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author = {Debnath, Bikash. and Singh, Waikhom. and Manna, Kuntal.}, title = {{Sources and toxicological effects of lead on human health}}, journal ={Indian Journal of Medical Specialities}, volume ={10}, number ={2}, pages = {66-71}, doi = {10.4103/INJMS.INJMS_30_18}, year = {2019}, abstract ={ Lead toxicity is one of the most hazardous metal toxicities. It can enter the body through lead-based paint, dust, water, soil, tableware, and folk medicines. Children are especially prone to develop lead toxicity. Lead acts by inducing oxidative stress due to inefficient replenishment of glutathione. Lead can also cause hemolytic anemia due to disruption of the cellular membrane by lipid peroxidation. Lead toxicity also affects neurotransmitter levels and causes severe health issues related to organ damage, some even leading to death. The main aim of this review article is to summarize lead toxicity detection, its sources, and its mechanism including various toxicological effects on human health. It also focuses on the prevention and treatment of lead toxicity. }, URL ={http://www.ijms.in/article.asp?issn=0976-2884;year=2019;volume=10;issue=2;spage=66;epage=71;aulast=Debnath;t=6}, eprint ={http://www.ijms.in/article.asp?issn=0976-2884;year=2019;volume=10;issue=2;spage=66;epage=71;aulast=Debnath;t=6} }
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Why Do Newborns Breathe So Fast?
Why Do Newborns Breathe So Fast?
8 Apr 2022 | 2 min Read
Tinystep
Author | 2574 Articles
Doctors usually instruct the parents to observe and keep tabs on the breathing patterns of your baby.
Why do they breathe so fast?
Rapid breathing and panting are two things that are predominant in newborns. Since the baby has just come out of the womb after 9 months of long sleep, he tries to adapt and get habituated with the world outside. Basically, his body tries to get accustomed to the new surroundings and that’s exactly what brings in a change in the breathing pattern.
Newborns have a higher rate of breathing than the adults. Their chest cavity gets filled up completely with air, unlike adults. There are no air pockets present, so they don’t have air reserves, so their breathing rate is too high. With age, the body begins to mature up too, so they will develop air pockets naturally and their breathing will normalise soon after. As long as your baby keeps smiling and giggling you shouldn’t be worried at all.
Watch out for the breathing pattern at night:
Newborns have a tendency of breathing rapidly and with each breath, their breaths get deeper and slower. They breathe in cycles and this is called periodic breathing. Sometimes they also pause while breathing.
If you’re still worried, you can do the following:
-Listen to your baby’s breathing pattern by placing your ear next to the baby’s mouth and nose and hear the sound of their breath.
-Observe your baby’s breathing pattern by seeing the up and down movement of the chest.
-If you want to feel those little breaths, just put your cheek close to your baby’s nose and feel those warm little breaths.
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Suggestions offered by doctors on BabyChakra are of advisory nature i.e., for educational and informational purposes only. Content posted on, created for, or compiled by BabyChakra is not intended or designed to replace your doctor's independent judgment about any symptom, condition, or the appropriateness or risks of a procedure or treatment for a given person.
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Adopting a plant-based diet could help tip the scales in your favor. A five-year study of 71,751 adults published in the Journal of the Academy of Nutrition and Dietetics found that vegetarians tend to be slimmer than meat-eaters even though both groups eat about the same number of calories daily. Researchers say it may be because carnivores consume more fatty acids and fewer weight-loss promoting nutrients, like fiber, than herbivores do. Go green to find out if it works for you.
During adolescence and early adulthood, women need to consume foods rich in calcium to build peak (maximum) bone mass. This will reduce the risk of developing osteoporosis, a progressive condition where there is a loss of bone that leaves those affected more susceptible to fractures. Women also need an adequate iron intake because they lose iron through menstruation. Women also need an adequate intake of calories to support energy and nutritional needs in order for the body to function properly. The amount of calories that an individual needs varies for each person and is based on age, gender and activity level. As a general recommendation, women between 23 and 50 years of age generally need between 1,700 and 2,200 calories per day to maintain their current energy needs and body weight. Older women generally require fewer calories to support and sustain energy needs. Consuming fewer than 1,500 calories per day, even in attempts to lose weight, can put women at nutritional risk and can result in malnutrition and poor health. For more information on how to calculate one’s nutritional needs, go to www.choosemyplate.gov and insert your personal information. The 2005 Dietary Guidelines for Americans is another reference or guide to assist you in learning to eat a balanced and nutritious diet for good health.
Calcium: Although some bone loss is inevitable with age, women can slow the process by getting enough calcium and vitamin D. Women between the ages of 50 and 70 need 1200 mg of calcium and 600 IU of Vitamin D a day. Women older than 70 require 1200 mg of calcium and 800 IU of Vitamin D a day. Because the skin becomes less efficient at converting sunlight to vitamin D as we age, older women may need more vitamin D in the form of supplements. Talk to your doctor.
Our findings identified gaps and limitations in the evaluation, scope, targeting, and delivery platforms of nutrition interventions in low- and middle-income countries. First, the monitoring and evaluation of nutrition programs that reported on women's nutrition outcomes was generally inadequate. Many of the studies we identified included small-scale efficacy trials. Although there were many large-scale programs that targeted women and adolescent girls with nutrition-specific and nutrition-sensitive approaches, they lacked rigorous evaluation. Whether the evidence about women's outcomes was limited because they are not systematically measured or because they are not well reported is not clear. Negative results are often not published, and many evaluations of nutrition interventions that are conducted by the same groups responsible for implementing them are typically presented positively. This may have also skewed our findings. More intentional research-quality program evaluation, including of large-scale programs, would provide a stronger evidence base. Of the studies identified in this review, many reported on short-term findings such as changes in knowledge, dietary behaviors, and program coverage. They were limited in their ability to report clinical and anthropometric outcomes for women, the duration of those outcomes, and the feasibility of scaling up programs. There is also a need for systematic, long-term evaluations of interventions whose effects on nutrition outcomes are more distal (e.g., nutrition education compared with micronutrient supplementation). The effects of multisectoral interventions are even more complex to measure. However, frameworks exist to evaluate complex interventions (102) and could be utilized to evaluate the impact of interventions across the life course.
×
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Muscle strain, poor blood circulation to eat pineapple
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Excessive lead to human body vitamins, minerals and calories deficiency, supplements can provide the necessary nutrients bananas and relieve negative emotions with the brain. Like brain food rich in vitamin B6, and bananas are rich in this vitamin such as bananas, can help people boost morale, improve work efficiency. Bananas contain large amounts of β-carotene. When the body lacks this kind of material, the eye becomes painful, dry, dull eyes, dehydration less God, more bananas not only reduce these symptoms can also relieve eye fatigue to some extent, prevent premature aging eyes . Pineapple fruit nutritious, according to analysis per 100 grams of total sugar pulp containing 12 – 16 grams, 0.6 grams of organic acids, protein 0.4 – 0.5 g, crude fiber 0.3 – 0.5 grams, and contain a variety of vitamins, including vitamin C content of up to 42 mg. In addition, calcium, iron, phosphorus and other rich content. As a fresh pineapple, golden flesh, rich flavor, sweet and sour taste, crisp and juicy, loved by everyone.
After the muscle strain, tissue inflammation, poor blood circulation, pain, swelling injured area. Pineapple contains bromelain components have anti-inflammatory effect, can promote tissue repair. Nutrients oranges are rich in dietary fiber, vitamins A, B, C, phosphorus, and malic acid. Citrus fruits contain antioxidants that can protect the human immune system, inhibit cancer cell growth, in which the content of antioxidants of all fruits oranges in most. Lack of vitamin B1 people susceptible to athlete’s foot problems. In this case the most suitable choice oranges, which are rich in vitamin B1, and helps glucose metabolism.
tumblr_mlyylcAWtI1snzn9uo1_1280
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Review
Overview on Percutaneous Therapies of Disc Diseases
1
S. Giovanni Battista Ordine di Malta Hospital, 00148 Rome, Italy
2
Department of Diagnostic Imaging and Interventional Radiology, General Hospital, University of Rome, Tor Vergata, 00133 Rome, Italy
3
ASSL Cagliari, Radiology PO SS Trinità, ATS Sardinia, 08100 Nuoro, Italy
4
Department of Radiology, University of Massachusetts, 55 Lake Avenue North, Worcester, MA 01655, USA
*
Author to whom correspondence should be addressed.
Medicina 2019, 55(8), 471; https://doi.org/10.3390/medicina55080471
Submission received: 13 May 2019 / Revised: 2 August 2019 / Accepted: 7 August 2019 / Published: 12 August 2019
Abstract
:
Low back pain is an extremely common pathology affecting a great share of the population, in particular, young adults. Many structures can be responsible for pain such as intervertebral discs, facet joints, nerve roots, and sacroiliac joints. This review paper focuses on disc pathology and the percutaneous procedures available to date for its treatment. For each option, we will assess the indications, technical aspects, advantages, and complications, as well as outcomes reported in the literature and new emerging trends in the field.
1. Introduction
The term low back pain (LBP) describes a clinical entity characterized by algic symptoms in the lumbar region that hamper normal daily activities, with consequences on overall quality of life [1].
It is estimated that about 80% of all people, during the course of their lives, will suffer from at least one episode of LBP, with a one-year prevalence rate in the US between 5–20% [1,2].
In the great majority of cases, it constitutes an isolated and self-limited event as testified by complete functional recovery rates, with a rest-only approach and no treatment, of 60% at 1 week and 95% at 12 weeks. However, there is a high incidence of relapsing episodes and, in some cases, the duration of symptoms can exceed 12 months, which is identified as “chronic low back pain” [2].
Low back pain, mainly chronic disease, carries enormous social and economic costs; it represents the most frequent cause of disability among young adults (age < 45 years) and is thus the first cause of absence from work [1,3].
In the settings of LBP, there are a few structures known to act as pain generators; a great share of events is usually caused by intervertebral disc disease, nerve root inflammation, and/or zygapophyseal joint degeneration. Degenerative disc changes are usually associated with vascular and nervous fiber infiltration from the outer portions of the annulus fibrosus (AF) into the deeper structures of the disc, leading to symptoms; on the other hand, a bulging disc may cause compression and, therefore, inflammation of the adjacent nerve root, resulting in neurogenic pain from the affected fibers [3].
The sacroiliac joint may also be responsible for lumbar pain in up to 15–30% of cases, usually located below the L5 level [4].
For the purposes of this article, we will focus on disc pathology, its clinical presentation, and the current treatments available.
The intervertebral disc is responsible for up to 40% of LBP cases; that percentage is even greater among young adults (<45), where the disc is the first structure involved following stressful mechanical events acting on the spine [4].
Kirkardy Willis first described disc degeneration as a key component of LBP in 1983, introducing the concept of mechanical instability [5].
Yet, before a mechanical deficit, the disc goes through a complex series of biological changes, mainly due to metabolic dysfunction of the nucleus pulposus (NP) cells, the main producers of the disc extracellular matrix [6].
The matrix is continuously produced and reabsorbed by the cells of the NP, in a constant equilibrium between lytic enzymes (MMP and ADAMS) and growth factors (BMP, GDF). Inflammatory molecules, such as TNF-a and IL-1, also promote degradation of the matrix [7].
Repeated mechanical solicitations lead to increased reabsorptions of the matrix and a poor production in terms of its quality. This causes an unbalanced force distribution, extending the disease to the AF, because of the inability to withstand the mechanical load generated through daily activities alone [8].
The genesis of discogenic pain (low back pain and neuralgia) is related to herniation of the intervertebral disc, caused by annulus fibrosus fissuration with the subsequent release of nucleus pulposus. Histopathophysiological effects include the mechanical pressure effect, inflammatory reaction, and neovascularization [9].
Mechanical effects cause direct pressure on nerve roots or on vessels, causing ischemia and inflammatory reactions, which stimulate the immune system in producing phospholipase A2, prostaglandin, leukotriene, and matrix metalloproteinase [10].
Proposed treatments for such conditions include conservative therapy, injections, and percutaneous and surgical procedures.
Minimally invasive percutaneous interventions, apart from epidural injections of corticosteroids and analgesics, include decompression techniques (mechanical, thermal, or chemical), biomaterial implantation, and disc cell therapies.
In this paper, we will review the technical aspects and clinical outcomes of the main percutaneous procedures available today.
2. Techniques
In the settings of LBP, the standard approach is a 4–6 week conservative therapy course with analgesics, NSAIDs, physical therapies, and/or bracing with a combination of epidural injections. Percutaneous injections, in association with physiotherapy, can be performed as an intermediate step between conservative therapy, percutaneous decompression techniques, and surgical options. Percutaneous therapies include injections via an interlaminar, caudal, or transforaminal approach; mechanical, thermal or chemical decompression; and biomaterial implantations/disc cell therapies [9,11,12,13,14,15,16,17,18] (Table 1).
Mechanical, Thermal, or Chemical Decompression Techniques
A patient primary inclusion criterion for percutaneous therapies is the presence of discogenic pain (low back pain and neuralgia) from an intervertebral disc herniation that occupies less than one-third or half of the canal diameter in MRI that has also failed to resolve after conservative therapy for about 4–6 weeks and at least one session of steroid injection. Symptoms have to be consistent with the segmental level where the herniation is present in MRI [9,11,14,15,19].
Absolute contraindications for the percutaneous technique, which prompt emergent surgical management, include sphincter dysfunction, extreme sciatica, and a progressive neurologic deficit, along with the impossibility of obtaining patient-informed consent. Other contraindications are asymptomatic herniation, sequestered disc fragment, local or systemic infection, and spondylolisthesis [9,11,14,15,19]. In the case of hemorrhagic diathesis alterations, those must be corrected, and anticoagulant therapy should be interrupted according to international guidelines.
All the procedures are primarily performed via fluoroscopic guidance, although CT and MRI are both viable [9,11,14,15,20]. Recently, an endoscopic fiber-optic approach was proposed [21].
With the sterile technique, in accordance with the Cardiovascular and Interventional Radiological Society of Europe Standards of Practice for percutaneous treatment of intervertebral disks [22], the patient is placed in the prone position. Whenever fluoroscopy is used as a guiding modality, the target disc should be centered and vertebral end plates aligned in the A–P projection. Rotation of the fluoroscopy beam at ~45° (the spinous process should point toward the contralateral facet joint) produces the “Scottie dog” projection (Figure 1). In this projection, under continuous fluoroscopy, the trocar, usually an 18-G spinal needle with variable length (9–15 cm), is advanced until the periphery of the disc is reached. Fluoroscopic projections in the A–P and lateral projection are used to verify the proper trocar positioning. Then, in the lateral projection, the trocar is advanced within the disc. The final position of the needle tip should be within the anterior third of the disc space in the lateral projection and toward the midline in the A–P projection midway between the two endplates (Figure 2). Whenever computed tomography is used as a guiding modality, the access point on the skin is selected and marked. While checking the correct path with sequential scans, the trocar is advanced within the disc utilizing a posterolateral approach through the aforementioned route. For the L5–S1 intervertebral disc, alternative techniques include the use of curved trocars or posterior extra-thecal access through the lateral epidural space. When the correct positioning is obtained and verified, decompression is performed through the trocar.
Cervical intervertebral discs are usually treated utilizing an antero-lateral approach with the patient in the supine position. The trocar is advanced, with prior subluxation of the larynx, between the larynx and jugular–carotid vessel. Due to the presence of the esophagus on the left side, the right-sided approach is preferred. When fluoroscopic guidance is used, the correct position is deemed to be within the posterior third in the lateral projection and, as for the lumbar discs, toward the midline in A–P projections. With CT guidance, the entry point on the skin is marked and the trocar is advanced through the route described before [17].
Mechanical percutaneous decompression devices include high-rotation-per-minute (RPM) devices with spiral tips, metallic wires/laminae, or water/pneumatically driven suction-cutting probes, which remove approximately 1–3 g of disc material anterior to herniation via a 17-G cannula in the lumbar disc and 19-G in the cervical disc; some of those devices use the Archimedes’ screw principle to extract material from the nucleus pulposus (Figure 3) [9,11,14,15]. Endoscopic discectomy is performed via a postero-lateral route, which provides a way to decompress nerve roots by aspiring the herniated part of the disk [23].
Thermal percutaneous techniques inhibit intradiscal cytokines that are associated with intervertebral disc degeneration, destroy nociceptors in the periphery of the annulus, and fuse collagen annular fibers with resultant shrinkage at the disc periphery [11].Those thermal techniques include lasers, radiofrequency (with continuous or pulsed RF energy delivery), and nucleoplasty [9,14,15,20,24,25,26].
Even if percutaneous laser disc decompression (PLDD) can be performed with different kinds of lasers (diode, Nd:YAG, KTP, CO2, Ho:YAG), the therapeutic principle is the same: By introducing a laser probe (0.4mm) within the middle of the intervertebral disc, a small volume of nucleus pulposus (mainly composed of water) is vaporized by the energy generated by the laser beam. This reduces intradiscal pressure and subsequently produces retraction of the herniated component toward the center of the disc. To avoid risk of complications, pulsed laser energy delivery is necessary, in order to allow for dissipation of the heat generated after every single pulse and before administration of the next one. There are no statistically significant differences in outcomes and complications between those different varieties of lasers, with the exception of CO2, which requires a metal cannula for laser beam administration, whose heating may cause thermal nerve root damage [27].
Continuous RF (CRF) uses high-frequency EM waves to induce coagulative necrosis in target tissue, which occurs at temperatures between 60 °C and 80 °C. Pulsed RF (PRF) uses radiofrequency current in short, high-voltage bursts followed by a “stop” phase that allows heat elimination, generally keeping tissue at a temperature of ~40 °C. While the former generates necrosis in the target tissue, PRF seems to involve a temperature-independent pathway by rapidly changing the electrical field, which influences the production of anti-inflammatory cytokines [24,28].
The nucleoplasty wand, via low-temperature plasma field-controlled ablation, channels the postero-lateral to the antero-medial aspect of the annulus, with minimal risk of thermal injury. During advancement and sequential clockwise rotation of the wand, the ablation creates six channels at the 2, 4, 6, 8, 10, and 12 o’clock positions, at a speed of 0.5 cm/s using120 volts of energy with resultant temperatures of 50–70 °C. During retraction instead, the coagulation effect denaturizes type II collagen and proteoglycans, shrinking the surrounding collagen and widening the channel (~1mm) (Figure 4) [26].
A comparison between conservative therapy and mechanical decompression favors the latter in terms of efficacy, resulting in more significant and long-lasting pain relief in those patients treated with percutaneous techniques [29].
Chemical percutaneous decompression techniques are mainly based on the utilization of two compounds: the oxygen–ozone mixture and radiopaque gelified ethanol.
O2–O3 therapy is based on the injection of a mixture of O2 and O3 gas inside the nucleus pulposus, in order to reduce the intradiscal pressure, compression on the surrounding structures, and, consequently, associated pain. While withdrawing the needle from its intradiscal position, the gas mixture is often also administered in the soft tissues surrounding the inflamed nerve root (Figure 5) [30,31].
The properties of intradiscal ozone administration are well known in clinical practice [32], ranging from nucleus pulposus depressurization to immuno-modulant effects. Although the biochemical mechanisms at the base are not fully comprehended, recent studies have shown a glycosaminoglycan lysis ozone mediated, which reacts with fragmented proteoglycans in causing dehydration of the disc; an interaction was also observed with the intradiscal cytokines, generating an anti-inflammatory response [31,33].
O2–O3therapy currently constitutes one of the most used techniques in symptomatic disc herniation.
Radiopaque gelified ethanol intradiscal administration represents an emerging minimally invasive procedure in the management of disc pathology; the effect of ethanol on biological tissues has long been known and used by many interventionists during their procedures. The adjunction of ethyl-cellulose and tungsten provides more viscosity (to reduce diffusivity) and radiopacity, respectively, to the compound [34,35].
The solution produces local necrosis within the nucleus pulposus resulting in dehydration and mechanical retraction of the bulging disc [36]. Additionally, the gelified compound has hydrophilic properties, able to generate fluid inflow from the periphery toward the core of the nucleus pulposus; In addition, the deposition and precipitation of the gel particles result in a “prosthesis” effect at the injection site [34]. A total amount of 0.8mL is usually sufficient for the treatment of a single lumbar herniated disc. Its use is also considered effective in the cervical spinal segment (Figure 6 and Figure 7) [37,38].
Percutaneous disk decompression techniques show a pain reduction success rate between 75 and 80%, with long-term stable effects and a significant reduction in the Oswestry disability index (ODI) and visual analogue scale (VAS) values post-procedurally and during follow-up examinations [9,11,14,15,30,32,39,40]: comparative studies among those techniques do not favor one in particular [41,42].
Several randomized prospective trials comparing conservative therapy, infiltrations, and decompression techniques have demonstrated the superiority of the latter in producing a better and longer lasting pain reduction [25,29]. Further trials have been conducted analyzing and comparing the percutaneous decompression, open discectomy, or micro-discectomy procedures, reporting no statistically significant differences in outcomes among these therapies [43,44,45]. Percutaneous techniques, however, compared to open disc surgery, cause only minimal degeneration of the surrounding tissues, in particular, of muscles, which are a pivotal structure in the support of the degenerated intervertebral disc and are considerably more cost-effective (25–30%) [46].
Complications are encountered rarely, with spondylodiscitis being the most severe (0.24%). Iatrogenic complications, such as the puncture of the dural sac and cord and nerve root damage, as well as hemorrhage, are significantly less frequent [1].
Nevertheless, randomized and observational trials are needed to further confirm this evidence [47,48,49].
3. Biomaterial Implantationand Disc Cell Therapies
A relatively new approach for degenerative disc disease (DDD) treatment is based on the implantation of biomaterials, in particular, hydrogel-based compounds with the aim of nucleus pulposus regeneration in a disc with a fairly intact annulus fibrosus [50].
In this application, there are no definitive criteria that must be satisfied to achieve procedural success; the current focus is on developing materials with properties similar to those of the native structure, allowing for better integration of implants without displacement, migration, or rupture. In addition, the goal of restoring disc function, as in disc height and range of motion, must be pursued [51,52].
Mainly described in animal models, the clinical translation of implanted biomaterials can only occur with reliable evidence of durability and the ability to maintain their properties and integrity through repetitive solicitation, and the lack of hypothetically provoking a local or systemic immune response [51,53,54].
Proposed biomaterials for DDD can be biologically derived or synthetically produced. The formers (e.g., agarose, alginate, hyaluronate) possess good biocompatibility with the native environment but inferior performances in comparison to synthetic ones, mainly constituting poli-vinyl-alcohol (PVA) and related polymers. As such, a combination of those elements has been tested in many studies in order to improve the mechanical and biochemical properties of the implanted materials [55].
Moreover, biomaterials derived from silk have recently gained attention in this field and are objects of several studies assessing the effectiveness and security of their implantation [56].
Finally, some biomaterials (typically of natural origin, such as hyaluronate and collagen) have been proposed to act only as carriers for cell delivery to the nucleus pulposus, aiming to provide an environment supporting cell-mediated disc regeneration [51,56].
There is a continuously increasing interest in the use of cellular therapies for disc regeneration in the degenerative disc disease. Those mainly consist of the use of platelet-rich plasma (PRP) and stem cells (MSC).
Platelet-rich plasma (PRP) is obtained by concentrating platelets and other blood components from an autologous sample of blood. The platelets, growth factors, and cytokines in the solution augment collagen content and production, accelerate tissue regeneration, and promote angiogenesis [57].
PRP appears to inhibit the inflammatory effect of TNF-alfa and Interleukin-1 on nucleus pulposus cells [58].
Even if multiple studies demonstrate its effectiveness and safety with a modest reduction in VAS and ODI score, no significant results have been observed in the early stages, because of the time required for the treatment effect to occur, although more trials are needed to confirm its effectiveness [59,60].
Stem cell therapy consists of the transplantation of MSCs in the nucleus pulposus of the affected disc. Those cells, capable of aggrecan production, have led to an increase in disc water content and height in human models (demonstrated with MRI) with a sensible improvement in pain and functional status [61,62].
A single study described a clinical improvement at a 1year follow-up after intradiscal injection of MSCs [60].
A major drawback of this procedure is cell extravasation, potentially causing complications such as discitis, tumorigenesis, osteophytes, and spinal stenosis [63,64].
4. Conclusions
Percutaneous intervertebral disc procedures are practical and reproducible treatments for symptomatic intervertebral disc herniations that have failed a combination of 4–6 weeks of conservative therapy associated with a session of steroid infiltration, carrying a success rate of 75–80% and rare complications (~0.5%), with spondylodiscitis being the most severe (0.24%). Sterile techniques and prophylactic antibiotics are a prerequisite. Imaging guidance allows clinical success with a markedly decreased complication rate.
There is no definitive evidence regarding the difference in efficacy between surgical options and the percutaneous decompression technique, although the latter results in only minimal destruction of the surrounding structures, in particular, of muscles, which support the altered intervertebral disc, and are considerably more cost-effective.
In conclusion, percutaneous intervertebral disc therapeutic techniques are viable as a valid treatment before surgery, for the treatment of symptomatic herniation of both the cervical and lumbar spine.
Author Contributions
Conceptualization, Methodology, Resources, Project Administration: S.M. (Salvatore Masala); Supervision: S.M. (Salvatore Masala), S.M. (Stefano Marcia), F.M.; Investigation, Writing—Original Draft: A.L., F.S. Writing—Review and Editing, Visualization: S.M. (Stefano Marcia), F.M.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Procedure under fluoroscopic guidance. (A) Angiographic suite. (B) Oblique (~45°) “Scottie-dog” projection.
Figure 1. Procedure under fluoroscopic guidance. (A) Angiographic suite. (B) Oblique (~45°) “Scottie-dog” projection.
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Figure 2. (A) Needle trajectory obtained via CT guidance. (B) Patient with symptomatic L4–L5 intervertebral disc herniation. Antero-posterior fluoroscopic view: discography shows correct needle positioning.
Figure 2. (A) Needle trajectory obtained via CT guidance. (B) Patient with symptomatic L4–L5 intervertebral disc herniation. Antero-posterior fluoroscopic view: discography shows correct needle positioning.
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Figure 3. Mechanical decompression of herniated L4–L5 disk. (A) Decompression device (mechanical high-rotation-per-minute device with spiral tips) is placed via postero-lateral access under fluoroscopic guidance. (B) Part of the disk is removed.
Figure 3. Mechanical decompression of herniated L4–L5 disk. (A) Decompression device (mechanical high-rotation-per-minute device with spiral tips) is placed via postero-lateral access under fluoroscopic guidance. (B) Part of the disk is removed.
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Figure 4. Antero-posterior fluoroscopic view. L4–L5 intervertebral disc nucleoplasty: tip of the wand (white arrow) during ablation, performed clockwise.
Figure 4. Antero-posterior fluoroscopic view. L4–L5 intervertebral disc nucleoplasty: tip of the wand (white arrow) during ablation, performed clockwise.
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Figure 5. O2/O3: (A) intradiscal and (B) peri-radicular injection in patient with right lumbosciatalgia from L3-L4 herniated disk. Postero-lateral access is obtained via CT.
Figure 5. O2/O3: (A) intradiscal and (B) peri-radicular injection in patient with right lumbosciatalgia from L3-L4 herniated disk. Postero-lateral access is obtained via CT.
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Figure 6. Radiopaque gelified ethanol for L5–S1 disc herniation: (A) Lateral fluoroscopic view: notice radiopaque gel in the L5–S1 disc. (B,C) Post-intervention follow-up CT exam shows optimal intradiscal distribution of the solution.
Figure 6. Radiopaque gelified ethanol for L5–S1 disc herniation: (A) Lateral fluoroscopic view: notice radiopaque gel in the L5–S1 disc. (B,C) Post-intervention follow-up CT exam shows optimal intradiscal distribution of the solution.
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Figure 7. Radiopaque gelified ethanol for cervical disc pathology. Patient with symptomatic C5–C6 intervertebral disc herniation. (A,B) Antero-posterior and lateral fluoroscopic view. Access to the disc is obtained with an antero-lateral approach under fluoroscopic guidance prior to subluxation of the larynx, between the larynx and jugular–carotid vessel. In the cervical tract, a lower quantity of gel is usually injected (ca. 0,3 mL).
Figure 7. Radiopaque gelified ethanol for cervical disc pathology. Patient with symptomatic C5–C6 intervertebral disc herniation. (A,B) Antero-posterior and lateral fluoroscopic view. Access to the disc is obtained with an antero-lateral approach under fluoroscopic guidance prior to subluxation of the larynx, between the larynx and jugular–carotid vessel. In the cervical tract, a lower quantity of gel is usually injected (ca. 0,3 mL).
