highly associated with SLE. They are a very specific marker for the disease, with some studies quoting nearly 100%. Data on sensitivity ranges from 25 to 85%. Anti-dsDNA antibody levels, known as titres, correlate with disease activity in SLE; high levels indicate more active lupus. The presence of anti-dsDNA antibodies is also linked with lupus nephritis and there is evidence they are the cause. Some anti-dsDNA antibodies are cross reactive with other antigens found on the glomerular basement membrane (GBM) of the kidney, such as heparan sulphate, collagen IV, fibronectin and laminin. Binding to these antigens within the kidney could cause inflammation and complement fixation, resulting in kidney damage. Presence of high DNA-binding and low C3 levels have been shown to have extremely high predictive value (94%) for the diagnosis of SLE. It is also possible that the anti-dsDNA antibodies are internalised by cells when they bind membrane antigens and then are displayed on the cell surface. This could promote inflammatory responses by T-cells within the kidney. It is important to note that not all anti-dsDNA antibodies are associated with lupus nephritis and that other factors can cause this symptom in their absence. The antigen of anti-dsDNA antibodies is double stranded DNA.
=== Anti-histone antibodies ===
Anti-histone antibodies are found in the serum of up to 75–95% of people with drug-induced lupus and 75% of idiopathic SLE. Unlike anti-dsDNA antibodies in SLE, these antibodies do not fix complement. Although they are most commonly found in drug induced lupus, they are also found in some cases of SLE, scleroderma, rheumatoid arthritis and undifferentiated connective tissue disease. Many drugs are known to cause drug induced lupus and they produce various antigenic targets within the nucleosome that are often cross reactive with several histone proteins and DNA. Procainamide causes a form of drug-induced lupus that produces antibodies to the histone H2A and H2B complex.
=== Anti-gp210 and anti-p62 ===
Both anti-glycoprotein-210 (anti-gp210) and anti-nucleoporin 62 (anti-p62) antibodies are antibodies to components of the nuclear membrane and are found in primary biliary cirrhosis (PBC). Each antibody is present in approximately 25–30% of PBC. The antigens of both antibodies are constituents of the nuclear membrane. gp210 is a 200kDa protein involved in anchoring components of the nuclear pore to the nuclear membrane. The p62 antigen is a 60kDa nuclear pore complex.
=== Anti-centromere antibodies ===
Anti-centromere antibodies are associated with limited cutaneous systemic sclerosis, also known as CREST syndrome, primary biliary cirrhosis and proximal scleroderma. There are six known antigens, which are all associated with the centromere; CENP-A to CENP-F. CENP-A is a 17kDa histone H3-like protein. CENP-B is an 80kDa DNA binding protein involved in the folding of heterochromatin. CENP-C is a 140kDa protein involved in kinetochore assembly. CENP-D is a 50kDa protein of unknown function, but may be homologous to another protein involved in chromatin condensation, RCC1. CENP-E is a 312kDa protein from the kinesin motor protein family. CENP-F is a 367kDa protein from the nuclear matrix that associates with the kinetochore in late G2 phase during mitosis. CENP-A, B and C antibodies are most commonly found (16–42% of systemic sclerosis) and are associated with Raynaud's phenomenon, telangiectasias, lung involvement and early onset in systemic sclerosis.
Anti-centromere antibodies are found in approximately 60% of patients with limited systemic scleroderma and in 15% of those with the diffuse form of scleroderma. The specificity of this test is >98%. Thus, a positive anti-centromere antibody finding is strongly suggestive of limited systemic scleroderma. Anti-centromere antibodies present early in the course of disease and are notably predictive of limited cutaneous involvement and a decreased likelihood of aggressive internal organ involvement, such as fibrosis in the lungs.
When present in primary biliary cirrhosis, ACAs are prognostic of portal hypertension such that serum ACA levels correlate with the severity of portal hypertension.
=== Anti-sp100 ===
Anti-sp100 antibodies are found in approximately 20–30% of primary biliary cirrhosis (PBC). They are found in few individuals without PBC, and therefore are a very specific marker of the disease. The sp100 antigen is found within nuclear bodies; large protein complexes in the nucleus that may have a role in cell growth and differentiation.
=== Anti-PM-Scl ===
Anti-PM-Scl antibodies are found in up to 50% of polymyositis/systemic sclerosis (PM/SSc) overlap syndrome. Around 80% of individuals with antibodies present in their blood serum will have the disorder. The presence of the antibodies is linked to limited cutaneous involvement of PM/SSc overlap syndrome. The antigenic targets of the antibodies are components of the RNA-processing exosome complex in the nucleolus. There are ten proteins in this complex and antibodies to eight of them are found at varying frequencies; PM/Scl-100 (70–80%), PM/Scl-75 (46–80%), hRrp4 (50%), hRrp42 (21%), hRrp46 (18%), hCs14 (14%), hRrp41 (10%) and hRrp40 (7%).
=== Anti-DFS70 antibodies ===
Anti-DFS70 antibodies generate a dense fine speckled pattern in indirect immunofluorescence and are found in normals and in various conditions, but are not associated with a systemic autoimmune pathology. Therefore, they can be used to help to rule out such conditions in ANA positive individuals. A significant number of patients are diagnosed as systemic lupus erythematosus or undifferentiated connective tissue disease largely based on a positive ANA. In case no defined autoantibody can be detected (e.g. anti-ENA antibodies), the testing of anti-DFS70 antibodies is recommended to verify the diagnosis. Anti-DFS70 antibody tests are available as CE-marked tests. Until now, no FDA cleared assay is available.
== ANA test ==
The presence of ANAs in blood can be confirmed by a screening test. Although there are many tests for the detection of ANAs, the most common tests used for screening are indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Following detection of ANAs, various subtypes are determined.
=== Indirect immunofluorescence ===
Indirect immunofluorescence is one of the most commonly used tests for ANAs. Typically, HEp-2 cells are used as a substrate to detect the antibodies in human serum. Microscope slides are coated with HEp-2 cells and the serum is incubated with the cells. If the said and targeted antibodies are present then they will bind to the antigens on the cells; in the case of ANAs, the antibodies will bind to the nucleus. These can be visualised by adding a fluorescent tagged (usually FITC or rhodopsin B) anti-human antibody that binds to the antibodies. The molecule will fluoresce when a specific wavelength of light shines on it, which can be seen under the microscope. Depending on the antibody present in the human serum and the localisation of the antigen in the cell, distinct patterns of fluorescence will be seen on the HEp-2 cells. Levels of antibodies are analysed by performing dilutions on blood serum. An ANA test is considered positive if fluorescence is seen at a titre of 1:40/1:80. Higher titres are more clinically significant as low positives (≤1:160) are found in up to 20% of healthy individuals, especially the elderly. Only around 5% of the healthy population have ANA titres of 1:160 or higher.
==== HEp-2 ====
Until around 1975, when HEp-2 cells were introduced, animal tissue was used as the standard substrate for immunofluorescence. HEp-2 cells are currently one of the most common substrates for ANA detection by immunofluorescence.
Originally started a laryngeal carcinoma strain, the cell line was contaminated and displaced by HeLa cells, and has now been identified as actually HeLa cells.
They are superior to the previously used animal tissues because of their large size and the high rate of mitosis (cell division) in the cell line. This allows the detection of antibodies to mitosis-specific antigens, such as centromere antibodies. They also allow identification of anti-Ro antibodies, because acetone is used for fixation of the cells (other fixatives can wash the antigen away).
There are many nuclear staining patterns seen on HEp-2 cells: homogeneous, speckled, nucleolar, nuclear membranous, centromeric, nuclear dot and pleomorphic. The homogeneous pattern is seen when the condensed chromosomes and interphase chromatin stain. This pattern is associated with anti-dsDNA antibodies, antibodies to nucleosomal components, and anti-histone antibodies. There are two speckled patterns: fine and coarse. The fine speckled pattern has fine nuclear staining with unstained metaphase chromatin, which is associated with anti-Ro and anti-La antibodies. The coarse staining pattern has coarse granular nuclear staining, caused by anti-U1-RNP and anti-Sm antibodies. The nucleolar staining pattern is associated with many antibodies including anti-Scl-70, anti-PM-Scl, anti-fibrillarin and anti-Th/To. Nuclear membrane staining appears as a fluorescent ring around the cell nucleus and are produced by anti-gp210 and anti-p62 antibodies. The centromere pattern shows multiple nuclear dots in interphase and mitotic cells, corresponding to the number of chromosomes in the cell. Nuclear dot patterns show between 13 and 25 nuclear dots in interphase cells and are produced by anti-sp100 antibodies. Pleomorphic pattern is caused by antibodies to the proliferating cell nuclear antigen. Indirect immunofluorescence has been shown to be slightly superior compared to ELISA in detection of ANA from HEp-2 cells.
==== Crithidia luciliae ====
Crithidia luciliae are haemoflaggelate single celled protists. They are used as a substrate in immunofluorescence for the detection of anti-dsDNA antibodies. They possess an organelle known as the kinetoplast which is a large mitochondrion with a network of interlocking circular dsDNA molecules. After incubation with serum containing anti-dsDNA antibodies and fluorescent-labelled anti-human antibodies, the kinetoplast will fluoresce. The lack of other nuclear antigens in this organelle means that using C. luciliae as a substrate allows for the specific detection of anti-dsDNA antibodies.
=== ELISA ===
Enzyme-linked immunosorbent assay (ELISA) uses antigen-coated microtitre plates for the detection of ANAs. Each well of a microtitre plate is coated with either a single antigen or multiple antigens to detect specific antibodies or to screen for ANAs, respectively. The antigens are either from cell extracts or recombinant. Blood serum is incubated in the wells of the plate and is washed out. If antibodies that bind to antigen are present then they will remain after washing. A secondary anti-human antibody conjugated to an enzyme such as horseradish peroxidase is added. The enzyme reaction will produce a change in colour of the solution that is proportional to the amount of antibody bound to the antigen. There are significant differences in the detection of ANA by immunofluorescence and different ELISA kits and there is only a marginal agreement between these. A clinician must be familiar with the differences in order to evaluate the outcomes of the various assays.
=== Sensitivity ===
The following table lists the sensitivity of different types of ANAs for different diseases.
Some ANAs appear in several types of disease, resulting in lower specificity of the test. For example, IgM-rheumatoid factor (IgM-RF) have been shown to cross-react with ANA giving falsely positive immunofluorescence. Positive ANA as well as anti-DNA antibodies have been reported in patients with autoimmune thyroid disease. ANA can have a positive test result in up to 45% of people with autoimmune thyroid conditions or rheumatoid arthritis and up to 15% of people with HIV or hepatitis C. As per Lupus Foundation of America, "about 5% of the general population will have a positive ANA. However, at least 95% of the people who have a positive ANA do not have lupus. A positive ANA test can sometimes run in families, even if family members have no evidence of lupus." On the other hand, they say, although 95% of the patients who actually have lupus test positive for ANA, "Only a small percentage have a negative ANA, and many of those have other antibodies (such as anti-phospholipid antibodies, anti-Ro, anti-SSA) or their ANA converted from positive to negative from steroids, cytotoxic medications, or uremia (kidney failure)."
== History ==
The LE cell was discovered in bone marrow in 1948 by Hargraves et al. In 1957 Holborow et al. first demonstrated ANA using indirect immunofluorescence. This was the first indication that processes affecting the cell nucleus were responsible for SLE. In 1959 it was discovered that serum from individuals with SLE contained antibodies that precipitated with saline extracts of nuclei, known as extractable nuclear antigens (ENAs). This led to the characterisation of ENA antigens and their respective antibodies. Thus, anti-Sm and anti-RNP antibodies were discovered in 1966 and 1971, respectively. In the 1970s, the anti-Ro/anti-SS-A and anti-La/anti-SS-B antibodies were discovered. The Scl-70 antibody was known to be a specific antibody to scleroderma in 1979, however the antigen (topoisomerase-I) was not characterised until 1986. The Jo-1 antigen and antibody were characterised in 1980.
== See also ==
Anti-neutrophil cytoplasmic antibody (ANCA)
Rheumatoid factor
== References ==
== External links ==
Autoimmunityblog – HEp-2 ANA summary
Antinuclear+antibodies at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Greidinger EL, Hoffman, DO, Robert W. (31 January 2003). "CE update [chemistry | immunology]: Antinuclear Antibody Testing: Methods, Indications, and Interpretation". Laboratory Medicine. 34 (2): 113–117. doi:10.1309/VUB90VTPMEWV3W0F. | Wikipedia/Anti-nuclear_antibody |
The immune network theory is a theory of how the adaptive immune system works, that has been developed since 1974 mainly by Niels Jerne and Geoffrey W. Hoffmann. The theory states that the immune system is an interacting network of lymphocytes and molecules that have variable (V) regions. These V regions bind not only to things that are foreign to the vertebrate, but also to other V regions within the system. The immune system is therefore seen as a network, with the components connected to each other by V-V interactions.
It has been suggested that the phenomena that the theory describes in terms of networks are also explained by clonal selection theory.
The scope of the symmetrical network theory developed by Hoffmann includes the phenomena of low dose and high dose tolerance, first reported for a single antigen by Avrion Mitchison, and confirmed by Geoffrey Shellam and Sir Gustav Nossal, the helper and suppressor roles of T cells, the role of non-specific accessory cells in immune responses, and the very important phenomenon called I-J. Jerne was awarded the Nobel Prize for Medicine or Physiology in 1984 partly for his work towards the clonal selection theory, as well as his proposal of the immune network concept.
The immune network theory has also inspired a subfield of optimization algorithms similar to artificial neural networks.
== The symmetrical immune network theory ==
Heinz Kohler was involved in early idiotypic network research and was the first to suggest that idiotypic network interactions are symmetrical. He developed a detailed immune network theory based on symmetrical stimulatory, inhibitory and killing interactions. It offers a framework for understanding a large number of immunological phenomena based on a small number of postulates. The theory involves roles for B cells that make antibodies, T cells that regulate the production of antibodies by B cells, and non-specific accessory cells (A cells).
Antibodies called IgG have two V regions and a molecular weight of 150,000. A central role in the theory is played by specific T cell factors, which have a molecular weight of approximately 50,000, and are postulated in the theory to have only one V region. Hoffmann has proposed that for brevity specific T cell factors should be called tabs. Tabs are able to exert a powerful suppressive effect on the production of IgG antibodies in response to foreign substances (antigens), as was demonstrated rigorously by Takemori and Tada. Hoffmann and Gorczynski have reproduced the Takemori and Tada experiment, confirming the existence of specific T cell factors. In the symmetrical network theory tabs are able to block V regions and also to have a stimulatory role when bound to a tab receptor on A cells. Symmetrical stimulatory interactions follow from the postulate that activation of B cells, T cells and A cells involves cross-linking of receptors.
The symmetrical network theory has been developed with the assistance of mathematical modeling. In order to exhibit immune memory to any combination of a large number of different pathogens, the system has a large number of stable steady states. The system is also able to switch between steady states as has been observed experimentally. For example, low or high doses of an antigen can cause the system to switch to a suppressed state for the antigen, while intermediate doses can cause the induction of immunity.
== I-J, the I-J paradox, and a resolution of the I-J paradox ==
The theory accounts for the ability of T cells to have regulatory roles in both helping and suppressing immune responses. In 1976 Murphy et al. and Tada et al. independently reported a phenomenon in mice called I-J. From the perspective of the symmetrical network theory, I-J is one of the most important phenomena in immunology, while for many immunologists who are not familiar with the details of the theory, I-J "does not exist". In practice I-J is defined by anti-I-J antibodies, that are produced when mice of certain strains are immunized with tissue of certain other strains; see Murphy et al. and Tada et al., op cit. I-J was found by these authors to map to within the Major Histocompatibility Complex, but no gene could be found at the site where I-J had been mapped in numerous experiments. The absence of I-J gene(s) within the MHC at the place where I-J had been mapped became known as the "I-J paradox". This paradox resulted in regulatory T cells and tabs, which both express I-J determinants, falling out of favour, together with the symmetrical network theory, that is based on the existence of tabs. In the meantime however, it has been shown that the I-J paradox can be resolved in the context of the symmetrical network theory.
The resolution of the I-J paradox involves a process of mutual selection (or "co-selection") of regulatory T cells and helper T cells, meaning that (a) those regulatory T cells are selected that have V regions with complementarity to as many helper T cells as possible, and (b) helper T cells are selected not only on the basis of their V regions having some affinity for MHC class II, but also on the basis of the V regions having some affinity for the selected regulatory T cell V regions. The helper T cells and regulatory T cells that are co-selected are then a mutually stabilizing construct, and for a given mouse genome, more than one such mutually stabilizing set can exist. This resolution of the I-J paradox leads to some testable predictions.
However, considering the importance of the (unfound) I-J determinant for the theory, the I-J paradox solution is still subject to strong criticism, e.g.Falsifiability.
== Relevance for understanding HIV pathogenesis ==
An immune network model for HIV pathogenesis was published in 1994 postulating that HIV-specific T cells are preferentially infected (Hoffmann, 1994, op cit.). The publication of this paper was followed in 2002 with the publication of a paper entitled "HIV preferentially infects HIV specific CD4+ T cells."
Under the immune network theory, the main cause for progression to AIDS after HIV infection is not the direct killing of infected T helper cells by the virus. Following an infection with HIV that manages to establish itself, there is a complex interaction between the HIV virus, the T helper cells that it infects, and regulatory T cells. These three quasispecies apply selective pressure on one another and co-evolve in such a way that the viral epitopes eventually come to mimick the V regions of the main population of T regulatory cells. Once this happens, anti-HIV antibodies can bind to and kill most of the host's T regulatory cell population. This results in the dysregulation of the immune system, and eventually to other further anti-self reactions, including against the T helper cell population. At that point, the adaptive immune system is completely compromised and AIDS ensues. Hence in this model, the onset of AIDS is primarily an auto-immune reaction triggered by the cross-reaction of anti-HIV antibodies with T regulatory cells. Once this induced auto-immunity sets in, removing the HIV virus itself (for instance via HAART) would not be sufficient to restore proper immune function. The co-evolution of the quasispecies mentioned above will take a variable time depending on the initial conditions at the time of infection (i.e. the epitopes of the first infection and the steady state of the host's immune cell population), which would explain why there is a variable period, which differs greatly between individual patients, between HIV infection and the onset of AIDS. It also suggests that conventional vaccines are unlikely to be successful, since they would not prevent the auto-immune reaction. In fact such vaccines may do more harm in certain cases, since if the original infection comes from a source with a "mature" infection, those virions will have a high affinity for anti-HIV T helper cells (see above), and so increasing the anti-HIV population via vaccination only serves to provide the virus with more easy targets.
== An HIV vaccine concept based on immune network theory ==
A hypothetical HIV vaccine concept based on immune network theory has been described. The vaccine concept was based on a network theory resolution of the Oudin-Cazenave paradox. This is a phenomenon that makes no sense in the context of clonal selection, without taking idiotypic network interactions into account. The vaccine concept comprised complexes of an anti-anti-HIV antibody and an HIV antigen, and was designed to induce the production of broadly neutralizing anti-HIV antibodies. A suitable anti-anti-HIV antibody envisaged for use in this vaccine is the monoclonal antibody 1F7, which was discovered by Sybille Muller and Heinz Kohler and their colleagues. This monoclonal antibody binds to all of six well characterized broadly neutralizing anti-HIV antibodies.
== A more general vaccine based on immune network theory ==
A vaccine concept based on a more recent extension of immune network theory and also based on much more data has been described by Reginald Gorczynski and Geoffrey Hoffmann. The vaccine typically involves three immune systems, A, B and C that can be combined to make an exceptionally strong immune system in a treated vertebrate C. In mouse models the vaccine has been shown to be effective in the prevention of inflammatory bowel disease; the prevention of tumour growth and prevention of metastases in a transplantable breast cancer; and in the treatment of an allergy. The immune system of C is stimulated by a combination of A anti-B (antigen-specific) and B anti-anti-B (antiidiotypic) antibodies. The former stimulate anti-anti-B T cells and the latter stimulate anti-B T cells within C. Mutual selection ("co-selection") of the anti-B and anti-anti-B T cells takes the system to a new stable steady state in which there are elevated levels of these two populations of T cells. An untreated vertebrate C with self antigens denoted C is believed to have a one-dimensional axis of lymphocytes that is defined by co-selection of anti-C and anti-anti-C lymphocytes. The treated vertebrate C has a two dimensional system of lymphocytes defined by co-selection of both anti-C and anti-anti-C lymphocytes and co-selection of anti-B and anti-anti-B lymphocytes. Experiments indicate that the two-dimensional system is more stable than the one-dimensional system.
== References ==
== Further reading ==
G. W. Hoffmann (2010). "An improved version of the symmetrical immune network theory". arXiv:1004.5107 [nlin.AO].
Parisi G (1990). "A simple model for the immune network". Proc. Natl. Acad. Sci. USA. 87 (1): 429–433. Bibcode:1990PNAS...87..429P. doi:10.1073/pnas.87.1.429. PMC 53277. PMID 2296597.
A. Osterhaus; F. Uytdehaag, eds. (1990). Idiotype Networks in Biology and Medicine. Elsevier Science Publishers B.V. p. 310. ISBN 978-0-444-81343-5.
Cohen, I. Bernard; Atlan, Henri; Cohen, Irun R. (1989). Theories of immune networks. Berlin: Springer-Verlag. ISBN 978-0-387-51678-3. | Wikipedia/Immune_network_theory |
A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer can be assembled as dimer of dimers with two homodimer subunits (such as sorbitol dehydrogenase), or two heterodimer subunits (such as hemoglobin).
== Subunit interactions in tetramers ==
The interactions between subunits forming a tetramer is primarily determined by non covalent interaction. Hydrophobic effects, hydrogen bonds and electrostatic interactions are the primary sources for this binding process between subunits. For homotetrameric proteins such as sorbitol dehydrogenase (SDH), the structure is believed to have evolved going from a monomeric to a dimeric and finally a tetrameric structure in evolution. The binding process in SDH and many other tetrameric enzymes can be described by the gain in free energy which can be determined from the rate of association and dissociation.
The above image shows the assembly of the four subunits (A,B,C and D) in SDH.
== Hydrogen bonds between subunits ==
Hydrogen bonding networks between subunits has been shown to be important for the stability of the tetrameric quaternary protein structure. For example, a study of SDH which used diverse methods such as protein sequence alignments, structural comparisons, energy calculations, gel filtration experiments and enzyme kinetics experiments, could reveal an important hydrogen bonding network which stabilizes the tetrameric quaternary structure in mammalian SDH.
== Tetramers in immunology ==
In immunology, MHC tetramers can be used in tetramer assays, to quantify numbers of antigen-specific T cells (especially CD8+ T cells). MHC tetramers are based on recombinant class I molecules that, through the action of bacterial BirA, have been biotinylated. These molecules are folded with the peptide of interest and β2M and tetramerized by a fluorescently labeled streptavidin. (Streptavidin binds to four biotins per molecule.) This tetramer reagent will specifically label T cells that express T cell receptors that are specific for a given peptide-MHC complex. For example, a Kb/FAPGNYPAL tetramer will specifically bind to Sendai virus specific cytotoxic T cell in a C57BL/6 mouse. Antigen specific responses can be measured as CD8+, tetramer+ T cells as a fraction of all CD8+ lymphocytes.
The reason for using a tetramer, as opposed to a single labeled MHC class I molecule is that the tetrahedral tetramers can bind to three TCRs at once, allowing specific binding in spite of the low (1 micromolar) affinity of the typical class I-peptide-TCR interaction.
MHC class II tetramers can also be made, although these are more difficult to work with practically.
== Homotetramers and heterotetramers ==
A homotetramer is a protein complex made up of four identical subunits which are associated but not covalently bound. Conversely, a heterotetramer is a 4-subunit complex where one or more subunits differ.
Examples of homotetramers include:
enzymes like beta-glucuronidase (pictured)
export factors such as SecB from Escherichia coli
magnesium ion transporters such as CorA.
lectins such as Concanavalin A
IMPDH and IMPDH2
Examples of heterotetramers include haemoglobin (pictured), the NMDA receptor, some aquaporins, some AMPA receptors, as well as some enzymes.
=== Purification of heterotetramers ===
Ion-exchange chromatography is useful for isolating specific heterotetrameric protein assemblies, allowing purification of specific complexes according to both the number and the position of charged peptide tags. Nickel affinity chromatography may also be employed for heterotetramer purification.
=== Intragenic complementation ===
Multiple copies of a polypeptide encoded by a gene often can form an aggregate referred to as a multimer. When a multimer is formed from polypeptides produced by two different mutant alleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. When a mixed multimer displays increased functionality relative to the unmixed multimers, the phenomenon is referred to as intragenic complementation. In humans, argininosuccinate lyase (ASL) is a homotetrameric enzyme that can undergo intragenic complementation. An ASL disorder in humans can arise from mutations in the ASL gene, particularly mutations that affect the active site of the tetrameric enzyme. ASL disorder is associated with considerable clinical and genetic heterogeneity which is considered to reflect the extensive intragenic complementation occurring among different individual patients.
== References ==
== External links ==
T-cell Group - Cardiff University | Wikipedia/Tetramer_protein |
Vitamin D-binding protein (DBP), also/originally known as gc-globulin (group-specific component), is a protein that in humans is encoded by the GC gene. DBP is genetically the oldest member of the albuminoid family and appeared early in the evolution of vertebrates.
== Structure ==
Human GC is a glycosylated alpha-globulin, ~58 kDa in size. Its 458 amino acids are coded for by 1690 nucleotides on chromosome 4 (4q11–q13). The primary structure contains 28 cysteine residues forming multiple disulfide bonds. GC contains 3 domains. Domain 1 is composed of 10 alpha helices, domain 2 of 9, and domain 3 of 4.
== Function ==
Vitamin D-binding protein belongs to the albumin gene family, together with human serum albumin and alpha-fetoprotein. It is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types.
It is able to bind the various forms of vitamin D including ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), the 25-hydroxylated forms (calcifediol), and the active hormonal product, 1,25-dihydroxyvitamin D (calcitriol). The major proportion of vitamin D in blood is bound to this protein. It transports vitamin D metabolites between skin, liver and kidney, and then on to the various target tissues.
As Gc protein-derived macrophage activating factor it is a Macrophage Activating Factor (MAF) that has been tested for use as a cancer treatment that would activate macrophages against cancer cells.
=== Interactive pathway map ===
== Production ==
It is synthesized by hepatic parenchymal cells and secreted into the blood circulation.
== Regulation ==
The transcription factors HFN1α is a positive regulator while HFN1β is a dominant negative regulator of DBP expression.
== Variation ==
Many genetic variants of the GC gene are known. They produce 6 main haplotypes and 3 main protein variants (Gc1S, Gc1F and Gc2). The genetic variations are associated with differences in circulating 25-hydroxyvitamin D levels. They have been proposed to account for some of the differences in vitamin D status in different ethnic groups, and have been found to correlate with the response to vitamin D supplementation.
== References ==
== Further reading ==
== External links ==
Overview of all the structural information available in the PDB for UniProt: P02774 (Vitamin D-binding protein) at the PDBe-KB. | Wikipedia/Vitamin_D-binding_protein |
Carbohydrate–protein interactions are the intermolecular and intramolecular interactions between protein and carbohydrate moieties. These interactions form the basis of specific recognition of carbohydrates by lectins. Carbohydrates are important biopolymers and have a variety of functions. Often carbohydrates serve a function as a recognition element. That is, they are specifically recognized by other biomolecules. Proteins which bind carbohydrate structures are known as lectins. Compared to the study of protein–protein and protein–DNA interaction, it is relatively recent that scientists get to know the protein–carbohydrate binding.
Many of these interactions involved carbohydrates found at the cell surface, as part of a membrane glycoprotein or glycolipid. These interactions can play a role in cellular adhesion and other cellular recognition events. Intramolecular carbohydrate–protein interactions refer to interactions between glycan and polypeptide moieties in glycoproteins or the glycosylated proteins.
== Classification ==
Generally, there are two types of protein carbohydrate binding important in biological processes: Lectin and antibody.
=== Lectin ===
Lectin is a kind of protein that can bind to carbohydrate with their carbohydrate recognition domains (CRDs). We could use different CRD to classify them.
==== C-type ====
Ca2+ is required to activate the binding. Ca2+ binds to the protein and carbohydrate by non covalent bond. Mannose-binding protein (MBP) contains the C-type CRD.
==== P-type ====
Two types mannose-6-phosphate can recognize phosphorylated saccharide. One is cation-dependent and the other does not require cation to activate.
==== I-type ====
I-type lectin named from the immunoglobulin-like domain. Sialoadhesin is one of the I-type lectin, which binds specifically to sialic acid.
=== Antibody ===
Most antibodies have the similar structure except the hypervariable region which is called the antigen binding site. This region is constituted by the combination of various amino acids. When the antigen is a kind of carbohydrate (Polysaccharide), the binding could be regarded as a protein-carbohydrate interaction.
== Biological function ==
Protein–carbohydrate interactions play an important role in biological function.
Cell adhesion
Signal Transduction
Host-Pathogen Recognition
Inflammation
Stabilization of protein structure
== Methods of study ==
X-ray crystallography
Just like other organic molecule study, X-ray crystallography is a very useful tool to know the detail information on the interaction between carbohydrate and protein.
NMR Study
By using titration, NOESY(Nuclear Overhauser Effect SpectroscopY), CIDNP experiments, the specificity and affinity of binding, association constants and equilibrium thermodynamic parameters of carbohydrate–protein binding can be studied.
Molecular Modeling
In many cases, the conformation information is required, however, sometimes it is not able to get directly from the experiments. So the knowledge-based model building approach is used.
Fluorescence Spectrometry
Fluorescence spectrometry is a useful tool and has its advantages: no procedure for separation and plenty of ways to get fluorophore source: there are some of amino acids and ligands that have fluorophore after they are activated.
Dual polarisation interferometry
Dual polarisation interferometry is a label free analytical technique for measuring interactions and associated conformational changes.
== Advances in the study of protein–carbohydrate binding ==
Microarray-Based Study by Metal Nanoparticle Probes
Recently, studies by using metal nanoparticle probes to detect the carbohydrate–protein interactions were reported. Use of gold and silver nanoparticle probes in resonant light scattering (RLS) gives particular high sensitivity. Zhenxin Wang and coworker the same principle applied this method to detect the interaction between carbohydrate and protein.
Carbohydrate biosensor
As Lectin can strongly bind to specific carbohydrate, scientists develop several lectin-based carbohydrate biosensors. Designed lectin contains specific groups can be detected by analytical method.
Isothermal Titration Calorimetry
== References == | Wikipedia/Protein–carbohydrate_interaction |
Protein sequencing is the practical process of determining the amino acid sequence of all or part of a protein or peptide. This may serve to identify the protein or characterize its post-translational modifications. Typically, partial sequencing of a protein provides sufficient information (one or more sequence tags) to identify it with reference to databases of protein sequences derived from the conceptual translation of genes.
The two major direct methods of protein sequencing are mass spectrometry and Edman degradation using a protein sequenator (sequencer). Mass spectrometry methods are now the most widely used for protein sequencing and identification but Edman degradation remains a valuable tool for characterizing a protein's N-terminus.
== Determining amino acid composition ==
It is often desirable to know the unordered amino acid composition of a protein prior to attempting to find the ordered sequence, as this knowledge can be used to facilitate the discovery of errors in the sequencing process or to distinguish between ambiguous results. Knowledge of the frequency of certain amino acids may also be used to choose which protease to use for digestion of the protein. The misincorporation of low levels of non-standard amino acids (e.g. norleucine) into proteins may also be determined. A generalized method often referred to as amino acid analysis for determining amino acid frequency is as follows:
Hydrolyse a known quantity of protein into its constituent amino acids.
Separate and quantify the amino acids in some way.
=== Hydrolysis ===
Hydrolysis is done by heating a sample of the protein in 6 M hydrochloric acid to 100–110 °C for 24 hours or longer. Proteins with many bulky hydrophobic groups may require longer heating periods. However, these conditions are so vigorous that some amino acids (serine, threonine, tyrosine, tryptophan, glutamine, and cysteine) are degraded. To circumvent this problem, Biochemistry Online suggests heating separate samples for different times, analysing each resulting solution, and extrapolating back to zero hydrolysis time. Rastall suggests a variety of reagents to prevent or reduce degradation, such as thiol reagents or phenol to protect tryptophan and tyrosine from attack by chlorine, and pre-oxidising cysteine. He also suggests measuring the quantity of ammonia evolved to determine the extent of amide hydrolysis.
=== Separation and quantitation ===
The amino acids can be separated by ion-exchange chromatography then derivatized to facilitate their detection. More commonly, the amino acids are derivatized then resolved by reversed phase HPLC.
An example of the ion-exchange chromatography is given by the NTRC using sulfonated polystyrene as a matrix, adding the amino acids in acid solution and passing a buffer of steadily increasing pH through the column. Amino acids are eluted when the pH reaches their respective isoelectric points. Once the amino acids have been separated, their respective quantities are determined by adding a reagent that will form a coloured derivative. If the amounts of amino acids are in excess of 10 nmol, ninhydrin can be used for this; it gives a yellow colour when reacted with proline, and a vivid purple with other amino acids. The concentration of amino acid is proportional to the absorbance of the resulting solution. With very small quantities, down to 10 pmol, fluorescent derivatives can be formed using reagents such as ortho-phthaldehyde (OPA) or fluorescamine.
Pre-column derivatization may use the Edman reagent to produce a derivative that is detected by UV light. Greater sensitivity is achieved using a reagent that generates a fluorescent derivative. The derivatized amino acids are subjected to reversed phase chromatography, typically using a C8 or C18 silica column and an optimised elution gradient. The eluting amino acids are detected using a UV or fluorescence detector and the peak areas compared with those for derivatised standards in order to quantify each amino acid in the sample.
== N-terminal amino acid analysis ==
Determining which amino acid forms the N-terminus of a peptide chain is useful for two reasons: to aid the ordering of individual peptide fragments' sequences into a whole chain, and because the first round of Edman degradation is often contaminated by impurities and therefore does not give an accurate determination of the N-terminal amino acid. A generalised method for N-terminal amino acid analysis follows:
React the peptide with a reagent that will selectively label the terminal amino acid.
Hydrolyse the protein.
Determine the amino acid by chromatography and comparison with standards.
There are many different reagents which can be used to label terminal amino acids. They all react with amine groups and will therefore also bind to amine groups in the side chains of amino acids such as lysine - for this reason it is necessary to be careful in interpreting chromatograms to ensure that the right spot is chosen. Two of the more common reagents are Sanger's reagent (1-fluoro-2,4-dinitrobenzene) and dansyl derivatives such as dansyl chloride. Phenylisothiocyanate, the reagent for the Edman degradation, can also be used. The same questions apply here as in the determination of amino acid composition, with the exception that no stain is needed, as the reagents produce coloured derivatives and only qualitative analysis is required. So the amino acid does not have to be eluted from the chromatography column, just compared with a standard. Another consideration to take into account is that, since any amine groups will have reacted with the labelling reagent, ion exchange chromatography cannot be used, and thin-layer chromatography or high-pressure liquid chromatography should be used instead.
== C-terminal amino acid analysis ==
The number of methods available for C-terminal amino acid analysis is much smaller than the number of available methods of N-terminal analysis. The most common method is to add carboxypeptidases to a solution of the protein, take samples at regular intervals, and determine the terminal amino acid by analysing a plot of amino acid concentrations against time. This method will be very useful in the case of polypeptides and protein-blocked N termini. C-terminal sequencing would greatly help in verifying the primary structures of proteins predicted from DNA sequences and to detect any posttranslational processing of gene products from known codon sequences.
== Edman degradation ==
The Edman degradation is a very important reaction for protein sequencing, because it allows the ordered amino acid composition of a protein to be discovered. Automated Edman sequencers are now in widespread use, and are able to sequence peptides up to approximately 50 amino acids long. A reaction scheme for sequencing a protein by the Edman degradation follows; some of the steps are elaborated on subsequently.
Break any disulfide bridges in the protein with a reducing agent like 2-mercaptoethanol. A protecting group such as iodoacetic acid may be necessary to prevent the bonds from re-forming.
Separate and purify the individual chains of the protein complex, if there are more than one.
Determine the amino acid composition of each chain.
Determine the terminal amino acids of each chain.
Break each chain into fragments under 50 amino acids long.
Separate and purify the fragments.
Determine the sequence of each fragment.
Repeat with a different pattern of cleavage.
Construct the sequence of the overall protein.
=== Digestion into peptide fragments ===
Peptides longer than about 50–70 amino acids long cannot be sequenced reliably by the Edman degradation. Because of this, long protein chains need to be broken up into small fragments that can then be sequenced individually. Digestion is done either by endopeptidases such as trypsin or pepsin or by chemical reagents such as cyanogen bromide. Different enzymes give different cleavage patterns, and the overlap between fragments can be used to construct an overall sequence.
=== Reaction ===
The peptide to be sequenced is adsorbed onto a solid surface. One common substrate is glass fibre coated with polybrene, a cationic polymer. The Edman reagent, phenylisothiocyanate (PITC), is added to the adsorbed peptide, together with a mildly basic buffer solution of 12% trimethylamine. This reacts with the amine group of the N-terminal amino acid.
The terminal amino acid can then be selectively detached by the addition of anhydrous acid. The derivative then isomerises to give a substituted phenylthiohydantoin, which can be washed off and identified by chromatography, and the cycle can be repeated. The efficiency of each step is about 98%, which allows about 50 amino acids to be reliably determined.
=== Protein sequencer ===
A protein sequenator is a machine that performs Edman degradation in an automated manner. A sample of the protein or peptide is immobilized in the reaction vessel of the protein sequenator and the Edman degradation is performed. Each cycle releases and derivatises one amino acid from the protein or peptide's N-terminus and the released amino-acid derivative is then identified by HPLC. The sequencing process is done repetitively for the whole polypeptide until the entire measurable sequence is established or for a pre-determined number of cycles.
== Identification by mass spectrometry ==
Protein identification is the process of assigning a name to a protein of interest (POI), based on its amino-acid sequence. Typically, only part of the protein’s sequence needs to be determined experimentally in order to identify the protein with reference to databases of protein sequences deduced from the DNA sequences of their genes. Further protein characterization may include confirmation of the actual N- and C-termini of the POI, determination of sequence variants and identification of any post-translational modifications present.
=== Proteolytic digests ===
A general scheme for protein identification is described.
The POI is isolated, typically by SDS-PAGE or chromatography.
The isolated POI may be chemically modified to stabilise Cysteine residues (e.g. S-amidomethylation or S-carboxymethylation).
The POI is digested with a specific protease to generate peptides. Trypsin, which cleaves selectively on the C-terminal side of Lysine or Arginine residues, is the most commonly used protease. Its advantages include i) the frequency of Lys and Arg residues in proteins, ii) the high specificity of the enzyme, iii) the stability of the enzyme and iv) the suitability of tryptic peptides for mass spectrometry.
The peptides may be desalted to remove ionizable contaminants and subjected to MALDI-TOF mass spectrometry. Direct measurement of the masses of the peptides may provide sufficient information to identify the protein (see Peptide mass fingerprinting) but further fragmentation of the peptides inside the mass spectrometer is often used to gain information about the peptides’ sequences. Alternatively, peptides may be desalted and separated by reversed phase HPLC and introduced into a mass spectrometer via an ESI source. LC-ESI-MS may provide more information than MALDI-MS for protein identification but uses more instrument time.
Depending on the type of mass spectrometer, fragmentation of peptide ions may occur via a variety of mechanisms such as collision-induced dissociation (CID) or post-source decay (PSD). In each case, the pattern of fragment ions of a peptide provides information about its sequence.
Information including the measured mass of the putative peptide ions and those of their fragment ions is then matched against calculated mass values from the conceptual (in-silico) proteolysis and fragmentation of databases of protein sequences. A successful match will be found if its score exceeds a threshold based on the analysis parameters. Even if the actual protein is not represented in the database, error-tolerant matching allows for the putative identification of a protein based on similarity to homologous proteins. A variety of software packages are available to perform this analysis.
Software packages usually generate a report showing the identity (accession code) of each identified protein, its matching score, and provide a measure of the relative strength of the matching where multiple proteins are identified.
A diagram of the matched peptides on the sequence of the identified protein is often used to show the sequence coverage (% of the protein detected as peptides). Where the POI is thought to be significantly smaller than the matched protein, the diagram may suggest whether the POI is an N- or C-terminal fragment of the identified protein.
=== De novo sequencing ===
The pattern of fragmentation of a peptide allows for direct determination of its sequence by de novo sequencing. This sequence may be used to match databases of protein sequences or to investigate post-translational or chemical modifications. It may provide additional evidence for protein identifications performed as above.
=== N- and C-termini ===
The peptides matched during protein identification do not necessarily include the N- or C-termini predicted for the matched protein. This may result from the N- or C-terminal peptides being difficult to identify by MS (e.g. being either too short or too long), being post-translationally modified (e.g. N-terminal acetylation) or genuinely differing from the prediction. Post-translational modifications or truncated termini may be identified by closer examination of the data (i.e. de novo sequencing). A repeat digest using a protease of different specificity may also be useful.
=== Post-translational modifications ===
Whilst detailed comparison of the MS data with predictions based on the known protein sequence may be used to define post-translational modifications, targeted approaches to data acquisition may also be used. For instance, specific enrichment of phosphopeptides may assist in identifying phosphorylation sites in a protein. Alternative methods of peptide fragmentation in the mass spectrometer, such as ETD or ECD, may give complementary sequence information.
=== Whole-mass determination ===
The protein’s whole mass is the sum of the masses of its amino-acid residues plus the mass of a water molecule and adjusted for any post-translational modifications. Although proteins ionize less well than the peptides derived from them, a protein in solution may be able to be subjected to ESI-MS and its mass measured to an accuracy of 1 part in 20,000 or better. This is often sufficient to confirm the termini (thus that the protein’s measured mass matches that predicted from its sequence) and infer the presence or absence of many post-translational modifications.
=== Limitations ===
Proteolysis does not always yield a set of readily analyzable peptides covering the entire sequence of POI. The fragmentation of peptides in the mass spectrometer often does not yield ions corresponding to cleavage at each peptide bond. Thus, the deduced sequence for each peptide is not necessarily complete. The standard methods of fragmentation do not distinguish between leucine and isoleucine residues since they are isomeric.
Because the Edman degradation proceeds from the N-terminus of the protein, it will not work if the N-terminus has been chemically modified (e.g. by acetylation or formation of Pyroglutamic acid). Edman degradation is generally not useful to determine the positions of disulfide bridges. It also requires peptide amounts of 1 picomole or above for discernible results, making it less sensitive than mass spectrometry.
== Predicting from DNA/RNA sequences ==
In biology, proteins are produced by translation of messenger RNA (mRNA) with the protein sequence deriving from the sequence of codons in the mRNA. The mRNA is itself formed by the transcription of genes and may be further modified. These processes are sufficiently understood to use computer algorithms to automate predictions of protein sequences from DNA sequences, such as from whole-genome DNA-sequencing projects, and have led to the generation of large databases of protein sequences such as UniProt. Predicted protein sequences are an important resource for protein identification by mass spectrometry.
Historically, short protein sequences (10 to 15 residues) determined by Edman degradation were back-translated into DNA sequences that could be used as probes or primers to isolate molecular clones of the corresponding gene or complementary DNA. The sequence of the cloned DNA was then determined and used to deduce the full amino-acid sequence of the protein.
== Bioinformatics tools ==
Bioinformatics tools exist to assist with interpretation of mass spectra (see de novo peptide sequencing), to compare or analyze protein sequences (see sequence analysis), or search databases using peptide or protein sequences (see BLAST).
== Applications to cryptography ==
The difficulty of protein sequencing was recently proposed as a basis for creating k-time programs, programs that run exactly k times before self-destructing. Such a thing is impossible to build purely in software because all software is inherently clonable an unlimited number of times.
== See also ==
Proteomics
DNA sequencing
Klaus Biemann
Donald F. Hunt
Matthias Mann
John R. Yates
== References ==
== Further reading == | Wikipedia/Protein_sequencing |
Dirigent proteins are members of a class of proteins which dictate the stereochemistry of a compound synthesized by other enzymes. The first dirigent protein was discovered in Forsythia intermedia. This protein has been found to direct the stereoselective biosynthesis of (+)-pinoresinol from coniferyl alcohol monomers:
Lignan biosynthesis is catalysed by oxidative enzymes. In the test tube the reaction results in a heterogeneous mixture of dimeric compounds. When a dirigent protein is present during the reaction, one stereoisomer of one compound is highly enriched. Dirigent proteins appear to possess no oxidative radical forming activity of their own; in the absence of oxidative enzyme, no reaction will occur.
Recently, a second, enantiocomplementary dirigent protein was identified in Arabidopsis thaliana, which directs enantioselective synthesis of (-)-pinoresinol.
== Activity ==
In lignan biosynthesis, oxidative enzymes perform proton coupled electron transfer to remove a hydrogen atom from monolignols, forming a radical intermediate. These intermediates then couple in a radical termination reaction to form one of a variety of dimers, known as lignans. In vitro reactions of coniferyl alcohol (a common monolignol) in the presence of oxidative enzymes produce a wide variety of different dimers at varying concentrations. When dirigent protein from "Forsythia intermedia" is present, production of (+)-pinoresinol is greatly enriched, and other products are far less abundant. Because this enrichment is so pronounced, the enzyme is hypothesized to produce (+)-pinoresinol exclusively, and to compete with the non-protein-mediated coupling reaction, which produces a heterologous mix of products. This has been confirmed by analyzing the various mixtures produced with different concentrations of dirigent proteins present. The mechanism by which this stereoselectivity is achieved is not well understood at this time. However, since no reaction proceeds in the absence of oxidative enzymes, dirigent protein does not itself appear to catalyze the oxidation of coniferyl alcohol to form radicals.
The activity of dirigent protein from Forsythia intermedia is specific to coniferyl alcohol. When other monolignols, such as p-coumaryl alcohol and sinapyl alcohol, are reacted in vitro with oxidative enzymes in the presence of dirigent protein, they produce a heterologous mixture of products indistinguishable from identical experiments in the absence of dirigent protein.
== Structure ==
Circular dichroism experiments have shown that the secondary structure of dirigent protein from Forsythia intermedia is composed primarily of β-pleated sheets and loop structures. The tertiary structure has not been solved, but the protein has been confirmed to be dimeric. Each dimer has a single binding site for coniferyl alcohol, for a total of two binding sites. One coniferyl alcohol can bind to each site, so that the reaction geometry between the two is confined, increasing the production of (+)-pinoresinol and inhibiting the production of other products.
== Biological importance ==
In the absence of dirigent protein, pinoresinol is a relatively minor product of lignas biosynthesis. When dirigent protein is present, it becomes the major product. The biological significance of (+)-pinoresinol in plants is not fully understood, but it has been found to be effective as a feeding deterrent against ants in caterpillars of the cabbage butterfly, which obtain the compound from their diet. It may serve a similar defensive purpose in Forsythia intermedia.
== References == | Wikipedia/Dirigent_protein |
Glycan-Protein interactions represent a class of biomolecular interactions that occur between free or protein-bound glycans and their cognate binding partners. Intramolecular glycan-protein (protein-glycan) interactions occur between glycans and proteins that they are covalently attached to. Together with protein-protein interactions, they form a mechanistic basis for many essential cell processes, especially for cell-cell interactions and host-cell interactions. For instance, SARS-CoV-2, the causative agent of COVID-19, employs its extensively glycosylated spike (S) protein to bind to the ACE2 receptor, allowing it to enter host cells. The spike protein is a trimeric structure, with each subunit containing 22 N-glycosylation sites, making it an attractive target for vaccine search.
Glycosylation, i.e., the addition of glycans (a generic name for monosaccharides and oligosaccharides) to a protein, is one of the major post-translational modification of proteins contributing to the enormous biological complexity of life. Indeed, three different hexoses could theoretically produce from 1056 to 27,648 unique trisaccharides in contrast to only 6 peptides or oligonucleotides formed from 3 amino acids or 3 nucleotides respectively. In contrast to template-driven protein biosynthesis, the "language" of glycosylation is still unknown, making glycobiology a hot topic of current research given their prevalence in living organisms.
The study of glycan-protein interactions provides insight into the mechanisms of cell-signaling and allows to create better-diagnosing tools for many diseases, including cancer. Indeed, there are no known types of cancer that do not involve erratic patterns of protein glycosylation.
== Thermodynamics of Binding ==
The binding of glycan-binding proteins (GBPs) to glycans could be modeled with simple equilibrium. Denoting glycans as
G
{\displaystyle G}
and proteins as
P
{\displaystyle P}
:
P
r
o
t
e
i
n
(
P
)
+
G
l
y
c
a
n
(
G
)
⇌
P
G
{\displaystyle Protein(P)+Glycan(G)\rightleftharpoons PG}
With an associated equilibrium constant of
K
a
=
[
P
G
]
[
P
]
[
G
]
{\displaystyle K_{a}={\frac {[PG]}{[P][G]}}}
Which is rearranged to give dissociation constant
K
d
{\displaystyle K_{d}}
following biochemical conventions:
K
d
=
[
P
]
[
G
]
[
P
G
]
{\displaystyle K_{d}={\frac {[P][G]}{[PG]}}}
Given that many GBPs exhibit multivalency, this model may be expanded to account for multiple equilibria:
P
+
G
⇌
P
G
{\displaystyle P+G\rightleftharpoons PG}
P
G
+
G
⇌
P
G
2
{\displaystyle PG+G\rightleftharpoons PG_{2}}
…
{\displaystyle \dots }
P
G
n
−
1
+
G
⇌
P
G
n
{\displaystyle PG_{n-1}+G\rightleftharpoons PG_{n}}
Denoting cumulative equilibrium of binding with
i
{\displaystyle i}
ligands as
P
+
i
G
⇌
P
G
i
{\displaystyle P+iG\rightleftharpoons PG_{i}}
With corresponding equilibrium constant:
β
i
=
[
P
G
i
]
[
P
]
[
G
]
i
{\displaystyle \beta _{i}={\frac {[PG_{i}]}{[P][G]^{i}}}}
And writing material balance for protein (
c
P
{\displaystyle c_{P}}
denotes the total concentration of protein):
c
P
=
[
P
]
+
[
P
G
]
+
⋯
+
[
P
G
n
]
{\displaystyle c_{P}=[P]+[PG]+\dots +[PG_{n}]}
Expressing the terms through an equilibrium constant, a final result is found:
c
P
=
[
P
]
(
1
+
β
1
[
G
]
+
⋯
+
β
n
[
G
]
n
{\displaystyle c_{P}=[P](1+\beta _{1}[G]+\dots +\beta _{n}[G]^{n}}
The concentration of free protein is, thus:
[
P
]
=
c
P
1
+
∑
i
=
1
n
β
i
[
G
]
i
{\displaystyle [P]={\frac {c_{P}}{1+\sum _{i=1}^{n}{\beta _{i}[G]^{i}}}}}
If
n
=
1
{\displaystyle n=1}
, i.e. there is only one carbohydrate receptor domain, the equation reduces to
[
P
]
=
c
P
1
+
β
1
[
G
]
{\displaystyle [P]={\frac {c_{P}}{1+\beta _{1}[G]}}}
With increasing
i
{\displaystyle i}
the concentration of free protein decreases; hence, the apparent
K
D
{\displaystyle K_{D}}
decreases too.
== Binding with aromatic rings ==
The chemical intuition suggests that the glycan-binding sites may be enriched in polar amino acid residues that form non-covalent interactions, such as hydrogen bonds, with polar carbohydrates. Indeed, a statistical analysis of carbohydrate-binding pockets shows that aspartic acid and asparagine residues are present twice as often as would be predicted by chance. Surprisingly, there is an even stronger preference for aromatic amino acids: tryptophan has a 9-fold increase in prevalence, tyrosine a 3-fold one, and histidine a 2-fold increase. It has been shown that the underlying force is the
C
H
−
π
{\displaystyle CH-\pi }
interaction between the aromatic
π
{\displaystyle \pi }
system and the
C
−
H
{\displaystyle C-H}
in carbohydrate as shown in Figure 1. The
C
H
−
π
{\displaystyle CH-\pi }
interaction is identified if the
θ
⩽
40
{\displaystyle \theta \leqslant 40}
°, the
C
H
−
π
{\displaystyle CH-\pi }
distance (distance from
C
{\displaystyle C}
to
X
{\displaystyle X}
) is less than 4.5Å.
=== Effects of stereochemistry ===
This
C
H
−
π
{\displaystyle CH-\pi }
interaction strongly depends on the stereochemistry of the carbohydrate molecule. For example, consider the top (
β
{\displaystyle \beta }
) and bottom (
α
{\displaystyle \alpha }
) faces of
β
{\displaystyle \beta }
-D-Glucose and
β
{\displaystyle \beta }
-D-Galactose. It has been shown that a single change in the stereochemistry at C4 carbon shifts preference for aromatic residues from
β
{\displaystyle \beta }
side (2.7 fold preference for glucose) to the
α
{\displaystyle \alpha }
side (14 fold preference for galactose).
=== Effects of electronics ===
The comparison of electrostatic surface potentials (ESPs) of aromatic rings in tryptophan, tyrosine, phenylalanine, and histidine suggests that electronic effects also play a role in the binding to glycans (see Figure 2). After normalizing the electron densities for surface area, the tryptophan still remains the most electron rich acceptor of
C
H
−
π
{\displaystyle CH-\pi }
interactions, suggesting a possible reason for its 9-fold prevalence in carbohydrate binding pockets. Overall, the electrostatic potential maps follow the prevalence trend of
Trp
>>
Tyr
>
(
Phe
)
>
His
{\displaystyle {\ce {Trp >> Tyr > (Phe) > His}}}
.
== Carbohydrate-binding partners ==
There are many proteins capable of binding to glycans, including lectins, antibodies, microbial adhesins, viral agglutinins, etc.
=== Lectins ===
Lectins is a generic name for proteins with carbohydrate-recognizing domains (CRD). Although it became almost synonymous with glycan-binding proteins, it does not include antibodies which also belong to the class.
Lectins found in plants and fungi cells have been extensively used in research as a tool to detect, purify, and analyze glycans. However, useful lectins usually have sub-optimal specificities. For instance, Ulex europaeus agglutinin-1 (UEA-1), a plant-extracted lectin capable of binding to human blood type O antigen, can also bind to unrelated glycans such as 2'-fucosyllactose, GalNAcα1-4(Fucα1-2)Galβ1-4GlcNAc, and Lewis-Y antigen.
=== Antibodies ===
Although antibodies exhibit nanomolar affinities toward protein antigens, the specificity against glycans is very limited. In fact, available antibodies may bind only <4% of the 7000 mammalian glycan antigens; moreover, most of those antibodies have low affinity and exhibit cross-reactivity.
=== Lambodies ===
In contrast with jawed vertebrates whose immunity is based on variable, diverse, and joining gene segments (VDJs) of immunoglobulins, the jawless invertebrates, such as lamprey and hagfish, create a receptor diversity by somatic DNA rearrangement of leucine-rich repeat (LRR) modules that are incorporate in *vlr* genes (variable leukocyte receptors). Those LRR form 3D structures resembling curved solenoids that selectively bind specific glycans.
A study from University of Maryland has shown that lamprey antibodies (lambodies) could selectively bind to tumor-associated carbohydrate antigens (such as Tn and TF
α
{\displaystyle \alpha }
) at nanomolar affinities. The T-nouvelle antigen (Tn) and TF
α
{\displaystyle \alpha }
are present in proteins in as much as 90% of different cancer cells after post-translational modification, whereas in healthy cells those antigens are much more complex. A selection of lambodies that could bind to aGPA, a human erythrocyte membrane glycoprotein that is covered with 16 TF
α
{\displaystyle \alpha }
moieties, through magnetic-activated cell sorting (MACS) and fluorescence-activated cell sorting (FACS) has yielded a leucine-rich lambody VLRB.aGPA.23. This lambody selectively stained (over healthy samples) cells from 14 different types of adenocarcinomas: bladder, esophagus, ovary, tongue, cheek, cervix, liver, nose, nasopharynx, greater omentum, colon, breast, larynx, and lung. Moreover, patients whose tissues stained positive with VLRB.aGPA.23 had a significantly smaller survival rate.
A close look at the crystal structure of VLRB.aGPA.23 reveals a tryptophan residue at position 187 right over the carbohydrate binding pocket.
=== Multivalency in structure ===
Many glycan binding proteins (GBPs) are oligomeric and typically contain multiple sites for glycan binding (also called carbohydrate-recognition domains). The ability to form multivalent protein-ligand interactions significantly enhances the strength of binding: while
K
D
{\displaystyle K_{D}}
values for individual CRD-glycan interactions may be in the mM range, the overall affinity of GBP towards glycans may reach nanomolar or even picomolar ranges. The overall strength of interactions is described as avidity
K
D
{\displaystyle K_{D}}
(in contrast with an affinity
K
D
{\displaystyle K_{D}}
which describes single equilibrium). Sometimes the avidity is also called an apparent
K
D
{\displaystyle K_{D}}
to emphasize the non-equilibrium nature of the interaction.
Common oligomerization structures of lectins are shown below. For example, galectins are usually observed as dimers, while intelectins form trimers and pentraxins assemble into pentamers. Larger structures, like hexameric Reg proteins, may assemble into membrane penetrating pores. Collectins may form even more bizarre complexes: bouquets of trimers or even cruciform-like structures (e.g. in SP-D).
== Current Research ==
Given the importance of glycan-protein interactions, there is an ongoing research dedicated to the a) creation of new tools to detect glycan-protein interactions and b) using those tools to decipher the so-called sugar code.
=== Glycan Arrays ===
One of the most widely used tools for probing glycan-protein interactions is glycan arrays. A glycan array usually is an NHS- or epoxy-activated glass slides on which various glycans were printed using robotic printing. These commercially available arrays may contain up to 600 different glycans, specificity of which has been extensively studied.
Glycan-protein interactions may be detected by testing proteins of interest (or libraries of those) that bear fluorescent tags. The structure of the glycan-binding protein may be deciphered by several analytical methods based on mass-spectrometry, including MALDI-MS, LC-MS, tandem MS-MS, and/or 2D NMR.
=== Bioinformatics driven research ===
Computational methods have been applied to search for parameters (e.g. residue propensity, hydrophobicity, planarity) that could distinguish glycan-binding proteins from other surface patches. For example, a model trained on 19 non-homologous carbohydrate binding structures was able to predict carbohydrate-binding domains (CRDs) with an accuracy of 65% for non-enzymatic structures and 87% for enzymatic ones. Further studies have employed calculations of Van der Waals energies of protein-probe interactions and amino acid propensities to identify CRDs with 98% specificity at 73% sensitivity. More recent methods can predict CRDs even from protein sequences, by comparing the sequence with those for which structures are already known.
=== Sugar code ===
In contrast with protein studies, where a primary protein structure is unambiguously defined by the sequence of nucleotides (the genetic code), the glycobiology still cannot explain how a certain "message" is encoded using carbohydrates or how it is "read" and "translated" by other biological entities.
An interdisciplinary effort, combining chemistry, biology, and biochemistry, studies glycan-protein interactions to see how different sequences of carbohydrates initiate different cellular responses.
== See also ==
Protein-protein interactions
Glycobiology
== References == | Wikipedia/Glycan-protein_interactions |
Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.