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Table 1. Percutaneous intervertebral disc techniques
Table 1. Percutaneous intervertebral disc techniques
TechniqueMethod
Mechanical decompressionMechanical high RPM spiral tips or metallic laminae probes
Water-driven suction-cutting probe
Pneumatically driven suction-cutting probe
Herniotome
Thermal decompressionPercutaneous laser decompression
Intradiscal electrothermaltherapy
Intervertebral disc nucleoplasty
Pulsed radiofrequency
Chemical decompressionRadiopaque gelified ethanol
Ozonetherapy
Biomateral implantationHydrogel
Cellular therapiesPlatelet-rich plasma, stem cell therapy
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MDPI and ACS Style
Masala, S.; Salimei, F.; Lacchè, A.; Marcia, S.; Massari, F. Overview on Percutaneous Therapies of Disc Diseases. Medicina 2019, 55, 471. https://doi.org/10.3390/medicina55080471
AMA Style
Masala S, Salimei F, Lacchè A, Marcia S, Massari F. Overview on Percutaneous Therapies of Disc Diseases. Medicina. 2019; 55(8):471. https://doi.org/10.3390/medicina55080471
Chicago/Turabian Style
Masala, Salvatore, Fabio Salimei, Adriano Lacchè, Stefano Marcia, and Francesco Massari. 2019. "Overview on Percutaneous Therapies of Disc Diseases" Medicina 55, no. 8: 471. https://doi.org/10.3390/medicina55080471
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1a01aa77535b9ecfb87b9fc36adbcd2f
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1,941,602,873,835,687,000
|
Using next-generation RNA sequencing to examine ischemic changes induced by cold blood cardioplegia on the human left ventricular myocardium transcriptome
Jochen D. Muehlschlegel, Danos C. Christodoulou, David McKean, Joshua Gorham, Erica Mazaika, Mahyar Heydarpour, Grace Lee, Steven R. DePalma, Tjorvi E. Perry, Amanda A. Fox, Stanton K. Shernan, Christine E. Seidman, Sary F. Aranki, Jon G. Seidman, Simon C. Body
Research output: Contribution to journalArticlepeer-review
21 Scopus citations
Abstract
Background: The exact mechanisms that underlie the pathological processes of myocardial ischemia in humans are unclear. Cardiopulmonary bypass with cardioplegic arrest allows the authors to examine the whole transcriptional profile of human left ventricular myocardium at baseline and after exposure to cold cardioplegia-induced ischemia as a human ischemia model. Methods: The authors obtained biopsies from 45 patients undergoing aortic valve replacement surgery at baseline and after an average of 79 min of cold cardioplegic arrest. Samples were RNA sequenced and analyzed with the Partek® Genomics Suite (Partek Inc., St. Louis, MO) for differential expression. Ingenuity Pathway Analysis (Ingenuity Systems, Redwood City, CA) and Biobase ExPlain (Biobase GmbH, Wolfenbuettel, Germany) systems were used for functional and pathway analyses. Results: Of the 4,098 genes with a mean expression value greater than 5, 90% were down-regulated and 9.1% were up-regulated. Of those, 1,241 were significantly differentially expressed. Gene ontology analysis revealed significant down-regulation in immune inflammatory response and complement activation categories and highly consistent was the down-regulation of intelectin 1, proteoglycan, and secretory leukocyte peptidase inhibitor. Up-regulated genes of interest were FBJ murine osteosarcoma viral oncogene homolog and the hemoglobin genes hemoglobin α1 (HBA1) and hemoglobin β. In addition, analysisof transcription factor-binding sites revealed interesting targets in factors regulating reactive oxygen species production, apoptosis,immunity, cytokine production, and inflammatory response.Conclusions: The authors have shown that the human left ventricle exhibits significant changes in gene expression inresponse to cold cardioplegia-induced ischemia during cardiopulmonary bypass, which provides great insight into thepathophysiology of ventricular ischemia, and thus, may help guide efforts to reduce myocardial damage during surgery.
Original languageEnglish (US)
Pages (from-to)537-550
Number of pages14
JournalAnesthesiology
Volume122
Issue number3
DOIs
StatePublished - Mar 4 2015
ASJC Scopus subject areas
• Anesthesiology and Pain Medicine
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1a01aa77535b9ecfb87b9fc36adbcd2f
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6,817,617,320,185,613,000
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Ventilatory efficiency is superior to peak oxygen uptake for prediction of lung resection cardiovascular complications
Authors
MAZÚR Andrej BRAT Kristián HOMOLKA Pavel MERTA Zdeněk SVOBODA Michal BRATOVÁ Monika ŠRÁMEK Vladimír OLSON Lyle ČUNDRLE Ivan
Year of publication 2022
Type Article in Periodical
Magazine / Source PLoS ONE
MU Faculty or unit
Faculty of Medicine
Citation
Web https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0272984#abstract0
Doi http://dx.doi.org/10.1371/journal.pone.0272984
Keywords ventilatory efficiency; cardiovascular complications; peak oxygen consumption
Description Introduction Ventilatory efficiency (VE/VCO2 slope) has been shown superior to peak oxygen consumption (VO2) for prediction of post-operative pulmonary complications in patients undergoing thoracotomy. VE/VCO2 slope is determined by ventilatory drive and ventilation/perfusion mismatch whereas VO2 is related to cardiac output and arteriovenous oxygen difference. We hypothesized pre-operative VO2 predicts post-operative cardiovascular complications in patients undergoing lung resection. Methods Lung resection candidates from a published study were evaluated by post-hoc analysis. All of the patients underwent preoperative cardiopulmonary exercise testing. Post-operative cardiovascular complications were assessed during the first 30 post-operative days or hospital stay. One-way analysis of variance or the Kruskal–Wallis test, and multivariate logistic regression were used for statistical analysis and data summarized as median (IQR). Results Of 353 subjects, 30 (9%) developed pulmonary complications only (excluded from further analysis), while 78 subjects (22%) developed cardiovascular complications and were divided into two groups for analysis: cardiovascular only (n = 49) and cardiovascular with pulmonary complications (n = 29). Compared to patients without complications (n = 245), peak VO2 was significantly lower in the cardiovascular with pulmonary complications group [19.9 ml/kg/min (16.5–25) vs. 16.3 ml/kg/min (15–20.3); P<0.01] but not in the cardiovascular only complications group [19.9 ml/kg/min (16.5–25) vs 19.0 ml/kg/min (16–23.1); P = 0.18]. In contrast, VE/VCO2 slope was significantly higher in both cardiovascular only [29 (25–33) vs. 31 (27–37); P = 0.05] and cardiovascular with pulmonary complication groups [29 (25–33) vs. 37 (34–42); P<0.01)]. Logistic regression analysis showed VE/VCO2 slope [OR = 1.06; 95%CI (1.01–1.11); P = 0.01; AUC = 0.74], but not peak VO2 to be independently associated with post-operative cardiovascular complications. Conclusion VE/VCO2 slope is superior to peak VO2 for prediction of post-operative cardiovascular complications in lung resection candidates.
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5. Evolutionary genetics and neuroscience
5.a) Brain memory inheritance
Section VI of the General Theory of the Conditional Evolution of Life proposes the EDI Study - Evolution and Design of the Intelligence to validate the theory and essential aspects of evolutionary genetics and neuroscience of the intelligence.
The statistical research on the evolutionary genetics of the intelligence and cognitive neuroscience achieved great results and it is available online in the book the EDI Study.
While in the analysis of the intelligence it is possible to speak about a general intelligence; in memory studies is not feasible due to its variety.
A type of statistical research might deal with the evolution of mathematical memory; the memory that it demands certainty in the answers, and which should behave like the evolution of intelligence.
At the same time, it would not be surprising that other types of memory, like normal memory, or the memory capacity related to the language, that have the characteristic of admitting errors, were consequence of the same genetic information, but under the assumption of not external verification.
In other words, for the linguistic memory our brain with the information of both ancestors develops a mechanism without requiring the confirmation between both. Something similar could happen with the intuition that sometimes is very powerful but one cannot be certain about it.
The verification of inheritability of memory requires a much more complicated model of evolutionary genetics than that of intelligence and it will be necessary to have measures of partial capacities for the different potentials of the memory stratum or from the special memories.
Neuroscience should provide models of the brain’s functioning to allow studies about memory in depth, but despite the advances produced, it seems that a solid model still does not exist.
The figure shows us the effect on the cognitive capacities of possible descendants within the opposite assumption to the VGI method. The expression of the capacities will follow an additive mathematical law instead of the law of intersection that we have studied in the evolutionary genetics of the intelligence.
The figure design implies a simplification of the model of evolutionary genetics and neuroscience; it supposes that the addition is equal to the potential of the major gene, thinking that the whole potential of the minor is included in the major one.
Capacity of the descendants
without VIG method
Capacity of the descendants without VIG method
This is the case of the evolutionary genetics of normal memory. Something similar to the relation between evolution of mathematical and normal memory can occur with the evolution of the intuition, which sometimes is very powerful but one cannot rely on it, with regard to the evolution of the intelligence.
In any case, an evolutionary genetics and cognitive neuroscience model for medium and long term normal memory needs to take into account the following aspects:
• Reliability of normal memory
The effective potential of normal memory will depend on a similar mechanism to the intuition that would imply the opposite hypothesis of the functionality of the method of verification of the genetic information VIG.
In other words, the mentioned potential in neuroscience will follow the rule opposite to the general intelligence described in the book about Intelligence, Intuition, Language and Creativity of the Cognitive Global Theory.
The basic reasoning in the evolutionary genetics context is that a mistake from the normal memory is not very serious and therefore it does not require the levels of reliability that guarantees the cited VIG method.
• The effect of simple complementariness between intelligence and memory
If we think about the functional complementarity of the intelligence and memory in neuroscience, it might assume that each additional unit, for example, of intelligence will increase the total potential not in a unit, but in the quantity of the total memory. In these cases, the complementarity might follow a mathematical law of more or less attenuated multiplication.
The section about Complementary Characters and the Origin of the Species in title IV of the online book of the General Theory of the Conditional Evolution of Life comments this effect of complementariness from a more general point of view of evolutionary genetics.
• The effect of complex complementariness between intelligence and memory
Memory depends on its genetic structure and on the power of manager of the said structure or intelligence; therefore, its efficiency will result from the effects of complementarity to occur.
The effect of complex complementariness takes place due to the involvement of the intelligence in the processes of global information system of the memory; it is to say, the intelligence as a memory manager, and not of his logical typical processes.
In neuroscience, the intelligent reasoning capacity of the brain will depend on the logical processor and the available information (simple complementarity effect); but at the same time, the available information depends on the above-mentioned processor, when it worked for the classification and storage of the information in the memory (complex complementarity effect)
5.b) Language, linguistic memory and linguistic reasoning
In the specific case of the research in evolutionary genetics and neuroscience of linguistic memory, the brain might act choosing a word, for example, depending on the first proposals that it would receive from the storage system of linguistic memory.
It is opportune to emphasize that, in this occasion, it is a matter neither of the employment of the method of verification of the genetic information VIG, proposed for the evolution of the intelligence, nor of his opposite but of a different one. Let us remember that in the VIG method it expected to receive all the proposals of the involved mechanism and needed a great uniformity (verification) to the acceptance whereas, in the opposite case, only needed a certain majority. Now the acceptance takes place on the first proposals with a minimum repetition.
Let's say, to clarify with numerical information the previous paragraph, that there would be validated the first five words which are repeated 50 times; in this way, it is not necessary to wait for the completion of work of thousands of million neurons that might be involved in the process.
Carrying on with this argument, and remembering that the manager of the memory is similar enough to the intelligence; It would be the linguistic memory manager the one that would act proposing the first words that its internal mechanism provides it.
The global language process would have as primary elements, on the one hand, the linguistic memory, that conceptually contains the stated manager of this type of memory and, on the other hand, the language manager in strict sense, who is the oral expression manager of thoughts and feelings.
In other words, the language manager as well as the linguistic memory manager applies neither the method of verification of the genetic information VIG, proposed for the evolution of the intelligence, nor opposite, but a different one, which would act in an intuitive form but much faster than the intuition.
The complementarity power of two characters that, as in this case, do not demand the method of verification of the genetic information VIG, it should be far superior to that of the individual characters when they apply the VIG. This could be the reason that the capacity of human language and its evolutionary genetics are surprising from the perspective of the neuroscience.
The inheritance and evolution of this combined power might be a subject of study through statistical analysis because there are methods to measure the variables involved.
A philosophical trend supports a strong constituent of genetics in language. The linguist Noam Chomsky is the most important representative of the above-mentioned trend, called innatism in contraposition to the constructivism trend. Chomsky affirmed, many years ago, to have identified common elements to all the languages of the human beings, what it meant a genetic predisposition to the language development.
The genetic nature of the language has met reinforced by the recent development of a particular gene that it significantly affects to the construction of phrases of language without affecting other personal capacities, or what we might denominate general intelligence, of the individuals in the genealogy of an entire family subject of study.
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Browsing: Osteoarthritis
Comprehensive Information, Resources, and Support on Osteoarthritis
Laminectomy is done to create a space by removing the lamina, which is the back part of the vertebra that covers the spinal canal. Your doctor will also remove bone spurs or other structures that cause spinal stenosis.
Non-surgical spinal decompression therapy is a type of motorized traction that can relieve your back pain due to spinal stenosis. The therapy aims to stretch the spine gently, thereby changing the force and position of the spine. The purpose of therapy is to relieve pain and promote a healing environment for the spine.
Our joints have a natural shock absorber called cartilage. Cartilage is smooth, elastic, and rubber-like material that provides cushioning effect to the bones at joints. It reduces the friction between two bones, making them work smoothly. As people age, their joints become stiff and the cartilage becomes more susceptible to wear and tear.
Arthritis is an inflammation of the joints. There are various types of arthritis, osteoarthritis being the most common form. Osteoarthritis (OA or degenerative arthritis) is a skeletal complication caused by cartilage loss in a joint. It can occur anywhere in the body, but the most common sites are hips, knees, elbows, and spine.
Thumb arthritis is a condition when cartilage wears away from the ends of the bones that form the joint at the base of the thumb. As a result, bones rub together, creating friction and harm the joint, causing pain and other symptoms.
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Category Archives: Hormones
smoking 1
Safeguarding life from tobacco addiction
Safeguarding life
Safeguarding life from tobacco addiction by quitting smoking
Safeguarding life from tobacco addiction: The duty of care we owe one another
While the authorities who’re charged with the duty of safeguarding life from the effects of tobacco and cigarette addiction are busy licensing more manufacturing firms and their distributors in the market, very innocent consumers of the substances continue to suffer disease and sickness across the globe. For how long shall we be in this bondage of addiction? Must we out of our actions be introducing our children to the drug by sending them to the shops for our supplies? Is it fair for our mothers to intoxicate their unborn children with nicotine while still in the womb? What about the association we have husbands and wife where one is smoking and the other is not should we be intimate, by way of kissing and risk contracting complications out of secondhand smoke? Ideally, there are very fundamental questions that we must address boldly by taking health precautions against the effects of tobacco addiction in the current generation.
How then should we begin? We sought the expert opinion of professionals from the home of addiction solutions at AWAREmed Health and Wellness Resource Center under the able leadership of doctor Dalal Akoury (MD) and also the founder of the facility. Doctor Akoury says that when it comes to all addictive substances and particularly the cigarette addiction, the only way to fully protect yourself and your loved ones from the dangerous chemicals in both the actual cigarette smoking and secondhand smoke is through embracing100% smoke-free environments. In one of the forums when lecturing some clients, one of them asked, how possible is that? From an addict point of view this could be a challenge, however professionally this is possible you could start by opening the windows for easy circulation of air; sitting in a separate area with smokers and avoiding designated area for smoking; or using ventilation, air conditioning, or a fan these strategies, however, will only succeed in reducing the concentration of the cigarette smoke but may not necessarily eliminate secondhand smoke exposure completely. It, therefore, means that if you are a smoker, the single best way to protect your family is to quit smoking.
Safeguarding life from tobacco addiction: Latest research findings
Addiction is a developmental disorder that begins in adolescence, and sometimes as early as childhood. Recent advances have provided more insight into why teens put themselves at risk for addiction through risk-taking and thrill-seeking behaviors. These behaviors are likely to happen due to the fact that the part of the brain responsible for judgment, decision-making, and control of emotional responses the prefrontal cortex is the last area of the brain to mature. But there may be other factors. Dr. Dalal Akoury and her team of experts have established that a chemical in tobacco smoke, acetaldehyde, may play a role in addicting adolescents to smoking. In the study, adolescent laboratory rats increased their intake of nicotine when it was combined with acetaldehyde while the adult rats did not. That is just a hint of why health precautions against the effects of tobacco use are very important. You may want to consult further with doctor Akoury in any other pending concerns you have.
Safeguarding life from tobacco addiction: The duty of care we owe one another
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Cigarette
Incapacitating hormone balance by smoking
Incapacitating hormone balance
Incapacitating hormone balance by smoking
Incapacitating hormone balance by smoking: Nicotine irritability
There is no doubt that nicotine is harmful to human health. Everybody knows this. However, what many women may not know is that besides all the risk like heart complications, lung conditions, several cancers and osteoporosis, cigarette smoking is also incapacitating hormone balance. Many women are the concern with other problems like how cigarette affects their beauty, fatigue and nutrient depletion because that is what can be physically seen outright. All that has been mention are closely associated with cigarette smoking but for the purpose of this article, we want to look at how nicotine causes hormone imbalances. According to experts from AWAREmed Health and Wellness Resource Center, several research has established that premenopausal women who smoke have the higher risk of infertility, complications during the menstrual cycle and even get into early menopause. Besides that, it is also becoming evident that cigarette smoking also affects menopausal hormones.
Incapacitating hormone balance by smoking: Why you need to quit smoking
What is stated above is just a drop in the ocean when it comes to the risks associated with smoking. Therefore the evidence of how bad smoking is to your health is very overwhelming. And just a quick reminder, your consistent morning cough should alert you of the damage smoking is causing to your lungs. Remember that every stick of cigarette robes you off the much-needed energy in your body’s daily needs.
Quitting smoking will, therefore, enable you to keep your hormones well balanced. And when this is achieved, you will experience more mood stability and put to check your weight. Remember that even using nicotine patches and gum instead of smoking will help, because the chemicals added to cigarette tobacco and created by burning tobacco are thought to be those responsible for most of the negative side effects. In other words, it’s not the nicotine itself that’s so very harmful, it’s the delivery system. You can choose today to be free from all these challenges by calling doctor Dalal Akoury MD for a more professional direction about all the addictive elements of cigarette smoking and how it sabotages hormone balance.
Incapacitating hormone balance by smoking: Menopausal women
In menopausal women, cigarette smoking raises adrenal hormones such as cortisol (a stress hormone), and androgens (male hormones) such as androstenedione and dehydroepiandrosterone (DHEA). Chronically high cortisol levels create unstable blood sugar, which in turn causes high blood glucose and insulin which stimulates the ovaries to produce androgens. It, therefore, means that in a menopausal woman, the ovaries have slackened in the production of estrogen and progesterone, nonetheless, the production of androgens can continue well into her eighties. Androgens without the balance of estrogen and progesterone are the source of much-dreaded hair loss and whiskers in older women and cigarette smoking magnifies these effects.
Quitting smoking, combined with strategies to balance hormones such as bioidentical hormone replacement therapy (BHRT), stress management, exercise, and reduction of sugar and refined carbohydrates, has dramatic potential to improve overall health, stabilize mood, increase energy, increase weight loss and improve sleep and that explains why you need to quit smoking now if not immediately.
Incapacitating hormone balance by smoking: Nicotine irritability
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drug-addiction-treatment-1024×682
Brains communication system
Brains communication system
Brains communication system can be very vulnerable to drug addiction and needs to be free from any substances of abuse
Brains communication system: Addiction chemical alteration to the brains functions
New neural pathways are formed as an addiction develops. This is because addiction chemical alteration to the brain’s communication system takes effect with such intoxications. In other words, when you take drugs away, the brain will revert again to form new neural pathways. Neuroplasticity explains why the initial period of recovery is difficult and uncomfortable. But the good news is that this difficulty is only temporal. Speaking to the experts at AWAREmed Health and Wellness Resource Center about addiction chemical alteration, doctor Akoury MD registers that this piece of information is very helpful to especially when attempting recovery. From our previous illustration where a tree fell on the usual pathway and so you needed to navigate to get through, some difficulties could be experiencedd. In the same way, when undertaking the recovery journey in addiction treatment, it can be difficult and uncomfortable while these new neural pathways are forming. As long as the recovering person does not give up during this initial period of discomfort, new neural pathways will form that support recovery. These new pathways will become more established and better developed over time. As they do, recovery becomes easier and more comfortable thereby defeating any addiction chemical alteration to the functions of the brain.
Brains communication system: Effects of addictive substances
Going by the facts mentioned above about the adaptive and the dynamic qualities of our brains to ensure our survival, I want to be persuaded that you are now somewhere as far as keeping your brain healthy. The next point I want to raise on how addiction changes the brain’s communication pathways may be quite unfortunate. Why do I say so, it is because the brain’s ability to be so adaptive is also at the root of addiction. Doctor Akoury says that the brain has the ability to adapt not only to the harmless substances and activities but also to the strong effects of addictive drugs and activities. And when it does, there will be damaging changes happening in the brain regions which are associated with reward including the memory and emotion, decision-making and stress regulations. These changes to our brain make the repeated use of addictive substances or activities very compelling. The good news is that our brains’ neuroplasticity allows us to correct these changes! Therefore, although addiction chemical alteration leads to structural changes in the brain, we are capable of learning new coping skills. The brain’s plasticity allows these new coping skills to be imprinted.
Finally, we will be discussing these structural changes in the next series of articles and we want to urge you not to go away but to stay with us on the link and where possible invite a friend too. In the meantime having such powerful information about the most sensitive organ in your body the brain is very helpful in keeping you healthy. I am saying so because when you know, you will not do things that will cause harm to your health, and if you have already caused an injury, then you can take measures to remedy the situation by scheduling an appointment with doctor Dalal Akoury to professionally take your through the recovery treatment process today.
Brains communication system: Addiction chemical alteration to the brains functions
http://www.awaremednetwork.com/
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losing-weight
Weight loss accuracy in children
Weight loss accuracy
Weight loss accuracy in children when done well, will impact in them when they grow up
Weight loss accuracy in children: Healthy lifestyle all round
What life has to offer can be good or bad? It is for you and me to make good choices over the abundance of life providence. One of the choices we make is child up-keep. What we do in this will impact on their lives for generations to come. And looking at our surrounding, we have a very intimidating neighborhood. Right from lifestyle to anything you can think of. Children are brought up knowing only of junk foods and inactive behaviors brought about by technology. Issues of weight complications are on the rise and that is why it is important that we take seriously weight loss accuracy in our children. In order to bring up healthy children, doctor Dalal Akoury MD President and founder of AWAREmed health and wellness resource center shares with us about the importance of healthy diet and physical activeness.
Weight loss accuracy in children: Eating healthy meals and snacks
• Have structured mealtimes and snacks on a schedule. Model and insist on good meal habits remember that eating less breakfast and more dinner or skipping breakfast increase the risk for obesity.
• Don’t mistake healthy eating for dieting. Eating large amounts of high calorie food and frequent snacking have become commonplace. Bad eating habits become accepted as normal eating habits. Eating healthful foods in a healthy manner is not the same as dieting.
• The food emphasis should be on a variety of vegetables, with half your plate being vegetables and fruits. Grains should be whole grains.
• Keep only healthy foods in your home. Keeping junk food around for other family members, and trying to “police” what your child eats, only promotes sneak eating.
Weight loss accuracy in children: Encouraging physical activities
• Encourage physical activity. As kids move into adolescence, their levels of activity tend to drop too low. Do active things together as a family, like bike riding, hiking, walking and swimming. Here are some great ideas for helping to get your child and your family more active.
• Build activity into your family’s daily life with household chores, walking to school, parking farther from buildings and taking the stairs. Decreasing inactivity works better for long-term weight loss than focusing on vigorous aerobic exercise. It’s also an easier lifestyle change for your family to make!
• Make sure your kid gets outside during daylight hours. You could make it a policy in your family that unless the weather is bad, your children play outdoors after school. This encourages physical activity, and rules out the inactive pursuits of TV and other media.
Finally, I will again make emphasis on the prevention as this is the best way to keep healthy all the days of our kids live. However, knowing that this may have passed you, and you are already struggling with weight gain. All is not lost for you. You can schedule for an appointment with the experts at AWAREmed Health and Wellness Resource Center and doctor Akoury will take you through the weight loss program professionally leaving you with a much healthier weight and great life a head of you.
Weight loss accuracy in children: Healthy lifestyle all round
https://www.awaremed.com/wp-admin
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weight loss
Keeping good health practices on holiday
Keeping good health
Keeping good health practices on holiday will enable you to impact positively to your children and the next generation
Keeping good health practices on holiday: Weight loss goals and tips
It’s easy to underestimate the toll that the season takes physically, psychologically, and emotionally. To avoid gaining weight, you need commitment and awareness. It’s best to do this as a group, remember that even one or two friends whom you can call upon to talk about eating concerns is good enough so long as this will help you in keeping good health practices before, during and after the holidays. Besides group work, doctor Dalal Akoury MD President and founder of AWAREmed Health and Wellness Resource Center recommends the following as some of the weight loss tips you can engage:
Keeping good health practices on holiday: Identifying the difficult situations
One of the best outcomes of a calorie chat group is identifying the situations that cause you to overindulge. For instance you may choose to eat raw vegetables or a piece of fruit before going out. This way you will have something in my stomach and will not be hungry when you get there. Remember that alcohol is one of the biggest enemy to weight loss. If you have to have a feeling of belonging, you may choose to serve your guest champagne and staff your bottle with sparkling water. Remember that it is not the champagne that matters, but the real deal is that you’re celebrating with your good friends.
Keeping good health practices on holiday: Being honest with yourself
Besides the precautions you take, it’s important to understand other, more subtle tricks you use to justify overindulgence. We all tell ourselves stories that are the same, time after time, like ‘if I overeat Friday or Saturday, I’ll be extra good Monday morning. Other familiar half-truths are: I’ve eaten an extra thousand calories so I’ll do an extra session at the gym, or ‘I’ll eat what I want tonight and worry about it tomorrow. Remember that even after doing your best, possibilities of relapsing is still very inevitable. When this happens you are likely to become discourage and vulnerable to other common pitfalls. This should not be the reason for you to abandon your entire plan of enjoying the holidays simply because you made a mistake. The best thing you can do in such circumstances is to put it behind you and forge ahead with your weight loss plans.
Finally, it is not a crime to take time out periodically just to relax and put all the work busy schedule aside. After all why do we work if we can’t take time and share our provisions in parties, holidays and such other uniting occasions. I appreciate that you may not have the ability to effectively avoid unhealthy feeding habits during the holidays. These difficulties can easily be addressed by the professionals at AWAREmed Health and Wellness Resource Center. Therefore for lasting and permanent solution schedule for an appointment with the doctor Akoury today and your life will change drastically for the good of your general body structure.
Keeping good health practices on holiday: Weight loss goals and tips
http://www.integrativeaddictionconference.com/wp-admin
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Tricks to identify and fix the neurological impact of ‘long Covid-19’ on your body
Published on:13 August 2021, 09:30am IST
It is being observed that mental health issues are a consequence of long Covid-19, but how is it possible to identify and fix them? Here’s all you need to know.
Dr Dhanashri Chonkar
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covid-19 and mental health
The neurological impact of Covid-19 is much more than you know. Image courtesy: Shutterstock
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Are you experiencing short-term memory loss? Do you feel confused, unable to concentrate? Do you feel agitated with the slightest provocation?
Well, then these are very common neurological symptoms post the covid-19 infection. In the early months of the pandemic, doctors struggled to keep patients breathing, and focused mainly on treating damage to the lungs and the circulatory system. But even then, evidence for neurological effects was accumulating. Some people hospitalized with covid-19 were experiencing delirium – they were confused, disorientated, anxious, depressed, experienced Insomnia and were agitated. Not only this, but some experienced these cognitive impairments months after they made full recovery from the infection. The rate of cognitive impairment was much higher than expected.
Also, read: Can mental health affect your heart health?