== History ==
In 1970, Günter Blobel conducted experiments on protein translocation across membranes. Blobel, then an assistant professor at Rockefeller University, built upon the work of his colleague George Palade. Palade had previously demonstrated that non-secreted proteins were translated by free ribosomes in the cytosol, while secreted proteins (and target proteins, in general) were translated by ribosomes bound to the endoplasmic reticulum (ER). Candidate explanations at the time postulated a processing difference between free and ER-bound ribosomes, but Blobel hypothesized that protein targeting relied on characteristics inherent to the proteins, rather than a difference in ribosomes. Supporting his hypothesis, Blobel discovered that many proteins have a short amino acid sequence at one end that functions like a postal code specifying an intracellular or extracellular destination. He described these short sequences (generally 13 to 36 amino acids residues) as signal peptides or signal sequences and was awarded the 1999 Nobel prize in Physiology for the same.
== Signal peptides ==
Signal peptides serve as targeting signals, enabling cellular transport machinery to direct proteins to specific intracellular or extracellular locations. While no consensus sequence has been identified for signal peptides, many nonetheless possess a characteristic tripartite structure:
A positively charged, hydrophilic region near the N-terminal.
A span of 10 to 15 hydrophobic amino acids near the middle of the signal peptide.
A slightly polar region near the C-terminal, typically favoring amino acids with smaller side chains at positions approaching the cleavage site.
After a protein has reached its destination, the signal peptide is generally cleaved by a signal peptidase. Consequently, most mature proteins do not contain signal peptides. While most signal peptides are found at the N-terminal, in peroxisomes the targeting sequence is located on the C-terminal extension. Unlike signal peptides, signal patches are composed by amino acid residues that are discontinuous in the primary sequence but become functional when folding brings them together on the protein surface. Unlike most signal sequences, signal patches are not cleaved after sorting is complete. In addition to intrinsic signaling sequences, protein modifications like glycosylation can also induce targeting to specific intracellular or extracellular regions.
== Protein translocation ==
Since the translation of mRNA into protein by a ribosome takes place within the cytosol, proteins destined for secretion or a specific organelle must be translocated. This process can occur during translation, known as co-translational translocation, or after translation is complete, known as post-translational translocation.
=== Co-translational translocation ===
Most secretory and membrane-bound proteins are co-translationally translocated. Proteins that reside in the endoplasmic reticulum (ER), golgi or endosomes also use the co-translational translocation pathway. This process begins while the protein is being synthesized on the ribosome, when a signal recognition particle (SRP) recognizes an N-terminal signal peptide of the nascent protein. Binding of the SRP temporarily pauses synthesis while the ribosome-protein complex is transferred to an SRP receptor on the ER in eukaryotes, and the plasma membrane in prokaryotes. There, the nascent protein is inserted into the translocon, a membrane-bound protein conducting channel composed of the Sec61 translocation complex in eukaryotes, and the homologous SecYEG complex in prokaryotes. In secretory proteins and type I transmembrane proteins, the signal sequence is immediately cleaved from the nascent polypeptide once it has been translocated into the membrane of the ER (eukaryotes) or plasma membrane (prokaryotes) by signal peptidase. The signal sequence of type II membrane proteins and some polytopic membrane proteins are not cleaved off and therefore are referred to as signal anchor sequences. Within the ER, the protein is first covered by a chaperone protein to protect it from the high concentration of other proteins in the ER, giving it time to fold correctly. Once folded, the protein is modified as needed (for example, by glycosylation), then transported to the Golgi for further processing and goes to its target organelles or is retained in the ER by various ER retention mechanisms.
The amino acid chain of transmembrane proteins, which often are transmembrane receptors, passes through a membrane one or several times. These proteins are inserted into the membrane by translocation, until the process is interrupted by a stop-transfer sequence, also called a membrane anchor or signal-anchor sequence. These complex membrane proteins are currently characterized using the same model of targeting that has been developed for secretory proteins. However, many complex multi-transmembrane proteins contain structural aspects that do not fit this model. Seven transmembrane G-protein coupled receptors (which represent about 5% of the genes in humans) mostly do not have an amino-terminal signal sequence. In contrast to secretory proteins, the first transmembrane domain acts as the first signal sequence, which targets them to the ER membrane. This also results in the translocation of the amino terminus of the protein into the ER membrane lumen. This translocation, which has been demonstrated with opsin with in vitro experiments, breaks the usual pattern of "co-translational" translocation which has always held for mammalian proteins targeted to the ER. A great deal of the mechanics of transmembrane topology and folding remains to be elucidated.
=== Post-translational translocation ===
Even though most secretory proteins are co-translationally translocated, some are translated in the cytosol and later transported to the ER/plasma membrane by a post-translational system. In prokaryotes this process requires certain cofactors such as SecA and SecB and is facilitated by Sec62 and Sec63, two membrane-bound proteins. The Sec63 complex, which is embedded in the ER membrane, causes hydrolysis of ATP, allowing chaperone proteins to bind to an exposed peptide chain and slide the polypeptide into the ER lumen. Once in the lumen the polypeptide chain can be folded properly. This process only occurs in unfolded proteins located in the cytosol.
In addition, proteins targeted to other cellular destinations, such as mitochondria, chloroplasts, or peroxisomes, use specialized post-translational pathways. Proteins targeted for the nucleus are also translocated post-translationally through the addition of a nuclear localization sequence (NLS) that promotes passage through the nuclear envelope via nuclear pores.
== Sorting of proteins ==
=== Mitochondria ===
While some proteins in the mitochondria originate from mitochondrial DNA within the organelle, most mitochondrial proteins are synthesized as cytosolic precursors containing uptake peptide signals. Unfolded proteins bound by cytosolic chaperone hsp70 that are targeted to the mitochondria may be localized to four different areas depending on their sequences. They may be targeted to the mitochondrial matrix, the outer membrane, the intermembrane space, or the inner membrane. Defects in any one or more of these processes has been linked to health and disease.
==== Mitochondrial matrix ====
Proteins destined for the mitochondrial matrix have specific signal sequences at their beginning (N-terminus) that consist of a string of 20 to 50 amino acids. These sequences are designed to interact with receptors that guide the proteins to their correct location inside the mitochondria. The sequences have a unique structure with clusters of water-loving (hydrophilic) and water-avoiding (hydrophobic) amino acids, giving them a dual nature known as amphipathic. These amphipathic sequences typically form a spiral shape (alpha-helix) with the charged amino acids on one side and the hydrophobic ones on the opposite side. This structural feature is essential for the sequence to function correctly in directing proteins to the matrix. If mutations occur that mess with this dual nature, the protein often fails to reach its intended destination, although not all changes to the sequence have this effect. This indicates the importance of the amphipathic property for the protein to be correctly targeted to the mitochondrial matrix.Proteins targeted to the mitochondrial matrix first involves interactions between the matrix targeting sequence located at the N-terminus and the outer membrane import receptor complex TOM20/22. In addition to the docking of internal sequences and cytosolic chaperones to TOM70. Where TOM is an abbreviation for translocase of the outer membrane. Binding of the matrix targeting sequence to the import receptor triggers a handoff of the polypeptide to the general import core (GIP) known as TOM40. The general import core (TOM40) then feeds the polypeptide chain through the intermembrane space and into another translocase complex TIM17/23/44 located on the inner mitochondrial membrane. This is accompanied by the necessary release of the cytosolic chaperones that maintain an unfolded state prior to entering the mitochondria. As the polypeptide enters the matrix, the signal sequence is cleaved by a processing peptidase and the remaining sequences are bound by mitochondrial chaperones to await proper folding and activity. The push and pull of the polypeptide from the cytosol to the intermembrane space and then the matrix is achieved by an electrochemical gradient that is established by the mitochondrion during oxidative phosphorylation. In which a mitochondrion active in metabolism has generated a negative potential inside the matrix and a positive potential in the intermembrane space. It is this negative potential inside the matrix that directs the positively charged regions of the targeting sequence into its desired location.
==== Mitochondrial inner membrane ====
Targeting of mitochondrial proteins to the inner membrane may follow 3 different pathways depending upon their overall sequences, however, entry from the outer membrane remains the same using the import receptor complex TOM20/22 and TOM40 general import core. The first pathway for proteins targeted to the inner membrane follows the same steps as those designated to the matrix where it contains a matrix targeting sequence that channels the polypeptide to the inner membrane complex containing the previously mentioned translocase complex TIM17/23/44. However, the difference is that the peptides that are designated to the inner membrane and not the matrix contain an upstream sequence called the stop-transfer-anchor sequence. This stop-transfer-anchor sequence is a hydrophobic region that embeds itself into the phospholipid bilayer of the inner membrane and prevents translocation further into the mitochondrion. The second pathway for proteins targeted to the inner membrane follows the matrix localization pathway in its entirety. However, instead of a stop-transfer-anchor sequence, it contains another sequence that interacts with an inner membrane protein called Oxa-1 once inside the matrix that will embed it into the inner membrane. The third pathway for mitochondrial proteins targeted to the inner membrane follow the same entry as the others into the outer membrane, however, this pathway utilizes the translocase complex TIM22/54 assisted by complex TIM9/10 in the intermembrane space to anchor the incoming peptide into the membrane. The peptides for this last pathway do not contain a matrix targeting sequence, but instead contain several internal targeting sequences.
==== Mitochondrial intermembrane space ====
If instead the precursor protein is designated to the intermembrane space of the mitochondrion, there are two pathways this may occur depending on the sequences being recognized. The first pathway to the intermembrane space follows the same steps for an inner membrane targeted protein. However, once bound to the inner membrane the C-terminus of the anchored protein is cleaved via a peptidase that liberates the preprotein into the intermembrane space so it can fold into its active state. One of the greatest examples for a protein that follows this pathway is cytochrome b2, that upon being cleaved will interact with a heme cofactor and become active. The second intermembrane space pathway does not utilize any inner membrane complexes and therefor does not contain a matrix targeting signal. Instead, it enters through the general import core TOM40 and is further modified in the intermembrane space to achieve its active conformation. TIM9/10 is an example of a protein that follows this pathway in order to be in the location it needs to be to assist in inner membrane targeting.
==== Mitochondrial outer membrane ====
Outer membrane targeting simply involves the interaction of precursor proteins with the outer membrane translocase complexes that embeds it into the membrane via internal-targeting sequences that are to form hydrophobic alpha helices or beta barrels that span the phospholipid bilayer. This may occur by two different routes depending on the preprotein internal sequences. If the preprotein contains internal hydrophobic regions capable of forming alpha helices, then the preprotein will utilize the mitochondrial import complex (MIM) and be transferred laterally to the membrane. For preproteins containing hydrophobic internal sequences that correlate to beta-barrel forming proteins, they will be imported from the aforementioned outer membrane complex TOM20/22 to the intermembrane space. In which they will interact with TIM9/10 intermembrane-space protein complex that transfers them to sorting and assembly machinery (SAM) that is present in the outer membrane that laterally displaces the targeted protein as a beta-barrel.
=== Chloroplasts ===
Chloroplasts are similar to mitochondria in that they contain their own DNA for production of some of their components. However, the majority of their proteins are obtained via post-translational translocation and arise from nuclear genes. Proteins may be targeted to several sites of the chloroplast depending on their sequences such as the outer envelope, inner envelope, stroma, thylakoid lumen, or the thylakoid membrane. Proteins are targeted to Thylakoids by mechanisms related to Bacterial Protein Translocation. Proteins targeted to the envelope of chloroplasts usually lack cleavable sorting sequence and are laterally displaced via membrane sorting complexes. General import for the majority of preproteins requires translocation from the cytosol through the Toc and Tic complexes located within the chloroplast envelope. Where Toc is an abbreviation for the translocase of the outer chloroplast envelope and Tic is the translocase of the inner chloroplast envelope. There is a minimum of three proteins that make up the function of the Toc complex. Two of which, referred to as Toc159 and Toc34, are responsible for the docking of stromal import sequences and both contain GTPase activity. The third known as Toc 75, is the actual translocation channel that feeds the recognized preprotein by Toc159/34 into the chloroplast.
==== Stroma ====
Targeting to the stroma requires the preprotein to have a stromal import sequence that is recognized by the Tic complex of the inner envelope upon being translocated from the outer envelope by the Toc complex. The Tic complex is composed of at least five different Tic proteins that are required to form the translocation channel across the inner envelope. Upon being delivered to the stroma, the stromal import sequence is cleaved off via a signal peptidase. This delivery process to the stroma is currently known to be driven by ATP hydrolysis via stromal HSP chaperones, instead of the transmembrane electrochemical gradient that is established in mitochondria to drive protein import. Further intra-chloroplast sorting depends on additional target sequences such as those designated to the thylakoid membrane or the thylakoid lumen.
==== Thylakoid lumen ====
If a protein is to be targeted to the thylakoid lumen, this may occur via four differently known routes that closely resemble bacterial protein transport mechanisms. The route that is taken depends upon the protein delivered to the stroma being in either an unfolded or metal-bound folded state. Both of which will still contain a thylakoid targeting sequence that is also cleaved upon entry to the lumen. While protein import into the stroma is ATP-driven, the pathway for metal-bound proteins in a folded state to the thylakoid lumen has been shown to be driven by a pH gradient.
==== Thylakoid membrane ====
Proteins bound for the membrane of the thylakoid will follow up to four known routes that are illustrated in the corresponding figure shown. They may follow a co-translational insertion route that utilizes stromal ribosomes and the SecY/E transmembrane complex, the SRP-dependent pathway, the spontaneous insertion pathway, or the GET pathway. The last of the three are post-translational pathways originating from nuclear genes and therefor constitute the majority of proteins targeted to the thylakoid membrane. According to recent review articles in the journal of biochemistry and molecular biology, the exact mechanisms are not yet fully understood.
=== Both chloroplasts and mitochondria ===
Many proteins are needed in both mitochondria and chloroplasts. In general the dual-targeting peptide is of intermediate character to the two specific ones. The targeting peptides of these proteins have a high content of basic and hydrophobic amino acids, a low content of negatively charged amino acids. They have a lower content of alanine and a higher content of leucine and phenylalanine. The dual targeted proteins have a more hydrophobic targeting peptide than both mitochondrial and chloroplastic ones. However, it is tedious to predict if a peptide is dual-targeted or not based on its physio-chemical characteristics.
=== Nucleus ===
The nucleus of a cell is surrounded by a nuclear envelope consisting of two layers, with the inner layer providing structural support and anchorage for chromosomes and the nuclear lamina. The outer layer is similar to the endoplasmic reticulum (ER) membrane. This envelope contains nuclear pores, which are complex structures made from around 30 different proteins. These pores act as selective gates that control the flow of molecules into and out of the nucleus.
While small molecules can pass through these pores without issue, larger molecules, like RNA and proteins destined for the nucleus, must have specific signals to be allowed through. These signals are known as nuclear localization signals, usually comprising short sequences rich in positively charged amino acids like lysine or arginine.
Proteins called nuclear import receptors recognize these signals and guide the large molecules through the nuclear pores by interacting with the disordered, mesh-like proteins that fill the pore. The process is dynamic, with the receptor moving the molecule through the meshwork until it reaches the nucleus.
Once inside, a GTPase enzyme called Ran, which can exist in two different forms (one bound to GTP and the other to GDP), facilitates the release of the cargo inside the nucleus and recycles the receptor back to the cytosol. The energy for this transport comes from the hydrolysis of GTP by Ran. Similarly, nuclear export receptors help move proteins and RNA out of the nucleus using a different signal and also harnessing Ran's energy conversion.
Overall, the nuclear pore complex works efficiently to transport macromolecules at high speed, allowing proteins to move in their folded state and ribosomal components as complete particles, which is distinct from how proteins are transported into most other organelles.
=== Endoplasmic reticulum ===
The endoplasmic reticulum (ER) plays a key role in protein synthesis and distribution in eukaryotic cells. It's a vast network of membranes where proteins are processed and sorted to various destinations, including the ER itself, the cell surface, and other organelles like the Golgi apparatus, endosomes, and lysosomes. Unlike other organelle-targeted proteins, those headed for the ER start to be transferred across its membrane while they're still being made.
==== Protein synthesis and sorting ====
There are two types of proteins that move to the ER: water-soluble proteins, which completely cross into the ER lumen, and transmembrane proteins, which partly cross and embed themselves within the ER membrane. These proteins find their way to the ER with the help of an ER signal sequence, a short stretch of hydrophobic amino acids.
Proteins entering the ER are synthesized by ribosomes. There are two sets of ribosomes in the cell: those bound to the ER (making it look 'rough') and those floating freely in the cytosol. Both sets are identical but differ in the proteins they synthesize at a given moment. Ribosomes that are making proteins with an ER signal sequence attach to the ER membrane and start the translocation process. This process is energy-efficient because the growing protein chain itself pushes through the ER membrane as it elongates.
As the mRNA is translated into a protein, multiple ribosomes may attach to it, creating a structure called a polyribosome. If the mRNA is coding for a protein with an ER signal sequence, the polyribosome attaches to the ER membrane, and the protein begins to enter the ER while it is still being synthesized.
===== Guided entry of soluble proteins =====
In the process of protein synthesis within eukaryotic cells, soluble proteins that are destined for the endoplasmic reticulum (ER) or for secretion out of the cell are guided to the ER by a two-part system. Firstly, a signal-recognition particle (SRP) in the cytosol attaches to the emerging protein's ER signal sequence and the ribosome itself. Secondly, an SRP receptor located in the ER membrane recognizes and binds to the SRP. This interaction temporarily slows down protein synthesis until the SRP and ribs complex binds to the SRP receptor on the ER.
Once this binding occurs, the SRP is released, and the ribosome is transferred to a protein translocator in the ER membrane, allowing protein synthesis to continue. The polypeptide chain of the protein is then threaded through a channel in the translocator into the ER lumen. The signal sequence of the protein, typically at the beginning (N-terminus) of the polypeptide chain, plays a dual role. It not only targets the ribosome to the ER but also triggers the opening of the translocator. As the protein is fed through the translocator, the signal sequence stays attached, allowing the rest of the protein to move through as a loop. A signal peptidase inside the ER then cuts off the signal sequence, which is subsequently discarded into the lipid bilayer of the ER membrane and broken down.
Finally, once the last part of the protein (the C-terminus) passes through the translocator, the entire soluble protein is released into the ER lumen, where it can then fold and undergo further modifications or be transported to its final destination.
====== Mechanisms of transmembrane protein integration ======
Transmembrane proteins, which are partly integrated into the ER membrane rather than released into the ER lumen, have a complex assembly process. The initial stages are similar to soluble proteins: a signal sequence starts the insertion into the ER membrane. However, this process is interrupted by a stop-transfer sequence—a string of hydrophobic amino acids—which causes the translocator to halt and release the protein laterally into the membrane. This results in a single-pass transmembrane protein with one end inside the ER lumen and the other in the cytosol, and this orientation is permanent.
Some transmembrane proteins use an internal signal (start-transfer sequence) instead of one at the N-terminus, and unlike the initial signal sequence, this start-transfer sequence isn't removed. It begins the transfer process, which continues until a stop-transfer sequence is encountered, at which point both sequences become anchored in the membrane as alpha-helical segments.
In more complex proteins that span the membrane multiple times, additional pairs of start- and stop-transfer sequences are used to weave the protein into the membrane in a fashion akin to a sewing machine. Each pair allows a new segment to cross the membrane and adds to the protein's structure, ensuring it is properly embedded with the correct arrangement of segments inside and outside the ER membrane.
=== Peroxisomes ===
Peroxisomes contain a single phospholipid bilayer that surrounds the peroxisomal matrix containing a wide variety of proteins and enzymes that participate in anabolism and catabolism. Peroxisomes are specialized cell organelles that carry out specific oxidative reactions using molecular oxygen. Their primary function is to remove hydrogen atoms from organic molecules, a process that results in the production of hydrogen peroxide (H2O2). Within peroxisomes, an enzyme called catalase plays a critical role. It uses the hydrogen peroxide generated in the earlier reaction to oxidize various other substances, including phenols, formic acid, formaldehyde, and alcohol. This is known as the "peroxidative" reaction.
Peroxisomes are particularly important in liver and kidney cells for detoxifying harmful substances that enter the bloodstream. For example, they are responsible for oxidizing about 25% of the ethanol we consume into acetaldehyde. Additionally, catalase within peroxisomes can break down excess hydrogen peroxide into water and oxygen and thus preventing potential damage from the build-up of H2O2. Since it contains no internal DNA like that of the mitochondria or chloroplast all peroxisomal proteins are encoded by nuclear genes. To date there are two types of known Peroxisome Targeting Signals (PTS):
Peroxisome targeting signal 1 (PTS1): a C-terminal tripeptide with a consensus sequence (S/A/C)-(K/R/H)-(L/A). The most common PTS1 is serine-lysine-leucine (SKL). The initial research that led to the discovery of this consensus observed that when firefly luciferase was expressed in cultured insect cells it was targeted to the peroxisome. By testing a variety of mutations in the gene encoding the expressed luciferase, the consensus sequence was then determined. It has also been found that by adding this C-terminal sequence of SKL to a cytosolic protein that it becomes targeted for transport to the peroxisome. The majority of peroxisomal matrix proteins possess this PTS1 type signal.
Peroxisome targeting signal 2 (PTS2): a nonapeptide located near the N-terminus with a consensus sequence (R/K)-(L/V/I)-XXXXX-(H/Q)-(L/A/F) (where X can be any amino acid).
There are also proteins that possess neither of these signals. Their transport may be based on a so-called "piggy-back" mechanism: such proteins associate with PTS1-possessing matrix proteins and are translocated into the peroxisomal matrix together with them.
In the case of cytosolic proteins that are produced with the PTS1 C-terminal sequence, its path to the peroxisomal matrix is dependent upon binding to another cytosolic protein called pex5 (peroxin 5). Once bound, pex5 interacts with a peroxisomal membrane protein pex14 to form a complex. When the pex5 protein with bound cargo interacts with the pex14 membrane protein, the complex induces the release of the targeted protein into the matrix. Upon releasing the cargo protein into the matrix, pex5 dissociation from pex14 occurs via ubiquitinylation by a membrane complex comprising pex2, pex12, and pex10 followed by an ATP dependent removal involving the cytosolic protein complex pex1 and pex6. The cycle for pex5 mediated import into the peroxisomal matrix is restored after the ATP dependent removal of ubiquitin and is free to bind with another protein containing a PTS1 sequence. Proteins containing a PTS2 targeting sequence are mediated by a different cytosolic protein but are believed to follow a similar mechanism to that of those containing the PTS1 sequence.
== Diseases ==
Protein transport is defective in the following genetic diseases:
Mohr–Tranebjaerg syndrome
Zellweger syndrome
Adrenoleukodystrophy (ALD).
Refsum disease
Parkinson's disease
Hypercholesterolemia, atherosclerosis, obesity, and diabetes
== In bacteria and archaea ==
As discussed above (see protein translocation), most prokaryotic membrane-bound and secretory proteins are targeted to the plasma membrane by either a co-translation pathway that uses bacterial SRP or a post-translation pathway that requires SecA and SecB. At the plasma membrane, these two pathways deliver proteins to the SecYEG translocon for translocation. Bacteria may have a single plasma membrane (Gram-positive bacteria), or an inner membrane plus an outer membrane separated by the periplasm (Gram-negative bacteria). Besides the plasma membrane the majority of prokaryotes lack membrane-bound organelles as found in eukaryotes, but they may assemble proteins onto various types of inclusions such as gas vesicles and storage granules.
=== Gram-negative bacteria ===
In gram-negative bacteria proteins may be incorporated into the plasma membrane, the outer membrane, the periplasm or secreted into the environment. Systems for secreting proteins across the bacterial outer membrane may be quite complex and play key roles in pathogenesis. These systems may be described as type I secretion, type II secretion, etc.
=== Gram-positive bacteria ===
In most gram-positive bacteria, certain proteins are targeted for export across the plasma membrane and subsequent covalent attachment to the bacterial cell wall. A specialized enzyme, sortase, cleaves the target protein at a characteristic recognition site near the protein C-terminus, such as an LPXTG motif (where X can be any amino acid), then transfers the protein onto the cell wall. Several analogous systems are found that likewise feature a signature motif on the extra-cytoplasmic face, a C-terminal transmembrane domain, and cluster of basic residues on the cytosolic face at the protein's extreme C-terminus. The PEP-CTERM/exosortase system, found in many Gram-negative bacteria, seems to be related to extracellular polymeric substance production. The PGF-CTERM/archaeosortase A system in archaea is related to S-layer production. The GlyGly-CTERM/rhombosortase system, found in the Shewanella, Vibrio, and a few other genera, seems involved in the release of proteases, nucleases, and other enzymes.
== Bioinformatic tools ==
Minimotif Miner is a bioinformatics tool that searches protein sequence queries for a known protein targeting sequence motifs.
Phobius predicts signal peptides based on a supplied primary sequence.
SignalP predicts signal peptide cleavage sites.
LOCtree Archived 2021-12-21 at the Wayback Machine predicts the subcellular localization of proteins.
== Notes ==
== See also ==
Bulk flow
COPI
COPII
Clathrin
LocDB
PSORTdb
Signal peptide
== References ==
== External links ==
Protein+Transport at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Protein_translocation |
In biochemistry, globular proteins or spheroproteins are spherical ("globe-like") proteins and are one of the common protein types (the others being fibrous, disordered and membrane proteins). Globular proteins are somewhat water-soluble (forming colloids in water), unlike the fibrous or membrane proteins. There are multiple fold classes of globular proteins, since there are many different architectures that can fold into a roughly spherical shape.
The term globin can refer more specifically to proteins including the globin fold.
== Globular structure and solubility ==
The term globular protein is quite old (dating probably from the 19th century) and is now somewhat archaic given the hundreds of thousands of proteins and more elegant and descriptive structural motif vocabulary. The globular nature of these proteins can be determined without the means of modern techniques, but only by using ultracentrifuges or dynamic light scattering techniques.
The spherical structure is induced by the protein's tertiary structure. The molecule's apolar (hydrophobic) amino acids are bounded towards the molecule's interior whereas polar (hydrophilic) amino acids are bound outwards, allowing dipole–dipole interactions with the solvent, which explains the molecule's solubility.
Globular proteins are only marginally stable because the free energy released when the protein folded into its native conformation is relatively small. This is because protein folding requires entropic cost. As a primary sequence of a polypeptide chain can form numerous conformations, native globular structure restricts its conformation to a few only. It results in a decrease in randomness, although non-covalent interactions such as hydrophobic interactions stabilize the structure.
=== Protein folding ===
Although it is still unknown how proteins fold up naturally, new evidence has helped advance understanding. Part of the protein folding problem is that several non-covalent, weak interactions are formed, such as hydrogen bonds and Van der Waals interactions. Via several techniques, the mechanism of protein folding is currently being studied. Even in the protein's denatured state, it can be folded into the correct structure.
Globular proteins seem to have two mechanisms for protein folding, either the diffusion-collision model or nucleation condensation model, although recent findings have shown globular proteins, such as PTP-BL PDZ2, that fold with characteristic features of both models. These new findings have shown that the transition states of proteins may affect the way they fold. The folding of globular proteins has also recently been connected to treatment of diseases, and anti-cancer ligands have been developed which bind to the folded but not the natural protein. These studies have shown that the folding of globular proteins affects its function.
By the second law of thermodynamics, the free energy difference between unfolded and folded states is contributed by enthalpy and entropy changes. As the free energy difference in a globular protein that results from folding into its native conformation is small, it is marginally stable, thus providing a rapid turnover rate and effective control of protein degradation and synthesis.
== Role ==
Unlike fibrous proteins which only play a structural function, globular proteins can act as:
Enzymes, by catalyzing organic reactions taking place in the organism in mild conditions and with a great specificity. Different esterases fulfill this role.
Messengers, by transmitting messages to regulate biological processes. This function is done by hormones, i.e. insulin etc.
Transporters of other molecules through membranes
Stocks of amino acids.
Regulatory roles are also performed by globular proteins rather than fibrous proteins.
Structural proteins, e.g., actin and tubulin, which are globular and soluble as monomers, but polymerize to form long, stiff fibers
== Members ==
Among the most known globular proteins is hemoglobin, a member of the globin protein family. Other globular proteins are the alpha, beta and gamma (IgA, IgD, IgE, IgG and IgM) globulin. See protein electrophoresis for more information on the different globulins. Nearly all enzymes with major metabolic functions are globular in shape, as well as many signal transduction proteins.
Albumins are also globular proteins, although, unlike all of the other globular proteins, they are completely soluble in water. They are not soluble in oil.
== References == | Wikipedia/Globular_proteins |
Protein quinary structure refers to the features of protein surfaces that are shaped by evolutionary adaptation to the physiological context of living cells. Quinary structure is thus the fifth level of protein complexity, additional to protein primary, secondary, tertiary and quaternary structures. As opposed to the first four levels of protein structure, which are relevant to isolated proteins in dilute conditions, quinary structure emerges from the crowdedness of the cellular context, in which transient encounters among macromolecules are constantly occurring.
In order to perform their functions, proteins often need to find a specific counterpart to which they will bind in a relatively long encounter. In a very crowded cytosol, in which proteins engage in a vast and complex network of attracting and repelling interactions, such search becomes challenging, because it involves sampling a huge space of possible partners, of which very few will be productive. A solution to this challenge requires that proteins spend as little time as possible on each encounter, so that they can explore a larger number of surfaces, while simultaneously making this interaction as intimate as possible, so if they do come across the right partner, they will not miss it. In this sense, quinary structure is the result of a series of adaptations present in protein surfaces, which allow proteins to navigate the complexity of the cellular environment.