Short and long-term impact of covid-19 on the brain
Covid-19 can damage the brain directly by causing encephalitis (inflammation of the brain) of any severity. This itself can have devastating effects on the patient. It can also cause a stroke in any age group. Plus, it can cause systemic inflammation that can also lead to indirect neurological damage. Last year, we found that several patients with covid-19 suffered strokes. Earlier, people with co-morbidities and over the age of 65 were more at risk, but now we see evidence that even younger individuals are at seven times the risk of suffering from a stroke during or after covid-19.
covid-19 and mental health
Covid-19 has led to an increase in the cases of depression and anxiety. Image courtesy: Shutterstock
Short-term impact of Covid-19 on the brain
• Encephalitis of any severity, leaving temporary or permanent residual damage on the cognitive and other brain function
• Acute ischemic brain strokes – seen in all age groups of patients with or without comorbidities
• Guillain-Barre Syndrome (GBS) – covid-19 being a viral infection, GBS is known to occur after any viral infection
Also, read: World Organ Donation Day: How has Covid-19 impacted organ donation?
Long-term impact of Covid-19 on the brain
Cognitive impairment was noticed in patients with covid-19 infection, which was reversible or partially reversible, and lasted up to 4-7 months. A lot of research is needed to see the long-term effect on nervous tissues. A long-term Italian study reveals that such patients who had no symptoms of cognitive impairment during infection developed them after six months from recovery. Nearly 37.4 % of cases were having cognitive deficit and hyposmia (decreased sense of smell).
Apart from this, people have been reporting brain fog and some longer-term headaches they hadn’t experienced before. That seems to be a pretty core phenomenon in patients who have prolonged covid-19 symptomatology after recovering from the primary infection.
Now, there are hypotheses that say, the neurological symptoms might be a result of overstimulation of the immune system. So, these scenarios require entirely different treatments. More studies need to be conducted to further establish the neurological impact of covid-19. Having said that, people wonder how to identify the neurological impact of covid-19, or rather differentiate it from other brain-related issues.
covid-19 and mental health
You must take care of your mental health. Image courtesy: Shutterstock
Identifying neurological symptoms of Covid-19
Some of the symptoms are:
• Fatigue
• Memory, lack of concentration or sleep problems
• Muscle pain or headache
• Loss of smell or taste
• Depression or Anxiety
• Persistent postural dizziness
• Worsened symptoms after physical or mental activities
Reducing the impact
A one-size-fits-all approach to treat long-covid will not work. Therefore, a holistic approach is a must. One should refrain from following trending solutions claiming to fix all such symptoms. A personalized assessment and tailored nutritional management along with physical and psychological coaching are needed to help faster recovery. To lessen its impact, people need to do all things that will help in improving brain health
• Try yoga and meditation to improve focus & attention after consulting your doctor
• Focus your mind by dealing with the things that are distracting you
• Eat well and stay active
• Speak to your doctor and learn effective brain exercises
• Avoid alcohol and refrain from self-medication
• Avoid any medications that might cloud the way your brain works
Moreover, it is also important that we create and encourage a conducive work environment for everyone recovering from post-covid symptoms. Employers must encourage programs to build individuals’ knowledge and confidence to manage their symptoms. The bottom line is that early assessment along with personalized monitoring and management is essential for all people with long-covid symptoms.
Dr Dhanashri Chonkar Dr Dhanashri Chonkar
Dr Dhanashri Chonkar, Consultant Neurology, Fortis Hospital Mulund
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NATURAL INGREDIENTS FOR PAIN TREATMENT
0
51
Pain could come in different forms but knowing how to manage it is important. A pain management clinic would tell you to take note of when you have a toothache, spinal pain, or some other kind of aggravation, your most memorable motivation might be to go after a pain prescription. Many individuals depend on prescriptions, however, they can accompany a gamble of secondary effects, drug collaborations, and abuse.
While specific conditions might require a solution or over-the-counter (OTC) torment medicine, it might likewise be feasible to discover a portion of the help you want from an assortment of regular painkillers. Numerous spices and flavours have a long history of being utilized to ease irritation and agony.
Rosemary is another rejuvenating ointment that might assuage torment. A few specialists or the pain management clinic express that the rosemary plant, Rosmarinus officinalis L., may assist with treating migraine, muscle and bone torment, and seizures. Rosemary may likewise decrease aggravation, loosen up smooth muscles, and lift memory. Weaken rejuvenating ointments in a transporter oil like olive oil. Utilize three to five drops of rejuvenating ointment for every ounce of transporter oil.
This flavour has been utilized to alleviate joint inflammation, agony and indigestion, and to lessen irritation. It’s muddled the way that turmeric neutralizes torment or irritation, yet its action might be because of a substance called curcumin, which has mitigating properties. Turmeric is typically protected to utilize, yet high portions or long-haul use might cause heartburn. Likewise, individuals with gallbladder sickness ought to try not to utilize turmeric.
Resveratrol is tracked down in red wine, grapes and berries, resveratrol is known to make numerous gainful impacts, including against disease, cerebrum defence and even life-dragging benefits. As of late, scientists revealed that the substance deals with a cell level for torment guidelines.
Your body is intended for development. Amusingly, if you’re not moving much since you’re in torment, your idleness can exacerbate the aggravation. Delicate stretches can assist you with keeping up with your portability and scope of movement — and keep torment under control. The pain management clinic can assist you with finding stretches and practices that are suitable for your one-of-a-kind circumstance.
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@article {4104, title = {Graft-vs-host disease as a complication of lung transplantation.}, journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation//J Heart Lung Transplant}, volume = {25}, year = {2006}, month = {2006}, pages = {1175 - 7}, publisher = {Smith,Douglas M. Department of Pathology, Baylor University Medical Center, Dallas, Texas 75246, USA. dsmith@baylorhealth.edu}, address = {United States}, abstract = {We report a rare case of acute graft-vs-host disease (aGVHD) after a lung transplant. The patient presented with advanced disease manifested by skin rash, fever, diarrhea, liver dysfunction and severe pancytopenia. He went on to die of sepsis and multi-organ failure. aGVHD is a disease often confused with drug reactions or viral infection; therefore, it is important to have a high index of suspicion and to confirm the diagnosis early with tests for donor cell chimerism. Effective treatment is elusive but we are learning a great deal about the underlying mechanisms of this disease and hope to develop better treatment.}, keywords = {*Graft vs Host Disease/et [Etiology], *Lung Transplantation/ae [Adverse Effects], *Postoperative Complications/im [Immunology], Chimerism, Diagnosis, Differential, Disease Progression, Fatal Outcome, Graft vs Host Disease/di [Diagnosis], Graft vs Host Disease/im [Immunology], Histocompatibility Testing, Humans, Lung Transplantation/im [Immunology], Lung Transplantation/pa [Pathology], Male, Middle Aged, Postoperative Complications/di [Diagnosis], T-Lymphocytes/pa [Pathology], Tissue Donors}, isbn = {1557-3117}, author = {Smith, Douglas M and Agura, Edward D and Ausloos, Ken and Ring, W Steves and Domiati-Saad, Rana and Klintmalm, Goran B} }
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-784,834,950,487,891,500
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Co-development of a nanomedicine treatment and companion diagnostic test for castration-resistant prostate cancer
Recognition: NWOVeniScientific
Description
Prostate cancer (PC) is one of the deadliest types of cancer in males worldwide. Early stage PC is often curable but many patients develop castration-resistant prostate cancer (CRPC), resulting in lethal end-stage disease. Prostate specific antigen (PSA) plasma levels have been traditionally exploited for diagnosis and prognosis. However, PSA screening is characterized by high variability leading to false-positive outcomes. Advanced therapies are required for the treatment of CRPC, guided by a reliable companion diagnostic test (CDx) for patient selection and to monitor therapeutic efficacy. The aim of this proposal is to co-develop for the first time a nanomedicine combination therapy and a CDx based on extracellular vesicles (EVs) for the treatment of CRPC. I will employ tumor-targeted nanomedicines to deliver more drug to the tumor and reduce side
effects when compared to free drug. The treatment comprises microfluidics-prepared lipid nanoparticles (LNPs) containing siRNAs that target essential CRPC genes, combined with LNPs loaded with the cytotoxic anti-cancer agent docetaxel to achieve synergistic therapeutic effects. Regarding the CDx, EVs have created excitement as potential biomarker candidates. EVs are released by cells as means of intercellular communication and can be detected in bodily fluids. The number of EVs and their composition is altered in CRPC, raising opportunities to exploit them in a CDx. As EVs provide a fingerprint of
their parental cell, EVs can be considered as liquid biopsies which provide more
information than standard biomarker measurements and are much less invasive than prostate biopsies. I will collect blood and urine samples during the preclinical evaluation of the proposed treatment for EV analysis by surface markers, protein content and RNA content. The co-development of a nanomedicine combination treatment for CRPC and a CDx is a rational strategy that has the potential to advance into clinical evaluation and
ultimately improve patient survival.
Degree of recognitionNational
Fingerprint
Nanomedicine
Castration
Routine Diagnostic Tests
Prostatic Neoplasms
docetaxel
Therapeutics
Prostate-Specific Antigen
Nanoparticles
Neoplasms
Biomarkers
Lipids
Biopsy
Microfluidics
Neoplasm Genes
Dermatoglyphics
Therapeutic Uses
Extracellular Vesicles
Pharmaceutical Preparations
Patient Selection
Prostate
|
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1a01aa77535b9ecfb87b9fc36adbcd2f
|
-2,540,282,004,940,673,000
|
User: Guest Login
Document type:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Author(s):
McGough, JM; Yang, D; Huang, S; Georgi, D; Hewitt, SM; Röcken, C; Tänzer, M; Ebert, MP; Liu, K
Title:
DNA methylation represses IFN-gamma-induced and signal transducer and activator of transcription 1-mediated IFN regulatory factor 8 activation in colon carcinoma cells.
Abstract:
IFN regulatory factor 8 (IRF8) is both constitutively expressed and IFN-gamma inducible in hematopoietic and nonhematopoietic cells. We have shown that IRF8 expression is silenced by DNA methylation in human colon carcinoma cells, but the molecular mechanism underlying methylation-dependent IRF8 silencing remains elusive. In this study, we observed that IRF8 protein level is inversely correlated with the methylation status of the IRF8 promoter and the metastatic phenotype in human colorectal car... »
Journal title abbreviation:
Mol Cancer Res
Year:
2008
Journal volume:
6
Journal issue:
12
Pages contribution:
1841-51
Language:
eng
Fulltext / DOI:
doi:10.1158/1541-7786.MCR-08-0280
Pubmed ID:
http://view.ncbi.nlm.nih.gov/pubmed/19074829
Print-ISSN:
1541-7786
TUM Institution:
II. Medizinische Klinik und Poliklinik (Gastroenterologie)
BibTeX
|
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|
1a01aa77535b9ecfb87b9fc36adbcd2f
|
5,337,346,744,405,785,000
|
Simultaneous image-guided and endoscopic navigation without rigid cranial fixation: Application in infants: Technical case report
Francesco T. Mangano, David D. Limbrick, Jeffrey R. Leonard, Sung Park Tae, Matthew D. Smyth
Research output: Contribution to journalArticlepeer-review
31 Scopus citations
Abstract
OBJECTIVE AND IMPORTANCE: Infants and young children demonstrate a variety of intraventricular and periventricular lesions. Endoscopy has proven useful in the treatment of many of these lesions, but its benefit is limited if it is applied to complex loculated cysts or if the disease is concealed by normal ependymal boundaries. In adults and older children, endoscopy can be augmented by the simultaneous use of frameless stereotaxy, but this combined modality has not been possible in infants and young children without rigid cranial fixation. We describe a method of achieving simultaneous stereotactic and endoscopic navigation in infants and young children by using a pinless, frameless stereotactic assembly. CLINICAL PRESENTATION: The first patient was a 6-week-old boy with macrocephaly and a bulging fontanelle. Computed tomographic and magnetic resonance imaging revealed a complex arachnoid cyst and obstructive hydrocephalus. The second patient was a 7-month-old, ex-premature (27-wk gestational age) boy who developed posthemorrhagic hydrocephalus. He underwent multiple shunt revisions, one of which was complicated by enterococcal ventriculitis. Despite bilateral ventriculoperitoneal shunts, he developed increasing head circumference, listlessness, and irritability. Imaging revealed an enlarged, multiloculated, and asymmetric ventricular system. INTERVENTION: Simultaneous image-guided and endoscopic neuronavigation was implemented in both patients. Before the procedure, a cranial reference arc was secured to the outer table of the cranium through a small incision adjacent to the operative field. After the stereotactic apparatus was registered, the software was used to plan a trajectory for the approach. A burr hole was then made, and a rigid 6-mm endoscope was inserted for direct visualization. Once advanced past the endoscopic port tip, the electromagnetic coil stylet was used to stereotactically track position and identify areas for fenestration, biopsy, and catheter insertion. CONCLUSION: Endoscopic views of complex hydrocephalus and arachnoid cysts alone are often difficult to interpret. Simultaneous image-guided and endoscopic neuronavigation may be advantageous in the management of complex cases that are anatomically related to the ventricular system in infants for whom rigid cranial fixation could lead to increased procedure-related morbidity.
Original languageEnglish
Pages (from-to)ONS-E377.a-ONS-E377.e
JournalNeurosurgery
Volume58
Issue numberSUPPL. 2
DOIs
StatePublished - Apr 1 2006
Keywords
• Arachnoid cyst
• Hydrocephalus
• Intraventricular neuronavigation
• Neuroendoscopy
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-8,247,685,420,621,588,000
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evidence-based blog of Filippo Dibari
Maize porridge enriched with a micronutrient powder containing low-dose iron as NaFeEDTA, but not amaranth grain flour, reduces anemia and iron deficiency in Kenyan preschool children.
In Under-nutrition on October 6, 2012 at 6:06 am
Macharia-Mutie CW, Moretti D, Van den Briel N, Omusundi AM, Mwangi AM, Kok FJ, Zimmermann MB, Brouwer ID
J Nutrition 142: 1756-1763, 2012
Abstract
Few studies have evaluated the impact of fortification with iron-rich foods such as amaranth grain and multi-micronutrient powder (MNP) containing low doses of highly bioavailable iron to control iron deficiency anemia (IDA) in children.
We assessed the efficacy of maize porridge enriched with amaranth grain or MNP to reduce IDA in Kenyan preschool children. In a 16-wk intervention trial, children (n = 279; 12-59 mo) were randomly assigned to: unrefined maize porridge (control; 4.1 mg of iron/meal; phytate:iron molar ratio 5:1); unrefined maize (30%) and amaranth grain (70%) porridge (amaranth group; 23 mg of iron/meal; phytate:iron molar ratio 3:1); or unrefined maize porridge with MNP (MNP group; 6.6 mg iron/meal; phytate:iron molar ratio 2.6:1; 2.5 mg iron as NaFeEDTA).
Primary outcomes were anemia and iron status with treatment effects estimated relative to control. At baseline, 38% were anemic and 30% iron deficient.
Consumption of MNP reduced the prevalence of anemia [-46% (95% CI: -67, -12)], iron deficiency [-70% (95% CI: -89, -16)], and IDA [-75% (95% CI: -92, -20)]. The soluble transferrin receptor [-10% (95% CI: -16, -4)] concentration was lower, whereas the hemoglobin (Hb) [2.7 g/L (95% CI: 0.4, 5.1)] and plasma ferritin [40% (95% CI: 10, 95)] concentrations increased in the MNP group. There was no significant change in Hb or iron status in the amaranth group.
Consumption of maize porridge fortified with low-dose, highly bioavailable iron MNP can reduce the prevalence of IDA in preschool children. In contrast, fortification with amaranth grain did not improve iron status despite a large increase in iron intake, likely due to high ratio of phytic acid:iron in the meal.
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Multiple fundus images of our 47-year-old patient's left eye. What do you notice, and how should it be managed?
History
A 47-year-old white female presented with a chief complaint of a floater in her left eye that had persisted for four weeks. The patient explained that she first noticed the moving spot after being accidently hit near the eye by another person while out dancing. Her systemic and ocular histories were unremarkable. She reported no known allergies of any kind.
Diagnostic Data
Her best-corrected entering visual acuity measured 20/20 OU at distance and near. Her external examination was normal, with no sign of afferent pupillary defect. The biomicroscopic examination of the anterior segment was normal. She exhibited no evidence of iris neovascularization. Her intraocular pressure measured 15mm Hg OU. We documented peripheral pathologies in both eyes. The pertinent clinical findings are illustrated in the photograph.
Your Diagnosis
How would you approach this case? Does the patient require any additional tests? What is your diagnosis? How would you manage this patient? What is the likely prognosis?
Discussion
Additional diagnostic testing included indirect stereo-biomicroscopic examination of the fundus, color and brightness testing to rule out optic nerve involvement, photdocumentation and optical coherence tomography (OCT). The diagnosis in this case is uncomplicated posterior vitreous detachment OS. The vitreous is an extracellular matrix that forms a transparent hydrophilic gel.1-5
It is principally composed of water (98% to 99.7%).1-3 The vitreous serves as a conduit for nutrients to reach the lens and retina; offers structural support that stabilizes the volume of the globe; and may regulate eye growth and shape during fetal development.1-4
To maintain transparency, the vitreous functions as a barrier to cellular invasion and diffusion of macromolecules from surrounding intraocular tissues.3 In the gel state, the vitreous lowers oxygen tension in the retina and lens.3,5
The vitreous can be divided into two parts: the central nucleus and the peripheral cortex.1,2,6 The nucleus has a lower collagen fibril density than the cortex.2 Collagen fibrils in this region generally run in an anterior-to-posterior direction. Anteriorly, the fibrils blend with those of the basal vitreous; posteriorly, they insert into the surrounding vitreous cortex shell (cortical vitreous).2
The cortical vitreous is a thin layer (100µm to 300µm ) that lies adjacent to the lens, ciliary body and zonules anteriorly, and adjacent to the retina posteriorly.1-3 The cortical vitreous encircles the nuclear vitreous. The posterior vitreous cortex consists of densely packed, type II collagen fibrils and contains the highest vitreal concentration of hyaluronic acid (HA).7 It is absent over the optic nerve head and thins over the macular region.2
Here, the collagen fibrils run parallel to the retina and do not insert directly into the internal limiting membrane (ILM).3 The condensation of peripheral cortical collagen fibrils forms a false anatomic membrane. Anteriorly, it is termed the anterior hyaloid membrane (AHM). This structure runs adjacent to the lens zonules and the posterior surface of the lens, and anterior to the ora serrata. The false anatomic membrane posterior to the ora serrata is termed the posterior hyaloid membrane. It runs adjacent to the retina.2,6
The AHM is in direct contact with the aqueous humor and thus behaves like a membrane, separating these two ocular compartments.3,6 Cloquet’s canal (or the hyaloid canal) is a remnant of the embryonic hyaloid system. It runs from the posterior pole of the lens to the optic nerve head.2,6 This canal widens anteriorly to form the patellar fossa and posteriorly to form the Area of Martegiani over the optic disc.6
The void formed between the lens and the patellar fossa is known as Berger’s space.6 The primary vitreous is the innermost segment, and is derived from surface ectoderm. It provides support for the developing eye and serves as the primordial vascular supply. It reaches its most vascular stage near the ninth week of gestation. Shortly after this time, these vessels begin to atrophy and are replaced by the clear, avascular, secondary adult vitreous that originates from neuroectoderm and mesoderm. Lastly, the tertiary vitreous forms the lens zonules. It is primarily derived from neuroectoderm.6 Attachments between the vitreous and retina typically occur in areas where the ILM is the thinnest. Attachment locations include the vitreous base, the margins of the optic disc (when this area detaches, it produces the classic circular Weiss or Vogt ring observed in our patient), the back of the crystalline lens in contact with the hyloidocapsular ligament of Wieger, the 500µm-diameter foveola, along large retinal vessels, and at sites of abnormal vitreoretinal adhesion such as lattice margins.1,2,6-8
The strongest attachment occurs at the vitreous base, which is located 3mm to 4mm across the ora serrata and pars plana.2 Here, there is a high concentration of collagen fibrils orientated perpendicular to the base that insert into the pars plana and the anterior retina via defects in the ILM, where they merge with a network of collagen fibrils on the cellular side of the membrane.3 A false ligament, the hyaloideocapsular ligament of Wieger, is a circular attachment between the margin of the patellar fossa and the posterior surface of the lens.1,2
It was previously believed that the posterior vitreous collagen fibrils directly inserted into the ILM, but recent findings suggest that an extracellular matrix composed of laminin, fibronectin and sulfated proteoglycans interface and act as a “molecular glue.”7,9 Postmortem studies of vitreous structure confirm two major degenerations of the vitreous: liquefaction (synchysis) and collagen fibril aggregation (syneresis).9
• Synchysis refers to liquefaction of the vitreous, and typically is a senile process accelerated by myopia, inflammation, trauma, hereditary vitreoretinal syndromes (e.g., Stickler and Marfan syndromes), retinal vascular diseases, aphakia and vitreous hemorrhage.2,8,10-14
Synchysis is the most common degenerative change in the vitreous, and may present as early as age four.2,3 Senile synchysis may be caused by aggregation and redistribution of the collagen fibrils. This phenomenon leaves pockets of liquefaction known as lacunae that are devoid of collagen fibrils.3,10,15,16 These lacunae initially develop centrally; however, they often enlarge and coalesce.2 Lacunae are evident on slit-lamp biomicroscopy as pockets of optically empty space, with an absence of the characteristic fine fibrillar structure.2
• Syneresis, or a collapse of the vitreous secondary to collagen fiber aggregation, is the other major vitreous degeneration.2,9,12 When both synchysis and syneresis are present, collagen aggregates can be seen moving freely in the vitreous with ocular movement.2 The consequent shadows cast on the retina create the symptoms of floaters. Posterior vitreous detachment (PVD) refers to the separation of the cortical vitreous from the ILM anywhere posterior to vitreous base.2,17
The detachment may be localized, partial or complete.3 A complete PVD occurs when the posterior cortical vitreous is detached from the entire retina, including its adhesion to the optic nerve up to the posterior border of the vitreous base.3 At 50 years of age, the incidence of PVD in phakic eyes is grater than 50%––increasing to approximately 75% by age 65.18 Additionally, there is an increased risk for PVD in aphakic or pseudophakic eyes, myopes, and those with a history of trauma or intraocular inflammation.18
It is worth noting that women are prone to PVD at a younger age than men. This is likely because females experience reduced HA synthesis secondary to decreased postmenopausal estrogen levels.8,17 In our patient, biomicroscopic examination revealed an optically clear space filled with liquefied vitreous located between the detached posterior hyaloid and the retina.2 The pathognomic sign of a PVD is the presence of a clinically observable Weiss or Vogt ring overlying the optic disc.18 This ring represents circular attachment remnants of the posterior cortical vitreous to the site encircling the nerve (Area of Martegiani).18 A patient with an acute PVD may complain of newly visible floating spots that follow eye movement and continue to travel even after termination of the ocular movement.18
Another common symptom is photopsia, which is perceived as peripheral arcs or flashes of light secondary to mechanical retinal stimulation as the vitreous articulates with the retina at the attachment site.18 The process of PVD begins with synchysis of the vitreous and weakening of the posterior vitreoretinal adhesion.9 Enlargement of formed lucunae cause the posterior vitreal cortical wall overlying the involved area to thin.8,19 In general, as the vitreoretinal adhesion dissolves, it forms discontinuities within the posterior hyaloid––either via fissure evolution or a microbreak in the thin cortical vitreous layer.8,9,17 This allows synchytic vitreous to enter the subhyaloid space dissecting the posterior hyaloid from the ILM.9
Posterior vitreal detachments typically begin in a single quadrant of the perifovea (most often superior). Persistent attachments to the ILM remain at the fovea and optic nerve head.20 Over time, the perifoveal detachment enlarges to completely surround the persistent attachment at the fovea.20 Finally, detachment of the vitreous from the remaining foveal region produces a funnel-shaped configuration, with attachments at the optic disc and vitreous base. When the PVD releases from the optic nerve, the process is complete.18,20 One study outlined a grading system for age-related PVD:20
• Stage 1: Incomplete perifoveal PVD in up to three quadrants.
• Stage 2: Incomplete perifoveal PVD in all quadrants, with residual attachment to the fovea and optic disc.
• Stage 3: Incomplete PVD over the posterior pole, with residual attachment to the optic disc.
• Stage 4: Complete PVD. The researchers showed that even young, healthy eyes might exhibit incomplete or partial PVDs beginning as early as the fourth decade of life. Often, such partial detachments progress slowly for years before becoming complete.8,20 An anomalous PVD results when synchysis occurs without sufficient detachment from the ILM. This results in tractional effects at the interface.9 Those with genetic collagen diseases, such Marfan’s, Ehlers-Danlos and Stickler’s syndromes, have a higher incidence of anomalous PVD. These maladies also increase the risk of retinal complications at an early age.9,14,21
Anomalous PVD may result in vitreoschisis––a splitting of the posterior vitreous cortex and forward displacement of the vitreous body, leaving remnants of the outer layer firmly attached to the retina.22,23 Vitreoschisis is thought to play a role in the pathogenesis of macular pucker, macular holes and proliferative diabetic retinopathy.22-24 A common consequence of anomalous PVD is the development of vitreoretinal traction. On OCT, vitreoretinal traction––as opposed to vitreoretinal adherence without traction––presents as an attachment to the retina with associated tissue elevation, thickening and deformity.25 Deflection of the posterior hyaloid or vitreous strands often can be observed at that site.25 Complications of anomalous PVD result from anteriorly directed tension induced by the vitreous degeneration itself and/or dynamic traction associated with ocular movements.8 Ocular movements localize traction to areas of firm vitreoretinal adhesion.7
Most early-stage, anomalous PVD complications occur insidiously and are located in the posterior pole. Late-stage complications of complete anomalous PVD commonly develop in the periphery with acute symptoms, including retinal or optic disc hemorrhage, vitreous hemorrhage, retinal break or tear, and rhegmatogenous retinal detachment.8 Clearly, our patient exhibited a stage IV PVD without complications of maculopathy. We educated the patient that the floater would be less evident when her visual attention was occupied.
On the other hand––we informed her that, for at least for the next six months, the spot would be more noticeable when she was outside in bright sunlight or in rooms with white fluorescent lighting and/or lightly colored pastel walls. Again, we reiterated that this phenomenon would fade over time. We provided the patient with an Amsler grid for home monitoring and instructed her to inform us of any visual changes. We also asked her to return in three weeks for a dilated retinal examination to rule out additional complications. Further, we advised the patient to avoid contact sports and strenuous exercise until her follow-up appointment. Fortunately, she exhibited no complications at the three-week follow-up.
Thanks to Carolyn Majcher, OD, of San Antonio, and Julie Hutchinson, OD, of St. Loius, for their contributions to this case.
Majcher CE, Gurwood AS. The role of the vitreous in retinal disease. Rev Optom. 2012 Apr; 149(4):6-14 (suppl.). Khurana AK. Comprehensive ophthalmology. Delhi, India: New Age International; 2007:243-8.Le Goff MM, Bishop PN. Adult vitreous structure and postnatal changes. Eye (Lond). 2008 Oct;22(10):1214-22.Halfter W, Winzen U, Bishop PN, et al. Regulation of eye size by the retinal basement membrane and vitreous body. Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3586-94.Holekamp NM, Shui YB, Beebe DC. Vitrectomy surgery increases oxygen exposure to the lens: a possible mechanism for nuclear cataract formation. Am J Ophthalmol.2005 Feb;139(2):302-10.Schubert H, Kincaid M, Green R, et al. Anatomy and physiology. In: Regillo C, Brown G, Flynn H. Vitreoretinal disease: the essentials. New York: Thieme;1999:3-25.Sebag J, Hageman GS. Interfaces. Eur J Ophthalmol. 2000 Jan-Mar;10(1):1-3.Johnson MW. Posterior vitreous detachment: evolution and complications of its early stages. Am J Ophthalmol. 2010 Mar;149(3):371-82.Sebag J. Anomalous posterior vitreous detachment: a unifying concept in vitreo-retinal disease. Graefes Arch Clin Exp Ophthalmol. 2004 Aug;242(8):690-8.Bishop PN. Structural macromolecules and supramolecular organization of the vitreous gel. Prog Retin Eye Res. 2000 May;19(3):323-44.Bishop PN, Ayad S, Reardon AJ, et al. Type VI collagen is present in human and bovine vitreous. Biochem Biophys Res Commun. 1994 Aug 30;203(1):289-95.Bos KJ, Holmes DF, Kadler KE, et al. Axial structure of the heterotypic collagen fibrils of vitreous humour and cartilage. J Mol Biol. 2001 Mar 9;306(5):1011-22.Wenstrup RJ, Florer JB, Brunskill EW, et al. Type V collagen controls the initiation of collagen fibril assembly. J Biol Chem. 2004 Dec 17;279(51):53331-7.Maumenee IH. Vitreoretinal degeneration as a sign of generalized connective tissue diseases. Am J Ophthalmol. 1979 Sep;88(3 Pt 1):432-49.Sebag J. Pathology of the vitreous. In: Sebag J. The vitreous: structure, function, and pathobiology. New York: Springer-Verlag; 1989:97-147.Bishop PN, Holmes DF, Kadler KE, et al. Age-related changes on the surface of vitreous collagen fibrils. Invest Ophthalmol Vis Sci. 2004 Apr;45(4):1041-6.Sebag J. Development and aging of the vitreous. In: Sebag J. The vitreous: structure, function, and pathobiology. New York: Springer-Verlag; 1989:73-92. Tiedeman J, Mittra R, Han D, et al. Vitreous and retinal detachments. In: Regillo C, Brown G, Flynn H. Vitreoretinal disease: the essentials. New York: Thieme; 1999:65-86.Kishi S, Hagimura N, Shimizu K. The role of the premacular liquefied pocket and premacular vitreous cortex in idiopathic macular hole development. Am J Ophthalmol. 1996 Nov;122(5):622-8.Uchino E, Uemura A, Ohba N. Initial stages of posterior vitreous detachment in healthy eyes of older persons evaluated byoptical coherence tomography. Arch Ophthalmol. 2001 Oct;119(10):1475-9.Snead MP, Yates JR. Clinical and molecular genetics of Stickler syndrome. J Med Genet. 1999 May;36(5):353-9.Sebag J. Classifying posterior vitreous detachment: a new way to look at the invisible. Br J Ophthalmol. 1997 Jul;81(7):521.Sebag J, Gupta P, Rosen RR, et al. Macular holes and macular pucker: the role of vitreoschisis as imaged by optical coherence tomography/scanning laser ophthalmoscopy. Trans Am Ophthalmol Soc. 2007;105:121-9Sebag J. Diabetic vitreopathy. Ophthalmology. 1996 Feb;103(2):205-6.Martinez MR, Ophir A. Extrafoveal traction in retinal vein occlusion using spectral domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2011 Jun;249(6):811-20.
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@article{10.1167/iovs.14-15611, author = {Baker, Daniel H. and Simard, Mathieu and Saint-Amour, Dave and Hess, Robert F.}, title = "{Steady-State Contrast Response Functions Provide a Sensitive and Objective Index of Amblyopic DeficitsObjective Index of Amblyopic Deficits}", journal = {Investigative Ophthalmology & Visual Science}, volume = {56}, number = {2}, pages = {1208-1216}, year = {2015}, month = {02}, abstract = "{ Visual deficits in amblyopia are neural in origin, yet are difficult to characterize with functional magnetic resonance imagery (fMRI). Our aim was to develop an objective electroencephalography (EEG) paradigm that can be used to provide a clinically useful index of amblyopic deficits. We used steady-state visual evoked potentials (SSVEPs) to measure full contrast response functions in both amblyopic (n = 10, strabismic or mixed amblyopia, mean age: 44 years) and control (n = 5, mean age: 31 years) observers, both with and without a dichoptic mask. At the highest target contrast, the ratio of amplitudes across the weaker and stronger eyes was highly correlated (r = 0.76) with the acuity ratio between the eyes. We also found that the contrast response function in the amblyopic eye had both a greatly reduced amplitude and a shallower slope, but that surprisingly dichoptic masking was weaker than in controls. The results were compared with the predictions of a computational model of amblyopia and suggest a modification to the model whereby excitatory (but not suppressive) signals are attenuated in the amblyopic eye. We suggest that SSVEPs offer a sensitive and objective measure of the ocular imbalance in amblyopia and could be used to assess the efficacy of amblyopia therapies currently under development. }", issn = {1552-5783}, doi = {10.1167/iovs.14-15611}, url = {https://doi.org/10.1167/iovs.14-15611}, eprint = {https://iovs.arvojournals.org/arvo/content\_public/journal/iovs/933680/i1552-5783-56-2-1208.pdf}, }
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Amino acids are the nutrients that make up all proteins in the body. In bodybuilding, amino acids are emphasized because muscles are almost entirely composed of protein , that is, amino acids. The body uses them for its own growth, repair, strengthening and production of various hormones, antibodies and enzymes. Not only the growth of strength and “mass” of muscles depends on them, but also the restoration of physical and mental tone after training, catabolism , lipolysis of subcutaneous fat and even the intellectual activity of the brain – a source of motivational stimuli. In total, there are 20 proteinogenic amino acids, of which eight are the so-called “essential” or irreplaceable(the body cannot independently synthesize them in sufficient quantities), the rest are called interchangeable. There are also a number of amino acids that are not part of the protein structure, but play an important role in metabolism ( carnitine , ornithine , taurine , GABA )
Amino acids are one of the most popular forms of sports nutrition .
Amino Acids in Bodybuilding
Rating of amino acids in bodybuilding and fitness
Scientists have found that amino acids are extremely important for muscle recovery after exercise, muscle retention during a drying or weight loss cycle, and muscle growth . BCAAs play a special role in bodybuilding. Muscle tissue consists of 35% of them, BCAA have a large number of biological effects, and are released separately.
Exercise, even at moderate intensity, depletes 80% of all free amino acids – this emphasizes the importance of amino acid supplementation for rapid recovery and further muscle growth.
Amino Acids in Foods and Supplements (Equivalent Content)
Effects of amino acids
• Energy source . Amino acids are metabolized in a different way than carbohydrates, so the body can receive much more energy during training if the amino acid pool is full.
• Acceleration of protein synthesis . Amino acids stimulate the secretion of the anabolic hormone insulin , and also activate mTOR , two of these mechanisms that can trigger muscle growth. The amino acids themselves are used as building blocks for proteins.
• Suppression of catabolism . Amino acids have a strong anti-catabolic effect , which is especially necessary after training, as well as during a weight loss or drying cycle.
• Burning fat . Amino Acids Promote Fat Burning by Expressing Leptin in Adipocytes via mTOR
Benefit evaluation
There is no doubt that amino acids are very important and useful in bodybuilding, however, as mentioned above, protein consists of the same amino acids, it is protein that replenishes the need for amino acids in all people. Amino acids, as a sports supplement, differ from protein only in a higher absorption rate, and it is required only during and immediately after training, as well as in the morning. In addition, amino acids can be useful for losing weight, since they contain few calories, at the same time they well inhibit catabolism, reduce appetite and preserve muscles.
A significant disadvantage of amino acids is their high cost and small doses. If you are not under financial constraints, you can take 10 g of amino acids 4 times a day and get good results. On the other hand, you can take 20 grams of protein 4 times a day and you will get almost the same results in gaining muscle mass, as well as save 80% of money.
Conclusion
Complex amino acids have few advantages over whey protein and also lag behind (and are more expensive) than protein hydrolyzate . Give preference to protein and BCAA amino acids both when gaining muscle mass and when losing weight .
Гид по спортпиту для бегунов: аминокислоты и другие монокомпонентные добавки
Types of amino acids
Amino acid complexes differ in composition, amino acid ratio and degree of hydrolysis. Free-form amino acids, usually isolated (glutamine, arginine, glycine, and others), but complexes are also found. Hydrolysates are degraded proteins containing short amino acid chains that can be rapidly absorbed. Di- and tripeptide forms are essentially also hydrolysates, only the amino acid chains are shorter, and consist of 2 and 3 amino acids, respectively, and are absorbed very quickly. BCAA is a complex of three amino acids – leucine, isoleucine and valine, which are most in demand in the muscles, and are absorbed very quickly.
Many are confused when a manufacturer indicates a protein hydrolyzate in the composition or description , so there are often statements that it is actually a “compressed protein”. However, research has shown that hydrolyzed protein is absorbed faster than free forms of amino acids. This is probably due to the fact that di- and tripeptides require fewer active substances-transporters in the gastrointestinal tract.
The form Function and meaning Benefits disadvantages Recommendations for use
Free form Does not require digestion. Absorbed into the bloodstream quickly. They quickly enter the muscles, which helps prevent muscle catabolism. High price Recommended to be taken only before, during and after training.
Hydrolyzed form The fastest-absorbed form (as studies have shown, it is absorbed much faster than the free form) Muscle nutrition, prevention of catabolism, triggering of anabolic reactions. Contains amino acid chains that must be broken down before amino acids can enter the bloodstream. For maximum growth in strength and mass: 10 g before and 10 g after training. You can also take 10 g in the morning.
BCAA Essential Muscle Amino Acids. They serve as a source of energy and prevent catabolism, trigger muscle growth. They have a wide range of positive effects. Absorbed quickly. High price Heavy training: 4-5 g each before and after training.
Di- and tripeptide form Muscle nutrition, prevention of catabolism, triggering of anabolic reactions. Fast assimilation. High price. A rare product on the bodybuilding market. Usually taken in the same way as the hydrolyzed form.
Forms of amino acids
Amino acids are available in the form of powder, tablets, solutions, capsules, but all these forms are equivalent in effectiveness. There are also injectable forms of amino acids that are administered intravenously. It is not recommended to use amino acids injections, since it has no advantages over oral administration, but there is a high risk of complications and side reactions.
When to take amino acids
When gaining muscle mass , it is most advisable to take amino acids only before and after training, and also (optionally) in the morning, since at these times a high rate of amino acid intake is required. At other times, it is wiser to take protein . When losing weight, amino acids can be taken more often: before and after workouts, in the morning and in between meals, since the purpose of their use is to suppress catabolism, reduce appetite and preserve muscles.
Optimal doses
Amino acids are used in bodybuilding in a very wide range of doses. It is desirable that a single dose be at least 5 g, although the maximum result is achieved when using 10 – 20 g once. When buying amino acid complexes, pay attention to the dosage of the supplement. Some manufacturers make doses very low in order to increase the cost per unit weight of the product.
Combination with other additives
Amino acids can be combined with all types of sports nutrition, but they cannot always be mixed (drunk at the same time). Do not take amino acid complexes with protein, gainer , meal replacement or food together , as this reduces the rate of their absorption, which means that the meaning of their use is lost! Read the manufacturer’s recommendations carefully.
Side effects and safety
The duration of the amino acid intake is not limited, breaks and cycling are not required. Read the main article for more details: Harm and side effects
Quality control of amino acids
• Powdered amino acids, highly soluble in water, excluding BCAAs
• BCAA amino acids taste bitter
• Color and consistency as described on the label
• Packaging is properly sealed and meets factory standards
• Check the expiration date
Post Author: Inessa
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Now welcoming patients with Canadian Dental Care Plan (CDCP) coverage!
How To Tell If You Need a Dental Filling
If your dentist discovers that you have a cavity, you will likely need a dental filling to restore your tooth. Different types of dental fillings can be used. Today, our Burnaby dentist explains why you'd need a tooth filling and describes different types of fillings to consider.
What are dental fillings?
Fillings are used to restore the function, structure and appearance of a tooth that's been decayed or damaged, alleviating tooth pain you may be experiencing.
Why are dental fillings used?
These restorations can be used to repair cracks, broken teeth or tooth decay. They help restore functionality to the tooth and in some cases, dental fillings may be used to make cosmetic improvements to your smile.
What are some signs I may need a dental filling?
While you should visit a dentist to confirm whether you need a filling, there are some reliable signs that you may have a cavity that requires a tooth filling. If you notice any of these, book an appointment with your dentist as soon as possible:
1. You've lost a tooth filling and need a replacement.
2. You feel a sharp or throbbing pain in your tooth.
3. When you examine your teeth, you see a hole or dark spot.
4. Your tooth is broken or chipped.
5. Food keeps getting stuck between certain teeth.
6. Your tooth feels rough to the touch.
7. An existing tooth filling has broken or cracked.
What are dental fillings made of?
Dental fillings can be made of a number of materials, from amalgam to composite, porcelain and gold. While each of these materials is safe and long-lasting, they also each have their own advantages and disadvantages when it comes to repairing a cavity or decay. Here, our dentists provide advice on how to make the right dental choice for you.
Porcelain Fillings for Strength & Appearance
Also called inlays and onlays, porcelain fillings are brittle, hard, and made in combination with metal. Made in a dental lab and sent back to your dentist to place, these strong, tooth-coloured dental restorations are typically used on molars as they are more durable and longer lasting than a regular dental filling.
You’ll usually need to attend two dental appointments so your porcelain filling can be placed in your mouth.
Composite Fillings for a Natural Look & Feel
Because they are very similar in colour to natural teeth, composite fillings tend to blend in well with the surrounding teeth.
They look and feel natural, and are popular with patients who are concerned with how amalgam (grey) fillings may appear on teeth that are visible when they smile.
Dentists like composites because they are easy to sculpt and shape onto a tooth, and bond naturally to a tooth. This means your dentist won’t need to remove as much existing enamel when preparing the tooth.
Your dentist will remove tooth decay and add bonding material to the inside of the hole so the filling can be placed. Composite resin is then layered in the hole.
A curing light is used to harden each layer. When the last layer of resin has hardened, the filling will be carefully shaped to match your natural teeth.
Gold Fillings for Durability
Cast gold fillings are made using a model of your tooth. Created from a mix of gold combined with other materials such as copper and silver, a cast gold filling is created in a dental lab and sent back to your dentist.
It will then be cemented in place inside your mouth. Though this type of filling is considered the most durable (typically lasting 20 years or more) it is also the most costly. You'll also require at least two dental appointments to have it placed.
To learn more about composite dental fillings at Marine Way Dental Centre and to book an appointment, contact our Burnaby dentists today.
Discover Your Smile. Book an Appointment.
We are always accepting new patients at our office in South Burnaby. Get in touch today!
Request Appointment
Request Appointment (604) 437-6899
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Kortykosteroidy a tabletki antykoncepcyjne
On abrupt or overly rapid discontinuation of lorazepam, anxiety, and signs of physical withdrawal have been observed, similar to those seen on withdrawal from alcohol and barbiturates. Lorazepam, as with other benzodiazepine drugs, can cause physical dependence , addiction , and benzodiazepine withdrawal syndrome . The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur from standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen. [62] Rebound effects often resemble the condition being treated, but typically at a more intense level and may be difficult to diagnose. Withdrawal symptoms can range from mild anxiety and insomnia to more severe symptoms such as seizures and psychosis . The risk and severity of withdrawal are increased with long-term use, use of high doses, abrupt or over-rapid reduction, among other factors. Short-acting benzodiazepines such as lorazepam are more likely to cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines. [8]
Kortykosteroidy a tabletki antykoncepcyjne
kortykosteroidy a tabletki antykoncepcyjne
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http://buy-steroids.org
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Can I Drink Alkaline Water While Pregnant?
Alkaline water is usually known for its slightly higher pH value. It’s said to neutralize acid in the blood, improve metabolic activities and absorb nutrients effectively.
However, it’s critical to assure whether such benefits extend to pregnant women and if there are any potential risks. This article will delve into these questions.
We’ll as well provide some benefits, and if any, the risks associated with drinking alkaline water while pregnant.
Can I Drink Alkaline Water While Pregnant?
Yes, you can drink alkaline water while pregnant, regardless of the trimester you find yourself. This water type has a higher pH level higher than regular tap water, generally around 8 or 9 on the pH scale whereas regular tap water has a pH of around 7 – which also means it is less acidic.
Drinking alkaline water is not only safe during pregnancy, but it might also offer some health benefits, which we’ll discuss in detail at the next subsection.
That being said, it’s important to note that the body does not significantly benefit from alkaline water over regular water.
Even though it may help to stabilize the body’s pH level, it should be pointed out that the body’s normal mechanism typically maintains a stable pH balance.
So while you can safely drink it during pregnancy, it’s not necessarily superior to regular water.
Benefits of drinking alkaline water while pregnant
In fact, drinking alkaline water in pregnancy is a topic of debate and has not been conclusively proven to provide any extra health benefits than you’re getting from your balanced diet meals and your regular water intake.
Here are some proposed benefits:
Hydration
It may be less acidic and more savory to some people, making it easier to stay sufficiently hydrated during pregnancy. Proper hydration is very important for overall health of you and the little one.
Calcium content
It contains natural calcium, which can contribute to the health of both the mother and the baby. This promotes healthy bones in preggy moms and reduces calcium loss as well as perhaps developing healthy baby teeth and bones.
Antioxidants
Some alkaline waters are marketed as harboring antioxidant properties due to their higher pH levels. Antioxidants can help protect the body cells from free radical damage, which is very crucial for general health.
Reduced acid reflux
Some sources also suggest that when pregnant women drink alkaline water, it helps to minimize symptoms of acid reflux, which is a common pregnancy condition due to the hormonal changes and increased pressure on the belly.
Mineral content
Depending on where you’re getting your alkaline water or the brand, it may contain essential nutrients like potassium and magnesium, both of which are a requisite for bone and muscle health.
Maintenance of healthy body pH balance
Alkaline water might be helpful in maintaining a healthy pH balance in the body. This is particularly important during pregnancy given the body’s difficult task to support the growing baby.
Potential role in restoring pH balance during early pregnancy
In the first few months of pregnancy, most of the mother’s alkaline minerals are directed to the placenta for nourishing the growing baby.
This may result in an acidic discharge from the fetus, leading to the mother’s blood becoming acidic. Alkaline water potentially helps restore the pH balance.
While these potential benefits may sound promising, it’s important to bear in mind that scientific evidence supporting these claims is limited, and the effects of alkaline water predominantly vary for every pregnant woman.
Can alkaline water help morning sickness?
In fact, we can’t tell because there’s no direct evidence that suggest that that alkaline water can specifically help with morning sickness during pregnancy.
Morning sickness, which is characterized by nausea and frequent vomiting is a common thing, and its exact causes are not fully understood.
While several women may find relief from morning sickness through various methods like ginger supplements, acupressure or prescription medications specified by healthcare experts, there is no strong scientific basis to support that the idea that alkaline water – with its higher pH level – is an an effective remedy for morning sickness.
If you’re experiencing morning sickness during pregnancy and are seeking relief, it’s important to chat your doctor as they can provide better recommendations and suggest other modifications that are most appropriate for your specific situation.
Can alkaline water cause miscarriage?
Again, there is no evidence to suggest that drinking alkaline water in reasonable and moderate amounts would cause a miscarriage.
Miscarriages, which are oss of pregnancy before 20 weeks gestation, typically occur due to factors which are unrelated to the pH of the water you consume.
Common causes may include abnormalities in genetics, imbalances of hormones, infections and overly abusing drugs and alcohol.
That said, it’s important to ensue that the water you drink is always safe. Most tap water is safe, but if you have some concerns about the quality of your water source, then you should chat your doctor or local health department for guidance.
Additionally, overly drinking alkaline water can have negative effects on your health, but it’s unlikely to be a direct cause of miscarriage.
What is the best water to drink while pregnant?
Staying well hydrated during this journey is important for the health and well-being of both you and the baby.
And the best water to drink is a clean, safe and well balanced water. Here are some considerations:
• Tap water: In many developed countries including the US, tap water is safe to drink during pregnancy. It’s typically routinely treated and monitored for contaminants by local authorities. But you can go ahead and use a water filter if you have concerns about the taste or quality of your tap water.
• Filtered water: If you have doubts about the standard of your tap water, then you can install a whole house water softener to help the removal of impurities, such as chlorine, heavy metals, and other potential contaminants.
• Bottled water: if bottle water is what you prefer, then choose brands with a known source and a good reputation for the water quality. Ensure that the bottles are manufactured from BPA-free materials.
• Mineral water: Some women also choose this because they contain essential nutrients like calcium and magnesium, and that’s fine. Just be mindful of the sodium content in some mineral waters.
• Non-caffeinated beverages: Try to limit sugary drinks like soda and excessive caffeine during pregnancy. Water is the healthiest choice for staying hydrated.
Can I drink alkaline water while breastfeeding?
Drinking alkaline water while breastfeeding is considered safe in moderation, but should be in very moderate amounts. While this water ionized water won’t harm you or your breastfeeding baby, it’s important to rather maintain a balanced diet and avoid extreme dietary changes during this period.
Your body naturally regulates the pH levels in your bloodstream, and consuming alkaline water is unlikely to have any significant impact on your body’s pH balance.
It’s rather worth it if you prioritize a well-rounded diet that includes variety of foods to ensure you and the baby are getting all the good nutrients while helping you produce more milk.
But if you’re still interested in drinking alkaline water, then you ought to talk to your doctor, especially if you have specific health conditions.
What does alkaline water do for babies?
Alkaline water is not recommended for babies, toddlers or young children. Infants typically have a specific dietary and hydration needs. And their digestive systems are not fully developed to process certain substances.
Here are some important considerations regarding alkaline water for babies
Breast milk or formula
For the very first six moths of life, breast milk or formula should be the primary source of nutrition and hydration for babies. These sources are carefully balanced to meet their nutritional requirements, including the appropriate pH levsls.
Tap water
If you need to supplement your baby’s diet with water, it is generally recommended to use plain and filtered tap water that is safe for drinking. There is basically no need to provide alkaline water because it does not offer any specific benefits for infants.
Avoid alkaline water
Alkaline water can have a higer pH than what is required for babies’ digestive system. Giving it to a baby may disrupt their body’s pH balance and potential cause digestive discomfort or other issues.
Consult with a pediatrian
If you have concerns about your baby’s die and hydration needs, it’s important to talk to a pediatrician or healthcare expert. There can offer the right guidance on the most appropriate timing abd introduction of water and other liquids to your baby’s diet.
Remember that staying hydrated is very necessary while nursing, ubut you can achieve this by drinking regular, clean water. The most important thing is to maintain a healthy and balanced diet to support your health and the little one’s growth.
Who should avoid alkaline water?
While this water is generally safe for most people when taken in moderation, there are some people who may have to exercise strict caution or limit their intake altogether:
• People with kidney issues
• People on certain medications like antacids
• Infants
• People with gastrointestinal conditions
• Pregnant women
• Breastfeeding moms
• People who have specific dietary needs
Is alkaline water good for fertility?
There is no proof to support the impression that drinking alkaline water has an impact on fertility. Fertility is rather influenced by factors relating to genetics, hormonal balances, environmental factors and lifestyle options.
While some proponents of alkaline water claim it can improve fertility by creating a more alkaline environment in the body, it is worthy of note that know that the body’s pH leels are tightly regulated by the kidneys are respiratory system. So drinking alkaline water is unlikely to significantly change the body’s pH system.
Conclusion – Can Pregnant Women Drink Alkaline Water?
While pregnant women can safely drink alkaline water in moderation, it is important for them to prioritize their overall hydration and maintain balanced diet rich in these essential nutrients.
The pH level of water, whether it is alkaline or neutral, is not a critical factor in the health of expectant moms and their babies.
And there is even limited scientific proof to support these health claims associated with alkaline water. It should in no way substitute a proper prenatal care and nutrition.
While pregnant, focus on staying sufficiently hydrated with clean, safe drinking water which may include tap or filtered water. And as always, your doctor shouldn’t be left out in your decision to incorporate this vichy water.
References:
Webmd ( What Is Alkaline Water?) & Forbes (Alkaline Water: Benefits, Side Effects And Dangers – Health)
Georgina Austin, CNM
Georgina Austin, CNM
Hello! I'm Gina, a certified midwife, a writer, an experienced one of course, and a proud mother of twins, Noel and Noelle. With eleven years of maternity support experience and my own journey through motherhood, I offer reliable information on women's health here on this blog.
In addition to writing about pregnancy and breastfeeding, I cover topics like sexual health, birth control, egg donation, sibling relationships, and managing life with multiple children. So, whatever issue you're facing as a woman, I've got you covered!
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1a01aa77535b9ecfb87b9fc36adbcd2f
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All about probiotics
All about probiotics
What are probiotics?
Probiotics are good bacteria and yeasts that live naturally in our bodies. Unlike some bad bacteria and yeasts which cause people to fall sick, probiotics keep our body healthy. They help to digest food and can reduce the growth of harmful bacteria in your stomach and intestines.
What are they used for?
Many types of bacteria and yeasts can be considered probiotics and they have different benefits. Scientists are still trying to find out if different probiotics are helpful for different health problems.
Currently, studies have found that some probiotics may help to:
• Prevent diarrhoea caused by some types of infections
• Prevent diarrhoea when you take antibiotics
• Relieving symptoms of irritable bowel syndrome (IBS), a condition that causes stomach cramps, bloating, constipation or diarrhoea.
However, more information is still needed to confirm if probiotics are really effective for preventing or treating any health problem.
Where are probiotics found?
• Dairy products such as yoghurt and cultured milk drinks
• Fermented foods or drinks such as miso, tempeh, kimchi and kombucha
• Health supplements
Who Can Take Probiotics?
Probiotics appear to be safe for most people, including children and babies. Side effects are rare and can include mild stomach discomfort such as bloating and gas (flatulence).
However, if you suffer from serious health conditions or have a medical condition that affects your immune system, you should inform your doctor or pharmacist before starting any health supplements.
How are probiotics stored?
Probiotics may or may not have special storage instructions depending on the brand and type of bacteria or yeast in the product. Please consult your doctor or pharmacist if you have any questions.
Updated Aug 2023
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-7,913,139,288,336,853,000
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Scientific publications
Using a logistic model to predict malignancy of adnexal masses based on menopausal status, ultrasound morphology, and color Doppler findings
Alcázar JL, Jurado M.
Clínica Universitaria de Navarra, University of Navarre, Pamplona, Spain.
Magazine: Gynecologic Oncology
Date: May 1, 1998
Gynaecology and Obstetrics [SP]
Abstract
In the present study we aimed to develop a formula for predicting adnexal malignancy based on menopausal status, ultrasound morphology, and color Doppler findings. Logistic regression analysis was performed retrospectively in 79 adnexal masses (59 benign and 20 malignant) in 73 unselected and consecutive patients.
All these masses had been preoperatively evaluated using transvaginal color Doppler ultrasonography. In logistic analysis menopausal status (premenopausal vs postmenopausal), color Doppler findings (no flow or lowest resistance index >0.45 vs lowest resistance index
CITATION Gynecol Oncol. 1998 May;69(2):146-50
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The professionals of the Clínica perform continuous research and training, always to the benefit of the patient.
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Learn why we are different from other healthcare centers. Quality, speed, comfort and results.
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|
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During intense exercise, the body produces more lactate than it can break down and remove from the bloodstream. This leads to accumulation of lactate in the bloodstream.
Up to a certain threshold, the body can break down lactate at a rate where there is an increased concentration of lactate in the blood, but this concentration does not impede muscle function.
Higher intensity will cause this threshold to be exceeded so that lactate production exceeds lactate breakdown. The biochemical processes associated with increased lactate place muscle cells under stress. It is therefore important to determine the lactate threshold at which training is most effective.
An exercise test with lactate measurement is therefore useful to gain insight into cardiovascular training and to determine the right intensity to increase endurance without overtraining.
Lactate is an energy source and is metabolized by muscle cells. The more efficiently lactate is metabolized, the lower the blood lactate concentration will be during exercise. In addition, excess lactate is removed from the circulation more quickly during the post-workout period.
Lac [blood] = Lac [produced] Lac [decomposed]
Endurance athletes should aim for an elevated lactate threshold – a balance between lactate production and breakdown. Therefore, for training to achieve positive results and improve performance, it is recommended to exercise just below the anaerobic threshold.
Other names for lactate threshold are also; threshold , anaerobic threshold and the tipping point
Exercising at higher intensity levels will result in the anaerobic threshold being exceeded and cause a rapid increase in blood lactate concentration. This threshold varies from person to person and an individual’s threshold can be determined using an exercise test. In an exercise test, the walking speed gradually increases at defined intervals, eg on a treadmill or exercise bike or in a field test. The blood lactate concentration is measured at the end of each interval and plotted against the load value on a graph. The resulting curve indicates the threshold value. The greater the intensity of the athlete’s exercise at their anaerobic threshold indicates a fitter athlete.
If an exercise program is designed so that exercise takes place in the anaerobic threshold range, it can have a positive effect on metabolism, increase muscle contractions, improve muscle cell repair, increase blood capillaries and improve heart function. The body then produces energy more efficiently, even at higher intensity levels.
Would you also like to find out what your lactate threshold is? The HardloopSchool also conducts exercise tests. Contact us for more information.
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Could CBD Improve Sleep Quality?
Last updated:
Published:
As CBD is able to interact with receptors throughout the body, it has a wide range of effects that science is only just beginning to uncover. On potential effect is improving sleep quality, so we take a look at some of the research that has already been done.
HOW DOES CBD AFFECT SLEEP?
As most research into CBD and sleep is pre-clinical, it is hard to pinpoint exactly what is going on without much deeper research being carried out. There are a few ways that CBD has been suggested to affect sleep:
Firstly, CBD may improve quality of sleep as a side effect of another problem being addressed. For example, research has shown that cannabinoids are able to reduce pain and improve sleep. Sleep disorders are a common symptom of those that suffer from chronic pain, so it could be the case that as pain becomes more manageable, sleep improves as a result.