== Early observations ==
With the sense with which it is used today, the term quinary structure first appeared in the work of McConkey, in 1989. In his work, McConkey runs 2D electrophoresis gels on the total protein content of hamster (CHO) and human (HeLa) cells. In a 2D electrophoresis gel experiment, the coordinates of a protein depend on its molecular weight and its isoelectric point. Given the evolutionary distance between humans and hamsters, and considering evolutionary rates typical of mammals, one would expect a large number of substitutions to have occurred between hamsters and humans, a fraction of which would involve acidic (aspartate and glutamate) and basic (arginine and lysine) residues, resulting in changes in the isoelectric point of many proteins. Strikingly, hamster and human cells yielded almost identical fingerprints in the experiment, implying that many fewer of those substitutions actually took place. McConkey suggested in that paper that the reason why the proteins of humans and hamsters had not diverged as much he anticipated was that an additional selective pressure must have been related to the many non-specific “interactions that are inherently transient” experienced by proteins in the cytoplasm and which “constitute the fifth level of protein organization”.
== Protein interactions and quinary structure ==
Despite the crudeness of McConkey's experiment, his interpretation of the results have proved to be accurate. Rather than simply being hydrophilic, protein surfaces must have carefully been modulated by evolution and adapted to this network of weak interactions, often called quinary interactions. It is important to note that protein-protein interactions responsible for the emergence of quinary structure are fundamentally different from specific protein encounters. The latter are the result of relatively high-stability binding, often linked to functionally meaningful events –many of which have already been described – while the former are often interpreted as some background noise of physiologically unproductive misinteractions that complicate the interpretation of protein networks and need to be avoided, so that normal cellular functions can proceed.
The transient nature of these protein encounters complicates the study of quinary structure. Indeed, the interactions responsible for this upper level of protein organisation are weak and short-lived, and hence would not produce protein-protein complexes that could be isolated by conventional biochemical methods. Therefore, quinary structure can only be understood in vivo.
== In-cell NMR and quinary structure ==
In-cell NMR is an experimental technique prominent in the research field of protein quinary structure. The physical principle of in-cell NMR measurements is identical to that of conventional protein NMR, but the experiments rely on expressing high concentrations of the probe protein, which should remain soluble and contained in the cellular space; which introduces additional difficulties and limitations. However, these experiments provide critical insights about the cross-talk between a probe protein and the intracellular environment.
Early attempts at using in-cell NMR to study protein quinary structure were hindered by a limitation caused by the very phenomenon they were trying to understand. Many probe proteins tested in these experiments turned out to produce broad signals, near the detection limit of the method, when measured inside cells of Escherichia coli. In particular, these proteins seemed to tumble as if they had molecular weights much larger than those corresponding to their size. These observations seemed to indicate that the proteins were sticking to other macromolecules, which would have led to poor relaxation properties
Other in-cell NMR experiments showed that single amino acid changes of surface residues could be used to consistently modulate the tumbling of three different proteins inside bacterial cells. Charged and hydrophobic residues were shown to have the largest impact in protein intracellular mobility. In particular, more negatively charged proteins would tumble faster in comparison with near-null or positively charged proteins. In contrast, the presence of many hydrophobic residues in the protein surface would slow down protein intracellular tumbling. Protein dipole moment, a measure of charge separation across the protein, was shown to have a significant contribution to protein mobility, where high dipole moments would correlate with slower tumbling.
== References == | Wikipedia/Protein_quinary_structure |
Motor proteins are a class of molecular motors that can move along the cytoskeleton of cells. They do this by converting chemical energy into mechanical work by the hydrolysis of ATP.
== Cellular functions ==
Motor proteins are the driving force behind most active transport of proteins and vesicles in the cytoplasm. Kinesins and cytoplasmic dyneins play essential roles in intracellular transport such as axonal transport and in the formation of the spindle apparatus and the separation of the chromosomes during mitosis and meiosis. Axonemal dynein, found in cilia and flagella, is crucial to cell motility, for example in spermatozoa, and fluid transport, for example in trachea. The muscle protein myosin "motors" the contraction of muscle fibers in animals.
== Diseases associated with motor protein defects ==
The importance of motor proteins in cells becomes evident when they fail to fulfill their function. For example, kinesin deficiencies have been identified as the cause for Charcot-Marie-Tooth disease and some kidney diseases. Dynein deficiencies can lead to chronic infections of the respiratory tract as cilia fail to function without dynein. Numerous myosin deficiencies are related to disease states and genetic syndromes. Because myosin II is essential for muscle contraction, defects in muscular myosin predictably cause myopathies. Myosin is necessary in the process of hearing because of its role in the growth of stereocilia so defects in myosin protein structure can lead to Usher syndrome and non-syndromic deafness.
== Cytoskeletal motor proteins ==
Motor proteins utilizing the cytoskeleton for movement fall into two categories based on their substrate: microfilaments or microtubules. Actin-based motor proteins (myosin) move along microfilaments through interaction with actin, and microtubule motors (dynein and kinesin) move along microtubules through interaction with tubulin.
There are two basic types of microtubule motors: plus-end motors and minus-end motors, depending on the direction in which they "walk" along the microtubule cables within the cell.
=== Actin motors ===
==== Myosin ====
Myosins are a superfamily of actin motor proteins that convert chemical energy in the form of ATP to mechanical energy, thus generating force and movement. The first identified myosin, myosin II, is responsible for generating muscle contraction. Myosin II is an elongated protein that is formed from two heavy chains with motor heads and two light chains. Each myosin head contains actin and ATP binding site. The myosin heads bind and hydrolyze ATP, which provides the energy to walk toward the plus end of an actin filament. Myosin II are also vital in the process of cell division. For example, non-muscle myosin II bipolar thick filaments provide the force of contraction needed to divide the cell into two daughter cells during cytokinesis. In addition to myosin II, many other myosin types are responsible for variety of movement of non-muscle cells. For example, myosin is involved in intracellular organization and the protrusion of actin-rich structures at the cell surface. Myosin V is involved in vesicle and organelle transport. Myosin XI is involved in cytoplasmic streaming, wherein movement along microfilament networks in the cell allows organelles and cytoplasm to stream in a particular direction. Eighteen different classes of myosins are known.
Genomic representation of myosin motors:
Fungi (yeast): 5
Plants (Arabidopsis): 17
Insects (Drosophila): 13
Mammals (human): 40
Chromadorea ( nematode C. elegans): 15
=== Microtubule motors ===
==== Kinesin ====
Kinesins are a superfamily of related motor proteins that use a microtubule track in anterograde movement. They are vital to spindle formation in mitotic and meiotic chromosome separation during cell division and are also responsible for shuttling mitochondria, Golgi bodies, and vesicles within eukaryotic cells. Kinesins have two heavy chains and two light chains per active motor. The two globular head motor domains in heavy chains can convert the chemical energy of ATP hydrolysis into mechanical work to move along microtubules. The direction in which cargo is transported can be towards the plus-end or the minus-end, depending on the type of kinesin. In general, kinesins with N-terminal motor domains move their cargo towards the plus ends of microtubules located at the cell periphery, while kinesins with C-terminal motor domains move cargo towards the minus ends of microtubules located at the nucleus. Fourteen distinct kinesin families are known, with some additional kinesin-like proteins that cannot be classified into these families.
Genomic representation of kinesin motors:
Fungi (yeast): 6
Plants (Arabidopsis thaliana): 61
Insects (Drosophila melanogaster): 25
Mammals (human): 45
==== Dynein ====
Dyneins are microtubule motors capable of a retrograde sliding movement. Dynein complexes are much larger and more complex than kinesin and myosin motors. Dyneins are composed of two or three heavy chains and a large and variable number of associated light chains. Dyneins drive intracellular transport toward the minus end of microtubules which lies in the microtubule organizing center near the nucleus. The dynein family has two major branches. Axonemal dyneins facilitate the beating of cilia and flagella by rapid and efficient sliding movements of microtubules. Another branch is cytoplasmic dyneins which facilitate the transport of intracellular cargos. Compared to 15 types of axonemal dynein, only two cytoplasmic forms are known.
Genomic representation of dynein motors:
Fungi (yeast): 1
Plants (Arabidopsis thaliana): 0
Insects (Drosophila melanogaster): 13
Mammals (human): 14-15
=== Plant-specific motors ===
In contrast to animals, fungi and non-vascular plants, the cells of flowering plants lack dynein motors. However, they contain a larger number of different kinesins. Many of these plant-specific kinesin groups are specialized for functions during plant cell mitosis. Plant cells differ from animal cells in that they have a cell wall. During mitosis, the new cell wall is built by the formation of a cell plate starting in the center of the cell. This process is facilitated by a phragmoplast, a microtubule array unique to plant cell mitosis. The building of cell plate and ultimately the new cell wall requires kinesin-like motor proteins.
Another motor protein essential for plant cell division is kinesin-like calmodulin-binding protein (KCBP), which is unique to plants and part kinesin and part myosin.
== Other molecular motors ==
Besides the motor proteins above, there are many more types of proteins capable of generating forces and torque in the cell. Many of these molecular motors are ubiquitous in both prokaryotic and eukaryotic cells, although some, such as those involved with cytoskeletal elements or chromatin, are unique to eukaryotes. The motor protein prestin, expressed in mammalian cochlear outer hair cells, produces mechanical amplification in the cochlea. It is a direct voltage-to-force converter, which operates at the microsecond rate and possesses piezoelectric properties.
== See also ==
ATP synthase
Cytoskeleton
Protein dynamics
== References ==
== External links ==
MBInfo - What are Motor Proteins?
Ron Vale's Seminar: "Molecular Motor Proteins"
Biology of Motor Proteins Institute for Biophysical Chemistry, Göttingen
Jonathan Howard (2001), Mechanics of motor proteins and the cytoskeleton. ISBN 9780878933334 | Wikipedia/Motor_protein |
Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers – specifically polypeptides – formed from sequences of amino acids, which are the monomers of the polymer. A single amino acid monomer may also be called a residue, which indicates a repeating unit of a polymer. Proteins form by amino acids undergoing condensation reactions, in which the amino acids lose one water molecule per reaction in order to attach to one another with a peptide bond. By convention, a chain under 30 amino acids is often identified as a peptide, rather than a protein. To be able to perform their biological function, proteins fold into one or more specific spatial conformations driven by a number of non-covalent interactions, such as hydrogen bonding, ionic interactions, Van der Waals forces, and hydrophobic packing. To understand the functions of proteins at a molecular level, it is often necessary to determine their three-dimensional structure. This is the topic of the scientific field of structural biology, which employs techniques such as X-ray crystallography, NMR spectroscopy, cryo-electron microscopy (cryo-EM) and dual polarisation interferometry, to determine the structure of proteins.
Protein structures range in size from tens to several thousand amino acids. By physical size, proteins are classified as nanoparticles, between 1–100 nm. Very large protein complexes can be formed from protein subunits. For example, many thousands of actin molecules assemble into a microfilament.
A protein usually undergoes reversible structural changes in performing its biological function. The alternative structures of the same protein are referred to as different conformations, and transitions between them are called conformational changes.
== Levels of protein structure ==
There are four distinct levels of protein structure.
=== Primary structure ===
The primary structure of a protein refers to the sequence of amino acids in the polypeptide chain. The primary structure is held together by peptide bonds that are made during the process of protein biosynthesis. The two ends of the polypeptide chain are referred to as the carboxyl terminus (C-terminus) and the amino terminus (N-terminus) based on the nature of the free group on each extremity. Counting of residues always starts at the N-terminal end (NH2-group), which is the end where the amino group is not involved in a peptide bond. The primary structure of a protein is determined by the gene corresponding to the protein. A specific sequence of nucleotides in DNA is transcribed into mRNA, which is read by the ribosome in a process called translation. The sequence of amino acids in insulin was discovered by Frederick Sanger, establishing that proteins have defining amino acid sequences. The sequence of a protein is unique to that protein, and defines the structure and function of the protein. The sequence of a protein can be determined by methods such as Edman degradation or tandem mass spectrometry. Often, however, it is read directly from the sequence of the gene using the genetic code. It is strictly recommended to use the words "amino acid residues" when discussing proteins because when a peptide bond is formed, a water molecule is lost, and therefore proteins are made up of amino acid residues. Post-translational modifications such as phosphorylations and glycosylations are usually also considered a part of the primary structure, and cannot be read from the gene. For example, insulin is composed of 51 amino acids in 2 chains. One chain has 31 amino acids, and the other has 20 amino acids.
=== Secondary structure ===
Secondary structure refers to highly regular local sub-structures on the actual polypeptide backbone chain. Two main types of secondary structure, the α-helix and the β-strand or β-sheets, were suggested in 1951 by Linus Pauling. These secondary structures are defined by patterns of hydrogen bonds between the main-chain peptide groups. They have a regular geometry, being constrained to specific values of the dihedral angles ψ and φ on the Ramachandran plot. Both the α-helix and the β-sheet represent a way of saturating all the hydrogen bond donors and acceptors in the peptide backbone. Some parts of the protein are ordered but do not form any regular structures. They should not be confused with random coil, an unfolded polypeptide chain lacking any fixed three-dimensional structure. Several sequential secondary structures may form a "supersecondary unit".
=== Tertiary structure ===
Tertiary structure refers to the three-dimensional structure created by a single protein molecule (a single polypeptide chain). It may include one or several domains. The α-helices and β-pleated-sheets are folded into a compact globular structure. The folding is driven by the non-specific hydrophobic interactions, the burial of hydrophobic residues from water, but the structure is stable only when the parts of a protein domain are locked into place by specific tertiary interactions, such as salt bridges, hydrogen bonds, and the tight packing of side chains and disulfide bonds. The disulfide bonds are extremely rare in cytosolic proteins, since the cytosol (intracellular fluid) is generally a reducing environment.
=== Quaternary structure ===
Quaternary structure is the three-dimensional structure consisting of the aggregation of two or more individual polypeptide chains (subunits) that operate as a single functional unit (multimer). The resulting multimer is stabilized by the same non-covalent interactions and disulfide bonds as in tertiary structure. There are many possible quaternary structure organisations. Complexes of two or more polypeptides (i.e. multiple subunits) are called multimers. Specifically it would be called a dimer if it contains two subunits, a trimer if it contains three subunits, a tetramer if it contains four subunits, and a pentamer if it contains five subunits, and so forth. The subunits are frequently related to one another by symmetry operations, such as a 2-fold axis in a dimer. Multimers made up of identical subunits are referred to with a prefix of "homo-" and those made up of different subunits are referred to with a prefix of "hetero-", for example, a heterotetramer, such as the two alpha and two beta chains of hemoglobin.
=== Homomers ===
An assemblage of multiple copies of a particular polypeptide chain can be described as a homomer, multimer or oligomer. Bertolini et al. in 2021 presented evidence that homomer formation may be driven by interaction between nascent polypeptide chains as they are translated from mRNA by nearby adjacent ribosomes. Hundreds of proteins have been identified as being assembled into homomers in human cells. The process of assembly is often initiated by the interaction of the N-terminal region of polypeptide chains. Evidence that numerous gene products form homomers (multimers) in a variety of organisms based on intragenic complementation evidence was reviewed in 1965.
== Domains, motifs, and folds in protein structure ==
Proteins are frequently described as consisting of several structural units. These units include domains, motifs, and folds. Despite the fact that there are about 100,000 different proteins expressed in eukaryotic systems, there are many fewer different domains, structural motifs and folds.
=== Structural domain ===
A structural domain is an element of the protein's overall structure that is self-stabilizing and often folds independently of the rest of the protein chain. Many domains are not unique to the protein products of one gene or one gene family but instead appear in a variety of proteins. Domains often are named and singled out because they figure prominently in the biological function of the protein they belong to; for example, the "calcium-binding domain of calmodulin". Because they are independently stable, domains can be "swapped" by genetic engineering between one protein and another to make chimera proteins. A conservative combination of several domains that occur in different proteins, such as protein tyrosine phosphatase domain and C2 domain pair, was called "a superdomain" that may evolve as a single unit.
=== Structural and sequence motifs ===
The structural and sequence motifs refer to short segments of protein three-dimensional structure or amino acid sequence that were found in a large number of different proteins
=== Supersecondary structure ===
Tertiary protein structures can have multiple secondary elements on the same polypeptide chain. The supersecondary structure refers to a specific combination of secondary structure elements, such as β-α-β units or a helix-turn-helix motif. Some of them may be also referred to as structural motifs.
=== Protein fold ===
A protein fold refers to the general protein architecture, like a helix bundle, β-barrel, Rossmann fold or different "folds" provided in the Structural Classification of Proteins database. A related concept is protein topology.
== Protein dynamics and conformational ensembles ==
Proteins are not static objects, but rather populate ensembles of conformational states. Transitions between these states typically occur on nanoscales, and have been linked to functionally relevant phenomena such as allosteric signaling and enzyme catalysis. Protein dynamics and conformational changes allow proteins to function as nanoscale biological machines within cells, often in the form of multi-protein complexes. Examples include motor proteins, such as myosin, which is responsible for muscle contraction, kinesin, which moves cargo inside cells away from the nucleus along microtubules, and dynein, which moves cargo inside cells towards the nucleus and produces the axonemal beating of motile cilia and flagella. "[I]n effect, the [motile cilium] is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines...Flexible linkers allow the mobile protein domains connected by them to recruit their binding partners and induce long-range allostery via protein domain dynamics. "
Proteins are often thought of as relatively stable tertiary structures that experience conformational changes after being affected by interactions with other proteins or as a part of enzymatic activity. However, proteins may have varying degrees of stability, and some of the less stable variants are intrinsically disordered proteins. These proteins exist and function in a relatively 'disordered' state lacking a stable tertiary structure. As a result, they are difficult to describe by a single fixed tertiary structure. Conformational ensembles have been devised as a way to provide a more accurate and 'dynamic' representation of the conformational state of intrinsically disordered proteins.
Protein ensemble files are a representation of a protein that can be considered to have a flexible structure. Creating these files requires determining which of the various theoretically possible protein conformations actually exist. One approach is to apply computational algorithms to the protein data in order to try to determine the most likely set of conformations for an ensemble file. There are multiple methods for preparing data for the Protein Ensemble Database that fall into two general methodologies – pool and molecular dynamics (MD) approaches (diagrammed in the figure). The pool based approach uses the protein's amino acid sequence to create a massive pool of random conformations. This pool is then subjected to more computational processing that creates a set of theoretical parameters for each conformation based on the structure. Conformational subsets from this pool whose average theoretical parameters closely match known experimental data for this protein are selected. The alternative molecular dynamics approach takes multiple random conformations at a time and subjects all of them to experimental data. Here the experimental data is serving as limitations to be placed on the conformations (e.g. known distances between atoms). Only conformations that manage to remain within the limits set by the experimental data are accepted. This approach often applies large amounts of experimental data to the conformations which is a very computationally demanding task.
The conformational ensembles were generated for a number of highly dynamic and partially unfolded proteins, such as Sic1/Cdc4, p15 PAF, MKK7, Beta-synuclein and P27
== Protein folding ==
As it is translated, polypeptides exit the ribosome mostly as a random coil and folds into its native state. The final structure of the protein chain is generally assumed to be determined by its amino acid sequence (Anfinsen's dogma).
== Protein stability ==
Thermodynamic stability of proteins represents the free energy difference between the folded and unfolded protein states. This free energy difference is very sensitive to temperature, hence a change in temperature may result in unfolding or denaturation. Protein denaturation may result in loss of function, and loss of native state. The free energy of stabilization of soluble globular proteins typically does not exceed 50 kJ/mol. Taking into consideration the large number of hydrogen bonds that take place for the stabilization of secondary structures, and the stabilization of the inner core through hydrophobic interactions, the free energy of stabilization emerges as small difference between large numbers.
== Protein structure determination ==
Around 90% of the protein structures available in the Protein Data Bank have been determined by X-ray crystallography. This method allows one to measure the three-dimensional (3-D) density distribution of electrons in the protein, in the crystallized state, and thereby infer the 3-D coordinates of all the atoms to be determined to a certain resolution. Roughly 7% of the known protein structures have been obtained by nuclear magnetic resonance (NMR) techniques. For larger protein complexes, cryo-electron microscopy can determine protein structures. The resolution is typically lower than that of X-ray crystallography, or NMR, but the maximum resolution is steadily increasing. This technique is still a particularly valuable for very large protein complexes such as virus coat proteins and amyloid fibers.
General secondary structure composition can be determined via circular dichroism. Vibrational spectroscopy can also be used to characterize the conformation of peptides, polypeptides, and proteins. Two-dimensional infrared spectroscopy has become a valuable method to investigate the structures of flexible peptides and proteins that cannot be studied with other methods. A more qualitative picture of protein structure is often obtained by proteolysis, which is also useful to screen for more crystallizable protein samples. Novel implementations of this approach, including fast parallel proteolysis (FASTpp), can probe the structured fraction and its stability without the need for purification. Once a protein's structure has been experimentally determined, further detailed studies can be done computationally, using molecular dynamic simulations of that structure.
== Protein structure databases ==
A protein structure database is a database that is modeled around the various experimentally determined protein structures. The aim of most protein structure databases is to organize and annotate the protein structures, providing the biological community access to the experimental data in a useful way. Data included in protein structure databases often includes 3D coordinates as well as experimental information, such as unit cell dimensions and angles for x-ray crystallography determined structures. Though most instances, in this case either proteins or a specific structure determinations of a protein, also contain sequence information and some databases even provide means for performing sequence based queries, the primary attribute of a structure database is structural information, whereas sequence databases focus on sequence information, and contain no structural information for the majority of entries. Protein structure databases are critical for many efforts in computational biology such as structure based drug design, both in developing the computational methods used and in providing a large experimental dataset used by some methods to provide insights about the function of a protein.
== Structural classifications of proteins ==
Protein structures can be grouped based on their structural similarity, topological class or a common evolutionary origin. The Structural Classification of Proteins database and CATH database provide two different structural classifications of proteins. When the structural similarity is large the two proteins have possibly diverged from a common ancestor, and shared structure between proteins is considered evidence of homology. Structure similarity can then be used to group proteins together into protein superfamilies. If shared structure is significant but the fraction shared is small, the fragment shared may be the consequence of a more dramatic evolutionary event such as horizontal gene transfer, and joining proteins sharing these fragments into protein superfamilies is no longer justified. Topology of a protein can be used to classify proteins as well. Knot theory and circuit topology are two topology frameworks developed for classification of protein folds based on chain crossing and intrachain contacts respectively.
== Computational prediction of protein structure ==
The generation of a protein sequence is much easier than the determination of a protein structure. However, the structure of a protein gives much more insight in the function of the protein than its sequence. Therefore, a number of methods for the computational prediction of protein structure from its sequence have been developed. Ab initio prediction methods use just the sequence of the protein. Threading and homology modeling methods can build a 3-D model for a protein of unknown structure from experimental structures of evolutionarily-related proteins, called a protein family.
== See also ==
Biomolecular structure
Gene structure
Nucleic acid structure
PCRPi-DB
Ribbon diagram 3D schematic representation of proteins
== References ==
== Further reading ==
50 Years of Protein Structure Determination Timeline - HTML Version - National Institute of General Medical Sciences Archived 29 October 2018 at the Wayback Machine at NIH
== External links ==
Media related to Protein structures at Wikimedia Commons
Protein Structure drugdesign.org
[1] Method_for_the_Characterization_of_the_Three-Dimensional_Structure_of_Proteins_Employing_Mass_Spectrometric_Analysis_and_Experimental-Computational_Feedback_Modeling
[2] A_Method_for_the_Determination_of_the_Conformation_(Topology)_of_Proteins_Employing_Experimental-Computational_Feedback_Modeling | Wikipedia/Protein_conformation |
The Bradford protein assay (also known as the Coomassie protein assay) was developed by Marion M. Bradford in 1976. It is a quick and accurate spectroscopic analytical procedure used to measure the concentration of protein in a solution. The reaction is dependent on the amino acid composition of the measured proteins.
== Principle ==
The Bradford assay, a colorimetric protein assay, is based on an absorbance shift of the dye Coomassie brilliant blue G-250. The Coomassie brilliant blue G-250 dye exists in three forms: anionic (blue), neutral (green), and cationic (red). Under acidic conditions, the dye is red; as it loses acidity, the red form of the dye is converted into its blue form, binding to the protein being assayed. If there is no protein to bind, then the solution will remain brown. The dye forms a strong, noncovalent complex with the protein's carboxyl group by van der Waals force and amino group through electrostatic interactions. During the formation of this complex, the red form of Coomassie dye first donates its free electron to the ionizable groups on the protein, which causes a disruption of the protein's native state, consequently exposing its hydrophobic pockets. These pockets in the protein's tertiary structure bind non-covalently to the non-polar region of the dye via the first bond interaction (van der Waals forces) which position the positive amine groups in proximity with the negative charge of the dye. The bond is further strengthened by the second bond interaction between the two, the ionic interaction. When the dye binds to the protein, it causes a shift from 465 nm to 595 nm, which is why the absorbance readings are taken at 595 nm.
The cationic (unbound) form is green / red and has an absorption spectrum maximum historically held to be at 465 nm. The anionic bound form of the dye which is held together by hydrophobic and ionic interactions, has an absorption spectrum maximum historically held to be at 595 nm. The increase of absorbance at 595 nm is proportional to the amount of bound dye, and thus to the amount (concentration) of protein present in the sample.
Unlike other protein assays, the Bradford protein assay is less susceptible to interference by various chemical compounds such as sodium, potassium or even carbohydrates like sucrose, that may be present in protein samples. An exception of note is elevated concentrations of detergent. Sodium dodecyl sulfate (SDS), a common detergent, may be found in protein extracts because it is used to lyse cells by disrupting the membrane lipid bilayer and to denature proteins for SDS-PAGE. While other detergents interfere with the assay at high concentration, the interference caused by SDS is of two different modes, and each occurs at a different concentration. When SDS concentrations are below critical micelle concentration (known as CMC, 0.00333%W/V to 0.0667%) in a Coomassie dye solution, the detergent tends to bind strongly with the protein, inhibiting the protein binding sites for the dye reagent. This can cause underestimations of protein concentration in solution. When SDS concentrations are above CMC, the detergent associates strongly with the green form of the Coomassie dye, causing the equilibrium to shift, thereby producing more of the blue form. This causes an increase in the absorbance at 595 nm independent of protein presence.
Other interference may come from the buffer used when preparing the protein sample. A high concentration of buffer will cause an overestimated protein concentration due to depletion of free protons from the solution by conjugate base from the buffer. This will not be a problem if a low concentration of protein (subsequently the buffer) is used.
In order to measure the absorbance of a colorless compound a Bradford assay must be performed. Some colorless compounds such as proteins can be quantified at an Optical Density of 280 nm due to the presence of aromatic rings such as tryptophan, tyrosine and phenylalanine but if none of these amino acids are present then the absorption cannot be measured at 280 nm.
== Advantages ==
Many protein-containing solutions have the highest absorption at 280 nm in the spectrophotometer, the UV range. This requires spectrophotometers capable of measuring in the UV range, which many cannot. Additionally, the absorption maxima at 280 nm requires that proteins contain aromatic amino acids such as tyrosine (Y), phenylalanine (F) and/or tryptophan (W). Not all proteins contain these amino acids, a fact which will skew the concentration measurements. If nucleic acids are present in the sample, they would also absorb light at 280 nm, skewing the results further. By using the Bradford protein assay, one can avoid all of these complications by simply mixing the protein samples with the Coomassie brilliant blue G-250 dye (Bradford reagent) and measuring their absorbances at 595 nm, which is in the visible range and may be accurately measured by the use of a mobile smartphone camera.
The procedure for Bradford protein assay is very easy and simple to follow. It is done in one step where the Bradford reagent is added to a test tube along with the sample. After mixing well, the mixture almost immediately changes to a blue color. When the dye binds to the proteins through a process that takes about 2 minutes, a change in the absorption maximum of the dye from 465 nm to 595 nm in acidic solutions occurs. Additionally, protein binding triggers a metachromatic reaction, evidenced by the emergence of a species that absorbs light around 595 nm, indicative of the unprotonated form This dye creates strong noncovalent bonds with the proteins, via electrostatic interactions with the amino and carboxyl groups, as well as Van Der Waals interactions. Only the molecules that bind to the proteins in solution exhibit this change in absorption, which eliminates the concern that unbound molecules of the dye might contribute to the experimentally obtained absorption reading. This process is more beneficial since it is less pricey than other methods, easy to use, and has high sensitivity of the dye for protein.
After 5 minutes of incubation, the absorbance can be read at 595 nm using a spectrophotometer or a mobile smartphone camera (RGBradford method).
This assay is one of the fastest assays performed on proteins. The total time it takes to set up and complete the assay is under 30 minutes. The entire experiment is done at room temperature.
The Bradford protein assay can measure protein quantities as little as 1 to 20 μg. It is an extremely sensitive technique.
The dye reagent is a stable ready to use product prepared in phosphoric acid. It can remain at room temperature for up to 2 weeks before it starts to degrade.
Protein samples usually contain salts, solvents, buffers, preservatives, reducing agents and metal chelating agents. These molecules are frequently used for solubilizing and stabilizing proteins. Other protein assay like BCA and Lowry are ineffective because molecules like reducing agents interfere with the assay. Using Bradford can be advantageous against these molecules because they are compatible to each other and will not interfere.
The linear graph acquired from the assay (absorbance versus protein concentration in μg/mL) can be easily extrapolated to determine the concentration of proteins by using the slope of the line.
It is a sensitive technique. It is also very simple: measuring the OD at 595 nm after 5 minutes of incubation. This method can also make use of a Vis spectrophotometer or a mobile smartphone camera (RGBradford method).
== Disadvantages ==
The Bradford assay is linear over a short range, typically from 0 μg/mL to 2000 μg/mL, often making dilutions of a sample necessary before analysis. In making these dilutions, error in one dilution is compounded in further dilutions resulting in a linear relationship that may not always be accurate.