RESEARCH
There is also evidence to suggest that CBD may directly affect the sleep cycle, preventing anxiety-induced REM sleep suppression. Should this be the case, CBD may help promote the natural sleep cycle, and prevent its deviation in those suffering from anxiety or stress-related sleep disorders. This is backed up by further research that found CBD helped maintain NREM sleep stability.
RESEARCH
FURTHER RESEARCH
WHAT IT ALL MEANS
These findings are both exciting and sobering. Exciting because it shows that CBD could have potential in allowing people to get the rest they need. Sobering, because this is all initial research, with much more needed to definitively say whether CBD affects sleep and just how it does it. As such, CBD is not currently considered a sleep aid, and is only used as a dietary supplement. However, as with most CBD based research, things are very promising. Time will tell if CBD truly has what it takes.
Cibdol
Productfinder
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舌 が 白い 理由。 「舌が白い」は実は大病！？見逃してはいけない舌のSOSサイン
舌を磨いても舌が白いのは病気なの？｜ブログ
理由 舌 が 白い
さらにこの硫化水素は 病的ではない舌苔からも発生するため、健康上問題ないとは言え、 口臭の原因になります。 舌苔の 簡単な取り方！• 特に精神的なストレスや睡眠不足は大敵です。 人に感染させる恐れがあるため、他者とタオルや食器を共有しないようにする ＜病院に行く目安＞• ら これらの位置を矢印の方向にやさしくマッサージすることで、唾液が口の中に出るのを感じると思います。
20
なぜ？風邪で舌が痛くなる5つの原因｜どうやって治す？病院は何科を受診？
理由 舌 が 白い
白班は不規則な模様で、見た目が地図のようになります。 癖の口呼吸によるものの場合• 繰り返しになりますが、舌苔が多いということは口臭を放っている可能性も高いです。 しかし本人は 「妻にも言われたことあるけど、会社や友達にも何も言われないしなぁ」と、あまり納得していない様子。
13
舌が白い時の原因と病気や治す方法！風邪や胃腸との関係も
理由 舌 が 白い
なお、この病気の原因は明らかになっていませんが、タバコやアルコール、食物等による刺激や歯の詰め物などによる物理的・科学的な刺激の他、カンジダ症や貧血、ビタミン不足などによって起こりやすくなると言われています。 母乳・ミルクのカス 母乳やミルクは乳タンパク質や乳脂肪、乳糖、カルシウムなどの無機質の残渣（ミルクカス）が出て舌に付着しやすいんですが、普通は唾液などで洗い流されます。
13
舌が白いできものは病気なの？８つの原因と対処法について
理由 舌 が 白い
あまり力が入らないように、握らずに軽く指で持つ• 「口臭サプリ飲んでみたら？」と提案し、その後1年間色々な口臭対策サプリを飲んだようですが、それもいまいち効かず。 過剰に舌をブラシで磨いたことによって舌苔（ぜったい）は慢性化します。
なぜ？風邪で舌が痛くなる5つの原因｜どうやって治す？病院は何科を受診？
理由 舌 が 白い
上で舌苔の正体を• 免疫力の低下• 舌苔をとり除くことも大切ですが、「舌苔のできない環境に整えること」がもっとも重要となります。 膿汁・膿栓について詳しくは、『』をご参考にしてください。
17
なぜ？風邪で舌が痛くなる5つの原因｜どうやって治す？病院は何科を受診？
理由 舌 が 白い
舌苔（ぜったい）は、普通はほっておいてもきれいになるものです。
1
舌が白い時の原因と病気や治す方法！風邪や胃腸との関係も
理由 舌 が 白い
症状が悪化している場合は生活習慣の改善だけでは間に合わない場合もある。 マウスウォッシュを8種類ほど変える などなどしてきたとのこと。
13
舌が白い時の原因がヤバイ！病気か？胃腸に異常が起きている可能性（この差って何ですか?）
理由 舌 が 白い
米粒くらいの大きさの白っぽいただれが生じる• 食事の時はよく噛んで食べるようにする。 子供の舌が白くなる原因としては、以下の要因が考えられます。 また、アルコールは舌を乾燥させるので、飲酒の時には水を小まめに飲むのがコツです。
2
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Why does acne take so long to heal?
Probably everyone whose skin is prone to acne dreams of a acne treatment products that will work overnight.
Sadly there is no magic ingredient to treating acne.
So you then ask yourself the follow up questions, how long will it take for my acne-prone skin to look normal?
However, in order to alleviate acne-prone skin, a certain period of time is necessary.
This is mainly because acne-prone skin is a genetic and hormonal challenge with complex mechanisms.
Read on to find out more.
Can I Get Rid of Acne Prone Skin Overnight?
Forget it.
Blemishes cannot be magicked away overnight.
Realistically, from days to weeks are needed to alleviate acne-prone skin.
But why you ask?
Acne-Prone Skin Is Partially Genetic!
Acne is a partially genetic condition: in other words, it runs in the family. It's due to some people's genetic predisposition to produce a lot of sebum (skin oil), which clogs pores and creates a breeding ground for pimple-causing bacteria.
No acne treatment can change your genes.
So, should you have the genetic predisposition, it will take longer for acne treatments to show their effects.
But don't lose hope!
With the right acne treatment and a good skincare routine, you will start to see changes in your acne. And avoid the urge to pop pimples.
Acne-Prone Skin Is Hormone Related
Mild or severe acne-prone skin can have many causes, such as dietary habits, lifestyle, or medication.
However, hormones are among the main cause for some people.
Therefore, acne-prone skin may increase during puberty and the female menstrual cycle.
Acne-prone skin is common: it affects 80% of teenagers and 40% of adults.
Hormones such as androgens are produced in the testicles of men and the ovaries of women. They stimulate the sebaceous glands of the skin, which can lead to increased sebum production (basically excess oil is produced on your skin).
Oily skin is in turn an optimal breeding ground for pimples. Increased sebum production can cause pores to clog more easily, which can lead to blemishes.
Since hormonal acne is a complex process, it takes time to alleviate.
One effective treatment for hormonal acne in women is the birth control pill. It balances hormones and can lead to clear skin. This option should be discussed with your doctor.
If you are male, or do not want to take the birth control pill, there are professional products available at the pharmacy that can help soften acne-prone skin. Even the most comprehensive solution can take a few weeks to work.
Acne-Prone Skin Can Become Cystic Acne
Cystic acne is a severe form of acne-prone skin with deep, tender, red and swollen pimples called acne cysts.
Because the lesions are especially prone to infection, treating cystic acne takes some time. Your doctor may prescribe antibiotics, such as doxycycline, to kill the bacteria responsible for the cystic acne infection.
In most severe cases, your doctor will prescribe a powerful medication called isotretinoin (Accutane) to reduce the skin's excessive sebum production, making it drier and less prone to pimples.
Both strategies take time to work. However, after about a month, your skin should become clearer.
Acne is Also Affected By Dry Skin
Pimples, blemishes, and blackheads are common with oily skin, but you can also be acne-prone with dry skin.
Even with dry skin, the acne mechanisms are basically the same.
Pores become clogged with dead skin cells and sebum, and can thus become a breeding ground for a bacterium called P. acnes, which can multiply in blocked pores and cause infections (in other words, pimples) there.
Treating dry skin prone to acne can take longer, as it is especially important to take a decidedly gentle approach. Harsh skincare products can attack the skin and make it sensitive, as well as cause redness and flaking.
One way to treat dry skin prone to acne is with a hemp face wash. Hemp seed oil is high in linoleic acid, which thins out the skin's sebum allowing it to be flushed from pores more easily. And hemp seed oil is hydrating too, so you'll get a thorough cleanse without over-drying.
Just as with other forms of acne-prone skin, patience is the key to effective treatment and to keep your skin hydrated.
hemp skincare set with leaves and roots
How to Alleviate Acne breakouts
Acne prone skin is a chronic condition and can last for years, but with the right treatment you can get it under control in a matter of weeks. The trick is choosing the right treatment and then sticking with it!
Mitigating acne prone skin also starts with proper cleansing.
So When Will I Finally Get Rid Of My Pimples?
Pimples and blackheads always appear at the most inopportune moments. And of course, they can't be magicked away so easily. Whether on the face under makeup, on the chest, back, or other parts of the body, pimples are bad everywhere.
If the pimples are due to stress, medication, your diet or improper skincare, you have it in your own hands, so to speak, how long the pimples will stay. In addition, home remedies can help you in the fight against acne.
If a hormonal change is a reason, time helps on the one hand. And on the other hand, you can reduce skin irritation, redness, and itching within a few weeks with the right skin protection.
If you are more affected by fungal acne and have a lot of small pimples on your forehead that can't be squeezed, the typical blemish or acne treatments may not help.
It's best to talk to your doctor about possible therapy with antibiotics.
The Best Care for Acne-Prone Skin?
After cleansing, use a moisturizer for acne-prone skin. Some products combine active ingredients like salicylic acid to unclog pores, niacinamide to soothe irritation and vitamin C to prevent pimples. You can read more about these ingredients here.
There is no magic application to make pimples disappear overnight. But you can quickly calm irritation for a less reddened face and gradually soften your acne-prone skin for cleaner, more radiant skin in just a few weeks.
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Role Of CBD Flower Bud Smell In Anxiety And Stress
CBD stands for cannabidiol, which is a compound found mainly in the flowers of hemp plant. The use of CBD Flower near me is widespread all over the world, and its importance is increasing rapidly. Studies have shown that CBD may have anxiolytic (anxiety-reducing) effects. CBD interacts with the body’s endocannabinoid system, which plays a role in regulating stress and anxiety levels. It can also increase the levels of anandamide, a neurotransmitter known as the “bliss molecule,” which can help to promote a sense of calm and well-being. CBD flower may be particularly effective in managing anxiety and stress due to its rapid onset of effects. When smoked or vaped, CBD is absorbed quickly into the bloodstream, producing a near-instantaneous calming effect. This can be especially helpful for those experiencing acute anxiety or stress, such as before a public speaking event or an important meeting. Their potential benefit of CBD flower is that it help to improve sleep quality. Poor sleep is often linked to increased anxiety and stress levels, so improving sleep quality can be an important part of managing these conditions.
CBD has been shown to have sedative effects, which may help to promote relaxation and improve sleep quality.
It’s worth noting that while CBD flower may be a useful tool for managing anxiety and stress, it’s not a cure-all solution. It’s important to seek professional help if you’re experiencing persistent anxiety or stress that’s impacting your daily life. CBD flower should also be used responsibly, as smoking can have negative health effects and may be addictive for some individuals.
In a nutshell CBD flower has potential therapeutic effects in managing anxiety and stress, particularly due to its rapid onset of effects and potential to improve sleep quality. However, it should be used in conjunction with other treatments and with caution.
The Future Of CBD Flower And Its Potential As A Medical Treatment
CBD flower has gained popularity in recent years as a natural and non-psychoactive way to treat various health conditions. As research into the potential benefits of CBD continues to grow, it is becoming increasingly clear that CBD flower has significant potential as a medical treatment.
CBD Flower near me contains cannabidiol, a compound found in the cannabis plant that has been shown to have a range of therapeutic effects. CBD has been found to have anti-inflammatory, analgesic, anxiolytic, and antipsychotic properties, among others. These properties make it potentially useful in the treatment of a variety of medical conditions, including chronic pain, anxiety disorders, depression, and epilepsy.
As the use of CBD flower becomes more widespread, researchers are continuing to explore its potential as a medical treatment. There is evidence to suggest that CBD may be effective in treating certain types of seizures, as well as in reducing anxiety and improving sleep. CBD may also have potential as a treatment for other conditions, such as addiction, cancer, and autoimmune disorders.
However, it is important to note that research into the potential benefits of CBD flower is still in its early stages, and there is much more to learn about how CBD works and what its potential uses may be. Additionally, there are still legal and regulatory barriers to the widespread use of CBD as a medical treatment, which may limit its availability and accessibility.
While the future of CBD flower as a medical treatment is promising, there is still much to learn and much work to be done before its full potential can be realized.
Comparing CBD Flower With Other CBD Products
Unlike other CBD products, such as CBD oil, tinctures, or edibles, CBD flower is not processed or refined. Instead, it is harvested directly from the hemp plant and dried.
One of the main benefits of using CBD flower is that it contains all of the naturally occurring cannabinoids, terpenes, and flavonoids found in the hemp plant. This is known as the “entourage effect,” which suggests that the combination of all these compounds working together may produce greater therapeutic effects than each compound individually.CBD flower can be consumed in a variety of ways, such as smoking, vaping, or making it into tea or other infused products. When smoked or vaped, the effects are typically felt quickly, within minutes.
Compared to other CBD products, CBD hemp flower strain may offer more immediate relief for acute symptoms, such as pain or anxiety. It is also more customizable, as users can experiment with different strains and consumption methods to find what works best for them.However, CBD flower may not be the best choice for everyone. Some people may be sensitive to the smoke or vapor produced when consuming CBD flower, and smoking or vaping may not be a desirable option for those with respiratory issues. CBD flower may not be as convenient or discreet as other CBD products, such as capsules or gummies.
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bacteriophages
Health Tips
Bacteriophages are viruses that infect bacteria and are used as antibacterial drugs. Each bacteriophage is able to infect only certain types of bacteria, so the effect of bacteriophages is strictly specific and does not affect the normal human microflora.
The mechanism of action of bacteriophages is simple. The virus enters the cell of a pathogenic bacterium, invades its genome and begins to multiply. After the accumulation of a certain amount of new viral particles (virions) inside the bacterial cell, the cell is destroyed, the viruses come out and infect new bacterial cells.
There are two groups of bacteriophages: temperate and virulent.. Temperate phages slowly multiply inside the affected bacterial cell, are transmitted inside the bacterial colony from generation to generation, periodically destroying microbial cells. This effect is called lysogenic.
Virulent phages, having entered the cell of a microbe, begin to multiply rapidly, leading to the rapid death of the infected cell. This effect is called lytic.
Currently, phages are used in the treatment of infections caused by Klebsiella, Escherichia, Pseudomonas, Streptococcus, Staphylococcus, and Proteus.
Until the advent of antibiotics, bacteriophages were practically the only remedy for infectious diseases. With the advent of antibiotics, the situation has changed. More effective and easy-to-use preparations have appeared that do not require such a detailed selection as bacteriophages.
What, then, is the reason for the interest in bacteriophages now, when antibiotics are available everywhere?
It’s about sustainability. Bacteria lose their sensitivity to the action of antibiotics. The pharmaceutical industry relentlessly synthesizes others. However, it is known that the possibilities of synthesizing antibiotics are limited. Antibiotics adapt very hard to the action of bacteriophages, and, according to experts, microbes cannot develop resistance to a complex of several bacteriophages at all.
In addition, bacteriophages have practically no side effects, rarely cause allergic phenomena, and can be combined with any drugs.
Bacteriophages are currently well established in the treatment of urological diseases, purulent processes in surgery, as well as infectious intestinal diseases in newborns.
However, there are also disadvantages.
Bacteriophages are strictly specific, so it is very difficult to select them. If the desired bacteria is not found in the body, and those that caused the disease are slightly different, the virus stays in the body for about 2-6 days, and then is destroyed.
Treatment with bacteriophages is very long. If the course of antibiotic therapy usually requires 5-7 days, then bacteriophages are prescribed in three courses of 7-20 days with a short interval.
There is an opinion that bacteriophages can transfer parts of its genome from one bacterium to another – and hence pathogenicity, resistance to antibiotics, etc.
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Casos Clínicos
Aspergillus encephalitis with microabscesses in an immunocompetent patient
Recep Tekin[1] , Salih Hattapoğlu[2] and Rojbin Ceylan Tekin[3]
28/09/2023
A 28-year-old man presented to the emergency department with a 5-week history of severe headache, dizziness, and weakness in the right arm. Neurological examination revealed 3/5 strength in the right arm. Brain magnetic resonance imaging (MRI) of the brain showed a large hypointense lesion with thick peripheral contrast enhancement in the left periventricular area. The solid components appeared hyperintense after contrast enhancement, and microabscesses were observed in the basal ganglia, subcortical white matter, and left anterior thalamic area. On T2-weighted images, the large hypointense lesion caused a minimal mass effect, which was accompanied by significant peripheral edema (Figure 1). Diffusion-weighted imaging revealed several diffusely localized lesions with restricted diffusion in both hemispheres and the cerebellum (Figure 2). Multivoxel MR spectroscopy
FIGURE 1: A. Brain MRI showingT2-weighted images large hypointense lesion causing a minimal mass effect, accompanied by significant peripheral edema. B–C. Solid components are hyperintense after contrast enhancement (arrows).
FIGURE 2: Diffusion-weighted imaging revealed several diffusely localized lesions with restricted diffusion in both hemispheres and the cerebellum (arrows).
FIGURE 3: Pathological examination confirming the diagnosis of Aspergillus infection (arrowheads).
revealed significant elevation in lipid and lactate levels, indicating an abscess. A brain biopsy was performed and pathological examination confirmed the diagnosis of Aspergillus infection (Figure 3, arrowheads). The patient was treated with intravenous liposomal amphotericin B but died despite a 57-day course of antifungal therapy. Intracranial Aspergillus infection is a rare condition that is difficult to diagnose because of the lack of specific imaging features1-3.
REFERENCES
1. Brun S, Fekkar A, Busse A, Seilhean D, Lecsö M, Adler D, et al. Aspergillus flavus brain abscesses associated with hepatic amebiasis in a nonneutropenic man in Senegal. Am J Trop Med Hyg. 2009;81(4):583-6.
2. Lange N, Wantia N, Jörger AK, Wagner A, Liesche F, Meyer B, et al. J. Fungal brain infection-no longer a death sentence. Neurosurg Rev. 2021;44(4):2239-44.
3. Dal T, Tekin A, Tekin R, Deveci O, Fırat U, Mete M, et al. Soft Tissue Abscess Caused by Aspergillus Fumigatus in an Immunosuppressive Patient. Eur J Gen Med. 2013;10(2):118-22.
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Lean Body Mass Calculator
255
The Lean Body Mass Calculator computes a person’s estimated lean body mass (LBM) based on body weight, height, gender, and age. For comparison purposes, the calculator provides the results of multiple popular formulas.
It is similar to the Body Mass Index (BMI) calculator, Basal Metabolic Rate (BMR) calculator and the Body Fat Calculator because it calculates only one factor of your weight. However, it is different from other calculators due to the fact that it follows an entirely different formula and serves a different purpose.
Your lean body mass is the amount of weight you carry on your body that isn’t fat. The goal of any fitness enthusiast is to drop weight while keeping your lean body mass the same.
Lean body mass does not necessarily indicate fat-free mass. Lean body mass contains a small percentage of fat (roughly 3%) within the central nervous system (brain and spinal cord), the marrow of bones, and internal organs. It is measured in terms of density.
What is lean body mass?
A common misconception about lean body mass is that it equals a person’s ideal weight. However, the truth is that lean body mass is actually the sum of the weight of a person’s bones, muscles, organs, and blood-everything except for the fat. In other words, lean body mass has nothing to do with how “lean” a person would be if he/ she lost all that fat. In fact, it is impossible to stay alive without a minimal amount of fat in your body.
Why calculate lean body mass?
There is no concrete reason for calculating a person’s lean body mass since it does not tell a person how much weight they need to lose or gain. This calculator is mostly used by those who are curious to know how much they would weigh minus all the fat in their body.
Not a Substitute for Professional Help
Remember that the lean body mass calculator shows you only a part of your weight status. It is not a substitute for any guidance on weight loss. For ideas on how to lose or gain weight, it is best to get professional help. Your personal health trainer may take your BMI and Lean Body Mass into account but not rely on these factors entirely.
Difference Between BMI and Lean Body Mass
The BMI (Body Mass Index) of a person is calculated by taking into account the ratio of a person’s height and weight. It is used to calculate the amount of fat a person may have. BMI usually indicates whether a person is too thin or too fat based on their height weight ratio.
The lean body mass, on the other hand, is not used for fat reduction. It is only used to find out how much a person would weigh with 0% fat.
Reference
LBM is a part of body composition that is defined as the difference between total body weight and body fat weight. While the percentage of LBM is usually not computed, it is the complement of body fat percentage, and on average ranges between 60-90% of total body weight. Generally, men have a higher proportion of LBM than women do, and the dosages of some anesthetic agents, particularly water-soluble drugs, are routinely based on the LBM.
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If your baby is in a breech position, here’s all you need to know
During pregnancy, as your baby grows, have you ever felt the kicks or wiggles due to the twists and turns of the baby? Throughout the pregnancy, babies tend to move in the uterus, resulting in the mother feeling the kicks on their stomach, the baby’s head down in the pelvis one day, and on the upside near the rib cage the other day.
In most cases, when you are expecting and visit your doctor, you might have noticed your physician checking your baby’s position from time to time, especially during the last month. The check-up is done to know exactly about the baby’s position in the womb and Complications of Pregnancy if any, as it is directly linked with your labor and delivery. In the process of twists and turns, most of the babies move into the delivery position, i.e., head first, a week before the delivery time, but in a few cases, this does not happen. Under this condition, the feet or the butt of the baby are positioned to get delivered first, and in medical terms, this position is termed as breech position or presentation.
Positions of the Breech Baby
Depending on how the baby is in the uterus, there are mainly three positions of baby breech: complete, frank, and footling. Each position explains a different presentation of the baby in the uterus.
1. Complete breech baby
The complete breech presentation of the baby is when the butt points down, the legs are folded with the feet tucked in.
2. Frank breech baby
The frank breech presentation of the baby is when the butt points down and the legs are straight up with their feet near the face or head.
3. Footling breech baby
The footling breech presentation of the baby is when one or both of the feet point downwards with the butt being positioned towards the birth canal.
What causes a breech pregnancy?
The movement, twists, and turns of the baby in a pregnancy are considered normal as they are required to get the baby in place before delivery, but the breech position is something problematic. In a breech pregnancy, the baby does not move into the delivery position; instead it stays in a bottom-down position.
As per the reports and doctors, the exact causes of a breech pregnancy are not known, but there are several different reasons which may or may not be responsible for a baby’s position in the wrong way. The situations that follow are:
1. There are two or more babies.
2. If the baby is premature.
3. If there is an abnormal level of amniotic fluid.
4. If the mother has placenta previa.
5. If the woman has had several pregnancies.
Is it possible to turn a breech baby?
At the very first sign of this scenario of a breech baby, it is important for you to consult your doctor and accordingly plan on what to do further. To turn a baby, there are several ways with varying success rates depending on the reason for your baby's breech. As long as you are in consultation with your doctor and try a safe method, there is no harm. For people residing in the area of the UAE, you can visit the New Concept Clinic for Best Pregnancy Check Up in the UAE.
The possible ways mentioned below are the options of how you can turn the position of a breech baby into a normal one.
1. Medical methods
Under the medical techniques of turning a breech baby, there are two options to go with. The first is an external cephalic version, and the second is chiropractic care.
Through the EVC method, the doctor applies pressure or ultrasound to your stomach to turn your baby in the right position. It is performed around the 37th week of the pregnancy.
Through the chiropractic care method, the breech baby is turned naturally by decreasing the stress on a pregnant woman’s pelvic, uterus, and surrounding ligaments.
2. Natural methods
Under the natural methods of turning a breech baby, there are several options like inversion, usage of essential oils, music, acupuncture, etc. Under the inversion method, the breech baby is encouraged to tilt by standing in different positions, propping their hips, or using the stairs to make it move.
Using essential oils and music is another way of turning a baby. It includes using suitable essential oils on the stomach and using a headphone or a speaker at the bottom of the uterus to encourage them to turn.
Also ReadReproductive care if you are diagnosed with fibromyalgia during pregnancy
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Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology
Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.
Published in the journal: . PLoS Genet 7(12): e32767. doi:10.1371/journal.pgen.1002405
Category: Research Article
doi: 10.1371/journal.pgen.1002405
Summary
Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.
Introduction
DNA is continuously damaged by spontaneous hydrolytic decay, endogenous metabolites (e.g. reactive oxygen species, malondialdehyde), and environmental genotoxins. DNA lesions can give rise to irreversible mutations and chromosomal aberrations that may trigger carcinogenesis. Alternatively, DNA damage can cause replicative senescence and cell death, which promotes the process of aging [1]. Cumulative DNA damage has also been implicated in the functional deterioration and degeneration of long-living post-mitotic cells such as neurons [2]. To counteract the harmful effects of DNA injuries, cells have a variety of DNA surveillance and repair systems. The importance of these genome maintenance pathways for human health is well illustrated by a heterogeneous set of inherited syndromes that are associated with defects in specific DNA repair pathways resulting in cancer predisposition, developmental abnormalities, accelerated aging and neurodevelopmental or neurodegenerative abnormalities [1], [3][5].
Nucleotide excision repair (NER) is a key DNA repair pathway for removal of UV-induced DNA damage and a wide range of other helix-distorting lesions, including bulky chemical adducts and specific types of oxidative damage [1]. In NER the DNA lesion is removed as a part of a 25–30 nucleotide single-strand fragment excised via a multi-step reaction followed by resynthesis of the excised strand [4], [6][8]. NER can be divided into two subpathways that differ in the damage recognition step: While global genome NER (GG-NER) removes distorting DNA damage throughout the genome, transcription-coupled NER (TC-NER) specifically targets transcription-blocking lesions in the template strand of active genes to allow recovery of transcription after damage induction [1], [4], [7], [8]. Several NER proteins have functions beyond NER, which is particularly evident for the transcription/repair factor TFIIH, which is required for the local opening of the damaged DNA in NER, but in addition plays an essential role in transcription. Furthermore, several lines of evidence indicate that TC-NER components are involved in repair of transcription-blocking lesions independent of the NER core complex, putatively via recruitment of other repair mechanisms. The term transcription-coupled repair (TCR) has been used to designate this broader, still poorly defined repair process [7], [9], [10].
NER gene defects are associated with a heterogeneous set of rare clinical syndromes, whose characteristics can be explained by the type of NER pathway that is affected or by defects in additional functions of these NER components in other DNA repair pathways or transcription. Selective defects in GG-NER, resulting from mutations in the XPC and XPE (also termed UV-DDB2) genes encoding GG-NER-specific damage recognition proteins, cause xeroderma pigmentosum (XP), a photosensitivity syndrome characterized by UV-hypersensitivity, pigmentation abnormalities and UV-induced skin cancer predisposition [11], [12]. Cancer-predisposition in XP-C patients is explained by bulky lesions that accumulate over the entire genome causing mutations after replication [1]. Selective defects in TC-NER result from mutations in the genes encoding the proteins CSA or CSB, both of which are selectively recruited to stalled RNA polymerase II [13]. Mutations in CSB and CSA are associated with Cockayne syndrome (CS), a progeroid disorder characterized by cachectic dwarfism and progressive neurological abnormalities, in addition to skin photosensitivity [14][16]. CS patients do not show cancer predisposition, which is explained by the normal function of GG-NER, and indicates that TC-NER is not required for preventing cancer. On the other hand, most CS pathological features cannot be explained by the sole loss of TC-NER function as they do not occur in XP-A patients, which show a combined GG-NER/TC-NER deficiency, resulting from mutations in the gene encoding for the core NER protein XPA. Thus XP-A patients present with UV-hypersensitivity and skin cancer predisposition, like XP-C patients, usually in combination with progressive neurological abnormalities (see below) [17][19], but they do not develop cachectic dwarfism and other progeroid features of CS patients. This has led to the notion that the CS phenotype is largely the consequence of an overall TCR defect, i.e., the inability to rescue transcription arrested by NER- and non-NER-types of DNA damage [7], [20], [21]. In addition it has been suggested that CS is associated with transcriptional abnormalities independent of DNA lesions [7], [22], [23].
The complementarity of NER and TCR DNA repair pathways and disorders resulting from deficiencies in these processes is also illustrated by XPCS patients, which display both XP and CS symptoms. XPCS is caused by mutations in the XPB or XPD genes, both encoding helicases of the transcription/repair factor TFIIH, or in the XPG gene, encoding the endonuclease that mediates the 3′ incision of the excision step [24][27]. Mutations in the XPB and XPD genes may also cause pure XP or trichothiodystrophy (TTD), a disorder that is characterized by sulphur-deficient hair, in association with a variable spectrum of abnormalities that usually include neurodevelopmental deficits. Mutations that cause XP preferentially afflict the NER activity of TFIIH, while TTD mutations destabilize the TFIIH complex causing exhaustion of TFIIH in specific cell types [27]. The occurrence of CS symptoms in association with specific XPB and XPD mutations point to functions beyond NER and basal transcription presumably linked to non-NER TCR activities akin to CSA and CSB [22], [27][31]. XPG mutations associated with XPCS have been proposed to destabilize the interaction between XPG and TFIIH, while mutations causing XP disrupt its endonuclease activity, further pointing to a non-NER activity underlying CS symptoms [25], [26], [32].
The presence of progressive juvenile or adult onset neurological abnormalities in XP-A patients has provided a strong hint that the NER pathway is important for neuronal function and maintenance [14], [19], [33][36]. The neurological symptoms are characterized by progressive sensory and motor deficits, as well as cognitive deterioration and emotional abnormalities, and are associated with widespread neuronal degeneration in multiple brain areas and the spinal cord [17][19]. XP-C patients (who are only deficient in GG-NER) do not develop overt neurological symptoms, indicating that the neurodegenerative changes follow from TC-NER or a combined GG-NER and TC-NER dysfunction. A dominant role of the TC-NER pathway in the nervous system is also suggested by the occurrence of XP-A-like progressive neurological abnormalities in CS patients. However, in CS patients neuropathological changes are primarily characterized by myelin abnormalities, while neurons and their axons seem relatively unaffected [14], [35], [37], [38]. An additional complicating factor is formed by patients carrying CSA or CSB mutations that develop UV-sensitive syndrome, a disorder that is characterized by the skin abnormalities of CS in the absence of other CS features. The lack of typical CS features in these patients has been linked to residual TCR activities required for repair of oxidative DNA lesions, while TC-NER of UV-induced DNA lesions was deficient [39]. In sum, the data from XP and CS patients indicate that combined deficiency of GG-NER and TC-NER as in XP-A patients predominantly afflicts neurons, while deficiencies of TCR predominantly cause myelin problems. However, the precise mechanisms underlying the differential cellular vulnerabilities in XP and CS nervous system are still poorly defined, in particular in CS where distinct degenerative mechanisms may operate in oligodendrocytes and neurons [7], [22].
Although previous studies have shown that mouse models for XP, CS, XP-CS and TTD reliably recapitulate the repair defect (i.e. GG-NER and/or TC-NER/TCR), UV-sensitivity and skin cancer predisposition associated with the corresponding NER syndromes (Table 1 and Table 2), this does not apply to the neurological features [40]. In particular, Xpa−/− mice fail to exhibit obvious neurological symptoms and neuropathological changes observed in human XP-A [41][44]. Likewise, Csa−/− and Csb−/− mouse models for CS, except for photoreceptor-loss, do not show overt neurological abnormalities [45], [46]. However, a detailed systematic neuropathological analysis is still lacking. In the present study we reexamined various NER and TCR mutant mouse models for neurodegenerative abnormalities to assess and dissect the contribution of the different repair systems in preventing neurodegeneration. To permit analysis of the direct contribution of DNA repair defects to neurological functioning, in the absence of pathology elsewhere in the body due to systemic DNA repair deficiency, we have generated a Cre-lox-based conditional Xpa mouse model that enables inactivation of the Xpa gene selectively in neurons. In particular, we used this novel mouse model to examine the effect of combined NER and TCR deficiency on neuronal survival.
Tab. 1. NER defect and sensitivity to genotoxins of embryonic fibroblasts isolated from NER–deficient mouse models.
NER defect and sensitivity to genotoxins of embryonic fibroblasts isolated from NER–deficient mouse models.
Tab. 2. Cancer susceptibility and principal features of NER–deficient mice.
Cancer susceptibility and principal features of NER–deficient mice.
Results
Sporadic p53 activation in astrocytes and neurons throughout the central nervous system of Cockayne syndrome mice
As a first step to study the role of NER and TCR in maintaining neuronal integrity, we have re-examined six previously reported mutant mouse models for the presence of neuropathological abnormalities. These mouse lines consisted of Xpc−/− mice, in which only GG-NER is completely inactive [43], [47]; Xpa−/− mice, in which both GG-NER and TC-NER are fully deficient [41], [43]; Csa−/− and Csb−/− mice, in which TC-NER and presumably the entire TCR pathway is abrogated, but which have proficient GG-NER [45], [46], [48]; XpdXPCS mice (homozygous for the G602D XPCS mutation in the Xpd gene), which carry a partial GG-NER and a partial TCR defect [49]; and XpdTTD mice carrying Xpd alleles with the R722W TTD mutation, that also have a partial GG-NER and TCR defect, in addition to TFIIH instability causing transcriptional insufficiency in terminally differentiated cells with consequent brittle hair and nails (Table 1 and Table 2) [50], [51]. Consistent with their respective NER-deficiencies the mutant mice manifest various degrees of increased susceptibility to UV- and 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis (Table 1 and Table 2). TCR-deficient mice to varying extent exhibit other symptoms like reduced growth, osteoporosis, photoreceptor loss, liver and kidney aging, and reduced lifespan (Table 2) [20], [28], [44][56].
Consistent with previous reports [43][50] analysis of thionin- and hematoxylin/eosin-stained brain sections revealed that the gross anatomy and histological organization of all central nervous system regions of aforementioned mutant mice were indistinguishable from wild type animals at 6 months of age, precluding overt neurodevelopmental deficits or neuronal degeneration. Also the central nervous system of 70–100 week old Csb−/− and Xpa−/− mice appeared normal. Therefore, to examine the possible occurrence of subtle abnormalities, we employed immunohistological approaches. First, to determine whether central nervous system cells of the NER-deficient mice experience genotoxic stress, we studied the expression of the transcription factor p53, which is activated by multiple types of DNA damage [57]. p53-immunoreactive cells were not detected in the central nervous system of wild-type and XpdTTD mice. Instead, occasional cells with p53-immunoreactive nuclei were observed throughout the nervous system of Csa−/−, Csb−/− and XpdXPCS mice, while even more sporadic p53 induction was visible in Xpa−/− and Xpc−/− animals (Figure 1). p53-staining was associated with neurons (NeuN-positive cells; Figure 1A), astrocytes (GFAP- or S100-positive cells; Figure 1C and Figure S1), and sometimes oligodendrocytes (APC-positive cells; Figure S1). The relative amount of glial versus neuronal p53-staining varied per brain region, and to some extent per mouse model: in cerebellar cortex the large majority of p53-positive cells consisted of neurons, in the neocortex p53-positive cells were neurons or non-neuronal cells in equal amounts, while in spinal cord and the brainstem reticular formation p53-immunoreactivity was predominantly or almost exclusively associated with glia cells (Figure 1E and Figure S1). p53-immunoreactive neurons generally showed normal nuclear morphologies, in contrast to most p53-immunoreactive glial cells. For instance, a subset of p53-positive astrocytes in spinal cord and the brainstem reticular formation showed nuclei with a DAPI-negative centre that was intensely p53-positive (Figure S1). Another nuclear abnormality of p53-positive glia consisted of a larger nuclear size (Figure S1). Also in Xpa−/− and Xpc−/− nervous systems p53-positive cells consisted of both neurons and astrocytes, but their frequency was too low to allow systematic analysis of the relative proportion of neuronal versus non-neuronal cells in different brain areas. Taken together the data indicate that mice with a complete (Csa−/−, Csb−/−) or severe partial (XpdXPCS) TCR defect show nuclear p53 expression in sporadic neurons and glia throughout the nervous system, pointing to the occurrence of genotoxic stress.
p53 expression in brain and spinal cord of adult NER– and TCR–deficient mice.
Fig. 1. p53 expression in brain and spinal cord of adult NER– and TCR–deficient mice.
A–C) Double-labeling confocal images showing p53-NeuN (A, B) and p53-S100 (C) double-labeled cells in neocortex of a 25 week old Csb−/− mouse. Scale bars: 25 µm (A, B) and 10 µm (C). D, E) Bar graphs showing the density of p53-labeled cells, and the relative amount of p53- neurons (i.e. percentage of NeuN-positive p53-labeled). Values are means ± SE of 3 or 4 mice, while value per mouse is based on analysis of 4 (neocortex [NCx], cerebellar cortex [Cb]) or 10 (lumbar L4 spinal cord [SpC]) sections.
Microglia activation and astrocytosis in white matter regions of Cockayne syndrome Csa−/−, Csb−/−, and XpdXPCS mice
To further investigate the presence of degenerative changes in the nervous system of NER-deficient mice we examined microglia cells which proliferate and acquire activated morphologies in conditions of neuronal and glial damage [58], [59]. Immunostaining for Iba-1, a marker of all microglia cells and Mac2 (also known as galectin-3), a protein selectively expressed by activated phagocytosing microglia [58], did not, or only sporadically, reveal activated microglia cells in the nervous system of wild-type, Xpa−/−, Xpc−/− and XpdTTD mice (Figure 2 and Figure S2). In contrast, prominent levels of activated microglia were present throughout the nervous system of Csa−/−, Csb−/− mice and, to a somewhat lesser extent, XpdXPCS mice (Figure 2, Figures S2 and S3). Typically, Mac2-positive microglia cells occurred in small clusters in areas with myelinated fibers. Thus, in the forebrain Mac2-positive microglial cells were concentrated in the corpus callosum, the anterior commissure, the capsula interna and the fornix, while in the caudal brain high levels of activated microglia occurred in the cerebellar white matter, throughout the reticular formation and in fiber tracts in the brainstem (Figure 2, Figure S2 and Figure S3). We performed a more in-dept analysis of the time of onset and course of these features in Csb−/− mice at different ages. Prominent levels of Mac2-positive cells were already present before 10 weeks of age (not shown), and the density of Mac2-positive cells did not show a distinct increase with age (Figure 2G).
TCR–deficient mice show microglia and astrocyte activation in the white matter.
Fig. 2. TCR–deficient mice show microglia and astrocyte activation in the white matter.
A–F) Mac2-immunostaining of activated microglia in the medullary reticular formation of 25 week old wild-type and NER-deficient mice showing the presence of Mac2-positive microglia cells in the reticular formation of Csa−/− (B), Csb−/− (C) and XpdXPCS (E) mice. G) Bar graph showing the density of Mac2-labeled cells in the medullary reticular formation and corpus callosum of NER-mutant mice. Values are means ± SE of 3 or 4 mice, while values per mouse are based on analysis of 4 sections. H) Plot of Mac2-positive cells in selected transverse brain sections of 25 week old Csb−/− mouse illustrating the widespread distribution of activated microglial cells in regions containing myelinated axons such as the corpus callosum (cc), the internal capsule (ic), the fornix (f), the cerebellar white matter (wm), the mesencephalic (MesRF) and medullary reticular formation. No or a low number of Mac2- immunoreactive cells occur in grey matter regions, such as the Neocortex (NCx), the hippocampal subfields (DG [dentate gyrus], CA1 and CA3), amygdala (Am), piriform cortex (Pir), the cerebellar cortical granular (gl) and molecular layers (ml), and the medial (MVe) and lateral vestibular (LVe) nuclei. I–O) Photomicrographs and optical density measurements (O) of GFAP-immunoperoxidase staining in the medullary reticular formation of NER-deficient mice showing increased staining in Csa−/−, Csb−/− and XpdXPCS mice as compared to the other genotypes. Optical densities were determined from TIFF files using MetaMorph 4.6 image analysis software. Values are means ± SE of 3 mice, while values per mouse are from 3 sections. To minimize variability resulting from the staining procedure all sections used for the graph were stained in a single session using the same reagents. Scale bars: 50 µm (D, L).
To examine whether microglia activation is paralleled by changes in astrocytes, we also stained for glial fibrillary acidic protein (GFAP), an astrocytic protein up-regulated under conditions of neuronal injury. Increased GFAP staining was observed in the nervous system of mouse mutants that also showed microglial cell activation, i.e. Csa−/−, Csb−/− and XpdXPCS mice (Figure 2I–2O). Increased GFAP staining was most prominent in the brainstem reticular formation and spinal cord (Figure S4). No obvious changes in GFAP staining were noted in some white matter areas such as the corpus callosum and the capsula interna of Csa−/−, Csb−/− and XpdXPCS mice, which may be explained by relatively higher baseline GFAP-immunoreactivity in these areas in wild-type mice. To further examine astrocytic changes in white matter areas, we examined the expression of Hsp25 (also known as Hsp27 or Hspb1), a small heat shock protein that is expressed at high levels in a subset of astrocytes in conditions of injury [60]. Indeed Csa−/−, Csb−/− and XpdXPCS, but not Xpa−/−, Xpc−/− and XpdTTD nervous systems showed the appearance of intensely Hsp25-immunoreactive astrocytes in multiple regions including the brainstem reticular formation, spinal cord, the white matter of cerebellum and the corpus callosum forebrain (Figure S4).
The above data indicate that Csa−/−, Csb−/− and XpdXPCS mice show microglia and astrocyte activation in multiple central nervous system areas, indicative of the occurrence of cellular degeneration or another detrimental process. As these mutant mice also displayed p53-immunoreactive cells, we performed double labeling of p53 with Mac2 to determine whether p53-immunoreactive cells are contacted by phagocytosing microglia cells. However, Mac2-positive microglia cells were never found in the vicinity of p53 cells (Figure 3A). Instead, Mac2-positive microglia were frequently in close proximity of oligodendrocytes (Olig2 and APC-positive; Figure 3B, 3C), that otherwise showed a healthy appearance with normal DAPI-stained nuclei. These data indicate that glial abnormalities may be associated with subtle alterations in oligodendrocytes. To examine whether the presence of activated microglia was associated with myelin abnormalities, we performed double labeling of neurofilament-H and myelin basic protein to outline axons and their myelin sheets. No differences in myelin basic protein staining were observed in spinal white matter and corpus callosum of wild-type and Csb−/− mice (not shown).
Mac2-positive microglia cells enwrap oligodendrocytes in CS mice.
Fig. 3. Mac2-positive microglia cells enwrap oligodendrocytes in CS mice.
A) Double-labeling confocal images of p53 and Mac2 in DAPI-counterstained spinal cord section of Csb−/− mouse showing that Mac2-immunoreactive microglia cells do not colocalize with p53-labeled cells. B, C) Triple-labeling confocal images of Mac2 and the oligodendrocyte markers Olig2 and APC showing Mac2-immunoreactive microglia cells that closely embrace mature oligodendrocytes labeled by Olig2 and APC. The dashed line in (B) outlines the nucleus of the Mac2-positive microglia cell. Arrows in B and C indicate oligodendrocytes contacted by Mac2-positive microglia cells. D–F) Photomicrographs and bar graph of active caspase 3 immunoreactive cells in spinal cord of 25 week old Csa−/−, Csb−/− and XpdXPCS mice. Values are means ± SE of 3 or 4 mice, while value per mouse is based on analysis of 10 cervical spinal cord sections. Scale bars: 20 µm.
Finally, to determine whether Csa−/−, Csb−/− and XpdXPCS mice show increased levels of cell death of oligodendrocytes or other cells, we stained for active caspase 3, which is a final executioner caspase associated with multiple cell death pathways [61]. Very sporadically caspase 3 immunoreactive cells were observed in the nervous system of all mutant mouse models; all positive cells showing morphologies compatible with glial cells (Figure 3D, 3E). Quantitative analysis in spinal cord indicated that the number of active caspase 3-positive cells, although still very low, was higher in Csa−/−, Csb−/− and XpdXPCS mice as compared to the other genotypes (Figure 3F). It was not possible to determine whether the active caspase 3 cells represented oligodendrocytes or astrocytes because they did not stain for cellular markers such as GFAP, S100, APC ad NeuN. Consistent with active caspase 3 staining, a silver degeneration procedure, that outlines degenerating neurons and their processes, indicated that none of the NER mice showed detectable levels of neuronal degeneration at 26 weeks of age. Taken together the data show that Csa−/−, Csb−/− and XpdXPCS mice develop prominent microglia cell activation as well as astrocytic changes that may be mostly triggered by subtle oligodendrocyte abnormalities.
Neuron-specific inactivation of Xpa causes age-dependent neuronal loss in Csb−/− mice
The NER mouse models investigated above exhibited either no detectable neuronal abnormalities or evidence for only subtle neuronal dysfunction and degeneration, indicating that inactivation of NER or TCR pathways by itself is not sufficient to significantly affect long-term survival of neurons in mice. Previous studies disclosed synergistic deleterious effects of intercrossing XP (Xpa−/− or Xpc−/−) with CS (Csa−/−, Csb−/−, XpdXPCS) mice, resulting in double mutants with very short life span and dramatic progeroid features [49], [62][64]. This raises the possibility that neuronal degeneration may be achieved by inactivation of multiple NER components afflicting both NER and TCR pathways. However, the very short lifespan as well as the serious systemic abnormalities of the double mutant mice precludes systematic analysis of neuronal degeneration, which could also be an indirect consequence of impaired function of other organs and systems. To address this issue, we generated a Cre-lox-based conditional Xpa mouse model that enables selective inactivation of the Xpa gene in postnatal neurons of CS mouse lines and hence to study the effect of combined TCR and NER inactivation in neurons of adult mice that do not suffer from other severe deficits.
To establish a conditional Xpa knockout mouse model, we generated a targeting construct in which exon 4 of the Xpa gene is fused in frame to the mouse Xpa cDNA containing the remaining coding sequence and including a synthetic polyA sequence, followed by a PGK promoter-driven hygromycin selectable marker gene, and a LacZ-GFP fusion gene (Figure 4A). The splice acceptor-Murfi cassette ensures proper splicing and translational stops in all frames respectively when the Xpa gene is knocked out (Figure 4A). The functionality of this conditional genomic-cDNA fusion allele was tested in UV-hypersensitive Xpa−/− ES cells (Figure S5). These experiments showed that the Xpac conditional allele fully averted the UV-hypersensitivity of Xpa−/− ES cells (Figure S5). Next Xpac/+ ES cells, obtained by transfection of IB10 ES cells (Figure 4B), were used for blastocyst injections and subsequent generation of Xpac/+ mice. To determine whether Cre recombinase was capable of excising the floxed Xpa sequence in vivo, we generated Xpac/−/Cag-Cre mice by crossing Xpac/+ mice with Xpa+/− mice carrying a Cag-promotor driven Cre transgene (Cag-Cre), which drives Cre recombinase expression immediately after conception [65]. Southern blot analysis showed Cre-recombinase excision of the floxed sequence in Xpac/−/Cag-Cre embryos at ∼100% efficiency (Figure 4C). Consistent with ubiquitous recombination, Xpac/−/Cag-Cre embryos stained blue upon X-gal staining due to LacZ expression, while Xpac/− embryos remained unstained (Figure 4D). Xpac/−/Cag-Cre mouse embryonic fibroblasts (MEFs) like Xpa−/− MEFs [41] showed severe UV-hypersensitivity, while Xpac/− MEFs show wild-type UV-resistance, consistent with Cre-dependent inactivation of the conditional allele (Figure 4E). Next, we crossed Csb−/−/Xpac/+ and Csb−/−/Xpa+/−/Cag-Cre mice to obtain Csb−/−/Xpac/− and Csb−/−/Xpac/−/Cag-Cre mice. In line with the phenotype of Csb−/−/Xpa−/− mice [63], Csb−/−/Xpac/−Cag-Cre pups displayed severe postnatal growth deficits, cachexia, disturbed gait, and death before weaning, while Csb−/−/Xpac/− littermates did not develop overt pathology (Figure 4F). Taken together, these data demonstrate that we have generated a valid conditional Xpa mouse model that enables us to study the Csb−/−/Xpa−/− phenotype in a cell or tissue-specific manner.
Generation of conditional <i>Xpa<sup>c/−</sup></i> mouse with a floxed genomic/cDNA fusion construct.
Fig. 4. Generation of conditional Xpac/− mouse with a floxed genomic/cDNA fusion construct.
A) Schematic representation of the wild-type mouse Xpa locus (exon 2 to 6), the targeting construct, the conditional Xpa allele, and the conditional Xpa allele following Cre-recombinase-mediated inactivation. In addition the knock out allele with a neomycin (NEO) marker cassette, as present in the non-conditional Xpa mouse model is shown [41]. In the conditional construct, exon 4 was fused in frame to the mouse Xpa cDNA (containing the remaining coding sequence and including a synthetic polyA sequence), followed by a PGK promoter-driven hygromycin (HYGRO) selectable marker gene. LoxP sites were introduced in intron 3 and downstream of the hygromycin marker to allow Cre-mediated excision of the cDNA and hygromycin marker gene, yielding an Xpa allele lacking exon 4, known to act as a null allele. A LacZ-GFP fusion marker gene, preceded by a splice acceptor (SA) and an internal ribosomal entry (IRES) was included to allow visualization of inactivation of the conditional Xpa allele. Open and gray boxes represent exon and cDNA sequences, respectively. The splice acceptor-Murfi cassette ensures proper splicing and translational stops in all frames respectively when the Xpa gene is knocked out. B) Southern analysis of wild-type ES cell DNA transfected with the conditional Xpa construct. DNA was digested with EcoRI and hybridized with an intron 5/exon 6 probe, external to the targeting construct. Wild-type and targeted alleles gave fragments of 16 and 12 kb, respectively. C) Southern blot analysis of DNA from E13.5 Xpac/− and Xpac/−/Cag-Cre embryos. DNA was digested with EcoRV and hybridized with a LacZ probe. Intact and Cre-inactivated conditional Xpa alleles are represented by 2.4 and 10 kb fragments, respectively. D) LacZ staining of E13.5 Xpac/− and Xpac/−/Cag-Cre embryos, indicating inactivation of the conditional Xpa allele in Xpac/−/Cag-Cre embryos only. E) Survival of wild-type, Xpac/− and Xpac/−/Cag-Cre MEFs, exposed to increasing doses of UV-C light. F) Photograph of 16-day old Csb−/−/Xpac/− and Csb−/−/Xpac/−/Cag-Cre littermates, the latter showing severely reduced size.
To study the effect of Xpa inactivation in the absence of Csb, specifically in postnatal neurons, we crossed Csb−/−/Xpac/− mice with a calcium/calmodulin-dependent protein kinase IIα (CamKIIα) Cre transgenic line that expresses Cre-recombinase selectively in postnatal neurons throughout the forebrain [66], [67]. Forebrain-specific recombination was confirmed by PCR and analysis of LacZ expression. Csb−/−/Xpac/−/CamKIIα-Cre mice grew into young adulthood without any noticeable phenotype, showed a normal body weight and appearance at the age of 6 months, but from the age of 9–12 months became smaller and exhibited reduced weight as compared to littermates with other genotypes, i.e. CamKIIα-Cre, Csb−/−CamKIIα-Cre, Xpac/−CamKIIα-Cre and Csb−/−/Xpac/− littermates (Figure 5A, Figure S6). In addition, from 9–12 months of age, Csb−/−/Xpac/−/CamKII-Cre mice started to display seizure behavior, characterized by episodes of immobility. Subsequently, Csb−/−/Xpac/−/CamKII-Cre mice became moribund, all animals dying prematurely between the age of 12 and 22 months (Figure 5B), while animals from littermates with other genotypes survived up to 24 months (the oldest age examined). Analysis of locomotor behavior using the accelerating rotarod assay demonstrated that Csb−/−/Xpac/−/CamKIIα-Cre mice performed within the normal range at the age of 6 months, but showed reduced performance at 12 months (Figure S6). For further analysis of behavioral abnormalities, we used an open-field exploratory test. This test revealed that Csb−/−/Xpac/−/CamKIIα-Cre mice avoided exploration of the central part of the open field, which is considered a measure of anxiety-related behavior [68]. Total movement time and distance were the same as for the other groups ruling out impaired mobility as explanation for the difference in the test. The ratio of the ambulatory activity in the center and the total walking distance was already reduced at 3 months of age, and further declined at 6 and 12 months of age (Figure 5C).
Reduced lifespan, age-dependent behavioral abnormalities, and brain atrophy in forebrain neuron-specific knockout of <i>Xpa</i> in <i>Csb<sup>−/−</sup></i> mice.
Fig. 5. Reduced lifespan, age-dependent behavioral abnormalities, and brain atrophy in forebrain neuron-specific knockout of Xpa in Csb−/− mice.
A) Mean body weight of CamKIIα-Cre, Csb−/−CamKIIα-Cre, Xpac/−CamKIIα-Cre and Csb−/−/Xpac/−/CamKIIα-Cre mice. Values are means ± SE (n = 8 to 13/group). Note the loss of body weight in Csbm/m/Xpac/−/CamKIIα-Cre mice after the age of 25 weeks. * represent P<0.05, as compared to other groups of the same age (one-way Anova with Tukey's post-test). B) Survival curve of Csb−/−/Xpac/−/CamKIIα-Cre mice (n = 13) as compared to wild type and single mutant littermates (combined n = 13). C) Representative examples of open field plots (C2) and quantification of the distance moved in the center as compared to total distance moved (C1), showing reduced ambulatory behavior of Csb−/−/Xpac/−/CamKIIα-Cre mice (n = 6) in the center of the field. Note that the center/total distance ratio is already reduced in 3 month-old Csbm/m/Xpac/−/CamKIIα-Cre mice, and decreases upon further aging. * in panel C, P<0.05, compared to other groups of the same age (one-way Anova with Tukey's post test). D, E) Coronal 4 µm thick, haematoxylin/eosin-stained paraffin sections of 15 and 65 week old Xpac/−/CamKIIα-Cre and Csb−/−/Xpac/−/CamKIIα-Cre mouse brains; sections grossly correspond to sections 0.5 to 1 mm anterior to the bregma (D) and 1.5 to 2 mm posterior to the bregma (E) as depicted in the mouse brain atlas of Paxinos and Franklin [85]. 65 week old Csb−/−/Xpac/−/CamKIIα-Cre show dilated ventricles, and atrophy of the neocortex (NCx), hippocampus, the caudatus-putamen (CPu) and the septum. CA3, CA3 hippocampal subfields; DG, dentate gyrus; Th, thalamus; LS, lateral septum; lv, lateral ventricle. F) GFAP-immunoperoxidase staining in coronal brain sections of 65 week-old Xpac/−CamKIIα-Cre, Csb−/− and Csb−/−Xpac/−CamKIIα-Cre shows increased GFAP staining in the neocortex (NCx), hippocampus and amygdala of Csb−/−Xpac/−CamKIIα-Cre mice. GFAP staining in the thalamus (Th) was the same as in Xpac/−CamKIIα-Cre and Csb−/− mice.
Macroscopic examination of the brain of Csb−/−/Xpac/−/CamKIIα-Cre mice revealed no obvious changes at 3 months, mild atrophy of the cortex at 6 months, and severe atrophy of the cortex at older age (Figure S6). The sizes of olfactory bulbs, cerebellum and spinal cord were the same as in other groups. Analysis of coronal sections of 12–16 month-old Csb−/−/Xpac/−/CamKIIα-Cre brains showed a large reduction in cortical thickness, atrophy of other telencephalic areas (i.e. hippocampus, caudatus-putamen and septum), and dramatically enlarged lateral ventricles (Figure 5D, 5E). No abnormalities were observed in non-telencephalic areas, consistent with specific inactivation of the conditional Xpa allele in forebrain neurons. Atrophy of telencephalic areas was paralleled by a marked increase in GFAP immunoreactivity, while GFAP staining in other brain areas was the same as in Csb−/−/Xpac/− and Csb−/− mice (Figure 5F). Atrophied brain areas also showed loss of the neuronal somato-dendritic marker microtubule-associated protein 2 (MAP2), in particular in the hippocampal CA1 region, indicative of neuronal degeneration (Figure S7).
Staining for p53 revealed a prominent increase in the number of p53 immunoreactive neurons in the forebrain of Csb−/−/Xpac/−/CamKIIα-Cre mice as compared to Csb−/− mice and other genotypes that showed essentially no p53 immunoreactive cells (Figure 6A, 6D). In addition, Csb−/−/Xpac/−/CamKIIα-Cre forebrain exhibited a strong increase in neurons expressing ATF3 (Figure 6B, 6D), a stress-inducible transcription factor that is induced following genotoxic stress via p53-dependent and -independent pathways [69], [70]. Finally, direct evidence for neuronal degeneration was obtained by staining for active caspase 3 and by using a silver staining procedure: active caspase 3 staining revealed intensely stained neuronal profiles (Figure 6C, 6D). Similarly, the silver degeneration staining method outlined infrequent argyrophylic neuronal profiles, reflecting neurons that are in the process of dying. In addition, the silver staining uncovered high levels of argyrophilic axonal degeneration in the corpus callosum, the fimbria-fornix, the anterior commissure, and the cortifugal fiber bundles coursing in the capsula interna, the cerebral peduncle and the pyramidal tract (Figure 6E), which is consistent with the selective occurrence of neuronal degeneration in forebrain neurons. Together these data indicate that Csb−/−/Xpac/−/CamKII-Cre mice display chronic neuronal degeneration that in the long term has resulted in severe neuronal loss and atrophy of the forebrain regions.