Basic conditions and detergents, such as SDS, can interfere with the dye's ability to bind to the protein through its side chains.
The reagents in this method tend to stain the test tubes. Same test tubes cannot be used since the stain would affect the absorbance reading. This method is also time sensitive. When more than one solution is tested, it is important to make sure every sample is incubated for the same amount of time for accurate comparison.
A limiting factor in using Coomassie-based protein determination dyes stems from the significant variation in color yield observed across different proteins This limiting factor is notably evident in collagen-rich protein samples, like pancreatic extracts, where both the Lowry and Bradford methods tend to underestimate protein content.
It is also inhibited by the presence of detergents, although this problem can be alleviated by the addition of cyclodextrins to the assay mixture.
Much of the non-linearity stems from the equilibrium between two different forms of the dye which is perturbed by adding the protein. The Bradford assay linearizes by measuring the ratio of the absorbances, 595 over 450 nm. This modified Bradford assay is approximately 10 times more sensitive than the conventional one.
The Coomassie Blue G250 dye used to bind to the proteins in the original Bradford method readily binds to arginine and lysine groups of proteins. This is a disadvantage because the preference of the dye to bind to these amino acids can result in a varied response of the assay between different proteins. Changes to the original method, such as increasing the pH by adding NaOH or adding more dye have been made to correct this variation. Although these modifications result in a less sensitive assay, a modified method becomes sensitive to detergents that can interfere with sample.
== Future of Bradford Protein Assay ==
New modifications for an improved Bradford Protein Assay have been underway that specifically focuses on enhancing detection accuracy for collagen proteins. One notable modification involves incorporating small amounts, approximately .0035%, of sodium dodecyl sulfate (SDS). This inclusion of SDS has been shown to result in a fourfold increase in color response for three key collagen proteins—Collagen types I, III, and IV—while simultaneously decreasing the absorbance of non-collagen proteins.
This simple modification in the preparation of the reagent resulted in Bradford Assays to produce similar response curves for both collagen and non-collagen proteins, expanding the use of Bradford Assays in samples containing high collagen proteins.
== Sample Bradford procedure ==
=== Materials ===
Lyophilized bovine plasma gamma globulin
Coomassie brilliant blue 1
0.15 M NaCl
Spectrophotometer and cuvettes or a mobile smartphone camera (RGBradford method).
Micropipettes
=== Procedure (Standard Assay, 20-150 μg protein; 200-1500 μg/mL) ===
Prepare a series of standards diluted with 0.15 M NaCl to final concentrations of 0 (blank = No protein), 250, 500, 750 and 1500 μg/mL. Also prepare serial dilutions of the unknown sample to be measured.
Add 100 μL of each of the above to a separate test tube (or spectrophotometer tube if using a Spectronic 20).
Add 5.0 mL of Coomassie Blue to each tube and mix by vortex, or inversion.
Adjust the spectrophotometer to a wavelength of 595 nm, using the tube which contains no protein (blank).
Wait 5 minutes and read each of the standards and each of the samples at 595 nm wavelength.
Plot the absorbance of the standards vs. their concentration. Compute the extinction coefficient and calculate the concentrations of the unknown samples.
=== Procedure (Micro Assay, 1-10 μg protein/mL) ===
Prepare standard concentrations of protein of 1, 5, 7.5 and 10 μg/mL. Prepare a blank of NaCl only. Prepare a series of sample dilutions.
Add 100 μL of each of the above to separate tubes (use microcentrifuge tubes) and add 1.0 mL of Coomassie Blue to each tube.
Turn on and adjust a spectrophotometer to a wavelength of 595 nm, and blank the spectrophotometer using 1.5 mL cuvettes or use a mobile smartphone camera (RGBradford method).
Wait 2 minutes and read the absorbance of each standard and sample at 595 nm.
Plot the absorbance of the standards vs. their concentration. Compute the extinction coefficient and calculate the concentrations of the unknown samples.
== Using data obtained to find concentration of unknown ==
In summary, in order to find a standard curve, one must use varying concentrations of BSA (Bovine Serum Albumin) in order to create a standard curve with concentration plotted on the x-axis and absorbance plotted on the y-axis. Only a narrow concentration of BSA is used (2-10 ug/mL) in order to create an accurate standard curve. Using a broad range of protein concentration will make it harder to determine the concentration of the unknown protein. This standard curve is then used to determine the concentration of the unknown protein. The following elaborates on how one goes from the standard curve to the concentration of the unknown.
First, add a line of best fit, or Linear regression and display the equation on the chart. Ideally, the R2 value will be as close to 1 as possible. R represents the sum of the square values of the fit subtracted from each data point. Therefore, if R2 is much less than one, consider redoing the experiment to get one with more reliable data.
The equation displayed on the chart gives a means for calculating the absorbance and therefore concentration of the unknown samples. In Graph 1, x is concentration and y is absorbance, so one must rearrange the equation to solve for x and enter the absorbance of the measured unknown. It is likely that the unknown will have absorbance numbers outside the range of the standard. These should not be included calculations, as the equation given cannot apply to numbers outside of its limitations.
In a large scale, one must compute the extinction coefficient using the Beer-Lambert Law A=εLC in which A is the measured absorbance, ε is the slope of the standard curve, L is the length of the cuvette, and C is the concentration being determined. In a micro scale, a cuvette may not be used and therefore one only has to rearrange to solve for x.
In order to attain a concentration that makes sense with the data, the dilutions, concentrations, and units of the unknown must be normalized (Table 1). To do this, one must divide concentration by volume of protein in order to normalize concentration and multiply by amount diluted to correct for any dilution made in the protein before performing the assay.
== Alternative assays ==
Alternative protein assays include:
Ultraviolet–visible spectroscopy
RGBradford
Biuret protein assay
Lowry protein assay
BCA protein assay
Amido black protein assay
Colloidal gold protein assay
== References ==
== Further reading ==
Bradford, M.M. (1976), "Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding", Anal. Biochem., 72 (1–2): 248–254, doi:10.1016/0003-2697(76)90527-3, PMID 942051, S2CID 4359292
Zor, T.; Selinger, Z. (1996), "Linearization of the Bradford protein assay increases its sensitivity: theoretical and experimental studies", Anal. Biochem., 236 (2): 302–308, doi:10.1006/abio.1996.0171, PMID 8660509
Noble, James E.; Bailey, Marc J.A. (2009). "Chapter 8 Quantitation of Protein". Guide to Protein Purification, 2nd Edition. Methods in Enzymology. Vol. 463. pp. 73–95. doi:10.1016/S0076-6879(09)63008-1. ISBN 9780123745361. PMID 19892168.
Albright, Brian (2009), Mathematical Modeling with Excel, Jones & Bartlett Learning, p. 60, ISBN 978-0763765668
Stephenson, Frank Harold (2003), Calculations for molecular biology and biotechnology: a guide to mathematics in the laboratory, Academic Press, pp. 252, ISBN 978-0126657517
Dennison, C. (2013). A Guide to Protein Isolation. Springer Science & Business Media. p. 39. ISBN 978-94-017-0269-0.
Ibanez, Jorge G. (2007), Environmental chemistry: fundamentals, p. 60, ISBN 978-0387260617
== External links ==
Bradford assay chemistry
Variable Pathlength Spectroscopy
OpenWetWare | Wikipedia/Bradford_protein_assay |
A protein microarray (or protein chip) is a high-throughput method used to track the interactions and activities of proteins, and to determine their function, and determining function on a large scale. Its main advantage lies in the fact that large numbers of proteins can be tracked in parallel. The chip consists of a support surface such as a glass slide, nitrocellulose membrane, bead, or microtitre plate, to which an array of capture proteins is bound. Probe molecules, typically labeled with a fluorescent dye, are added to the array. Any reaction between the probe and the immobilised protein emits a fluorescent signal that is read by a laser scanner. Protein microarrays are rapid, automated, economical, and highly sensitive, consuming small quantities of samples and reagents. The concept and methodology of protein microarrays was first introduced and illustrated in antibody microarrays (also referred to as antibody matrix) in 1983 in a scientific publication and a series of patents. The high-throughput technology behind the protein microarray was relatively easy to develop since it is based on the technology developed for DNA microarrays, which have become the most widely used microarrays.
== Motivation for development ==
Protein microarrays were developed due to the limitations of using DNA microarrays for determining gene expression levels in proteomics. The quantity of mRNA in the cell often doesn't reflect the expression levels of the proteins they correspond to. Since it is usually the protein, rather than the mRNA, that has the functional role in cell response, a novel approach was needed. Additionally post-translational modifications, which are often critical for determining protein function, are not visible on DNA microarrays. Protein microarrays replace traditional proteomics techniques such as 2D gel electrophoresis or chromatography, which were time-consuming, labor-intensive and ill-suited for the analysis of low abundant proteins.
== Making the array ==
The proteins are arrayed onto a solid surface such as microscope slides, membranes, beads or microtitre plates. The function of this surface is to provide a support onto which proteins can be immobilized. It should demonstrate maximal binding properties, whilst maintaining the protein in its native conformation so that its binding ability is retained. Microscope slides made of glass or silicon are a popular choice since they are compatible with the easily obtained robotic arrayers and laser scanners that have been developed for DNA microarray technology. Nitrocellulose film slides are broadly accepted as the highest protein binding substrate for protein microarray applications.
The chosen solid surface is then covered with a coating that must serve the simultaneous functions of immobilising the protein, preventing its denaturation, orienting it in the appropriate direction so that its binding sites are accessible, and providing a hydrophilic environment in which the binding reaction can occur. It also needs to display minimal non-specific binding in order to minimize background noise in the detection systems. Furthermore, it needs to be compatible with different detection systems. Immobilising agents include layers of aluminium or gold, hydrophilic polymers, and polyacrylamide gels, or treatment with amines, aldehyde or epoxy. Thin-film technologies like physical vapour deposition (PVD) and chemical vapour deposition (CVD) are employed to apply the coating to the support surface.
An aqueous environment is essential at all stages of array manufacture and operation to prevent protein denaturation. Therefore, sample buffers contain a high percent of glycerol (to lower the freezing point), and the humidity of the manufacturing environment is carefully regulated. Microwells have the dual advantage of providing an aqueous environment while preventing cross-contamination between samples.
In the most common type of protein array, robots place large numbers of proteins or their ligands onto a coated solid support in a pre-defined pattern. This is known as robotic contact printing or robotic spotting. Another fabrication method is ink-jetting, a drop-on-demand, non-contact method of dispersing the protein polymers onto the solid surface in the desired pattern. Piezoelectric spotting is a similar method to ink-jet printing. The printhead moves across the array, and at each spot uses electric stimulation to deliver the protein molecules onto the surface via tiny jets. This is also a non-contact process. Photolithography is a fourth method of arraying the proteins onto the surface. Light is used in association with photomasks, opaque plates with holes or transparencies that allow light to shine through in a defined pattern. A series of chemical treatments then enables deposition of the protein in the desired pattern upon the material underneath the photomask.
The capture molecules arrayed on the solid surface may be antibodies, antigens, aptamers (nucleic acid-based ligands), affibodies (small molecules engineered to mimic monoclonal antibodies), or full length proteins. Sources of such proteins include cell-based expression systems for recombinant proteins, purification from natural sources, production in vitro by cell-free translation systems, and synthetic methods for peptides. Many of these methods can be automated for high throughput production but care must be taken to avoid conditions of synthesis or extraction that result in a denatured protein which, since it no longer recognizes its binding partner, renders the array useless.
Proteins are highly sensitive to changes in their microenvironment. This presents a challenge in maintaining protein arrays in a stable condition over extended periods of time. In situ methods — invented and published by Mingyue He and Michael Taussig in 2001 — involve on-chip synthesis of proteins as and when required, directly from the DNA using cell-free protein expression systems. Since DNA is a highly stable molecule it does not deteriorate over time and is therefore suited to long-term storage. This approach is also advantageous in that it circumvents the laborious and often costly processes of separate protein purification and DNA cloning, since proteins are made and immobilised simultaneously in a single step on the chip surface. Examples of in situ techniques are PISA (protein in situ array), NAPPA (nucleic acid programmable protein array) and DAPA (DNA array to protein array).
== Types of arrays ==
There are three types of protein microarrays that are currently used to study the biochemical activities of proteins.
Analytical microarrays are also known as capture arrays. In this technique, a library of antibodies, aptamers or affibodies is arrayed on the support surface. These are used as capture molecules since each binds specifically to a particular protein. The array is probed with a complex protein solution such as a cell lysate. Analysis of the resulting binding reactions using various detection systems can provide information about expression levels of particular proteins in the sample as well as measurements of binding affinities and specificities. This type of microarray is especially useful in comparing protein expression in different solutions. For instance the response of the cells to a particular factor can be identified by comparing the lysates of cells treated with specific substances or grown under certain conditions with the lysates of control cells. Another application is in the identification and profiling of diseased tissues.
Reverse phase protein microarray (RPPA) involve complex samples, such as tissue lysates. Cells are isolated from various tissues of interest and are lysed. The lysate is arrayed onto the microarray and probed with antibodies against the target protein of interest. These antibodies are typically detected with chemiluminescent, fluorescent or colorimetric assays. Reference peptides are printed on the slides to allow for protein quantification of the sample lysates. RPAs allow for the determination of the presence of altered proteins or other agents that may be the result of disease. Specifically, post-translational modifications, which are typically altered as a result of disease can be detected using RPAs.
== Functional protein microarrays ==
Functional protein microarrays (also known as target protein arrays) are constructed by immobilising large numbers of purified proteins and are used to identify protein–protein, protein–DNA, protein–RNA, protein–phospholipid, and protein–small-molecule interactions, to assay enzymatic activity and to detect antibodies and demonstrate their specificity. They differ from analytical arrays in that functional protein arrays are composed of arrays containing full-length functional proteins or protein domains. These protein chips are used to study the biochemical activities of the entire proteome in a single experiment.
The key element in any functional protein microarray-based assay is the arrayed proteins must retain their native structure, such that meaningful functional interactions can take place on the array surface. The advantages of controlling the precise mode of surface attachment through use of an appropriate affinity tag are that the immobilised proteins will have a homogeneous orientation resulting in a higher specific activity and higher signal-to-noise ratio in assays, with less interference from non-specific interactions.
== Detection ==
Protein array detection methods must give a high signal and a low background. The most common and widely used method for detection is fluorescence labeling which is highly sensitive, safe and compatible with readily available microarray laser scanners. Other labels can be used, such as affinity, photochemical or radioisotope tags. These labels are attached to the probe itself and can interfere with the probe-target protein reaction. Therefore, a number of label free detection methods are available, such as surface plasmon resonance (SPR), carbon nanotubes, carbon nanowire sensors (where detection occurs via changes in conductance) and microelectromechanical system (MEMS) cantilevers. All these label free detection methods are relatively new and are not yet suitable for high-throughput protein interaction detection; however, they do offer much promise for the future. Immunoassays on thiol-ene "synthetic paper" micropillar scaffolds have shown to generate a superior fluorescence signal.
Protein quantitation on nitrocellulose coated glass slides can use near-IR fluorescent detection. This limits interferences due to auto-fluorescence of the nitrocellulose at the UV wavelengths used for standard fluorescent detection probes.
== Applications ==
There are five major areas where protein arrays are being applied: diagnostics, proteomics, protein functional analysis, antibody characterization, and treatment development.
Diagnostics involves the detection of antigens and antibodies in blood samples; the profiling of sera to discover new disease biomarkers; the monitoring of disease states and responses to therapy in personalized medicine; the monitoring of environment and food. Digital bioassay is an example of using protein microarray for diagnostic purposes. In this technology, an array of microwells on a glass/polymer chip are seeded with magnetic beads (coated with fluorescent tagged antibodies), subjected to targeted antigens and then characterised by a microscope through counting fluorescing wells. A cost-effective fabrication platform (using OSTE polymers) for such microwell arrays has been recently demonstrated and the bio-assay model system has been successfully characterised.
Proteomics pertains to protein expression profiling i.e. which proteins are expressed in the lysate of a particular cell.
Protein functional analysis is the identification of protein–protein interactions (e.g. identification of members of a protein complex), protein–phospholipid interactions, small molecule targets, enzymatic substrates (particularly the substrates of kinases) and receptor ligands.
Antibody characterization is characterizing cross-reactivity, specificity and mapping epitopes.
Treatment development involves the development of antigen-specific therapies for autoimmunity, cancer and allergies; the identification of small molecule targets that could potentially be used as new drugs.
== Challenges ==
Despite the considerable investments made by several companies, proteins chips have yet to flood the market. Manufacturers have found that proteins are actually quite difficult to handle. Production of reliable, consistent, high-throughput proteins that are correctly folded and functional is fraught with difficulties as they often result in low-yield of proteins due to decreased solubility and formation of inclusion bodies. A protein chip requires a lot more steps in its creation than does a DNA chip.
There are a number of approaches to this problem which differ fundamentally according to whether the proteins are immobilised through non-specific, poorly defined interactions, or through a specific set of known interactions. The former approach is attractive in its simplicity and is compatible with purified proteins derived from native or recombinant sources but suffers from a number of risks. Most notable amongst these relate to the uncontrolled nature of the interactions between each protein and the surface; at best, this might give rise to a heterogeneous population of proteins in which active sites are sometimes occluded by the surface; at worst, it might destroy activity altogether due to partial or complete surface-mediated unfolding of the immobilised protein.
Challenges include: 1) finding a surface and a method of attachment that allows the proteins to maintain their secondary or tertiary structure and thus their biological activity and their interactions with other molecules, 2) producing an array with a long shelf life so that the proteins on the chip do not denature over a short time, 3) identifying and isolating antibodies or other capture molecules against every protein in the human genome, 4) quantifying the levels of bound protein while assuring sensitivity and avoiding background noise, 5) extracting the detected protein from the chip in order to further analyze it, 6) reducing non-specific binding by the capture agents, 7) the capacity of the chip must be sufficient to allow as complete a representation of the proteome to be visualized as possible; abundant proteins overwhelm the detection of less abundant proteins such as signaling molecules and receptors, which are generally of more therapeutic interest.
== See also ==
Microarray imprinting and surface energy patterning
Label-Free Detection techniques for protein microarrays
== References == | Wikipedia/Protein_microarray |
The hierarchical equations of motion (HEOM) technique derived by Yoshitaka Tanimura and Ryogo Kubo in 1989, is a non-perturbative approach developed to study the evolution of a density matrix
ρ
(
t
)
{\displaystyle \rho (t)}
of quantum dissipative systems. The method can treat system-bath interaction non-perturbatively as well as non-Markovian noise correlation times without the hindrance of the typical assumptions that conventional Redfield (master) equations suffer from such as the Born, Markovian and rotating-wave approximations. HEOM is applicable even at low temperatures where quantum effects are not negligible.
The hierarchical equation of motion for a system in a harmonic Markovian bath is
∂
∂
t
ρ
^
n
=
−
(
i
ℏ
H
^
A
×
+
n
γ
)
ρ
^
n
−
i
ℏ
V
^
×
ρ
^
n
+
1
+
i
n
ℏ
Θ
^
ρ
^
n
−
1
{\displaystyle {\frac {\partial }{\partial t}}{\hat {\rho }}_{n}=-\left({\frac {i}{\hbar }}{\hat {H}}_{A}^{\times }+n\gamma \right){\hat {\rho }}_{n}-{i \over \hbar }{\hat {V}}^{\times }{\hat {\rho }}_{n+1}+{in \over \hbar }{\hat {\Theta }}{\hat {\rho }}_{n-1}}
where the superscript
×
{\displaystyle ^{\times }}
denoting a commutator and the temperature-dependent super-operator
Θ
^
{\displaystyle {\hat {\Theta }}}
are defined below. The parameter
γ
{\displaystyle \gamma }
is the frequency width of the Drude spectral function
J
(
ω
)
{\displaystyle J(\omega )}
(see below).
== Equations of motion for the density matrix ==
HEOMs are developed to describe the time evolution of the density matrix
ρ
(
t
)
{\displaystyle \rho (t)}
for an open quantum system. It is a non-perturbative, non-Markovian approach to propagating in time a quantum state. Motivated by the path integral formalism presented by Feynman and Vernon, Tanimura derive the HEOM from a combination of statistical and quantum dynamical techniques.
Using a two level spin-boson system Hamiltonian
H
^
=
H
^
A
(
a
^
+
,
a
^
−
)
+
V
(
a
^
+
,
a
^
−
)
∑
j
c
j
x
^
j
+
∑
j
[
p
^
2
2
+
1
2
x
^
j
2
]
{\displaystyle {\hat {H}}={\hat {H}}_{A}({\hat {a}}^{+},{\hat {a}}^{-})+V({\hat {a}}^{+},{\hat {a}}^{-})\sum _{j}c_{j}{\hat {x}}_{j}+\sum _{j}\left[{\ {\hat {p}}^{2} \over {2}}+{\frac {1}{2}}{\hat {x}}_{j}^{2}\right]}
By writing the density matrix in path integral notation and making use of Feynman–Vernon influence functional, all the bath coordinates
x
j
{\displaystyle x_{j}}
in the interaction terms can be grouped into this influence functional which in some specific cases can be calculated in closed form.
Assuming a Drude spectral function
J
(
ω
)
=
∑
j
c
j
2
δ
(
ω
−
ω
j
)
=
ℏ
η
γ
2
ω
π
(
γ
2
+
ω
2
)
{\displaystyle J(\omega )=\sum \nolimits _{j}c_{j}^{2}\delta (\omega -\omega _{j})={\frac {\hbar \eta \gamma ^{2}\omega }{\pi (\gamma ^{2}+\omega ^{2})}}}
and a high temperature heat bath, taking the time derivative of the system density matrix, and writing it in hierarchical form yields (
n
=
0
,
1
,
…
{\displaystyle n=0,1,\ldots }
)
∂
∂
t
ρ
^
n
=
−
(
i
ℏ
H
^
A
×
+
n
γ
)
ρ
^
n
−
i
ℏ
V
^
×
ρ
^
n
+
1
+
i
n
ℏ
Θ
^
ρ
^
n
−
1
{\displaystyle {\frac {\partial }{\partial t}}{\hat {\rho }}_{n}=-\left({\frac {i}{\hbar }}{\hat {H}}_{A}^{\times }+n\gamma \right){\hat {\rho }}_{n}-{i \over \hbar }{\hat {V}}^{\times }{\hat {\rho }}_{n+1}+{in \over \hbar }{\hat {\Theta }}{\hat {\rho }}_{n-1}}
Here
Θ
{\displaystyle \Theta }
reduces the system excitation and hence is referred to as the relaxation operator:
Θ
^
=
−
η
γ
β
(
V
^
×
−
i
β
ℏ
γ
2
V
^
∘
)
{\displaystyle {\hat {\Theta }}=-{\frac {\eta \gamma }{\beta }}\left({\hat {V}}^{\times }-i{\frac {\beta \hbar \gamma }{2}}{\hat {V}}^{\circ }\right)}
with the inverse temperature
β
=
1
/
k
B
T
{\displaystyle \beta =1/k_{B}T}
and the following "super-operator" notation:
A
^
×
ρ
^
=
A
^
ρ
^
−
ρ
^
A
^
A
^
∘
ρ
^
=
A
^
ρ
^
+
ρ
^
A
^
{\displaystyle {\begin{aligned}{\hat {A}}^{\times }{\hat {\rho }}&={\hat {A}}{\hat {\rho }}-{\hat {\rho }}{\hat {A}}\\{\hat {A}}^{\circ }{\hat {\rho }}&={\hat {A}}{\hat {\rho }}+{\hat {\rho }}{\hat {A}}\end{aligned}}}
The counter
n
{\displaystyle n}
provides for
n
=
0
{\displaystyle n=0}
the system density matrix.
As with Kubo's stochastic Liouville equation in hierarchical form, it goes up to infinity in the hierarchy which is a problem numerically. Tanimura and Kubo, however, provide a method by which the hierarchy can be truncated to a finite set of
N
{\displaystyle N}
differential equations. This "terminator"
N
{\displaystyle N}
defines the depth of the hierarchy and is determined by some constraint sensitive to the characteristics of the system, i.e. frequency, amplitude of fluctuations, bath coupling etc. A simple relation to eliminate the
ρ
^
n
+
1
{\displaystyle {\hat {\rho }}_{n+1}}
term is
ρ
^
N
+
1
=
−
Θ
^
ρ
^
N
/
ℏ
γ
.
{\displaystyle {\hat {\rho }}_{N+1}=-{\hat {\Theta }}{\hat {\rho }}_{N}/\hbar \gamma .}
The closing line of the hierarchy is thus:
∂
∂
t
ρ
^
N
=
−
(
i
ℏ
H
^
A
×
+
N
γ
)
ρ
^
N
−
i
γ
ℏ
2
V
^
×
Θ
^
ρ
^
N
+
i
N
ℏ
Θ
^
ρ
^
N
−
1
{\displaystyle {\frac {\partial }{\partial t}}{\hat {\rho }}_{N}=-\left({\frac {i}{\hbar }}{\hat {H}}_{A}^{\times }+N\gamma \right){\hat {\rho }}_{N}-{i \over \gamma \hbar ^{2}}{\hat {V}}^{\times }{\hat {\Theta }}{\hat {\rho }}_{N}+{iN \over \hbar }{\hat {\Theta }}{\hat {\rho }}_{N-1}}
.
The HEOM approach allows information about the bath noise and system response to be encoded into the equations of motion. It cures the infinite energy problem of Kubo's stochastic Liouville equation by introducing the relaxation operator that ensures a return to equilibrium.
=== Computational cost ===
When the open quantum system is represented by
M
{\displaystyle M}
levels and
M
{\displaystyle M}
baths with each bath response function represented by
K
{\displaystyle K}
exponentials, a hierarchy with
N
{\displaystyle {\mathcal {N}}}
layers will contain:
(
M
K
+
N
)
!
(
M
K
)
!
N
!
{\displaystyle {\frac {\left(MK+{\mathcal {N}}\right)!}{\left(MK\right)!{\mathcal {N}}!}}}
matrices, each with
M
2
{\displaystyle M^{2}}
complex-valued (containing both real and imaginary parts) elements. Therefore, the limiting factor in HEOM calculations is the amount of RAM required, since if one copy of each matrix is stored, the total RAM required would be:
16
M
2
(
M
K
+
N
)
!
(
M
K
)
!
N
!
{\displaystyle 16M^{2}{\frac {\left(MK+{\mathcal {N}}\right)!}{\left(MK\right)!{\mathcal {N}}!}}}
bytes (assuming double-precision).
=== Implementations ===
The HEOM method is implemented in a number of freely available codes. A number of these are at the website of Yoshitaka Tanimura including a version for GPUs which used improvements introduced by David Wilkins and Nike Dattani. The nanoHUB version provides a very flexible implementation. An open source parallel CPU implementation is available from the Schulten group.
== See also ==
Quantum master equation
Open quantum system
Fokker–Planck equation
Quantum dynamical semigroup
Quantum dissipation
== References == | Wikipedia/Hierarchical_equations_of_motion |
Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein (the "template"). Homology modeling relies on the identification of one or more known protein structures likely to resemble the structure of the query sequence, and on the production of a sequence alignment that maps residues in the query sequence to residues in the template sequence. It has been seen that protein structures are more conserved than protein sequences amongst homologues, but sequences falling below a 20% sequence identity can have very different structure.
Evolutionarily related proteins have similar sequences and naturally occurring homologous proteins have similar protein structure.
It has been shown that three-dimensional protein structure is evolutionarily more conserved than would be expected on the basis of sequence conservation alone.
The sequence alignment and template structure are then used to produce a structural model of the target. Because protein structures are more conserved than DNA sequences, and detectable levels of sequence similarity usually imply significant structural similarity.
The quality of the homology model is dependent on the quality of the sequence alignment and template structure. The approach can be complicated by the presence of alignment gaps (commonly called indels) that indicate a structural region present in the target but not in the template, and by structure gaps in the template that arise from poor resolution in the experimental procedure (usually X-ray crystallography) used to solve the structure. Model quality declines with decreasing sequence identity; a typical model has ~1–2 Å root mean square deviation between the matched Cα atoms at 70% sequence identity but only 2–4 Å agreement at 25% sequence identity. However, the errors are significantly higher in the loop regions, where the amino acid sequences of the target and template proteins may be completely different.
Regions of the model that were constructed without a template, usually by loop modeling, are generally much less accurate than the rest of the model. Errors in side chain packing and position also increase with decreasing identity, and variations in these packing configurations have been suggested as a major reason for poor model quality at low identity. Taken together, these various atomic-position errors are significant and impede the use of homology models for purposes that require atomic-resolution data, such as drug design and protein–protein interaction predictions; even the quaternary structure of a protein may be difficult to predict from homology models of its subunit(s). Nevertheless, homology models can be useful in reaching qualitative conclusions about the biochemistry of the query sequence, especially in formulating hypotheses about why certain residues are conserved, which may in turn lead to experiments to test those hypotheses. For example, the spatial arrangement of conserved residues may suggest whether a particular residue is conserved to stabilize the folding, to participate in binding some small molecule, or to foster association with another protein or nucleic acid.
Homology modeling can produce high-quality structural models when the target and template are closely related, which has inspired the formation of a structural genomics consortium dedicated to the production of representative experimental structures for all classes of protein folds. The chief inaccuracies in homology modeling, which worsen with lower sequence identity, derive from errors in the initial sequence alignment and from improper template selection. Like other methods of structure prediction, current practice in homology modeling is assessed in a biennial large-scale experiment known as the Critical Assessment of Techniques for Protein Structure Prediction, or Critical Assessment of Structure Prediction (CASP).
== Motive ==
The method of homology modeling is based on the observation that protein tertiary structure is better conserved than amino acid sequence. Thus, even proteins that have diverged appreciably in sequence but still share detectable similarity will also share common structural properties, particularly the overall fold. Because it is difficult and time-consuming to obtain experimental structures from methods such as X-ray crystallography and protein NMR for every protein of interest, homology modeling can provide useful structural models for generating hypotheses about a protein's function and directing further experimental work.