Neurodegenerative changes in forebrain neuron-specific and Purkinje cell-specific knockout of <i>Xpa</i> in <i>Csb<sup>−/−</sup></i> mice.
Fig. 6. Neurodegenerative changes in forebrain neuron-specific and Purkinje cell-specific knockout of Xpa in Csb−/− mice.
A–D) Neurolucida plot (A), representative photomicrographs (B, C) and bar graph (D) of p53 (A, D), ATF3 (B, D) and active caspase 3 (C, D) staining in the cortex of 65 week old Csb−/− and Csb−/−Xpac/−CamKIIα-Cre mice showing an increase in the number of p53- and ATF3 immunoreactive cells and the appearance of caspase 3 labeled neurons in the cortex of Csb−/−Xpac/−CamKIIα-Cre mice. Values in bar graph in d represent means ± SE from 3 mice per group. E) Silver degeneration staining in the caudatus-putamen shows a high level of argyrophilic fibers in the capsula interna (ci) and corpus callosum (cc) of 16 month-old Csb−/−Xpac/−CamKIIα-Cre mice while no stained fibers occurred in these fiber tracts in wild-type (not shown), Csb−/− and Xpac/−CamKIIα-Cre mice. F–J) Photomicrographs of sagittal cerebellar sections of 25-week old Csb−/− (F1–J1) and Csb−/−Xpac/−L7-Cre mice (F2–J2). F) Silver degeneration staining shows a high level of argyrophilic fibers in the deep cerebellar nuclei (DCN) and the white matter (wm) of Csb−/−Xpac/−L7-Cre cerebellum (arrow in F2). G) GFAP-immunoperoxidase staining shows increased GFAP staining in the molecular (ml) and Purkinje cell (Pcl) layers Csb−/−Xpac/−L7-Cre cerebellar cortex, while no change occur in the granule cell layer (Gcl). H) Calbindin-immunoperoxidase staining reveals calbindin-negative regions in the molecular layer (arrow in H2) of Csb−/−Xpac/−L7-Cre cerebellar cortex. I) A number of Purkinje cells showed strong nuclear ATF3 staining (arrow in I2). Note that the ATF3 antibody also outlines Purkinje cells because of non-specific cytoplasmatic staining of these cells. J) Active caspase 3 antibody stains sporadic Purkinje cells in Csb−/−Xpac/−L7-Cre cerebellar cortex (arrow head in J2). Calibration Bars: Bars: 500 µm (F2), 100 (B1), 50 µm (E, H2), 25 µm (C1, J2).
The distribution of degenerative changes in Csb−/−/Xpac/−/CamKII-Cre mice is consistent with the specific inactivation of Xpa in forebrain neurons induced by CamKII-promotor driven Cre-recombinase expression [66], [67], and highlights the vulnerability of Csb-deficient forebrain neurons to loss of Xpa function. To determine the effect of Xpa inactivation in other neuronal populations of the Csb−/− brain, we crossed Csb−/−Xpac/− mice with a postnatal Purkinje cell specific Cre (L7-Cre) transgenic line [71] to obtain Csb−/−/Xpac/−/L7-Cre mice. Analysis of motor behavior with accelerating rotarod revealed no or very mild motor abnormalities in Csb−/−/Xpac/−/L7-Cre mice at the age of 3 and 6 months (the oldest age examined). However, neuropathological analysis disclosed multiple signs of selective Purkinje cell degeneration resembling pathological changes in forebrain neurons of Csb−/−/Xpac/−/CamKII-Cre mice (Figure 6). Abnormalities included the presence of argyrophilic axonal degeneration, specifically in the cerebellar white matter and cerebellar nuclei, i.e. the areas that contain Purkinje cell axons (Figure 6F), and sporadic argyrophilic debris in the molecular and Purkinje cell layer, while no argyrophilic changes occurred in other brain areas. In addition, the Purkinje and molecular layers also showed a strong increase in GFAP-immunoreactivity (Figure 6G), while staining for calbindin, a protein that in the cerebellum is selectively expressed in Purkinje cells, revealed calbindin-negative regions in the molecular layer, indicative of loss of Purkinje cells (Figure 6H). Furthermore, a subset of Purkinje cells (with morphologies varying from relatively normal to severely atrophic cells) displayed strong nuclear ATF3 staining (Figure 6I), which was distinct from the non-specific cytoplasmic staining of Purkinje cells produced by the ATF3 antibody. Nuclear ATF3 staining was not observed in Purkinje cells (nor other cerebellar neurons) of wild-type, Csb−/−, Csb−/−/Xpac/+/L7Cre, Csb−/−/Xpac/− and Xpac/−/L7-Cre, as well as forebrain-specific Csb−/−/Xpac/−/CamKII-Cre mice. Quantification of ATF3-immunoreactive Purkinje cells in mid-sagittal sections of 6 month-old Csb−/−/Xpac/−/L7-Cre mice (n = 3) indicated that 1.3±0.6% (Mean ± SE) of Purkinje cells were ATF3-positive. Finally, staining for active caspase 3 revealed infrequent (<1 in 5000) positive Purkinje cells (Figure 6J). In conclusion, the data obtained with Csb−/−/Xpac/−/L7-Cre mice further demonstrate that the addition of an Xpa defect to Csb-deficient neurons results in pronounced neuronal degeneration.
Discussion
To determine the importance of the NER and TCR DNA repair pathways for neuronal integrity and survival, we first conducted a comparative analysis of neuropathological abnormalities in six mouse models for the human syndromes XP, CS, XPCS and TTD. The major finding of this analysis is that CS-like/TCR-deficient Csa−/−, Csb−/− mice and, to a lesser extent, XpdXPCS mice, develop a characteristic set of mild degenerative changes that was predominantly characterized by microglia activation in regions with myelinated axons, in the absence of obvious signs of axonal degeneration. This microglia activation did not occur in the XP-like GG-NER-defective Xpc−/− and total NER-defective Xpa−/− mutant animals, nor in the TTD-like XpdTTD mouse. In view of very limited signs of neuronal degeneration in NER- and TCR-deficient mice, respectively, we also investigated the effect of combined NER- and TCR-deficiency on neuronal survival. For this purpose we generated a Cre-lox based conditional Xpa knockout mouse that was crossed with neuron-specific Cre lines and TCR-deficient Csb−/− mice. These experiments showed that combining NER and TCR-defects in neurons causes progressive neuronal degeneration and disclose a functional overlap as well as functional complementarity of the NER and TCR repair pathways.
Identification of a CS–like neuropathological phenotype in TCR–deficient mouse mutants
The abnormalities identified in the CS (Csa−/− and Csb−/−), and XPCS (XpdXPCS) mice consisted of 1) the presence of activated phagocytosing microglia cells in regions containing myelinated axons such as the corpus callosum, the brainstem reticular formation and the spinal cord; and 2) sporadic cells with intense p53-immunoreactive nuclei. Microglia activation was frequently accompanied by signs of astrocytosis indicative of a central nervous tissue injury response. We did not find an association between microglia activation and p53-positive cells, and neither was microglia activation associated with detectable axonal degeneration. However, activated microglia cells were often in close contact with oligodendrocytes. These data indicate that microglia activation follows from oligodendrocyte or myelin abnormalities. Previous electron microscopic analysis did not reveal abnormalities in the morphology and thickness of myelin sheets in Csb−/− mice [45], and in the current study, apart from evidence suggesting a minor increase in apoptosis of oligodendrocytes, we did not identify other overt oligodendrocytic abnormalities. Hence, the precise cellular abnormality that triggers microglia activation in myelinated regions of Csa−/−, Csb−/−, and XpdXPCS mice remains to be determined. Importantly, however, the presence of activated microglia is consistent with the notion that irregular patchy myelination with minimal axonal degeneration is a dominant neuropathological hallmark of CS [14], [22], [35], [37], [72]. Hence, our findings together with human neuropathological data strongly indicate that oligodendrocyte abnormalities are a prime defect in CS. We also show that XpdTTD mice, unlike XpdXPCS mice, do not develop microglia activation in myelinated areas. This is in line with the notion that myelin abnormalities in TTD patients and XpdTTD mice result from developmental deficits and arise via different mechanisms than in CS patients [14], [22]. Our data further illustrate that specific point mutations in the Xpd gene result in different cellular deficits and associated pathologies in the mouse, mimicking the different pathologies in patients [27], [31], [49].
The second abnormality that we identified in the CS (Csa−/− and Csb−/−) and the XPCS (XpdXPCS) mouse nervous systems consisted of sporadically distributed p53-immunoreactive neurons and astrocytes, and, albeit very infrequent, oligodendrocytes. p53-immunoreactive cells occurred in all brain areas, but the proportion of neuronal versus glial p53-immunoreactive cells varied among brain areas. Thus, in cortex and cerebellum a large proportion of p53-positive cells are neurons while in the brain stem and spinal cord the far majority, if not all, p53-positive cells are glial cells. The expression of p53, which is known to be activated by multiple types of DNA damage and which mediates neuronal degeneration [57], provides indirect evidence for the occurrence of genotoxic stress, which can be explained by cumulative DNA damage resulting from compromised DNA repair. Interestingly, a subset of p53-positive astrocytes showed abnormal nuclear morphologies, which is compatible with reports of astrocytic nuclear abnormalities in CS patients [38], [72], [73], and further indicate that astrocytes are vulnerable to loss of TCR function.
We did not observe abnormal nuclear morphology in p53-immunoreactive neurons, nor did we obtain direct evidence for ongoing neuronal death using two neuropathological markers for dying neurons, i.e. active caspase 3 immunoreactivity, and silver degeneration staining. However, the process of death and removal of individual neurons may occur within a few hours, making the in vivo detection of asynchronous sporadically distributed cell death challenging [74], [75]. Hence, our methods do not exclude the possibility of a low frequency of ongoing neuronal degeneration. The lack of an obvious neurodegenerative phenotype in the CS mouse models is compatible with the neuropathology of CS patients indicating relatively modest neuronal degeneration in most brain areas [35], [38], [72], [73]. Interestingly, cerebellar granule cells, which are among the most severely affected populations of neurons in CS patients [76], most frequently showed p53 immunoreactivity in the CS mice, indicative of a differential vulnerability of cerebellar granule cells to loss of TCR function in both CS patients and mouse models. Furthermore, p53-immunoreactive granule cells have been demonstrated in autopsy cases of CS [76].
Together our data indicate that Csa−/−, Csb−/−, and XpdXPCS mice reproduce the major aspects of CS neuropathology, albeit in a mild form, which may explain the absence of macroscopic neuropathological and obvious neurological deficits associated with CS. In this context it would be interesting to know whether patients with UV-sensitivity syndrome (UVSS), also carrying mutations in CSA and CSB genes, develop the same mild abnormalities. The presence of activated microglia in UVSS patients would support the notion of a continuum of CS phenotypes ranging from CS type II to UVSS [16] as also suggested by a CS patient with a CSB null mutation displaying adult-onset neurological symptoms [37]. As the pathologies of Csa−/−, Csb−/−, and XpdXPCS mice are relatively similar, our data also indicate that the CS neurodegenerative features can not be explained by molecular mechanisms that do not include all three proteins. Furthermore, the data indicate that the CS neurodegenerative changes result from deficits in a shared non-NER activity of these proteins as Xpa−/− mice with complete loss of GG-NER and TC-NER function did not reproduce the neuropathological features that we observed in Csa−/−, Csb−/−, and XpdXPCS mice (see below). This is consistent with a broader TCR process, which encompasses transcription-coupled repair of non-NER/non-distorting transcription-blocking lesions involving CS and TFIIH proteins.
A marginal nervous system phenotype in GG-NER– and entirely NER–deficient mice
The GG-NER-defective Xpc−/− and total NER-defective Xpa−/− mutant mice at 26 weeks of age showed very low levels of p53-immunoreactive neurons and astrocytes, which nevertheless was higher than in XpdTTD and wild-type mice of the same age, in which we did not detect any cells with nuclear p53 immunoreactivity throughout the nervous system. These data suggest that Xpa−/− and Xpc−/− mice have a central nervous system phenotype, albeit marginal. In case of Xpc−/− mice the phenotype is compatible with that of XP-C patients that, although neurologically and cognitively asymptomatic, may develop mild neurodegenerative changes [19]. However, in Xpa−/− mice the phenotype is very different from the severe progressive neurodegenerative changes of many XP-A patients, which develop juvenile or adult progressive neuronal degeneration throughout the central and peripheral nervous system depending on the severity of NER dysfunction [17], [19], [33], [34], [36]. Neurons from Xpa−/− mice display considerably increased sensitivity to UV radiation [77] and the cross-linking agent cisplatin [78], consistent with loss of NER function and excluding redundancy of NER activity by other proteins at least for the lesions induced by these agents. The discrepancies between human and rodents may follow from differences in the rate of production and type of DNA lesions caused by endogenous metabolites, and from the shorter lifespan of mice.
Synergistic effects of NER and TCR deficiencies in neuronal degeneration
To investigate the effect of combined NER and TCR-deficiency on neuronal survival, we generated a Cre-lox-based conditional Xpa mouse model to inactivate Xpa selectively in postnatal neurons in Csb−/− mice. The use of a conditional Xpa mouse model was required in view of our previous findings that global Csb−/−/Xpa−/− double mutant animals show degenerative changes in multiple organs as well as a very short life span [62], [63], precluding prolonged analysis of neurodegeneration and separation from direct and indirect consequences. Our data show that Csb−/− mice with neuron-specific inactivation of Xpa develop progressive neuronal degeneration, indicating that the XPA protein (and the NER pathway as a whole) is essential for the survival of mouse neurons in the absence of the CSB protein. The time course and distribution of neurodegenerative changes indicate that the affected neurons degenerate asynchronously over a prolonged time window. When Xpa is inactivated in forebrain neurons of Csb-deficient animals, mild behavioral abnormalities were observed at 3 months of age, while death, associated with severe atrophy of forebrain areas, occurred between 12–21 months of age. Analysis of the distribution of dying neurons, as identified by active caspase 3 or ATF3 staining, showed that the level of ongoing neuronal degeneration at a given time point was low. Similarly, in Csb-deficient mice with selective inactivation of Xpa in Purkinje cells which were analyzed at a single time point, a subset of Purkinje cells had disappeared (identified as loss of calbindin staining), a very small subset was in the process degenerating or dying (ATF3 and caspase 3 staining), while a subset showed a normal appearance consistent with asynchronous degeneration. Such an asynchronous neuronal degeneration is consistent with cell death resulting from the accumulation of stochastic DNA damage [79], [80], and strongly resembles the pattern of neuronal degeneration in Ercc1Δ/− mice that are impaired in several DNA repair systems, i.e. nucleotide excision repair, interstrand crosslink repair and double strand break repair [81].
Together, the data with conditional Xpa/Csb-deficient mice indicate that adult neurons in rodents are vulnerable to endogenous DNA lesions when deficient in both NER and TCR, but are able to cope with these lesions when either the TCR or NER pathway are defective. While the NER and TCR pathway share the TC-NER activity, they have non-overlapping activities consisting of GG-NER and the still poorly defined non-NER TCR activities. In neurons, factors of the GG-NER machinery, in particular XPC, have been shown to operate in a specialized type of transcription-associated repair, termed domain-associated repair (DAR). DAR operates on both strands in active genes, including regions of a gene that RNA polymerase II does not reach and has been proposed to complement TCR [80], and it may possibly mask or compensate for the loss of TCR [80]. This is supported by the demonstration that XPC-deficient mice that are selectively deficient in GG-NER when crossed with CSB-deficient mice have a similar phenotype as Csb−/−Xpa−/− mice [64]. Our data indicate that Xpc−/− and Xpa−/− animals develop similar marginal central nervous system phenotypes consisting of highly sporadic p53-positive cells. Together these data suggest that in mice Xpc is equally important as Xpa for the central nervous system. Also in man, XPC-deficiency may result in subtle neurodegenerative changes [19], although XPA-deficiencies results in much more severe neurodegenerative phenotypes [14], [17], [19].
Non-NER TCR has been proposed to operate in conditions of specific transcription-blocking oxidative DNA lesions, putatively via recruitment of alternative DNA repair pathways [7], [9], [10]. This explains why cells from CS mice and CS patients, unlike XPA-deficient cells, show increased vulnerability to some types of oxidative stress, and may more readily accumulate oxidative DNA lesions [9], [20], [39], [82]. In addition, increased levels of oxidative DNA lesions have been reported in brain tissue of Csb−/− mice [10]. Thus, the inability to cope with oxidative lesions may explain the pathological phenotype of CS mice, as well as the severe degenerative phenotype in the conditional Xpa-deficient Csb−/− mice. However, the precise identity of DNA lesions and the question whether the CS phenotype truly results from a repair deficiency remains to be further explored.
In summary, our data indicate that the GG-NER, TC-NER, and non-NER TCR mechanisms operate together in maintaining the integrity of neurons, and that the absence of one pathway aggravates the risk for deficiencies in other pathways, explaining the severe neurodegenerative phenotype in double mutants. The extent to which a combined deficiency of NER and TCR is detrimental to non-neuronal nervous systems cells remains to be determined in future studies by selectively inactivating Xpa in these cells in TCR deficient mice. We propose that neuron-specific inactivation of Xpa- in Csb-deficient mice represents a powerful model for studying XP neurological disease and the role of NER in neurons. As neurologic symptoms seen in XP are hallmark features of age-related neurodegenerative diseases these mice may also reproduce aspects of accelerated aging.
Materials and Methods
Mutant mice
Experiments were performed in accordance with the “Principles of laboratory animal care” (NIH publication no. 86-23) and the guidelines approved by the Erasmus University animal care committee. Animals used were Xpc−/−, knock-out for the Xpc gene [47], Xpa−/−, knock-out for the Xpa gene [41], Csa−/−, knock-out for the Csa gene [46], Csb−/−, in which the CS1AN patient mutation is mimicked resulting in a null mouse [45], XpdXPCS, homozygous for the G602D XPCS point mutation in the Xpd gene [49] and XpdTTD, carrying Xpd alleles with the R722W TTD mutation [50] bred in a pure C57BL/6J background.
To obtain a conditional Xpa knockout mouse model, we generated a targeting construct in which exon 4 was fused in frame to the mouse Xpa cDNA (containing the remaining coding sequence and including a synthetic polyA sequence), followed by a PGK promoter-driven hygromycin selectable marker gene (Figure 4A). A genomic clone containing 10 kb of the 129ola mouse Xpa locus (pMMXP3-6#13; [41]), was used to re-clone an approximately 10 kb size BamHI fragment, containing exon 3 to 6, into the psp72 vector. Following XbaI digestion, part of exon 4 and intron 4 was replaced by a cassette containing the mouse Xpa cDNA including the natural 3′ UTR and polyadenylation signal followed by a PGK promoter-driven hygromycin selectable marker and a LoxP site respectively. Next, the SmaI site downstream of the LoxP site was used to introduce a cassette containing a splice acceptor sequence (SA), an ochre stopcodon multiple reading frame insertion (Murfi) linker, a ribosomal entry site (IRES), and a LacZ/GFP fusion reporter gene (as a blunted SalI fragment). The SmaI site in intron 3 was used to insert a blunted XhoI-SalI loxP fragment from pGEM30 (kindly provided by Dr. W. Gu, University of Cologne). This targeting construct, which was designated pIP-Xpa-con, contains homologous arms of 4 kb at the 5′ end and 5 kb at the 3′ end.
The 129Ola-derived ES cell line IB10 was electroporated with NotI linearized pIP-Xpa-con DNA and cultured in gelatin-coated dishes as described before [45]. Hygromycin (Roche, 843555) was added 24 hr after electroporation to a final concentration of 100 µg/ml. Cells were maintained under selection for 7–8 days, after which clones were isolated and expanded in 24-well plates. Genomic DNA from individual hygromycin-resistant clones was digested with EcoRI and analyzed by Southern blotting using a 500 bp DraI fragment (“intron 5/exon 6” probe; obtained from a 7.5 kb PCR fragment spanning exon 5 and 6). EcoRI digested DNA from targeted ES clones was subsequently screened with the hygromycin (cDNA) probe to confirm proper homologous recombination at the 5′ end of the targeting construct.
For the generation of Xpac/− ES cells, we followed the same procedure as described above, except that Xpa−/− ES cells [54] were used. To test the functionality of the loxP sites, Xpac/+ ES cells were electroporated with a purCre plasmid (kindly provided by Dr. M. Jaegle, Erasmus MC) and cultured on gelatin dishes as described. Puromycin (Sigma, P7255) was added 24 hr after electroporation to a final concentration of 100 µg/ml. Cells were maintained under selection for 3 days. Genomic DNA from individual puromycin-resistant clones was digested with EcoRV and analyzed by Southern blotting using a 500 bp PCR fragment of the LacZ gene. Properly targeted IB10 ES clones were karyotyped and cells from two independent clones (selected for the presence of 40 chromosomes) were injected into 3.5-day-old C57BL/6J blastocysts. Male chimeric mice were mated with C57BL/6J females to obtain heterozygote offspring.
Heterozygous males and females were bred to Xpa+/− as well as Csb−/+ animals to ultimately obtain Xpac/−, Xpac/+ and Csb−/−/Xpac/− animals. Genotyping was initially performed by Southern blot analysis of genomic DNA obtained from tail biopsies of 8–10-day-old born pups. A description of PCR-based genotyping methods is given below. Xpac/− and Csb−/−/Xpac/− animals were also interbred with Cag-Cre [65], CamKII-Cre (line L7ag#13) [66], [67], and L7-Cre (line L7Cre-2, [71]) Cre-recombinase transgenic mice, which were kindly provided by A. de Wit (ErasmusMC), S. Zeitlin (Columbia University), and J.J. Barski (Max-Planck-Institute of Neurobiology, Martinsried, Germany), respectively.
Primary mouse embryonic fibroblasts from the various single and double mutant mouse models (three independent lines per genotype) were isolated from day 13.5 embryos and cultured as described before [83].
Mice and cells were genotyped by PCR for the wild-type and (conditional) mutant Xpa or Csb alleles using a primer mix that (per genotype) amplifies both the wild-type and targeted alleles in a single reaction [41]. The presence or absence of the conditional Xpa allele was detected by PCR using primers XpaFex3 (5′-TTT GAT CTG CCA ACG TGT G-3′) and XpaRex4 (5′-GCT TCG CTT CTG TCT TGG T-3′). The presence or absence of the Cre transgene was detected by PCR using primers 5′-GCA CGT TCA CCG GCA TCA AC-3′ and 5′-CGA TGC AAC GAG TGA TGA GGT TC-3′. Both products were amplified with the same PCR program: 5 min. 93°C, 1 min. 93°C, 1 min. 58°C, 2.5 min. 72°C (35 cycles of the latter three steps), 5 min. 72°C.
LacZ staining of embryos and cells
Cells or embryos were fixed for 30 minutes at 4°C in a buffer containing 1% paraformaldehyde, and subsequently washed 3×15 minutes with PBS/0.01% NP40. Cells or embryos were stained overnight at 37°C in dark in a staining solution containing 3.1 mM K3Fe(CN)6, 3.1 mM K4Fe(CN)6, 0.15 M NaCl, 1 mM MgCl2 and 1 mg/ml X-gal (Roche Applied Sciences, USA, IN). For tissues, the same procedure was used, except that the fixation time was extended to 3 hours.
DNA repair assays
Seeded cultures at a density of 1000 spontaneously immortalized MEFs on a 6 cm dish were exposed to different doses of UV-C (254 nm, Philips TUV lamp). The cells were allowed to grow for another 7 days after which the resulting clones were fixed, stained and counted. For each independent cell line, the amount of surviving clones at each dose of UV, 3 dishes per dose, was calculated as the percentage of clones on the plate without UV.
Behavioral assays
For the open field test, animals were placed for 30 min in a square (26×26×26 cm) open field box, equipped with photobeam sensors (TruScan E63 10–12, Coulbourn Instruments), and attached to a computer to record the following ambulatory parameters: total distance, center distance, total move time, center time and corner time. Each test session lasted 30 minutes, and data were collected in 5 minute intervals. The anxiety ratio was calculated by dividing center distance by total distance. Rotarod analyses were performed as described previously [84].
Immunohistochemical and histopathological procedures
Mice were anesthetized with pentobarbital and perfused transcardially with 4% paraformaldehyde, and brains were dissected out, weighed, and postfixed overnight in 4% paraformaldehyde at 4°C. For standard histological analyses brains were paraffin-embedded, sectioned at 4 µm and stained with haematoxylin/eosin solution. For other staining procedures brain specimen were embedded in gelatin blocks [81] and sectioned at 40 µm with a freezing microtome. Sections were processed, free floating, using immunofluorescence or a standard avidin-biotin–immunoperoxidase complex method (ABC; Vector Laboratories) with diaminobenzidine (0.05%) as the chromogen. In addition, a selected number of frozen sections were processed for a silver staining procedure that selectively labels dying neurons and their processes [81].
Immunoperoxidase-stained sections were analyzed and photographed using a Leica (Nussloch, Germany) DM-RB microscope and a Leica DC300 digital camera. Sections stained for immunofluorescence were analyzed with a Zeiss (Oberkochen, Germany) LSM 510 confocal laser scanning microscope using 40x/1.3 and 63x/1.4 oil-immersion objectives.
Primary antibodies reported in this study are as follows: mouse anti-APC (Calbiochem, clone CC-1, 1∶2000); rabbit anti-activating transcription factor 3 (ATF3; Santa Cruz Biotechnology, Santa Cruz, 1∶1000); rabbit anti-cleaved caspase 3 (Asp175; Cell Signaling Technology, 1∶200); mouse anti-calbindin (Sigma, clone CB-955, 1∶10000); rabbit anti-GFAP (DAKO, 1∶5000); mouse anti-GFAP (Sigma, clone G-A-5, 1∶20000); rabbit anti-HSP25 (Stressgen, 1∶7000); rabbit anti-Iba1 (WAKO Chemicals, 1∶ 2000); rat anti-Mac2 (Cedarlane, 1∶2000); mouse anti-MAP2 (Millipore, clone AP20, 1∶200); rat anti-myelin basic protein (Millipore, MAB386, 1∶500); mouse anti-NeuN (Millipore MAB377, 1∶2000); rabbit anti-neurofilament-H (Millipore, 1∶2000); rabbit anti-olig2 (IBL, 1∶2000); rabbit anti-p53 (Leica, 1∶2000); mouse anti-S100B (Sigma, clone 1B2, 1∶2000); and guinea pig anti-VGLUT1 (Millipore, 1∶2000). For avidin-biotin–peroxidase immunocytochemistry biotinylated secondary antibodies from Vector Laboratories (Burlingame, CA) diluted 1∶200 were used. FITC-, cyanine 3 (Cy3)-, and Cy5-conjugated secondary antibodies raised in donkey (Jackson ImmunoResearch, West Grove, PA) diluted at 1∶200 were used for immunofluorescence.
Immunoperoxidase-stained sections were analyzed and photographed using a Leica DM-RB microscope and a Leica DC300 digital camera. To determine the relative staining intensity of GFAP staining, sections were photographed using a 5× objective, and optical densities were determined from TIFF files using MetaMorph 4.6 image analysis software. Optical densities determined in rectangular areas of 200×250 µm. To minimize variability resulting from the staining procedure this analysis was performed with sections stained in a single immunostaining session.
Statistical analyses
Statistical analyses were done with GraphPad Prism software (San Diego, USA). Means from different age groups, and different transgenic mouse lines were compared using one-way-ANOVA with Tukey's post tests.
Supporting Information
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Zdroje
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Genetika Reprodukční medicína
Článek vyšel v časopise
PLOS Genetics
2011 Číslo 12
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An OB-GYN's guide to your preconception appointment
Reviewed by Health Guide Team,
Reviewed by Health Guide Team,
last updated: Aug 31, 2020
10 min read
While you may have heard about the several appointments you'll need during pregnancy, there's a very important visit that comes before even trying to conceive: the preconception appointment. The thing is, as useful as these appointments can be, they’re not often suggested by many healthcare providers — and not all patients know to request them.
I believe the preconception appointment is an excellent way to set yourself up for the healthiest pregnancy possible. That’s why I’ve put together this guide for the appointment, including what exactly the appointment is, what you can expect to talk about, and the questions I recommend asking your healthcare provider.
Modern Fertility
Fertility hormones shouldn’t be a mystery
What’s a preconception appointment?
A preconception appointment is a visit with your healthcare provider (either a general practitioner, OB-GYN, or midwife) where you can get all kinds of questions answered about fertility, getting pregnant, the early parts of pregnancy, and anything you need to know based on your medical history. This appointment ensures you’re getting medically accurate information right from a trustworthy source — plus, you’ll have the opportunity to talk through anything you need more insight into or don’t quite understand.