There are exceptions to the general rule that proteins sharing significant sequence identity will share a fold. For example, a judiciously chosen set of mutations of less than 50% of a protein can cause the protein to adopt a completely different fold. However, such a massive structural rearrangement is unlikely to occur in evolution, especially since the protein is usually under the constraint that it must fold properly and carry out its function in the cell. Consequently, the roughly folded structure of a protein (its "topology") is conserved longer than its amino-acid sequence and much longer than the corresponding DNA sequence; in other words, two proteins may share a similar fold even if their evolutionary relationship is so distant that it cannot be discerned reliably. For comparison, the function of a protein is conserved much less than the protein sequence, since relatively few changes in amino-acid sequence are required to take on a related function.
== Steps in model production ==
The homology modeling procedure can be broken down into four sequential steps: template selection, target-template alignment, model construction, and model assessment. The first two steps are often essentially performed together, as the most common methods of identifying templates rely on the production of sequence alignments; however, these alignments may not be of sufficient quality because database search techniques prioritize speed over alignment quality. These processes can be performed iteratively to improve the quality of the final model, although quality assessments that are not dependent on the true target structure are still under development.
Optimizing the speed and accuracy of these steps for use in large-scale automated structure prediction is a key component of structural genomics initiatives, partly because the resulting volume of data will be too large to process manually and partly because the goal of structural genomics requires providing models of reasonable quality to researchers who are not themselves structure prediction experts.
== Template selection and sequence alignment ==
The critical first step in homology modeling is the identification of the best template structure, if indeed any are available. The simplest method of template identification relies on serial pairwise sequence alignments aided by database search techniques such as FASTA and BLAST. More sensitive methods based on multiple sequence alignment – of which PSI-BLAST is the most common example – iteratively update their position-specific scoring matrix to successively identify more distantly related homologs. This family of methods has been shown to produce a larger number of potential templates and to identify better templates for sequences that have only distant relationships to any solved structure. Protein threading, also known as fold recognition or 3D-1D alignment, can also be used as a search technique for identifying templates to be used in traditional homology modeling methods. Recent CASP experiments indicate that some protein threading methods such as RaptorX are more sensitive than purely sequence(profile)-based methods when only distantly-related templates are available for the proteins under prediction. When performing a BLAST search, a reliable first approach is to identify hits with a sufficiently low E-value, which are considered sufficiently close in evolution to make a reliable homology model. Other factors may tip the balance in marginal cases; for example, the template may have a function similar to that of the query sequence, or it may belong to a homologous operon. However, a template with a poor E-value should generally not be chosen, even if it is the only one available, since it may well have a wrong structure, leading to the production of a misguided model. A better approach is to submit the primary sequence to fold-recognition servers or, better still, consensus meta-servers which improve upon individual fold-recognition servers by identifying similarities (consensus) among independent predictions.
Often several candidate template structures are identified by these approaches. Although some methods can generate hybrid models with better accuracy from multiple templates, most methods rely on a single template. Therefore, choosing the best template from among the candidates is a key step, and can affect the final accuracy of the structure significantly. This choice is guided by several factors, such as the similarity of the query and template sequences, of their functions, and of the predicted query and observed template secondary structures. Perhaps most importantly, the coverage of the aligned regions: the fraction of the query sequence structure that can be predicted from the template, and the plausibility of the resulting model. Thus, sometimes several homology models are produced for a single query sequence, with the most likely candidate chosen only in the final step.
It is possible to use the sequence alignment generated by the database search technique as the basis for the subsequent model production; however, more sophisticated approaches have also been explored. One proposal generates an ensemble of stochastically defined pairwise alignments between the target sequence and a single identified template as a means of exploring "alignment space" in regions of sequence with low local similarity. "Profile-profile" alignments that first generate a sequence profile of the target and systematically compare it to the sequence profiles of solved structures; the coarse-graining inherent in the profile construction is thought to reduce noise introduced by sequence drift in nonessential regions of the sequence.
== Model generation ==
Given a template and an alignment, the information contained therein must be used to generate a three-dimensional structural model of the target, represented as a set of Cartesian coordinates for each atom in the protein. Three major classes of model generation methods have been proposed.
=== Fragment assembly ===
The original method of homology modeling relied on the assembly of a complete model from conserved structural fragments identified in closely related solved structures. For example, a modeling study of serine proteases in mammals identified a sharp distinction between "core" structural regions conserved in all experimental structures in the class, and variable regions typically located in the loops where the majority of the sequence differences were localized. Thus unsolved proteins could be modeled by first constructing the conserved core and then substituting variable regions from other proteins in the set of solved structures. Current implementations of this method differ mainly in the way they deal with regions that are not conserved or that lack a template. The variable regions are often constructed with the help of a protein fragment library.
=== Segment matching ===
The segment-matching method divides the target into a series of short segments, each of which is matched to its own template fitted from the Protein Data Bank. Thus, sequence alignment is done over segments rather than over the entire protein. Selection of the template for each segment is based on sequence similarity, comparisons of alpha carbon coordinates, and predicted steric conflicts arising from the van der Waals radii of the divergent atoms between target and template.
=== Satisfaction of spatial restraints ===
The most common current homology modeling method takes its inspiration from calculations required to construct a three-dimensional structure from data generated by NMR spectroscopy. One or more target-template alignments are used to construct a set of geometrical criteria that are then converted to probability density functions for each restraint. Restraints applied to the main protein internal coordinates – protein backbone distances and dihedral angles – serve as the basis for a global optimization procedure that originally used conjugate gradient energy minimization to iteratively refine the positions of all heavy atoms in the protein.
This method had been dramatically expanded to apply specifically to loop modeling, which can be extremely difficult due to the high flexibility of loops in proteins in aqueous solution. A more recent expansion applies the spatial-restraint model to electron density maps derived from cryoelectron microscopy studies, which provide low-resolution information that is not usually itself sufficient to generate atomic-resolution structural models. To address the problem of inaccuracies in initial target-template sequence alignment, an iterative procedure has also been introduced to refine the alignment on the basis of the initial structural fit. The most commonly used software in spatial restraint-based modeling is MODELLER and a database called ModBase has been established for reliable models generated with it.
== Loop modeling ==
Regions of the target sequence that are not aligned to a template are modeled by loop modeling; they are the most susceptible to major modeling errors and occur with higher frequency when the target and template have low sequence identity. The coordinates of unmatched sections determined by loop modeling programs are generally much less accurate than those obtained from simply copying the coordinates of a known structure, particularly if the loop is longer than 10 residues. The first two sidechain dihedral angles (χ1 and χ2) can usually be estimated within 30° for an accurate backbone structure; however, the later dihedral angles found in longer side chains such as lysine and arginine are notoriously difficult to predict. Moreover, small errors in χ1 (and, to a lesser extent, in χ2) can cause relatively large errors in the positions of the atoms at the terminus of side chain; such atoms often have a functional importance, particularly when located near the active site.
== Model assessment ==
A large number of methods have been developed for selecting a native-like structure from a set of models. Scoring functions have been based on both molecular mechanics energy functions (Lazaridis and Karplus 1999; Petrey and Honig 2000; Feig and Brooks 2002; Felts et al. 2002; Lee and Duan 2004), statistical potentials (Sippl 1995; Melo and Feytmans 1998; Samudrala and Moult 1998; Rojnuckarin and Subramaniam 1999; Lu and Skolnick 2001; Wallqvist et al. 2002; Zhou and Zhou 2002), residue environments (Luthy et al. 1992; Eisenberg et al. 1997; Park et al. 1997; Summa et al. 2005), local side-chain and backbone interactions (Fang and Shortle 2005), orientation-dependent properties (Buchete et al. 2004a,b; Hamelryck 2005), packing estimates (Berglund et al. 2004), solvation energy (Petrey and Honig 2000; McConkey et al. 2003; Wallner and Elofsson 2003; Berglund et al. 2004), hydrogen bonding (Kortemme et al. 2003), and geometric properties (Colovos and Yeates 1993; Kleywegt 2000; Lovell et al. 2003; Mihalek et al. 2003). A number of methods combine different potentials into a global score, usually using a linear combination of terms (Kortemme et al. 2003; Tosatto 2005), or with the help of machine learning techniques, such as neural networks (Wallner and Elofsson 2003) and support vector machines (SVM) (Eramian et al. 2006). Comparisons of different global model quality assessment programs can be found in recent papers by Pettitt et al. (2005), Tosatto (2005), and Eramian et al. (2006).
Less work has been reported on the local quality assessment of models. Local scores are important in the context of modeling because they can give an estimate of the reliability of different regions of a predicted structure. This information can be used in turn to determine which regions should be refined, which should be considered for modeling by multiple templates, and which should be predicted ab initio. Information on local model quality could also be used to reduce the combinatorial problem when considering alternative alignments; for example, by scoring different local models separately, fewer models would have to be built (assuming that the interactions between the separate regions are negligible or can be estimated separately).
One of the most widely used local scoring methods is Verify3D (Luthy et al. 1992; Eisenberg et al. 1997), which combines secondary structure, solvent accessibility, and polarity of residue environments. ProsaII (Sippl 1993), which is based on a combination of a pairwise statistical potential and a solvation term, is also applied extensively in model evaluation. Other methods include the Errat program (Colovos and Yeates 1993), which considers distributions of nonbonded atoms according to atom type and distance, and the energy strain method (Maiorov and Abagyan 1998), which uses differences from average residue energies in different environments to indicate which parts of a protein structure might be problematic. Melo and Feytmans (1998) use an atomic pairwise potential and a surface-based solvation potential (both knowledge-based) to evaluate protein structures. Apart from the energy strain method, which is a semiempirical approach based on the ECEPP3 force field (Nemethy et al. 1992), all of the local methods listed above are based on statistical potentials. A conceptually distinct approach is the ProQres method, which was very recently introduced by Wallner and Elofsson (2006). ProQres is based on a neural network that combines structural features to distinguish correct from incorrect regions. ProQres was shown to outperform earlier methodologies based on statistical approaches (Verify3D, ProsaII, and Errat). The data presented in Wallner and Elofsson's study suggests that their machine-learning approach based on structural features is indeed superior to statistics-based methods. However, the knowledge-based methods examined in their work, Verify3D (Luthy et al. 1992; Eisenberg et al. 1997), Prosa (Sippl 1993), and Errat (Colovos and Yeates 1993), are not based on newer statistical potentials.
== Benchmarking ==
Several large-scale benchmarking efforts have been made to assess the relative quality of various current homology modeling methods. Critical Assessment of Structure Prediction (CASP) is a community-wide prediction experiment that runs every two years during the summer months and challenges prediction teams to submit structural models for a number of sequences whose structures have recently been solved experimentally but have not yet been published. Its partner Critical Assessment of Fully Automated Structure Prediction (CAFASP) has run in parallel with CASP but evaluates only models produced via fully automated servers. Continuously running experiments that do not have prediction 'seasons' focus mainly on benchmarking publicly available webservers. LiveBench and EVA run continuously to assess participating servers' performance in prediction of imminently released structures from the PDB. CASP and CAFASP serve mainly as evaluations of the state of the art in modeling, while the continuous assessments seek to evaluate the model quality that would be obtained by a non-expert user employing publicly available tools.
== Accuracy ==
The accuracy of the structures generated by homology modeling is highly dependent on the sequence identity between target and template. Above 50% sequence identity, models tend to be reliable, with only minor errors in side chain packing and rotameric state, and an overall RMSD between the modeled and the experimental structure falling around 1 Å. This error is comparable to the typical resolution of a structure solved by NMR. In the 30–50% identity range, errors can be more severe and are often located in loops. Below 30% identity, serious errors occur, sometimes resulting in the basic fold being mis-predicted. This low-identity region is often referred to as the "twilight zone" within which homology modeling is extremely difficult, and to which it is possibly less suited than fold recognition methods.
At high sequence identities, the primary source of error in homology modeling derives from the choice of the template or templates on which the model is based, while lower identities exhibit serious errors in sequence alignment that inhibit the production of high-quality models. It has been suggested that the major impediment to quality model production is inadequacies in sequence alignment, since "optimal" structural alignments between two proteins of known structure can be used as input to current modeling methods to produce quite accurate reproductions of the original experimental structure.
Attempts have been made to improve the accuracy of homology models built with existing methods by subjecting them to molecular dynamics simulation in an effort to improve their RMSD to the experimental structure. However, current force field parameterizations may not be sufficiently accurate for this task, since homology models used as starting structures for molecular dynamics tend to produce slightly worse structures. Slight improvements have been observed in cases where significant restraints were used during the simulation.
== Sources of error ==
The two most common and large-scale sources of error in homology modeling are poor template selection and inaccuracies in target-template sequence alignment. Controlling for these two factors by using a structural alignment, or a sequence alignment produced on the basis of comparing two solved structures, dramatically reduces the errors in final models; these "gold standard" alignments can be used as input to current modeling methods to produce quite accurate reproductions of the original experimental structure. Results from the most recent CASP experiment suggest that "consensus" methods collecting the results of multiple fold recognition and multiple alignment searches increase the likelihood of identifying the correct template; similarly, the use of multiple templates in the model-building step may be worse than the use of the single correct template but better than the use of a single suboptimal one. Alignment errors may be minimized by the use of a multiple alignment even if only one template is used, and by the iterative refinement of local regions of low similarity.
A lesser source of model errors are errors in the template structure. The PDBREPORT Archived 2007-05-31 at the Wayback Machine database lists several million, mostly very small but occasionally dramatic, errors in experimental (template) structures that have been deposited in the PDB.
Serious local errors can arise in homology models where an insertion or deletion mutation or a gap in a solved structure result in a region of target sequence for which there is no corresponding template. This problem can be minimized by the use of multiple templates, but the method is complicated by the templates' differing local structures around the gap and by the likelihood that a missing region in one experimental structure is also missing in other structures of the same protein family. Missing regions are most common in loops where high local flexibility increases the difficulty of resolving the region by structure-determination methods. Although some guidance is provided even with a single template by the positioning of the ends of the missing region, the longer the gap, the more difficult it is to model. Loops of up to about 9 residues can be modeled with moderate accuracy in some cases if the local alignment is correct. Larger regions are often modeled individually using ab initio structure prediction techniques, although this approach has met with only isolated success.
The rotameric states of side chains and their internal packing arrangement also present difficulties in homology modeling, even in targets for which the backbone structure is relatively easy to predict. This is partly due to the fact that many side chains in crystal structures are not in their "optimal" rotameric state as a result of energetic factors in the hydrophobic core and in the packing of the individual molecules in a protein crystal. One method of addressing this problem requires searching a rotameric library to identify locally low-energy combinations of packing states. It has been suggested that a major reason that homology modeling so difficult when target-template sequence identity lies below 30% is that such proteins have broadly similar folds but widely divergent side chain packing arrangements.
== Utility ==
Uses of the structural models include protein–protein interaction prediction, protein–protein docking, molecular docking, and functional annotation of genes identified in an organism's genome. Even low-accuracy homology models can be useful for these purposes, because their inaccuracies tend to be located in the loops on the protein surface, which are normally more variable even between closely related proteins. The functional regions of the protein, especially its active site, tend to be more highly conserved and thus more accurately modeled.
Homology models can also be used to identify subtle differences between related proteins that have not all been solved structurally. For example, the method was used to identify cation binding sites on the Na+/K+ ATPase and to propose hypotheses about different ATPases' binding affinity. Used in conjunction with molecular dynamics simulations, homology models can also generate hypotheses about the kinetics and dynamics of a protein, as in studies of the ion selectivity of a potassium channel. Large-scale automated modeling of all identified protein-coding regions in a genome has been attempted for the yeast Saccharomyces cerevisiae, resulting in nearly 1000 quality models for proteins whose structures had not yet been determined at the time of the study, and identifying novel relationships between 236 yeast proteins and other previously solved structures.
== See also ==
Protein structure prediction
Protein structure prediction software
Protein threading
Molecular replacement
== References == | Wikipedia/Homology_modeling |
Protein electrophoresis is a method for analysing the proteins in a fluid or an extract. The electrophoresis may be performed with a small volume of sample in a number of alternative ways with or without a supporting medium, namely agarose or polyacrylamide. Variants of gel electrophoresis include SDS-PAGE, free-flow electrophoresis, electrofocusing, isotachophoresis, affinity electrophoresis, immunoelectrophoresis, counterelectrophoresis, and capillary electrophoresis. Each variant has many subtypes with individual advantages and limitations. Gel electrophoresis is often performed in combination with electroblotting or immunoblotting to give additional information about a specific protein.
== Denaturing gel methods ==
=== SDS-PAGE ===
SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis, describes a collection of related techniques to separate proteins according to their electrophoretic mobility (a function of the molecular weight of a polypeptide chain) while in the denatured (unfolded) state. In most proteins, the binding of SDS to the polypeptide chain imparts an even distribution of charge per unit mass, thereby resulting in a fractionation by approximate size during electrophoresis.
SDS is a strong detergent agent used to denature native proteins to unfolded, individual polypeptides. When a protein mixture is heated to 100 °C in presence of SDS, the detergent wraps around the polypeptide backbone. In this process, the intrinsic charges of polypeptides becomes negligible when compared to the negative charges contributed by SDS. Thus polypeptides after treatment become rod-like structures possessing a uniform charge density, that is same net negative charge per unit length. The electrophoretic mobilities of these proteins will be a linear function of the logarithms of their molecular weights.
== Native gel methods ==
Native gels, also known as non-denaturing gels, analyze proteins that are still in their folded state. Thus, the electrophoretic mobility depends not only on the charge-to-mass ratio, but also on the physical shape and size of the protein.
=== Blue native PAGE ===
BN-PAGE is a native PAGE technique, where the Coomassie brilliant blue dye provides the necessary charges to the protein complexes for the electrophoretic separation. The disadvantage of Coomassie is that in binding to proteins it can act like a detergent causing complexes to dissociate. Another drawback is the potential quenching of chemoluminescence (e.g. in subsequent western blot detection or activity assays) or fluorescence of proteins with prosthetic groups (e.g. heme or chlorophyll) or labelled with fluorescent dyes.
=== Clear native PAGE ===
CN-PAGE (commonly referred to as Native PAGE) separates acidic water-soluble and membrane proteins in a polyacrylamide gradient gel. It uses no charged dye so the electrophoretic mobility of proteins in CN-PAGE (in contrast to the charge shift technique BN-PAGE) is related to the intrinsic charge of the proteins. The migration distance depends on the protein charge, its size and the pore size of the gel. In many cases this method has lower resolution than BN-PAGE, but CN-PAGE offers advantages whenever Coomassie dye would interfere with further analytical techniques, for example it has been described as a very efficient microscale separation technique for FRET analyses. Additionally, as CN-PAGE does not require the harsh conditions of BN-PAGE, it can retain the supramolecular assemblies of membrane protein complexes that would be dissociated in BN-PAGE.
=== Preparative native PAGE ===
The folded protein complexes of interest separate cleanly and predictably without the risk of denaturation due to the specific properties of the polyacrylamide gel, electrophoresis buffer solution, electrophoretic equipment and standard parameters used. The separated proteins are continuously eluted into a physiological eluent and transported to a fraction collector. In four to five PAGE fractions each the different metal cofactors can be identified and absolutely quantified by high-resolution ICP-MS. The associated structures of the isolated metalloproteins in these fractions can be specifically determined by solution NMR spectroscopy.
== Buffer systems ==
Most protein separations are performed using a "discontinuous" (or DISC) buffer system that significantly enhances the sharpness of the bands within the gel. During electrophoresis in a discontinuous gel system, an ion gradient is formed in the early stage of electrophoresis that causes all of the proteins to focus into a single sharp band. The formation of the ion gradient is achieved by choosing a pH value at which the ions of the buffer are only moderately charged compared to the SDS-coated proteins. These conditions provide an environment in which Kohlrausch's reactions determine the molar conductivity. As a result, SDS-coated proteins are concentrated to several fold in a thin zone of the order of 19 μm within a few minutes. At this stage all proteins migrate at the same migration speed by isotachophoresis. This occurs in a region of the gel that has larger pores so that the gel matrix does not retard the migration during the focusing or "stacking" event. Separation of the proteins by size is achieved in the lower, "resolving" region of the gel. The resolving gel typically has a much smaller pore size, which leads to a sieving effect that now determines the electrophoretic mobility of the proteins. At the same time, the separating part of the gel also has a pH value in which the buffer ions on average carry a greater charge, causing them to "outrun" the SDS-covered proteins and eliminate the ion gradient and thereby the stacking effect.
A very widespread discontinuous buffer system is the tris-glycine or "Laemmli" system that stacks at a pH of 6.8 and resolves at a pH of ~8.3-9.0. A drawback of this system is that these pH values may promote disulfide bond formation between cysteine residues in the proteins because the pKa of cysteine ranges from 8-9 and because reducing agent present in the loading buffer doesn't co-migrate with the proteins. Recent advances in buffering technology alleviate this problem by resolving the proteins at a pH well below the pKa of cysteine (e.g., bis-tris, pH 6.5) and include reducing agents (e.g. sodium bisulfite) that move into the gel ahead of the proteins to maintain a reducing environment. An additional benefit of using buffers with lower pH values is that the acrylamide gel is more stable at lower pH values, so the gels can be stored for long periods of time before use.
=== SDS gradient gel electrophoresis of proteins ===
As voltage is applied, the anions (and negatively charged sample molecules) migrate toward the positive electrode (anode) in the lower chamber, the leading ion is Cl− ( high mobility and high concentration); glycinate is the trailing ion (low mobility and low concentration). SDS-protein particles do not migrate freely at the border between the Cl− of the gel buffer and the Gly− of the cathode buffer. Friedrich Kohlrausch found that Ohm's law also applies to dissolved electrolytes. Because of the voltage drop between the Cl− and Glycine-buffers, proteins are compressed (stacked) into micrometer thin layers. The boundary moves through a pore gradient and the protein stack gradually disperses due to a frictional resistance increase of the gel matrix. Stacking and unstacking occurs continuously in the gradient gel, for every protein at a different position. For a complete protein unstacking the polyacrylamide-gel concentration must exceed 16% T. The two-gel system of "Laemmli" is a simple gradient gel. The pH discontinuity of the buffers is of no significance for the separation quality, and a "stacking-gel" with a different pH is not needed.
== Visualization ==
The most popular protein stain is Coomassie brilliant blue. It is an anionic dye, which non-specifically binds to proteins. Proteins in the gel are fixed by acetic acid and simultaneously stained. The excess dye incorporated into the gel can be removed by destaining with the same solution without the dye. The proteins are detected as blue bands on a clear background.
When more sensitive method than staining by Coomassie is needed, silver staining is usually used. Silver staining is a sensitive procedure to detect trace amounts of proteins in gels, but can also visualize nucleic acid or polysaccharides.
Visualization methods without using a dye such as Coomassie and silver are available on the market. For example Bio-Rad Laboratories markets ”stain-free” gels for SDS-PAGE gel electrophoresis. Alternatively, reversible fluorescent dyes, such as those from Azure Biosystems such as AzureRed or Azure TotalStain Q can be used.
Similarly as in nucleic acid gel electrophoresis, tracking dye is often used. Anionic dyes of a known electrophoretic mobility are usually included in the sample buffer. A very common tracking dye is Bromophenol blue. This dye is coloured at alkali and neutral pH and is a small negatively charged molecule that moves towards the anode. Being a highly mobile molecule it moves ahead of most proteins.
== Medical applications ==
In medicine, protein electrophoresis is a method of analysing the proteins mainly in blood serum. Before the widespread use of gel electrophoresis, protein electrophoresis was performed as free-flow electrophoresis (on paper) or as immunoelectrophoresis.
Traditionally, two classes of blood proteins are considered: serum albumin and globulin. They are generally equal in proportion, but albumin as a molecule is much smaller and lightly, negatively-charged, leading to an accumulation of albumin on the electrophoretic gel. A small band before albumin represents transthyretin (also named prealbumin). Some forms of medication or body chemicals can cause their own band, but it usually is small. Abnormal bands (spikes) are seen in monoclonal gammopathy of undetermined significance and multiple myeloma, and are useful in the diagnosis of these conditions.
The globulins are classified by their banding pattern (with their main representatives):
The alpha (α) band consists of two parts, 1 and 2:
α1 - α1-antitrypsin, α1-acid glycoprotein.
α2 - haptoglobin, α2-macroglobulin, α2-antiplasmin, ceruloplasmin.
The beta (β) band - transferrin, LDL, complement
The gamma (γ) band - immunoglobulin (IgA, IgD, IgE, IgG and IgM). Paraproteins (in multiple myeloma) usually appear in this band.
== See also ==
Affinity electrophoresis
Electroblotting
Electrofocusing
Fast parallel proteolysis (FASTpp)
Gel electrophoresis
Immunoelectrophoresis
Immunofixation
Native gel electrophoresis
Paraprotein
QPNC-PAGE
SDD-AGE
== References ==
== External links ==
Educational resource for protein electrophoresis
Gel electrophoresis of proteins Archived 2021-01-26 at the Wayback Machine | Wikipedia/Gel_electrophoresis_of_proteins |
Protein toxicity is the effect of the buildup of protein metabolic waste compounds, like urea, uric acid, ammonia, and creatinine. Protein toxicity has many causes, including urea cycle disorders, genetic mutations, excessive protein intake, and insufficient kidney function, such as chronic kidney disease and acute kidney injury. Symptoms of protein toxicity include unexplained vomiting and loss of appetite. Untreated protein toxicity can lead to serious complications such as seizures, encephalopathy, further kidney damage, and even death.
== Definition ==
Protein toxicity occurs when protein metabolic wastes build up in the body. During protein metabolism, nitrogenous wastes such as urea, uric acid, ammonia, and creatinine are produced. These compounds are not utilized by the human body and are usually excreted by the kidney. However, due to conditions such as renal insufficiency, the under-functioning kidney is unable to excrete these metabolic wastes, causing them to accumulate in the body and lead to toxicity. Although there are many causes of protein toxicity, this condition is most prevalent in people with chronic kidney disease who consume a protein-rich diet, specifically, proteins from animal sources that are rapidly digested and metabolized, causing the release of a high concentration of protein metabolic wastes in the blood stream rapidly.
== Causes and pathophysiology ==
Protein toxicity has a significant role in neurodegenerative diseases. Whether it is due to high protein intake, pathological disorders lead to the accumulation of protein waste products, the no efficient metabolism of the proteins, or oligomerization of the amino acids from proteolysis. The mechanism by which protein can lead to well known neurodegenerative diseases includes transcriptions dysfunction, propagation, pathological cytoplasmic inclusions, mitochondrial and stress granule dysfunction.
Ammonia, one of the waste products of protein metabolism, is very harmful, especially to the brain, where it crosses the blood brain barrier leading to a whole range of neurological dysfunctions from cognitive impairment to death. The brain has a mechanism to counteract the presence of this waste metabolite. One of the mechanisms involved in the impairment of the brain is the compromise of astrocyte potassium buffering, where astrocytes play a key role. However, as more ammonia crosses, the system gets saturated, leading to astrocyte swelling and brain edema.
Urea is another waste product that originates from protein metabolism in humans. However, urea is used by the body as a source of nitrogen essential for growth and life. The most relevant disorders on the urea cycle are genetic, leading to defective enzymes or transporters inhibiting the reabsorption of urate with the subsequent increase in ammonia levels, which is toxic.
High protein intake can lead to high protein waste, and this is different from protein poisoning since the issue relates to the high level of the waste metabolites. Usually, when protein consumption goes above one-third of the food we consumed, this situation presents. The liver has a limited capacity and will not deaminate proteins, leading to increased nitrogen in the body. The rate at which urea is excreted can not keep up with the rate at which it is produced. The catabolism of amino acids can lead to toxic levels of ammonia. Furthermore, there is a limited rate at which the gastrointestinal tract can absorb amino acids from proteins.
Uric acid is not a waste metabolite derived from protein metabolism, but many high protein diets also contain higher relative fractions of nucleic acids. One of the two types of nucleic acids, purines (the other being pyrimidines, which are not problematic), are metabolized to uric acid in humans when in excess, which can lead to problems, chiefly gout.
The kidneys play an essential role in the reabsorption and excretion of uric acid. Certain transporters located in the nephron in the apical and basolateral surfaces regulate uric acid serum levels. Uric acid is not as toxic as other nitrogen derivates. It has an antioxidant function in the blood at low levels. People with compromised kidneys will have a lower excretion of uric acid leading to several diseases, including further renal damage, cardiovascular disease, diabetes, and gout.
Creatinine might not be a direct indicator of protein toxicity; however, it is important to mention that creatinine could increase due to overwork by the kidneys exposed to high levels of protein waste. Also, high serum creatinine levels could indicate decreased renal filtration rate due to kidney disease, increase byproduct as a consequence of muscle breakdown, or high protein intake.
== Effects of a high protein diet ==
A high-protein diet is a health concern for those suffering from kidney disease. The main concern is that a high protein intake may promote further renal damage that can lead to protein toxicity. The physiological changes induced by an increased protein intake, such as an increased glomerular pressure and hyperfiltration, place further strain on already damaged kidneys. This strain can lead to proteins being inadequately metabolized and subsequently causing toxicity. A high-protein diet can lead to complications for those with renal disease and has been linked to further progression of the disease. The well-known Nurse's Health Study found a correlation between the loss of kidney function and an increased dietary intake of animal protein by people who had already been diagnosed with renal disease. This association suggests that a total protein intake that exceeds the recommendations may accelerate renal disease and lead to risk of protein toxicity within a diseased individual. For this reason, dietary protein restriction is a common treatment for people with renal disease in which proteinuria is present. Protein restricted individuals have been shown to have slower rates of progression of their renal diseases.
Several studies, however, have found no evidence of protein toxicity due to high protein intakes on kidney function in healthy people. Diets that regularly exceed the recommendations for protein intake have been found to lead to an increased glomerular filtration rate in the kidneys and also have an effect on the hormone systems in the body. It is well established that these physiological effects are harmful to individuals with renal disease, but research has not found these responses to be detrimental to those who are healthy and demonstrate adequate renal activity. In people with healthy kidney function, the kidneys work continuously to excrete the by-products of protein metabolism which prevents protein toxicity from occurring. In response to an increased consumption of dietary protein, the kidneys maintain homeostasis within the body by operating at an increased capacity, producing a higher amount of urea and subsequently excreting it from the body. Although some have proposed that this increase in waste production and excretion will cause increased strain on the kidneys, other research has not supported this. Currently, evidence suggests that changes in renal function that occur in response to an increased dietary protein intake are part of the normal adaptive system employed by the body to sustain homeostasis. In a healthy individual with well-functioning kidneys, there is no need for concern that an increased dietary protein intake will lead to protein toxicity and decreased renal function.
Protein toxicity and other metabolic disorders associated with chronic kidney failure have been shown to be related to more systemic complications such as atherosclerosis, anemia, malnutrition, and hyperparathyroidism.
== Symptoms ==
Unexplained vomiting and a loss of appetite are indicators of protein toxicity. If those two symptoms are accompanied by an ammonia quality on the breath, the onset of kidney failure is a likely culprit. People with kidney disease who are not on dialysis are advised to avoid consumption of protein if possible, as consuming too much accelerates the condition and can lead to death. Most of the problems stem from the accumulation of unfiltered toxins and wastes from protein metabolism.
Kidney function naturally declines with age due to the gradual loss of nephrons (filters) in the kidney.
Common causes of chronic kidney disease include diabetes, heart disease, long term untreated high blood pressure, as well as abuse of analgesics like ibuprofen, aspirin, and paracetamol. Kidney disease like the polycystic kidney disease can be genetic in nature and progress as the individual ages.
== Diagnosis ==
Under normal conditions in the body, ammonia, urea, uric acid, and creatinine are produced by protein metabolism and excreted through the kidney as urine. When these by-products cannot be excreted properly from the body they will accumulate and become highly toxic. Protein consumption is a major source of these waste products. An accumulation of these waste products can occur in people with kidney insufficiency who eat a diet rich in protein and therefore can not excrete the waste properly.
Blood urea nitrogen (BUN) test measures the amount of urea nitrogen in the blood. Increased levels of urea in the blood (uremia) is an indicator for poor elimination of urea from the body usually due to kidney damage. Increased BUN levels can be caused by kidney diseases, kidney stones, congestive heart failure, fever, and gastrointestinal bleedings. BUN levels can also be elevated in pregnant people and people whose diet consists mainly of protein.
Increased creatinine levels in the blood can also be a sign of kidney damage and inability to excrete protein waste by-products properly.
A confirmation of kidney disease or kidney failure is often obtained by performing a blood test which measures the concentration of creatinine and urea (blood urea nitrogen). A creatinine blood test and BUN test are usually performed together along with other blood panels for diagnosis.
== Treatment ==
Treatment options for protein toxicity can include renal replacement therapies like hemodialysis and hemofiltration.
Lifestyle modifications like a diet low in protein, decreased sodium intake, and exercise can also be in incorporated as part of a treatment plan.
Medications may also be prescribed depending on symptoms. Common medications prescribed for kidney diseases include hypertension medications like angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) as they have been found to be kidney protective. Diuretics may also be prescribed to facilitate with waste excretion as well as any fluid retention.
Kidney transplant surgery is another treatment option where a healthy kidney is donated from a living or deceased donor to the recipient.
== Complications ==
Accumulation of protein metabolic waste products in the body can cause diseases and serious complications such as gout, uremia, acute renal failure, seizure, encephalopathy, and death. These products of protein metabolism, including urea, uric acid, ammonia, and creatinine, are compounds that the human body must eliminate in order for the body to function properly.
The build up of uric acid causing high amount of uric acid in blood, is a condition called hyperuricemia. Long-standing hyperuricemia can cause deposition of monosodium urate crystals in or around joints, resulting in an arthritic condition called gout.
When the body is unable to eliminate urea, it can cause a serious medical condition called uremia, which is a high level of urea in blood. Symptoms of uremia include nausea, vomiting, fatigue, anorexia, weight loss, and change in mental status. If left untreated, uremia can lead to seizure, coma, cardiac arrest, and death.
When the body is unable to process or eliminate ammonia, such as in protein toxicity, this will lead to the build up of ammonia in the bloodstream, causing a condition called hyperammonemia. Symptoms of elevated blood ammonia include muscle weakness and fatigue. If left untreated, ammonia can cross the blood brain barrier and affect brain tissues, leading to a spectrum of neuropsychiatric and neurological symptoms including impaired memory, seizure, confusion, delirium, excessive sleepiness, disorientation, brain edema, intracranial hypertension, coma, and even death.
== Epidemiology ==
The prevalence of protein toxicity cannot be accurately quantified as there are numerous etiologies from which protein toxicity can arise.
Many people have protein toxicity as a result of chronic kidney disease (CKD) or end-stage renal disease (ESRD). The prevalence of CKD (all stages) from 1988 to 2016 in the U.S. has remained relatively consistent at about 14.2% annually. The prevalence of people who have received treatment for ESRD has increased to about 2,284 people per 1 million in 2018, up from 1927 people per 1 million in 2007. Prevalence of treated ESRD increases with age, is more prevalent in males than in females, and is higher in Native Hawaiians and Pacific Islanders over any other racial group. However, the prevalence of protein toxicity specifically is difficult to quantify as people who have diseases that cause protein metabolites to accumulate typically initiate hemodialysis before they become symptomatic.
Urea cycle disorders also cause toxic buildup of protein metabolites, namely ammonia. As of 2013, in the U.S., the incidence of urea cycle disorders has been estimated to be 1 case in every 31,000 births, resulting in about 113 new cases annually.
== Special populations ==
=== Neonates ===
Protein toxicity, specifically ammonia buildup, can affect preterm newborns that have serious defects in the urea cycle enzymes with almost no physical manifestations at birth. Clinical symptoms can manifest within a few days of birth, causing extreme illness and intellectual disability or death, if left untreated. Hyperammonemia in newborns can be diagnosed with visual cues like sepsis-like presentation, hyperventilation, fluctuating body temperature, and respiratory distress; blood panels can also be used to form differential diagnoses between hyperammonemia caused by urea cycle disorders and other disorders.
=== Neurodegenerative diseases ===
People who have neurodegenerative diseases like Huntington's disease, dementia, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), also often show symptoms of protein toxicity. Cellular deficits and genetic mutations caused by these neurodegenerative diseases can pathologically alter gene transcription, negatively affecting protein metabolism.
== See also ==
Proteopathy – damage caused by mis-folded proteins
== References ==
== Further reading == | Wikipedia/Protein_toxicity |
ENA/VASP homology proteins or EVH proteins are a family of closely related proteins involved in cell motility in vertebrate and invertebrate animals. EVH proteins are modular proteins that are involved in actin polymerization, as well as interactions with other proteins. Within the cell, ENA/VASP proteins are found at the leading edge of lamellipodia and at the tips of filopodia. ENA, the founding member of the family, was discovered in a fruit fly genetic screen for mutations that act as dominant suppressors of the AB non receptor tyrosine kinase. Invertebrate animals have one Ena homologue, whereas mammals have three, named Mena, VASP, and Evl.
ENA/VASP proteins promote the spatially regulated actin polymerization required for efficient chemotaxis in response to attractive and repulsive guidance cues. Mice lacking functional copies of all three family members display pleiotropic phenotypes including exencephaly, edema, failures in neurite formation, and embryonic lethality.
A sub-domain of EVH is the EVH1 domain.
== VASP ==
Vasodilator-stimulated phosphoprotein (VASP) 45-residue-long tetramerization protein domain which regulates actin dynamics in the cytoskeleton. This is vital for processes such as cell adhesion and cell migration.
== Function ==
Ena/VASP proteins are actin cytoskeletal regulatory proteins. Ena/VASP proteins are often found in dynamic actin structures like filopodia and lamellipodia, but the precise function in their formation is controversial. Ena/VASP proteins remain processively bound to growing barbed (+) ends of an actin filaments. They promote actin filament elongation both by delivering monomeric actin to the barbed (+) ends as well as protecting these ends from F-actin capping protein.
== Structure ==
The tetramerisation domain has a right-handed alpha helical coiled-coil structure.
== References == | Wikipedia/Ena/Vasp_homology_proteins |
In cell biology, protein turnover refers to the replacement of older proteins as they are broken down within the cell. Different types of proteins have very different turnover rates.
A balance between protein synthesis and protein degradation is required for good health and normal protein metabolism. More synthesis than breakdown indicates an anabolic state that builds lean tissues, more breakdown than synthesis indicates a catabolic state that burns lean tissues. According to D.S. Dunlop, protein turnover occurs in brain cells the same as any other eukaryotic cells, but that "knowledge of those aspects of control and regulation specific or peculiar to brain is an essential element for understanding brain function."
Protein turnover is believed to decrease with age in all senescent organisms including humans. This results in an increase in the amount of damaged protein within the body.
== Protein turnover in the exercise science ==
Four weeks of aerobic exercise has been shown to increase skeletal muscle protein turnover in previously unfit individuals. A diet high in protein increases whole body turnover in endurance athletes.
Some bodybuilding supplements claim to reduce the protein breakdown by reducing or blocking the number of catabolic hormones within the body. This is believed to increase anabolism. However, if protein breakdown falls too low then the body would not be able to remove muscle cells that have been damaged during workouts which would in turn prevent the growth of new muscle cells.
== References == | Wikipedia/Protein_turnover |
In thermodynamics, the thermodynamic free energy is one of the state functions of a thermodynamic system. The change in the free energy is the maximum amount of work that the system can perform in a process at constant temperature, and its sign indicates whether the process is thermodynamically favorable or forbidden. Since free energy usually contains potential energy, it is not absolute but depends on the choice of a zero point. Therefore, only relative free energy values, or changes in free energy, are physically meaningful.
The free energy is the portion of any first-law energy that is available to perform thermodynamic work at constant temperature, i.e., work mediated by thermal energy. Free energy is subject to irreversible loss in the course of such work. Since first-law energy is always conserved, it is evident that free energy is an expendable, second-law kind of energy. Several free energy functions may be formulated based on system criteria. Free energy functions are Legendre transforms of the internal energy.
The Gibbs free energy is given by G = H − TS, where H is the enthalpy, T is the absolute temperature, and S is the entropy. H = U + pV, where U is the internal energy, p is the pressure, and V is the volume. G is the most useful for processes involving a system at constant pressure p and temperature T, because, in addition to subsuming any entropy change due merely to heat, a change in G also excludes the p dV work needed to "make space for additional molecules" produced by various processes. Gibbs free energy change therefore equals work not associated with system expansion or compression, at constant temperature and pressure, hence its utility to solution-phase chemists, including biochemists.
The historically earlier Helmholtz free energy is defined in contrast as A = U − TS. Its change is equal to the amount of reversible work done on, or obtainable from, a system at constant T. Thus its appellation "work content", and the designation A (from German Arbeit 'work'). Since it makes no reference to any quantities involved in work (such as p and V), the Helmholtz function is completely general: its decrease is the maximum amount of work which can be done by a system at constant temperature, and it can increase at most by the amount of work done on a system isothermally. The Helmholtz free energy has a special theoretical importance since it is proportional to the logarithm of the partition function for the canonical ensemble in statistical mechanics. (Hence its utility to physicists; and to gas-phase chemists and engineers, who do not want to ignore p dV work.)
Historically, the term 'free energy' has been used for either quantity. In physics, free energy most often refers to the Helmholtz free energy, denoted by A (or F), while in chemistry, free energy most often refers to the Gibbs free energy. The values of the two free energies are usually quite similar and the intended free energy function is often implicit in manuscripts and presentations.
== Meaning of "free" ==
The basic definition of "energy" is a measure of a body's (in thermodynamics, the system's) ability to cause change. For example, when a person pushes a heavy box a few metres forward, that person exerts mechanical energy, also known as work, on the box over a distance of a few meters forward. The mathematical definition of this form of energy is the product of the force exerted on the object and the distance by which the box moved (Work = Force × Distance). Because the person changed the stationary position of the box, that person exerted energy on that box. The work exerted can also be called "useful energy", because energy was converted from one form into the intended purpose, i.e. mechanical use. For the case of the person pushing the box, the energy in the form of internal (or potential) energy obtained through metabolism was converted into work to push the box. This energy conversion, however, was not straightforward: while some internal energy went into pushing the box, some was diverted away (lost) in the form of heat (transferred thermal energy).
For a reversible process, heat is the product of the absolute temperature
T
{\displaystyle T}
and the change in entropy
S
{\displaystyle S}
of a body (entropy is a measure of disorder in a system). The difference between the change in internal energy, which is
Δ
U
{\displaystyle \Delta U}
, and the energy lost in the form of heat is what is called the "useful energy" of the body, or the work of the body performed on an object. In thermodynamics, this is what is known as "free energy". In other words, free energy is a measure of work (useful energy) a system can perform at constant temperature.
Mathematically, free energy is expressed as
A
=
U
−
T
S
{\displaystyle A=U-TS}
This expression has commonly been interpreted to mean that work is extracted from the internal energy
U
{\displaystyle U}
while
T
S
{\displaystyle TS}
represents energy not available to perform work. However, this is incorrect. For instance, in an isothermal expansion of an ideal gas, the internal energy change is
Δ
U
=
0
{\displaystyle \Delta U=0}
and the expansion work
w
=
−
T
Δ
S
{\displaystyle w=-T\Delta S}
is derived exclusively from the
T
S
{\displaystyle TS}
term supposedly not available to perform work. But it is noteworthy that the derivative form of the free energy:
d
A
=
−
S
d
T
−
P
d
V
{\displaystyle dA=-SdT-PdV}
(for Helmholtz free energy) does indeed indicate that a spontaneous change in a non-reactive system's free energy (NOT the internal energy) comprises the available energy to do work (compression in this case)
−
P
d
V
{\displaystyle -PdV}
and the unavailable energy
−
S
d
T
{\displaystyle -SdT}
. Similar expression can be written for the Gibbs free energy change.
In the 18th and 19th centuries, the theory of heat, i.e., that heat is a form of energy having relation to vibratory motion, was beginning to supplant both the caloric theory, i.e., that heat is a fluid, and the four element theory, in which heat was the lightest of the four elements. In a similar manner, during these years, heat was beginning to be distinguished into different classification categories, such as "free heat", "combined heat", "radiant heat", specific heat, heat capacity, "absolute heat", "latent caloric", "free" or "perceptible" caloric (calorique sensible), among others.
In 1780, for example, Laplace and Lavoisier stated: “In general, one can change the first hypothesis into the second by changing the words ‘free heat, combined heat, and heat released’ into ‘vis viva, loss of vis viva, and increase of vis viva.’" In this manner, the total mass of caloric in a body, called absolute heat, was regarded as a mixture of two components; the free or perceptible caloric could affect a thermometer, whereas the other component, the latent caloric, could not. The use of the words "latent heat" implied a similarity to latent heat in the more usual sense; it was regarded as chemically bound to the molecules of the body. In the adiabatic compression of a gas, the absolute heat remained constant but the observed rise in temperature implied that some latent caloric had become "free" or perceptible.
During the early 19th century, the concept of perceptible or free caloric began to be referred to as "free heat" or "heat set free". In 1824, for example, the French physicist Sadi Carnot, in his famous "Reflections on the Motive Power of Fire", speaks of quantities of heat ‘absorbed or set free’ in different transformations. In 1882, the German physicist and physiologist Hermann von Helmholtz coined the phrase ‘free energy’ for the expression
A
=
U
−
T
S
{\displaystyle A=U-TS}
, in which the change in A (or G) determines the amount of energy ‘free’ for work under the given conditions, specifically constant temperature.: 235
Thus, in traditional use, the term "free" was attached to Gibbs free energy for systems at constant pressure and temperature, or to Helmholtz free energy for systems at constant temperature, to mean ‘available in the form of useful work.’ With reference to the Gibbs free energy, we need to add the qualification that it is the energy free for non-volume work and compositional changes.: 77–79
An increasing number of books and journal articles do not include the attachment "free", referring to G as simply Gibbs energy (and likewise for the Helmholtz energy). This is the result of a 1988 IUPAC meeting to set unified terminologies for the international scientific community, in which the adjective ‘free’ was supposedly banished. This standard, however, has not yet been universally adopted, and many published articles and books still include the descriptive ‘free’.
== Application ==
Just like the general concept of energy, free energy has a few definitions suitable for different conditions. In physics, chemistry, and biology, these conditions are thermodynamic parameters (temperature
T
{\displaystyle T}
, volume
V
{\displaystyle V}
, pressure
p
{\displaystyle p}
, etc.). Scientists have come up with several ways to define free energy. The mathematical expression of Helmholtz free energy is:
A
=
U
−
T
S
{\displaystyle A=U-TS}
This definition of free energy is useful for gas-phase reactions or in physics when modeling the behavior of isolated systems kept at a constant volume. For example, if a researcher wanted to perform a combustion reaction in a bomb calorimeter, the volume is kept constant throughout the course of a reaction. Therefore, the heat of the reaction is a direct measure of the free energy change,
q
=
Δ
A
{\displaystyle q=\Delta A}
. In solution chemistry, on the other hand, most chemical reactions are kept at constant pressure. Under this condition, the heat
q
{\displaystyle q}
of the reaction is equal to the enthalpy change
Δ
H
{\displaystyle \Delta H}
of the system. Under constant pressure and temperature, the free energy in a reaction is known as Gibbs free energy
G
{\displaystyle G}
.
G
=
H
−
T
S
{\displaystyle G=H-TS}
These functions have a minimum in chemical equilibrium, as long as certain variables (
T
{\displaystyle T}
, and
V
{\displaystyle V}
or
p
{\displaystyle p}
) are held constant. In addition, they also have theoretical importance in deriving Maxwell relations. Work other than p dV may be added, e.g., for electrochemical cells, or f dx work in elastic materials and in muscle contraction. Other forms of work which must sometimes be considered are stress-strain, magnetic, as in adiabatic demagnetization used in the approach to absolute zero, and work due to electric polarization. These are described by tensors.
In most cases of interest there are internal degrees of freedom and processes, such as chemical reactions and phase transitions, which create entropy. Even for homogeneous "bulk" materials, the free energy functions depend on the (often suppressed) composition, as do all proper thermodynamic potentials (extensive functions), including the internal energy.
N
i
{\displaystyle N_{i}}
is the number of molecules (alternatively, moles) of type
i
{\displaystyle i}
in the system. If these quantities do not appear, it is impossible to describe compositional changes. The differentials for processes at uniform pressure and temperature are (assuming only
p
V
{\displaystyle pV}
work):
d
A
=
−
p
d
V
−
S
d
T
+
∑
i
μ
i
d
N
i
{\displaystyle \mathrm {d} A=-p\,\mathrm {d} V-S\,\mathrm {d} T+\sum _{i}\mu _{i}\,\mathrm {d} N_{i}\,}
d
G
=
V
d
p
−
S
d
T
+
∑
i
μ
i
d
N
i
{\displaystyle \mathrm {d} G=V\,\mathrm {d} p-S\,\mathrm {d} T+\sum _{i}\mu _{i}\,\mathrm {d} N_{i}\,}
where μi is the chemical potential for the ith component in the system. The second relation is especially useful at constant
T
{\displaystyle T}
and
p
{\displaystyle p}
, conditions which are easy to achieve experimentally, and which approximately characterize living creatures. Under these conditions, it simplifies to
(
d
G
)
T
,
p
=
∑
i
μ
i
d
N
i
{\displaystyle (\mathrm {d} G)_{T,p}=\sum _{i}\mu _{i}\,\mathrm {d} N_{i}\,}
Any decrease in the Gibbs function of a system is the upper limit for any isothermal, isobaric work that can be captured in the surroundings, or it may simply be dissipated, appearing as
T
{\displaystyle T}
times a corresponding increase in the entropy of the system and/or its surrounding.
An example is surface free energy, the amount of increase of free energy when the area of surface increases by every unit area.
The path integral Monte Carlo method is a numerical approach for determining the values of free energies, based on quantum dynamical principles.
=== Work and free energy change ===
For a reversible isothermal process, ΔS = qrev/T and therefore the definition of A results in
Δ
A
=
Δ
U
−
T
Δ
S
=
Δ
U
−
q
rev
=
w
rev
{\displaystyle \Delta A=\Delta U-T\Delta S=\Delta U-q_{\text{rev}}=w_{\text{rev}}}
(at constant temperature)
This tells us that the change in free energy equals the reversible or maximum work for a process performed at constant temperature. Under other conditions, free-energy change is not equal to work; for instance, for a reversible adiabatic expansion of an ideal gas,
Δ
A
=
w
rev
−
S
Δ
T
{\displaystyle \Delta A=w_{\text{rev}}-S\Delta T}
. Importantly, for a heat engine, including the Carnot cycle, the free-energy change after a full cycle is zero,
Δ
cyc
A
=
0
{\displaystyle \Delta _{\text{cyc}}A=0}
, while the engine produces nonzero work. It is important to note that for heat engines and other thermal systems, the free energies do not offer convenient characterizations; internal energy and enthalpy are the preferred potentials for characterizing thermal systems.
=== Free energy change and spontaneous processes ===
According to the second law of thermodynamics, for any process that occurs in a closed system, the inequality of Clausius, ΔS > q/Tsurr, applies. For a process at constant temperature and pressure without non-PV work, this inequality transforms into
Δ
G
<
0
{\displaystyle \Delta G<0}
. Similarly, for a process at constant temperature and volume,
Δ
A
<
0
{\displaystyle \Delta A<0}
. Thus, a negative value of the change in free energy is a necessary condition for a process to be spontaneous; this is the most useful form of the second law of thermodynamics in chemistry. In chemical equilibrium at constant T and p without electrical work, dG = 0.
== History ==
The quantity called "free energy" is a more advanced and accurate replacement for the outdated term affinity, which was used by chemists in previous years to describe the force that caused chemical reactions. The term affinity, as used in chemical relation, dates back to at least the time of Albertus Magnus.
From the 1998 textbook Modern Thermodynamics by Nobel Laureate and chemistry professor Ilya Prigogine we find: "As motion was explained by the Newtonian concept of force, chemists wanted a similar concept of ‘driving force’ for chemical change. Why do chemical reactions occur, and why do they stop at certain points? Chemists called the ‘force’ that caused chemical reactions affinity, but it lacked a clear definition."
During the entire 18th century, the dominant view with regard to heat and light was that put forth by Isaac Newton, called the Newtonian hypothesis, which states that light and heat are forms of matter attracted or repelled by other forms of matter, with forces analogous to gravitation or to chemical affinity.
In the 19th century, the French chemist Marcellin Berthelot and the Danish chemist Julius Thomsen had attempted to quantify affinity using heats of reaction. In 1875, after quantifying the heats of reaction for a large number of compounds, Berthelot proposed the principle of maximum work, in which all chemical changes occurring without intervention of outside energy tend toward the production of bodies or of a system of bodies which liberate heat.
In addition to this, in 1780 Antoine Lavoisier and Pierre-Simon Laplace laid the foundations of thermochemistry by showing that the heat given out in a reaction is equal to the heat absorbed in the reverse reaction. They also investigated the specific heat and latent heat of a number of substances, and amounts of heat given out in combustion. In a similar manner, in 1840 Swiss chemist Germain Hess formulated the principle that the evolution of heat in a reaction is the same whether the process is accomplished in one-step process or in a number of stages. This is known as Hess' law. With the advent of the mechanical theory of heat in the early 19th century, Hess's law came to be viewed as a consequence of the law of conservation of energy.
Based on these and other ideas, Berthelot and Thomsen, as well as others, considered the heat given out in the formation of a compound as a measure of the affinity, or the work done by the chemical forces. This view, however, was not entirely correct. In 1847, the English physicist James Joule showed that he could raise the temperature of water by turning a paddle wheel in it, thus showing that heat and mechanical work were equivalent or proportional to each other, i.e., approximately, dW ∝ dQ. This statement came to be known as the mechanical equivalent of heat and was a precursory form of the first law of thermodynamics.
By 1865, the German physicist Rudolf Clausius had shown that this equivalence principle needed amendment. That is, one can use the heat derived from a combustion reaction in a coal furnace to boil water, and use this heat to vaporize steam, and then use the enhanced high-pressure energy of the vaporized steam to push a piston. Thus, we might naively reason that one can entirely convert the initial combustion heat of the chemical reaction into the work of pushing the piston. Clausius showed, however, that we must take into account the work that the molecules of the working body, i.e., the water molecules in the cylinder, do on each other as they pass or transform from one step of or state of the engine cycle to the next, e.g., from (
P
1
,
V
1
{\displaystyle P_{1},V_{1}}
) to (
P
2
,
V
2
{\displaystyle P_{2},V_{2}}
). Clausius originally called this the "transformation content" of the body, and then later changed the name to entropy. Thus, the heat used to transform the working body of molecules from one state to the next cannot be used to do external work, e.g., to push the piston. Clausius defined this transformation heat as
d
Q
=
T
d
S
{\displaystyle dQ=TdS}
.
In 1873, Willard Gibbs published A Method of Geometrical Representation of the Thermodynamic Properties of Substances by Means of Surfaces, in which he introduced the preliminary outline of the principles of his new equation able to predict or estimate the tendencies of various natural processes to ensue when bodies or systems are brought into contact. By studying the interactions of homogeneous substances in contact, i.e., bodies, being in composition part solid, part liquid, and part vapor, and by using a three-dimensional volume-entropy-internal energy graph, Gibbs was able to determine three states of equilibrium, i.e., "necessarily stable", "neutral", and "unstable", and whether or not changes will ensue. In 1876, Gibbs built on this framework by introducing the concept of chemical potential so to take into account chemical reactions and states of bodies that are chemically different from each other. In his own words, to summarize his results in 1873, Gibbs states:
If we wish to express in a single equation the necessary and sufficient condition of thermodynamic equilibrium for a substance when surrounded by a medium of constant pressure p and temperature T, this equation may be written:
when δ refers to the variation produced by any variations in the state of the parts of the body, and (when different parts of the body are in different states) in the proportion in which the body is divided between the different states. The condition of stable equilibrium is that the value of the expression in the parenthesis shall be a minimum.
In this description, as used by Gibbs, ε refers to the internal energy of the body, η refers to the entropy of the body, and ν is the volume of the body.
Hence, in 1882, after the introduction of these arguments by Clausius and Gibbs, the German scientist Hermann von Helmholtz stated, in opposition to Berthelot and Thomas' hypothesis that chemical affinity is a measure of the heat of reaction of chemical reaction as based on the principle of maximal work, that affinity is not the heat given out in the formation of a compound but rather it is the largest quantity of work which can be gained when the reaction is carried out in a reversible manner, e.g., electrical work in a reversible cell. The maximum work is thus regarded as the diminution of the free, or available, energy of the system (Gibbs free energy G at T = constant, P = constant or Helmholtz free energy A at T = constant, V = constant), whilst the heat given out is usually a measure of the diminution of the total energy of the system (Internal energy). Thus, G or A is the amount of energy "free" for work under the given conditions.
Up until this point, the general view had been such that: “all chemical reactions drive the system to a state of equilibrium in which the affinities of the reactions vanish”. Over the next 60 years, the term affinity came to be replaced with the term free energy. According to chemistry historian Henry Leicester, the influential 1923 textbook Thermodynamics and the Free Energy of Chemical Reactions by Gilbert N. Lewis and Merle Randall led to the replacement of the term "affinity" by the term "free energy" in much of the English-speaking world.
== See also ==
Energy
Exergy
Merle Randall
Second law of thermodynamics
Superconductivity
== References == | Wikipedia/Free_energy_(thermodynamics) |
DNA-binding proteins are proteins that have DNA-binding domains and thus have a specific or general affinity for single- or double-stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove of B-DNA, because it exposes more functional groups that identify a base pair.
== Examples ==
DNA-binding proteins include transcription factors which modulate the process of transcription, various polymerases, nucleases which cleave DNA molecules, and histones which are involved in chromosome packaging and transcription in the cell nucleus. DNA-binding proteins can incorporate such domains as the zinc finger, the helix-turn-helix, and the leucine zipper (among many others) that facilitate binding to nucleic acid. There are also more unusual examples such as transcription activator like effectors.
== Non-specific DNA-protein interactions ==
Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin. In eukaryotes, this structure involves DNA binding to a complex of small basic proteins called histones. In prokaryotes, multiple types of proteins are involved. The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are therefore largely independent of the base sequence. Chemical modifications of these basic amino acid residues include methylation, phosphorylation and acetylation. These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription. Other non-specific DNA-binding proteins in chromatin include the high-mobility group (HMG) proteins, which bind to bent or distorted DNA. Biophysical studies show that these architectural HMG proteins bind, bend and loop DNA to perform its biological functions. These proteins are important in bending arrays of nucleosomes and arranging them into the larger structures that form chromosomes. Recently FK506 binding protein 25 (FBP25) was also shown to non-specifically bind to DNA which helps in DNA repair.
== Proteins that specifically bind single-stranded DNA ==
A distinct group of DNA-binding proteins are the DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein A is the best-understood member of this family and is used in processes where the double helix is separated, including DNA replication, recombination and DNA repair. These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.
== Binding to specific DNA sequences ==
In contrast, other proteins have evolved to bind to specific DNA sequences. The most intensively studied of these are the various transcription factors, which are proteins that regulate transcription. Each transcription factor binds to one specific set of DNA sequences and activates or inhibits the transcription of genes that have these sequences near their promoters. The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription. Alternatively, transcription factors can bind enzymes that modify the histones at the promoter. This alters the accessibility of the DNA template to the polymerase.
These DNA targets can occur throughout an organism's genome. Thus, changes in the activity of one type of transcription factor can affect thousands of genes. Thus, these proteins are often the targets of the signal transduction processes that control responses to environmental changes or cellular differentiation and development. The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to read the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are most accessible. Mathematical descriptions of protein-DNA binding taking into account sequence-specificity, and competitive and cooperative binding of proteins of different types are usually performed with the help of the lattice models. Computational methods to identify the DNA binding sequence specificity have been proposed to make a good use of the abundant sequence data in the post-genomic era. In addition, progress has happened on structure-based prediction of binding specificity across protein families using deep learning.
== Protein–DNA interactions ==
Protein–DNA interactions occur when a protein binds a molecule of DNA, often to regulate the biological function of DNA, usually the expression of a gene. Among the proteins that bind to DNA are transcription factors that activate or repress gene expression by binding to DNA motifs and histones that form part of the structure of DNA and bind to it less specifically. Also proteins that repair DNA such as uracil-DNA glycosylase interact closely with it.
In general, proteins bind to DNA in the major groove; however, there are exceptions. Protein–DNA interaction are of mainly two types, either specific interaction, or non-specific interaction. Recent single-molecule experiments showed that DNA binding proteins undergo of rapid rebinding in order to bind in correct orientation for recognizing the target site.
=== Design ===
Designing DNA-binding proteins that have a specified DNA-binding site has been an important goal for biotechnology. Zinc finger proteins have been designed to bind to specific DNA sequences and this is the basis of zinc finger nucleases. Recently transcription activator-like effector nucleases (TALENs) have been created which are based on natural proteins secreted by Xanthomonas bacteria via their type III secretion system when they infect various plant species.
=== Detection methods ===
There are many in vitro and in vivo techniques which are useful in detecting DNA-Protein Interactions. The following lists some methods currently in use: Electrophoretic mobility shift assay (EMSA) is a widespread qualitative technique to study protein–DNA interactions of known DNA binding proteins. DNA-Protein-Interaction - Enzyme-Linked ImmunoSorbant Assay (DPI-ELISA) allows the qualitative and quantitative analysis of DNA-binding preferences of known proteins in vitro. This technique allows the analysis of protein complexes that bind to DNA (DPI-Recruitment-ELISA) or is suited for automated screening of several nucleotide probes due to its standard ELISA plate formate. DNase footprinting assay can be used to identify the specific sites of binding of a protein to DNA at basepair resolution. Chromatin immunoprecipitation is used to identify the in vivo DNA target regions of a known transcription factor. This technique when combined with high throughput sequencing is known as ChIP-Seq and when combined with microarrays it is known as ChIP-chip. Yeast one-hybrid System (Y1H) is used to identify which protein binds to a particular DNA fragment. Bacterial one-hybrid system (B1H) is used to identify which protein binds to a particular DNA fragment. Structure determination using X-ray crystallography has been used to give a highly detailed atomic view of protein–DNA interactions.
Besides these methods, other techniques such as SELEX, PBM (protein binding microarrays), DNA microarray screens, DamID, FAIRE or more recently DAP-seq are used in the laboratory to investigate DNA-protein interaction in vivo and in vitro.
=== Manipulating the interactions ===
The protein–DNA interactions can be modulated using stimuli like ionic strength of the buffer, macromolecular crowding, temperature, pH and electric field. This can lead to reversible dissociation/association of the protein–DNA complex.
== See also ==
bZIP domain
ChIP-exo
Comparison of nucleic acid simulation software
DNA-binding domain
Helix-loop-helix
Helix-turn-helix
HMG-box
Leucine zipper
Lexitropsin (a semi-synthetic DNA-binding ligand)
Deoxyribonucleoprotein
Protein–DNA interaction site prediction software
RNA-binding protein
Single-strand binding protein
Zinc finger
== References ==
== External links ==
Protein-DNA binding: data, tools & models (annotated list, constantly updated)
Abalone tool for modeling DNA-ligand interactions.
DBD database of predicted transcription factors Uses a curated set of DNA-binding domains to predict transcription factors in all completely sequenced genomes
DNA-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Protein–DNA_interaction |
Protein–lipid interaction is the influence of membrane proteins on the lipid physical state or vice versa.
The questions which are relevant to understanding of the structure and function of the membrane are: 1) Do intrinsic membrane proteins bind tightly to lipids (see annular lipid shell), and what is the nature of the layer of lipids adjacent to the protein? 2) Do membrane proteins have long-range effects on the order or dynamics of membrane lipids? 3) How do the lipids influence the structure and/or function of membrane proteins? 4) How do peripheral membrane proteins which bind to the layer surface interact with lipids and influence their behavior?
== Binding of lipids to intrinsic membrane proteins in the bilayer ==
A large research effort involves approaches to know whether proteins have binding sites which are specific for particular lipids and whether the protein–lipid complexes can be considered to be long-lived, on the order of the time required for the turnover a typical enzyme, that is 10−3 sec. This is now known through the use of 2H-NMR, ESR, and fluorescent methods.
There are two approaches used to measure the relative affinity of lipids binding to specific membrane proteins. These involve the use of lipid analogues in reconstituted phospholipid vesicles containing the protein of interest:
1) Spin-labeled phospholipids are motionally restricted when they are adjacent to membrane proteins. The result is a component in the ESR spectrum which is broadened. The experimental spectrum can be analyzed as the sum of the two components, a rapidly tumbling species in the "bulk" lipid phase with a sharp spectrum, and a motionally restricted component adjacent to the protein. Membrane protein denaturation causes further broadening of ESR spin label spectrum and throws more light on membrane lipid-proteins interactions
2) Spin-labeled and brominated lipid derivatives are able to quench the intrinsic tryptophan fluorescence from membrane proteins. The efficiency of quenching depends on the distance between the lipid derivative and the fluorescent tryptophans.
== Perturbations of the lipid bilayer due to the presence of lateral membrane proteins ==
Most 2H-NMR experiments with deuterated phospholipids demonstrate that the presence of proteins has little effect on either the order parameter of the lipids in the bilayer or the lipid dynamics, as measured by relaxation times. The overall view resulting from NMR experiments is 1) that the exchange rate between boundary and free lipids is rapid, (107 sec−1), 2) that the order parameters of the bound lipid are barely affected by being adjacent to proteins, 3) that the dynamics of the acyl chain reorientations are slowed only slightly in the frequency range of 109 sec−1, and 4) that the orientation and the dynamics of the polar headgroups are similarly unaffected in any substantial manner by being adjacent to transmembrane proteins. 13C-NMR spectrum also gives information on specific lipid-protein interactions of biomembranes
Recent results using non labeled optical methods such as Dual Polarisation Interferometry which measure the birefringence(or order) within lipid bilayers have been used to show how peptide and protein interactions can influence bilayer order, specifically demonstrating the real time association to bilayer and critical peptide concentration after which the peptides penetrate and disrupt the bilayer order.
== Backbone and solid chain dynamics of membrane proteins ==
Solid-state NMR techniques have the potential to yield detailed information about the dynamics of individual amino acid residues within a membrane protein. However, the techniques can require large amounts (100–200 mg) of isotopically labeled proteins and are most informative when applied to small proteins where spectroscopic assignments are possible.
== Binding of peripheral membrane proteins to the lipid bilayer ==
Many peripheral membrane proteins bind to the membrane primarily through interactions with integral membrane proteins. But there is a diverse group of proteins which interact directly with the surface of the lipid bilayer. Some, such as myelin basic protein, and spectrin have mainly structural roles. A number of water-soluble proteins can bind to the bilayer surface transiently or under specific conditions.
Misfolding processes, typically exposing hydrophobic regions of proteins, often are associated with binding to lipid membranes and subsequent aggregation, for example, during neurodegenerative disorders, neuronal stress and apoptosis.
== See also ==
Annular lipid shell
Collodion bag
Lipid
== References ==
== Further reading ==
Robert B. Gennis. "Biomembranes, Molecular structure and function". Springer Verlag, New York, 1989.
H L Scott, Jr & T J Coe. "A theoretical study of lipid-protein interactions in bilayers". Biophys J. 1983 June; 42(3): 219–224. | Wikipedia/Protein–lipid_interaction |
A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents.
The peptide sequence that spans the membrane, or the transmembrane segment, is largely hydrophobic and can be visualized using the hydropathy plot. Depending on the number of transmembrane segments, transmembrane proteins can be classified as single-pass membrane proteins, or as multipass membrane proteins. Some other integral membrane proteins are called monotopic, meaning that they are also permanently attached to the membrane, but do not pass through it.
== Types ==
=== Classification by structure ===
There are two basic types of transmembrane proteins: alpha-helical and beta barrels. Alpha-helical proteins are present in the inner membranes of bacterial cells or the plasma membrane of eukaryotic cells, and sometimes in the bacterial outer membrane. This is the major category of transmembrane proteins. In humans, 27% of all proteins have been estimated to be alpha-helical membrane proteins.
Beta-barrel proteins are so far found only in outer membranes of gram-negative bacteria, cell walls of gram-positive bacteria, outer membranes of mitochondria and chloroplasts, or can be secreted as pore-forming toxins. All beta-barrel transmembrane proteins have simplest up-and-down topology, which may reflect their common evolutionary origin and similar folding mechanism.
In addition to the protein domains, there are unusual transmembrane elements formed by peptides. A typical example is gramicidin A, a peptide that forms a dimeric transmembrane β-helix. This peptide is secreted by gram-positive bacteria as an antibiotic. A transmembrane polyproline-II helix has not been reported in natural proteins. Nonetheless, this structure was experimentally observed in specifically designed artificial peptides.
=== Classification by topology ===
This classification refers to the position of the protein N- and C-termini on the different sides of the lipid bilayer. Types I, II, III and IV are single-pass molecules. Type I transmembrane proteins are anchored to the lipid membrane with a stop-transfer anchor sequence and have their N-terminal domains targeted to the endoplasmic reticulum (ER) lumen during synthesis (and the extracellular space, if mature forms are located on cell membranes). Type II and III are anchored with a signal-anchor sequence, with type II being targeted to the ER lumen with its C-terminal domain, while type III have their N-terminal domains targeted to the ER lumen. Type IV is subdivided into IV-A, with their N-terminal domains targeted to the cytosol and IV-B, with an N-terminal domain targeted to the lumen. The implications for the division in the four types are especially manifest at the time of translocation and ER-bound translation, when the protein has to be passed through the ER membrane in a direction dependent on the type.
== 3D structure ==
Membrane protein structures can be determined by X-ray crystallography, electron microscopy or NMR spectroscopy. The most common tertiary structures of these proteins are transmembrane helix bundle and beta barrel. The portion of the membrane proteins that are attached to the lipid bilayer (see annular lipid shell) consist mostly of hydrophobic amino acids.
Membrane proteins which have hydrophobic surfaces, are relatively flexible and are expressed at relatively low levels. This creates difficulties in obtaining enough protein and then growing crystals. Hence, despite the significant functional importance of membrane proteins, determining atomic resolution structures for these proteins is more difficult than globular proteins. As of January 2013 less than 0.1% of protein structures determined were membrane proteins despite being 20–30% of the total proteome. Due to this difficulty and the importance of this class of proteins methods of protein structure prediction based on hydropathy plots, the positive inside rule and other methods have been developed.
== Thermodynamic stability and folding ==
=== Stability of alpha-helical transmembrane proteins ===
Transmembrane alpha-helical (α-helical) proteins are unusually stable judging from thermal denaturation studies, because they do not unfold completely within the membranes (the complete unfolding would require breaking down too many α-helical H-bonds in the nonpolar media). On the other hand, these proteins easily misfold, due to non-native aggregation in membranes, transition to the molten globule states, formation of non-native disulfide bonds, or unfolding of peripheral regions and nonregular loops that are locally less stable.
It is also important to properly define the unfolded state. The unfolded state of membrane proteins in detergent micelles is different from that in the thermal denaturation experiments. This state represents a combination of folded hydrophobic α-helices and partially unfolded segments covered by the detergent. For example, the "unfolded" bacteriorhodopsin in SDS micelles has four transmembrane α-helices folded, while the rest of the protein is situated at the micelle-water interface and can adopt different types of non-native amphiphilic structures. Free energy differences between such detergent-denatured and native states are similar to stabilities of water-soluble proteins (< 10 kcal/mol).
=== Folding of α-helical transmembrane proteins ===
Refolding of α-helical transmembrane proteins in vitro is technically difficult. There are relatively few examples of the successful refolding experiments, as for bacteriorhodopsin. In vivo, all such proteins are normally folded co-translationally within the large transmembrane translocon. The translocon channel provides a highly heterogeneous environment for the nascent transmembrane α-helices. A relatively polar amphiphilic α-helix can adopt a transmembrane orientation in the translocon (although it would be at the membrane surface or unfolded in vitro), because its polar residues can face the central water-filled channel of the translocon. Such mechanism is necessary for incorporation of polar α-helices into structures of transmembrane proteins. The amphiphilic helices remain attached to the translocon until the protein is completely synthesized and folded. If the protein remains unfolded and attached to the translocon for too long, it is degraded by specific "quality control" cellular systems.
=== Stability and folding of beta-barrel transmembrane proteins ===
Stability of beta barrel (β-barrel) transmembrane proteins is similar to stability of water-soluble proteins, based on chemical denaturation studies. Some of them are very stable even in chaotropic agents and high temperature. Their folding in vivo is facilitated by water-soluble chaperones, such as protein Skp. It is thought that β-barrel membrane proteins come from one ancestor even having different number of sheets which could be added or doubled during evolution. Some studies show a huge sequence conservation among different organisms and also conserved amino acids which hold the structure and help with folding.
== 3D structures ==
=== Light absorption-driven transporters ===
Bacteriorhodopsin-like proteins including rhodopsin (see also opsin)
Bacterial photosynthetic reaction centres and photosystems I and II
Light-harvesting complexes from bacteria and chloroplasts
=== Oxidoreduction-driven transporters ===
Transmembrane cytochrome b-like proteins: coenzyme Q - cytochrome c reductase (cytochrome bc1 ); cytochrome b6f complex; formate dehydrogenase, respiratory nitrate reductase; succinate - coenzyme Q reductase (fumarate reductase); and succinate dehydrogenase. See electron transport chain.
Cytochrome c oxidases from bacteria and mitochondria
=== Electrochemical potential-driven transporters ===
Proton or sodium translocating F-type and V-type ATPases
=== P-P-bond hydrolysis-driven transporters ===
P-type calcium ATPase (five different conformations)
Calcium ATPase regulators phospholamban and sarcolipin
ABC transporters
General secretory pathway (Sec) translocon (preprotein translocase SecY)
=== Porters (uniporters, symporters, antiporters) ===
Mitochondrial carrier proteins
Major Facilitator Superfamily (Glycerol-3-phosphate transporter, Lactose permease, and Multidrug transporter EmrD)
Resistance-nodulation-cell division (multidrug efflux transporter AcrB, see multidrug resistance)
Dicarboxylate/amino acid:cation symporter (proton glutamate symporter)
Monovalent cation/proton antiporter (Sodium/proton antiporter 1 NhaA)
Neurotransmitter sodium symporter
Ammonia transporters
Drug/Metabolite Transporter (small multidrug resistance transporter EmrE - the structures are retracted as erroneous)
=== Alpha-helical channels including ion channels ===
Voltage-gated ion channel like, including potassium channels KcsA and KvAP, and inward-rectifier potassium ion channel Kirbac
Large-conductance mechanosensitive channel, MscL
Small-conductance mechanosensitive ion channel (MscS)
CorA metal ion transporters
Ligand-gated ion channel of neurotransmitter receptors (acetylcholine receptor)
Aquaporins
Chloride channels
Outer membrane auxiliary proteins (polysaccharide transporter) - α-helical transmembrane proteins from the outer bacterial membrane
=== Enzymes ===
Methane monooxygenase
Rhomboid protease
Disulfide bond formation protein (DsbA-DsbB complex)
=== Proteins with single transmembrane alpha-helices ===
Subunits of T cell receptor complex
Cytochrome c nitrite reductase complex
Glycophorin A dimer
Inovirus (filamentous phage) major coat protein
Pilin
Pulmonary surfactant-associated protein
Monoamine oxidases A and B
Fatty acid amide hydrolase
Cytochrome P450 oxidases
Corticosteroid 11β-dehydrogenases .
Signal Peptide Peptidase
=== Beta-barrels composed of a single polypeptide chain ===
Beta barrels from eight beta-strands and with "shear number" of ten (n=8, S=10). They include:
OmpA-like transmembrane domain (OmpA)
Virulence-related outer membrane protein family (OmpX)
Outer membrane protein W family (OmpW)
Antimicrobial peptide resistance and lipid A acylation protein family (PagP)
Lipid A deacylase PagL
Opacity family porins (NspA)
Autotransporter domain (n=12,S=14)
FadL outer membrane protein transport family, including Fatty acid transporter FadL (n=14,S=14)
General bacterial porin family, known as trimeric porins (n=16,S=20)
Maltoporin, or sugar porins (n=18,S=22)
Nucleoside-specific porin (n=12,S=16)
Outer membrane phospholipase A1(n=12,S=16)
TonB-dependent receptors and their plug domain. They are ligand-gated outer membrane channels (n=22,S=24), including cobalamin transporter BtuB, Fe(III)-pyochelin receptor FptA, receptor FepA, ferric hydroxamate uptake receptor FhuA, transporter FecA, and pyoverdine receptor FpvA
Outer membrane protein OpcA family (n=10,S=12) that includes outer membrane protease OmpT and adhesin/invasin OpcA protein
Outer membrane protein G porin family (n=14,S=16)
Note: n and S are, respectively, the number of beta-strands and the "shear number" of the beta-barrel
=== Beta-barrels composed of several polypeptide chains ===
Trimeric autotransporter (n=12,S=12)
Outer membrane efflux proteins, also known as trimeric outer membrane factors (n=12,S=18) including TolC and multidrug resistance proteins
MspA porin (octamer, n=S=16) and α-hemolysin (heptamer n=S=14) . These proteins are secreted.
== See also ==
Membrane topology
Transmembrane domain
Transmembrane receptors
== References == | Wikipedia/Transmembrane_protein |
Materials that are used for biomedical or clinical applications are known as biomaterials. The following article deals with fifth generation biomaterials that are used for bone structure replacement. For any material to be classified for biomedical applications, three requirements must be met. The first requirement is that the material must be biocompatible; it means that the organism should not treat it as a foreign object. Secondly, the material should be biodegradable (for in-graft only); the material should harmlessly degrade or dissolve in the body of the organism to allow it to resume natural functioning. Thirdly, the material should be mechanically sound; for the replacement of load-bearing structures, the material should possess equivalent or greater mechanical stability to ensure high reliability of the graft.
== Introduction ==
The biomaterial term is used for materials that can be used in biomedical and clinical applications. They are bioactive and biocompatible in nature. Currently, many types of metals and alloys (stainless steel, titanium, nickel, magnesium, Co–Cr alloys, Ti alloys), ceramics (zirconia, bioglass, alumina, hydroxyapatite) and polymers (acrylic, nylon, silicone, polyurethane, polycaprolactone, polyanhydrides) are used for load bearing applications. This includes dental replacements and bone joining or replacements for medical and clinical application. Therefore, their mechanical properties are very important. Mechanical properties of some biomaterials and bone are summarized in Table 1. Among them, hydroxyapatite is most widely studied bioactive and biocompatible material. However, it has lower Young's modulus and fracture toughness with a brittle nature. Hence, it is required to produce a biomaterial with good mechanical properties.
== Elastic modulus ==
Elastic modulus is simply defined as the ratio of stress to strain within the proportional limit. Physically, it represents the stiffness of a material within the elastic range when tensile or compressive loads are applied. It is clinically important because it indicates the selected biomaterial has similar deformable properties with the material it is going to replace. These force-bearing materials require high elastic modulus with low deflection. As the elastic modulus of material increases, fracture resistance decreases. It is desirable that the biomaterial elastic modulus is similar to that of bone. This is because if it is more than bone's elastic modulus then the load is borne by the material only; while the load is borne by bone only if it is less than bone material. The elastic modulus of a material is generally calculated by the bending test, because deflection can be easily measured in this case as compared to very small elongation in compressive or tensile load. However, biomaterials (for bone replacement) are usually porous and the sizes of the samples are small. Therefore, the nanoindentation test is used to determine the elastic modulus of these materials. This method has high precision and is convenient for micro-scale samples. Another method of elastic modulus measurement is the non-destructive method. It is also a clinically very good method because of its simplicity and repeatability since materials are not destroyed.
== Hardness ==
Hardness is a measure of plastic deformation and is defined as the force per unit area of indentation or penetration. Hardness is one of the most important parameters for comparing properties of materials. It is used for finding the suitability of the clinical use of biomaterials. Biomaterial hardness is desirable as equal to bone hardness. If higher than the biomaterial, then it penetrates in the bone. Higher hardness results in less abrasion. As said above, biomaterials sample are very small, therefore micro- and nano-scale hardness tests (Diamond Knoop and Vickers indenters) are used.
== Fracture strength ==
The strength of a material is defined as the maximum stress that can be endured before fracture occurs. Strength of biomaterials (bioceramics) is an important mechanical property because they are brittle. In brittle materials like bioceramics, cracks easily propagate when the material is subject to tensile loading, unlike compressive loading. A number of methods are available for determining the tensile strength of materials, such as the bending flexural test, the biaxial flexural strength test and the weibull approach. In bioceramics, flaws influence the reliability and strength of the material during implantation and fabrication. There are a number of ways that flaws can be produced in bioceramics such as thermal sintering and heating. It is important for bioceramics to have high reliability, rather than high strength.
The strength of brittle materials depends on the size of flaws distributed throughout the material. According to Griffith's theory of fracture in tension, the largest flaw or crack will contribute the most to the failure of a material. Strength also depends on the volume of a specimen since flaw size is limited to the size of the specimen's cross section. Therefore, the smaller the specimen (e.g., fibers), the higher the fracture strength. Porosity of implanted bioceramic has a tremendous influence on the physical properties. Pores are usually formed during processing of materials. Increasing the porosity and pore size means increasing the relative void volume and decreasing density; this leads to a reduction in mechanical properties and lowers the overall strength of bioceramic.
To use ceramics as self-standing implants that are able to withstand tensile stresses is a primary engineering design objective. Four general approaches have been used to achieve this objective:
1) use of the bioactive ceramic as a coating on a metal or ceramic substrate
2)strengthening of the ceramic, such as via crystallization of glass
3) use of fracture mechanics as a design approach and
4) reinforcing of the ceramic with a second phase.
For example, hydroxyapatite and other calcium phosphates bioceramics are important for hard tissue repair because of their similarity to the minerals in natural bone, and their excellent biocompatibility and bioactivity, but they have poor fatigue resistance and strength. Hence, bioinert ceramic oxides with high strength are used to enhance the densification and the mechanical properties of them.
== Fracture toughness ==
Fracture toughness is required to alter the crack propagation in ceramics. It is helpful to evaluate the serviceability, performance and long term clinical success of biomaterials. It is reported that the high fracture toughness material improved clinical performance and reliability as compare to low fracture toughness. It can be measured by many methods e.g. indentation fracture, indentation strength, single edge notched beam, single edge pre cracked beam and double cantilever beam.
== Fatigue ==
Fatigue is defined as failure of a material due to repeated/cyclic loading or unloading (tensile or compressive stresses). It is also an important parameter for biomaterial because cyclic load is applied during their serving life. In this cyclic loading condition, micro crack/flaws may be generated at the interface of the matrix and the filler. This micro crack can initiate permanent plastic deformation which results in large crack propagation or failure. During the cyclic load several factor also contribute to microcrack generation such as frictional sliding of the mating surface, progressive wear, residual stresses at grain boundaries, stress due to shear.
Table 1: Summary of mechanical properties of cortical bone and biomaterial
Fatigue fracture and wear have been identified as some of the major problems associated with implant loosening, stress-shielding and ultimate implant failure. Although wear is commonly reported in orthopaedic applications such as knee and hip joint prostheses, it is also a serious and often fatal experience in mechanical heart valves.
The selection of biomaterials for wear resistance unfortunately cannot rely only on conventional thinking of using hard ceramics, because of their low coefficient of friction and high modulus of elasticity. This is because ceramics are generally prone to brittle fracture (having a fracture toughness typically less than 1 MPa√m) and need absolute quality control to avoid fatigue fracture for medical device applications. The development of fatigue fracture and wear resistant biomaterials looks into the biocomposites of two or more different phases such as in interpenetrating network composites. The advantage of these composites is that one can incorporate controlled drug release chemicals, friction modifiers, different morphologies to enable better host–implant performance and chemical entities to reduce or aid removal of wear debris. Of equal importance are the tools developed to predict fatigue fracture/wear using new methodologies involving in vitro tests, computational modelling to obtain design stresses and fracture/wear maps to identify mechanisms.
== Viscoelasticity ==
Viscoelasticity, a material property characterized by the extrusion of dual solid and liquid-like behaviors, is typically found in an array of polymer-based biomaterials, including those used in biomedical devices as well as in clinical settings. From polymer-based surface coatings on drug-eluting stents to entangled tissue networks that have load-bearing capabilities and hydrogels that possess complex crosslinks, all of these examples display viscoelastic behavior. Often times, flow plasticity theory and linear elasticity are utilized to describe the rheological behavior of metals and other hard materials, yet they are not commonly used to elaborate on the material behavior of biomaterials. Viscoelasticity is often described in terms of its time-dependent material properties associated with its characteristic stress relaxation time. Additionally, the energy dissipation associated with the liquid-like portion of the response to an applied load can be funneled into the complex modulus, which is represented by two distinct categories: one real and one imaginary, for the viscoelastic response[10]. The viscoelastic response of a biomaterial can be modeled by linear mathematical models, and atypically a non-linear mathematical models that corresponds to the loading capabilities of the biomaterial in use.
=== Viscoelasticity in polymeric biomaterials ===
There is a tendency for polymeric biomaterials to display the same characteristics as solid, rigid materials over a short time span, in addition to exhibiting exceptional flow behavior over longer periods of time. This translates to long-term analysis and studies focused towards ensuring the mechanical integrity of these biomaterials to prevent potential deformation and mechanical failure once employed in a clinical setting. The viscoelastic behavior is typically dependent on factors such as the crosslink density, the average molecular weight, the degree of crystallinity, and the degree of entanglement as well as the general chemistry of the biomaterial. There are modeling programs employed to probe the material behavior over an array of temperatures and applied frequencies, as well as to decrease the potential for complexity in synthesizing polymers at the industrial level and for commercial use. The programs themselves often focus on decreasing the rate of mechanical and environmental degradation by focusing on probing the rate sensitivity as well as creep response[11]. For example, in polymeric grafts that act as replacements for tissues, the viscoelastic response is necessary to be mimicked to ensure ample biocompatibility and structural stability over the life-span of the material.
=== Viscoelasticity in tissue ===
Tissues themselves are, at their fundamental level, an amalgamation of entangled and crosslinked polymer networks that are composed of collagen, other organic compounds found in the human body, and long polymer chain structures. The degree at which entanglement occurs, crosslinking behavior between other compounds, and the interpenetration ability of excess polymer networks determines the outstanding character of a tissue network. Everything from macroscopic structural to atomistic-level arrangements in a tissue, such as the crimping behavior seen in tendons, can give way to nonlinear elastic behavior which can be highly expressed due to the intermolecular arrangements within the material. Since tissues are hydrolyzed to maintain biological function, this often affects their mechanical performance as it often results in the liquid component affecting the deformation response of the material. Additionally, the degree of crosslinking present in an individual crosslinked collagen network can be prone to the biological environment of said crosslinked network[12]. With that in mind, the time-dependent mechanical properties of tissues can be incredibly interdependent on molecular interactions and the chemical environment in which a specific tissue is native to. In comparison to other tissue, articular cartilage itself begins to enlarge when subjected to unloading and this puts the microstructure of the material into a state of tension. Articular cartilage, a native biomaterial, typically supplies a soft base for tail end of narrow bones located in synovial joints while providing lubrication capabilities that allow joints to interact without excess friction. The cartilage itself is composed of collagen fiber within an entangled gel-like structure. This tissue structure behaves similar to a viscoelastic solid in the sense that the response to strain under an excess load is dependent on the rate of the load. Furthermore, when a mechanical load is applied to the tissue, the fluid is forced out of the porous membranes of the biomaterial which exacerbates permanent deformation, while simultaneously stifling viscous flow and decreasing energy in the material overall. Overall, the viscoelastic characteristics and the viscous attributes in the liquid phase play a role in the dynamic behavior of tissue, and tissue-based materials.
== See also ==
== References ==
== Further reading ==
Ward, I.M. (1983). The Mechanical Properties of Solid Polymers. New York: Wiley.
Sychterz, C.J., Yang, A., and Engh, C.A. (1999). "Analysis of temporal wear patterns of porous-coated acetabular components: Distinguishing between true wear and so-called bedding-in". Journal of Bone and Joint Surgery (American), 81A(6), 821–30.
Saito, M., and Marumo, Y. (2010). "Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus". Osteoporosis International 21(2), 195–214.
Ichim, Q. Li, W. Li, M.V. Swain, J. Kieser (2007). "Modelling of fracture behaviour in biomaterials". Biomaterials 28(7). 1317–1326.
S.H Teoh (2000). "Fatigue of biomaterials: a review". International Journal of Fatigue 22(10). 825–837.
Bhatia, S. K. (2010). Biomaterials for clinical applications. Springer.
Hench, L. L. (1993). An introduction to bioceramics (Vol. 1). World Scientific. | Wikipedia/Mechanical_properties_of_biomaterials |
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