Before we dive in, a quick note: Not every healthcare provider will cover the exact same things in a preconception appointment. If any of these topics aren’t brought up, feel free to ask questions about anything you’d like to learn more about.
What can you expect to talk about in a preconception appointment?
A preconception appointment will most likely cover everything you need to know before trying for kids, as well as anything in your family or medical history that might make conception more difficult or potentially cause any issues during pregnancy. If you haven’t already gotten a Pap smear at a recent physical exam, you’ll sometimes have the opportunity to do that in this appointment.
Here’s a brief overview of what you might discuss:
• Your plans for kids
• When it makes sense for you to go off birth control (if you’re on it)
• How your birth control might impact ovulation (and for how long)
• Your medical, surgical, and family health history (including medications)
• Alcohol consumption and smoking (and their effects)
• How your body-fat percentage could affect conception
• Pre-pregnancy tests and vaccinations
• Prenatal vitamin recommendations
• How to actually start trying to conceive
Below, I’ll walk you through the specifics of each of these discussion topics and give you a quick list of questions you can bring to your appointment.
Your plans for kids (and when to go off birth control)
When you show up for your appointment, you’ll have the chance to talk with your healthcare provider about when you’d ideally like to conceive, how many kids you’d like to have, and how you’d like to conceive (i.e., using your eggs, uterus, your partner’s sperm, donor sperm, donor eggs, donor uterus, gestational carrier, etc.).
Depending on your answers, your healthcare provider can give you insight into when you might want to start trying to get pregnant (if you want a lot of kids, they might suggest you start earlier) and what plans you need to set in motion now. A big part of those plans, of course, is going off birth control if you’re on it.
You and your healthcare provider will go over any contraceptives you’ve been using and their potential effects on your cycle and fertility. To give you an idea of time-to-pregnancy after different types of birth control, here’s the percentage of people who got pregnant 12 months after stopping the following methods (according to one 2018 meta-analysis of 22 studies involving ex-contraceptive users ranging in age from late teens to early 40s):
• 74.7% of ex-implant users
• 77.74% of ex-injection users
• 87.04% of ex-oral contraceptive users
• 84.75% of ex-IUD users (no difference based on type of IUD)
If you’re on Depo-Provera (the birth control shot), your healthcare provider may recommend you stop the shots earlier than you would other types of birth control — that’s because Depo can affect ovulation for up to 22 months after stopping.
If you’re on hormonal birth control to manage the symptoms of health conditions like polycystic ovary syndrome (PCOS), endometriosis, uterine fibroids, or premenstrual dysphoric disorder (PMDD), you can talk with your doctor about alternative non-hormonal options (like over-the-counter pain medications).
Questions to ask:
1. Based on your plans for kids, when would your healthcare provider recommend going off birth control?
2. Can you expect a quick return to regular ovulation and cycles after going off your specific birth control method?
3. If you’re using hormonal birth control to manage symptoms, what can you take instead that won’t prevent pregnancy or impact conception?
Your medical, surgical, and family health history
Come to your appointment prepared to fill out a detailed intake form. This means writing down any medications you take and their doses, and talking to your family about their health history.
Your healthcare provider will likely ask detailed questions about your medical, surgical, and family history — and go over any medical conditions that might impact pregnancy or be impacted by pregnancy (i.e., thyroid conditions, polycystic ovary syndrome, high blood pressure, diabetes). They might also recommend testing for genetic conditions if your family history calls for it, and talk about any conditions that need to be treated (medically or surgically) before trying to conceive. (For example: The optimal thyroid-stimulating hormone, or TSH, level is 2.5 if you’re trying to get pregnant. If you've had thyroid issues in the past, you can talk to your healthcare provider about testing your TSH.)
If you have a history of irregular cycles, be sure to mention that to your healthcare provider. They can give you blood tests to measure your fertility hormones and see if there are any imbalances or other issues that might be causing the irregularity. Since those tests typically need to be done on day 3 of your cycle for the most accurate results, if you aren’t regularly ovulating or getting a period, your healthcare provider might trigger your period with progesterone and count that as bleeding as day 1. Preconception appointments become all the more important if your cycle is irregular because they can help you figure out what’s going on and determine the best steps to take for conception.
If you’ve given birth through cesarean section (aka C-section) in the past, this appointment is also a good time to talk to your healthcare provider about your delivery options. You can have a vaginal birth after C-section (or VBAC) or repeat C-section, but some hospitals and clinics don’t offer VBAC as an option. Why? An OB-GYN needs to be on-site 24/7 in case the birthing person experiences the very rare (only a 1% chance) but life-threatening complication of uterine rupture (tearing of the uterus) — and some hospitals and clinics don’t have a large enough staff to ensure that can happen. If you’re interested in a VBAC, you can check with your healthcare provider to see if that’s an option with your current care team.
Questions to ask:
1. Do any of the conditions in your personal or family health history indicate any testing needs before trying to conceive?
2. Does your cycle history indicate any testing needs before trying to conceive?
3. Could any of the conditions in your personal or family health history cause issues for conception or pregnancy? If so, what can you do to manage those issues?
4. Does your healthcare provider recommend any genetic testing before trying to conceive?
5. If you have a partner, does your healthcare provider recommend they go through any testing?
6. If you’ve given birth through C-section before and are interested in VBAC, is VBAC an option with your current care team?
Any medications you’re currently taking
Some of the medications you’re taking right now will be fine to continue taking if you get pregnant, but some will have to be stopped during pregnancy. Retin-A (an acne medication), many cholesterol medications, some psychiatric medications (like lithium), and ibuprofen are all examples of what cannot be taken during pregnancy. Talk to your healthcare provider about the ones you use regularly — they can work with you to find alternatives that won’t impact pregnancy.
Questions to ask:
1. Are any of your regular medications potentially harmful if you were to get pregnant?
2. If so, are there safer alternatives?
3. If you go off any medications while trying to get pregnant or while pregnant, when would it be safe to get back on them after giving birth?
Lifestyle changes or adjustments
Your healthcare provider will talk to you about modifications you can make to increase your chances of conception, like moderating alcohol and coffee consumption or quitting smoking.
The research is mixed around drinking alcohol while trying to get pregnant — many studies show that having 1-2 drinks a day won’t affect fertility, while some show that this level of moderate drinking can be harmful. That said, if you get pregnant, ACOG says no to drinking any amount of alcohol.
If you’re a heavy caffeine drinker, your healthcare provider might recommend cutting back to 1-2 cups of coffee a day.
When it comes to smoking, the science is pretty clear: Smoking cigarettes adversely affects fertility in both people with ovaries and people with sperm. That said, quitting can make a huge difference — and pretty quickly. In just three months after quitting, positive changes can be observed in egg quality.
Questions to ask:
1. How could your current alcohol or caffeine consumption level impact conception?
2. If you have a partner, does your healthcare provider recommend they evaluate alcohol consumption, too?
3. If you smoke, does your healthcare provider have recommendations for quitting?
Your weight and conception
People of all weights and sizes have gotten pregnant and gone on to have healthy pregnancies. That said, big weight fluctuations in either direction can affect your hormones and make getting pregnant more difficult — additionally, lower or higher body-fat percentages could also have an impact.
Your healthcare provider will likely discuss your weight and how it might play a role in your chances of conception or your pregnancy. They may also discuss how much weight gained during pregnancy can be expected based on your current weight. It’s important to remember, though, that all bodies are totally unique — your healthcare provider is here to answer your questions and give advice based on the data around other people’s experiences.
Questions to ask:
1. How might your body-fat percentage impact conception and pregnancy?
2. If you’re getting regular periods, are there other ways your body-fat percentage might affect things?
3. If you’re not getting regular periods, what’s the minimum weight gain or loss that could potentially restore regular cycles? Are there any other possible causes for the irregular periods?
Tests and vaccinations
Some sexually transmitted infections (STIs) can impact fertility, so it’s important to talk with your healthcare provider about making sure you’ve been recently tested — the same goes for your partner if you have one. (You will likely also have the chance to do STI testing in early pregnancy.)
In terms of vaccines, there are two you can’t get while pregnant: the varicella vaccine to prevent chickenpox and the measles, mumps, and rubella (MMR) vaccine. If you’re not already immune to these illnesses, your healthcare provider might recommend getting these vaccines prior to conceiving.
Questions to ask:
1. What STI tests or vaccines does your healthcare provider recommend before pregnancy?
2. Are there any vaccines that might need to be administered again before pregnancy because past immunity might have worn off?
When to start taking prenatal vitamins (and which ones to take)
At your preconception visit, your healthcare provider will likely recommend taking a prenatal vitamin. The American College of Obstetricians and Gynecologists (ACOG) has official guidelines for all reproductive-aged people with ovaries to take prenatal vitamins with 400 micrograms of folate to support fetal neural tube (brain and spine) development.*
Questions to ask:
1. Does your healthcare provider recommend any particular brand of prenatal vitamins?
2. Does your healthcare provider recommend any nutrients other than folate or folic acid?
3. Does anything in your medical history indicate you might need higher levels of any nutrients?
How to start trying to conceive
Your healthcare provider might have specific recommendations for the best ways to increase your chances of overlapping sex (with a partner who has a penis) with the time of your cycle when you’re the most fertile: the five days leading up to and the day of ovulation (when the ovary releases an egg for fertilization).
Depending on your healthcare provider, they might mention tracking ovulation to identify your fertile window. You can do this by monitoring ovulation test results, cervical mucus, or basal body temperature (BBT). You can absolutely ask for your healthcare provider to walk you through each of these methods, but here’s a refresher in case you’re curious now:
• Ovulation tests detect luteinizing hormone (LH) in your urine, which surges about 24-48 hours before ovulation. Other than an ultrasound, ovulation tests are one of the most accurate ovulation predictors because they rely on the biological factors (read: hormones) that are directly involved in the egg’s release.
• Cervical mucus tracking involves looking at the changes in the fluid produced by your cervix to pinpoint where you are in your menstrual cycle.
• BBT tracking uses your basal body temperature (your body’s temp at rest) to identify natural changes that indicate ovulation has occurred. Note that BBT is affected by a whole host of factors, making body temperature alone not a super accurate marker of ovulation.
Once you’ve identified your fertile window, your healthcare provider will likely recommend timing sex around those six days to improve the odds of sperm meeting egg at the right time. Talk to them about the exact number of times they suggest having sex during that period (every other day is a common rec).
If you’re considering or planning on using a fertility treatment, you can discuss the options with your healthcare provider (intrauterine insemination, or IUI, versus in-vitro fertilization, or IVF, versus at-home insemination). Your healthcare provider might have a recommendation for a local fertility clinic or have insight into any clinics you’re already considering.
Regardless of how you’re planning to conceive (with or without a fertility treatment), you can discuss your chances of conception each month of trying with your healthcare provider. Here’s what the data says: According to the American Society for Reproductive Medicine (ASRM), most 30-year-olds have a 20% chance of conceiving each month — and most 40-year-olds have a <5% chance of conceiving each month. Your chances could be impacted by a number of individual factors, so be sure to chat with your healthcare provider about what you might expect.
Your healthcare provider will typically suggest coming back in if you’re under 35 and haven’t gotten pregnant after a year of trying, or if you’re over 35, after six months of trying. If you experience two consecutive miscarriages or chemical pregnancies, that would also be a time to check in.
Questions to ask:
1. Does your healthcare provider recommend one way to track ovulation over another?
2. How often does your healthcare provider recommend having sex and over what period of time?
3. What does your healthcare provider believe your unique chances of conception per month are, based on the data?
4. Does your healthcare provider have any specific recommendations for when to check back in after trying to conceive for a certain period of time?
5. If you’re considering or planning on using a fertility treatment, does your healthcare provider have recommendations for fertility clinics or fertility specialists?
6. Can your healthcare provider walk you through the latest research around COVID-19 and pregnancy — and how the pandemic might impact your experience? (Modern Fertility also regularly updates this article.)
Can preconception counseling be part of your annual exam?
Traditionally, your annual physical exam includes a breast exam, pelvic exam, and Pap smear if you need it. A lot of the time, as you prepare for this annual visit, you might be thinking of specific health problems that have come up throughout that year. Theoretically, if a healthcare provider has the time, they can answer all of your questions about getting pregnant during that annual visit. But because of the exams that need to be conducted and the other topics or issues you might need to discuss, there often isn’t enough time to do it all.
Billing is also a factor. Under the Affordable Care Act, annual visits are totally covered. But any visits that specifically pertain to fertility would likely be medically coded differently and involve a copay or out-of-pocket costs — potentially complicating things if you want to combine an annual visit with a preconception visit.
The one good thing about COVID-19 is the healthcare system can now handle more telemedicine appointments. While you will have to go in for your annual visit so you can have the in-person exams I mentioned earlier, the preconception appointment can absolutely be done by video. You can bring up your interest in preconception care at your annual visit and schedule some follow-up time via video.
* This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
DISCLAIMER
If you have any medical questions or concerns, please talk to your healthcare provider. The articles on Health Guide are underpinned by peer-reviewed research and information drawn from medical societies and governmental agencies. However, they are not a substitute for professional medical advice, diagnosis, or treatment.
How we reviewed this article
Every article on Health Guide goes through rigorous fact-checking by our team of medical reviewers. Our reviewers are trained medical professionals who ensure each article contains the most up-to-date information, and that medical details have been correctly interpreted by the writer.
Current version
August 31, 2020
Written by
Jenn Conti, MD, MS, MSc
Fact checked by
Health Guide Team
About the medical reviewer
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1a01aa77535b9ecfb87b9fc36adbcd2f
|
6,926,751,527,668,863,000
|
Skip to search formSkip to main contentSkip to account menu
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PD 121981
Known as: PD-121981
National Institutes of Health
Papers overview
Semantic Scholar uses AI to extract papers important to this topic.
1994
1994
The unmasking of the low concentration effect of angiotensin II (AII) was identified within the concentration ranges of 10(-13… Expand
Highly Cited
1992
Highly Cited
1992
Angiotensin II (AII) elicits a positive inotropic response in cardiac muscle preparations from several species including humans… Expand
Highly Cited
1991
Highly Cited
1991
The angiotensin II (ANG II) receptor has recently been shown to exhibit subtypes with respect to antagonist binding. Of… Expand
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-4,814,557,723,555,741,000
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Skip to main content Skip to navigation
We care about your privacy. Read about your rights and how we protect your data. Get Details
Coronavirus Update:What patients and families need to know
Infectious Diseases
Fever of Unknown Origin
The body has several ways to maintain normal body temperature. The organs involved in helping with temperature regulation include the brain, skin, muscle, and blood vessels.
Infectious Mononucleosis
Infectious mononucleosis, also known as mononucleosis, mono, or glandular fever, is characterized by swollen lymph glands and chronic fatigue.
Influenza
Influenza (or flu) is a highly contagious viral infection and is one of the most severe illnesses of the winter season.
Lyme Disease
Lyme disease (LD) is a multi-stage, multi-system bacterial infection caused by the spirochete Borrelia burgdorferi, a spiral shaped bacterium that is most commonly transmitted by a tick bite.
Meningitis
Meningitis is usually caused by a bacterial or viral infection that invades the cerebral spinal fluid (CSF).
Sexually Transmitted Infections
If you’re having any kind of sex, it’s important for you to stay informed about STIs. To get started, take a look at the information and resources we have compiled to educate you about sexually transmitted diseases.
Skin and Soft Tissue Infections (Staph and MRSA)
Staphylococcus (Staph) is a germ that lives in our noses and on our skin. An infection can happen when the skin is open from a scratch or cut or an insect bite. MRSA are Staphylococcus bacteria that have become resistant to certain antibiotics, like penicillin, amoxicillin or augmentin.
Tuberculosis
Tuberculosis (TB) is a chronic bacterial infection that usually infects the lungs, although other organs are sometimes involved.
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Article Text
other Versions
PDF
Preoperative NT-proBNP and CRP Predict Perioperative Major Cardiovascular Events in Noncardiac Surgery
1. Jin-Ho Choi1,
2. Dae Kyoung Cho2,
3. Young-Bin Song1,
4. Joo-Yong Hahn1,
5. Seunghyuk Choi1,
6. Hyeon-Cheol Gwon1,
7. Duk-Kyung Kim1,
8. Sang Hoon Lee1,
9. Jae K Oh3,
10. Eun-Seok Jeon1,*
1. 1 Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea, Republic of;
2. 2 Jeju Hanmaeum General Hospital, Korea, Republic of;
3. 3 Mayo Clinic College of Medicine, Korea, Republic of
1. Correspondence to: , ; esjeon{at}skku.edu
Abstract
Objective: To investigate whether simple and non-invasive measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) and/or C-reactive protein (CRP) can predict perioperative major cardiovascular event (PMCE).
Design: Prospective, single center, cohort study.
Setting: A 1900-bed tertiary-care university hospital in Seoul, Korea
Design and patients: The predictive power of NT-proBNP, CRP, and Revised Cardiac Risk Index (RCRI) for the risk of PMCE (myocardial infarction, pulmonary edema, or cardiovascular death) were evaluated from a prospective cohort of 2054 elective major noncardiac surgery patients. Optimal cut-off values were derived from receiver operating characteristic curve (ROC) analysis.
Main outcome measurement: PMCE (myocardial infarction, pulmonary edema, or cardiovascular death) within postoperative 30 days.
Results: PMCE developed in a total of 290 patients (14.1%). Each increasing quartile of NT-proBNP or CRP level was associated with a greater risk of PMCE after adjustment for traditional clinical risk factors. The relative risk (RR) of highest versus lowest quartile was 5.2 for NT-proBNP (p<0.001) and 3.7 for CRP (p<0.001). Both NT-proBNP (cut-off = 301 ng/L) and CRP (cut-off = 3.4 mg/L) predicted PMCE better than RCRI (cut-off = 2) by ROC analysis (p<0.001). Moreover, the predictive power of RCRI (adjusted RR = 1.5) could be improved significantly by addition of CRP and NT-proBNP to RCRI (adjusted RR = 4.6) (p<0.001).
Conclusions: High preoperative NT-proBNP or CRP is a strong and independent predictor of perioperative major cardiovascular event in non-cardiac surgery. The predictive power of current clinical risk evaluation system would be strengthened by these biomarkers.
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top of page
London City
Kidney Disease
Kidney Disease
Kidney Disease
Your kidneys are two bean-shaped organs, each about the size of your fists. They are located near the middle of your back, just below the rib cage. Inside each kidney about a million tiny structures called nephrons filter blood. They remove waste products and extra water, which become urine.
The urine flows through tubes called ureters to your bladder, which stores the urine until you go to the bathroom.
Most kidney diseases attack the nephrons. This damage may leave kidneys unable to remove wastes. Causes can include genetic problems, injuries, or medicines. You are at greater risk for kidney disease if you have diabetes, high blood pressure, or a close family member with kidney disease. Chronic kidney disease damages the nephrons slowly over several years.
Other kidney problems include:
• Cancer
• Cysts
• Stones
• Infections
Your doctor can run tests to find out if you have kidney disease.
If your kidneys fail completely, a kidney transplant or dialysis can replace the work your kidneys normally do.
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Methyl Salicylate Menthol Topical: Uses – Side Effects – Warnings
Methyl Salicylate Menthol Topical is a medication commonly used for its analgesic and anti-inflammatory properties. It is a combination of methyl salicylate and menthol, which work together to provide relief from a variety of conditions. This article will explore the uses, benefits, side effects, and warnings associated with Methyl Salicylate Menthol Topical.
Uses
Methyl Salicylate Menthol Topical is primarily used for the temporary relief of minor aches and pains of muscles and joints. It is commonly used to treat conditions such as muscle strains, sprains, arthritis, and backaches. The medication works by providing a cooling sensation that helps to numb the area and reduce inflammation.
Benefits
One of the main benefits of Methyl Salicylate Menthol Topical is its fast-acting pain relief. The cooling sensation provided by the medication helps to alleviate discomfort and promote relaxation in the affected area. Additionally, it is easy to apply and does not require ingestion, making it a convenient option for individuals who prefer topical treatments.
Furthermore, Methyl Salicylate Menthol Topical has a vasodilatory effect, meaning it widens blood vessels. This increased blood flow can aid in the healing process and improve circulation in affected areas. The medication can also be used as a counterirritant, which means it produces a mild irritation that distracts the body from feeling pain in the affected area.
Side Effects
While Methyl Salicylate Menthol Topical is generally safe for most individuals, it is essential to be aware of potential side effects. Common side effects include skin irritation, redness, and a burning sensation at the application site. These reactions are usually mild and subside over time. However, if the side effects persist or worsen, it is advised to consult a healthcare professional.
In rare cases, some individuals may experience an allergic reaction to the medication. Signs of an allergic reaction include rash, itching, swelling, severe dizziness, or difficulty breathing. If any of these symptoms occur, immediate medical attention should be sought.
Warnings
While Methyl Salicylate Menthol Topical is available over the counter, it is important to follow certain precautions. Firstly, the medication should be used only as directed and not applied to broken or irritated skin. Avoid contact with eyes, mucous membranes, or open wounds.
It is crucial to inform your healthcare provider of any pre-existing medical conditions or allergies before using Methyl Salicylate Menthol Topical. This is particularly important if you have asthma, diabetes, liver disease, or are pregnant or breastfeeding.
Furthermore, Methyl Salicylate Menthol Topical should not be used in children under the age of 12 without medical supervision. Keep the medication out of reach of children to prevent accidental ingestion.
FAQs
Can Methyl Salicylate Menthol Topical be used for headaches?
No, Methyl Salicylate Menthol Topical is not recommended for headaches. It is primarily used for relieving minor aches and pains of muscles and joints.
How often can I apply Methyl Salicylate Menthol Topical?
The medication is typically applied to the affected area 3 to 4 times daily. However, it is essential to read and follow the instructions on the product label or consult a healthcare professional for specific usage guidelines.
Can I use Methyl Salicylate Menthol Topical with other medications?
It is generally safe to use Methyl Salicylate Menthol Topical with other medications. However, it is recommended to consult a healthcare professional if you are taking any other medications or have any underlying medical conditions.
How long does it take for Methyl Salicylate Menthol Topical to start working?
The cooling sensation provided by Methyl Salicylate Menthol Topical is usually felt almost immediately after application. However, the duration of pain relief may vary depending on the individual and the severity of the condition.
Can I use Methyl Salicylate Menthol Topical during pregnancy?
Pregnant or breastfeeding individuals should consult their healthcare provider before using Methyl Salicylate Menthol Topical. It is important to ensure the safety and suitability of the medication for both the mother and the baby.
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How Chiropractic Helps Alleviate Golfer’s Elbow
September 4, 2019
By Dr. Tripp Stover, D.C.
golfer's elbow and chiropracticGolfer’s elbow is a condition that affects far more than those who hit the golf course regularly. According to Dynamic Chiropractic, golfer’s elbow can affect violinists, construction workers, tennis players, bikers and more. Essentially, anyone who is prone to overusing the elbow can find themselves with pain inside the forearm and elbow, pain that is unlikely to go away without treatment. While medication and surgery are sometimes options for treatment, chiropractic provides a non-invasive, effective way to relieve golfer’s elbow without the many potential side-effects that come with surgery and prescription medications.
What is Golfer’s Elbow?
The joint and muscles on the inside of your elbow are activated during so many activities—pretty much every time you squeeze, grip or throw something, you use them. Even when you are doing less athletic activities like texting or typing at a keyboard, you are activating the muscles, tendons and ligaments surrounding your elbow. It is not surprising that they can be overused, especially during work activities or leisure activities that you love so much you play all the time.
Golfer’s elbow is considered an overuse injury—an injury caused by using one or more parts of the body so much that they cannot recover quickly enough. Inflammation becomes constant, scar tissue can develop and pain becomes a regular problem.
How Chiropractic Can Help Golfer’s Elbow
Chiropractic care is ideal for the treatment of golfer’s elbow. For some sufferers, coming to the chiropractor is the first and obvious choice. For others, going to the doctor is the first place they start.
Once they find that prescription medications are not alleviating the problem, they may be presented with the idea of surgery. Most people are hesitant to go through surgery if they do not have to, which is understandable. They reach out to a chiropractor because they are looking for any alternative that will help them heal without the pain and uncertainty that surgery brings.
At the chiropractor, you will find non-invasive, drug-free treatments that work to return your range of motion, reduce inflammation and break up the scar tissue in the soft tissues surrounding your elbow joint.
Chiropractic Treatment for Golfer’s Elbow
Once you visit a chiropractor you will be given a careful, thorough physical examination to determine the nature of your problem and its cause. With golfer’s elbow the problem is fairly obvious, so your chiropractor will focus on understanding exactly what your golfer’s elbow consists of—including your level of pain, your range of motion and the effects it is having on your day-to-day movement.
Some of the ways chiropractic can treat golfer’s elbow include:
Breaking up Scar Tissue
Scar tissue keeps your muscles from operating correctly and causes pain. Chiropractors have methods for breaking up scar tissue to return normal muscle function, including active release.
Returning Mobility
Joint manipulation from your chiropractor is designed to make your joints move properly. The chiropractor will gently move your elbow back and forth to realign it and to ensure that it goes as far as it should go, and no further.
Reducing Inflammation
Inflammation is what causes much of the pain you are experiencing in your elbow. Joint adjustments and breaking up scar tissue are excellent ways to reduce inflammation. As the inflammation reduces the body can heal more easily and the pain will lessen.
Get the Help You Need for Golfer’s Elbow
As you know, golfer’s elbow can be painful and make it difficult to do the things you need to do. Let us help you get some relief. Please contact our office today to schedule an appointment with our chiropractic team.
This article is copyrighted by Blogging Chiropractors for its Doctor of Chiropractic members and may not be copied or duplicated in any manner including printed or electronic media, regardless of whether for a fee or gratis without the prior written permission of Blogging Chiropractors.
Dr. Tripp Stover, D.C.
Dr. Stover grew up in Richmond. He has been married to his wife Andrea since 2000 and they make their home in Mechanicsville with their children, Avery and Garnett.
Dr. Tripp Stover, D.C.
related posts:
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AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE MANAGEMENT OF DIABETES MELLITUS
AACE Diabetes Mellitus Clinical Practice Guidelines Task Force
Medical Director, Endocrine and Metabolic Consultants Past President, American Association of Clinical Endocrinologists Past President, American College of Endocrinology Rockville, Maryland
Chairperson Helena W. Rodbard, MD, FACP, MACE
Task Force Members
Director, Ochsner Diabetes Clinical Research Unit; Section on Endocrinology, Diabetes, and Metabolic Diseases Associate Residency Program Director, Department of Internal Medicine, New Orleans, Louisiana Clinical Professor of Medicine, University of North Carolina, Division of Endocrinology, Chapel Hill, NC Assistant Clinical Professor of Medicine; Division of Endocrinology, Diabetes, and Bone Disease; Mount Sinai School of Medicine New York, New York Clinical Professor of Medicine; Division of Endocrinology, Diabetes, and Bone Disease; Mount Sinai School of Medicine Immediate Past President, American College of Endocrinology Past President, American Association of Clinical Endocrinologists, New York, New York Medical Director, Metabolic Institute of America Senior Scientific Consultant, Metabolic Endocrine Education Foundation, Tarzana, California Clinical Professor of Medicine, University of Missouri-Kansas City School of Medicine, President, American Association of Clinical Endocrinologists, North Kansas City, Missouri Professor of Medicine and Voluntary Faculty, University of Miami School of Medicine, Past President, American College of Endocrinology Past President, American Association of Clinical Endocrinologists, Hollywood, Florida CEO & Chief Scientific Officer, Sansum Diabetes Research Institute, Adjunct Professor Biomolecular Science and Engineering, University of California-Santa Barbara Clinical Professor of Medicine, University of Southern California, Keck School of Medicine, Santa Barbara, CA Clinical Professor of Medicine, University of Arizona College of Medicine, Past President, American College of Endocrinology, Phoenix, Arizona Associate Clinical Professor of Medicine and Director of Metabolic Support; Division of Endocrinology, Diabetes, and Bone Disease; Mount Sinai School of Medicine, New York, New York Assistant Clinical Professor of Medicine, George Washington University School of Medicine, Washington, DC Endocrine, Diabetes and Osteoporosis Clinic (EDOC), Sterling, Virginia
Lawrence Blonde, MD, FACP, FACE
Susan S. Braithwaite, MD, FACP, FACE Elise M. Brett, MD, FACE
Rhoda H. Cobin, MD, MACE
Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Paul S. Jellinger, MD, MACE
Lois G. Jovanovic, MD, FACE
Philip Levy, MD, FACE
Jeffrey I. Mechanick, MD, FACP, FACE, FACN Farhad Zangeneh, MD, FACP, FACE Medical Writer Christopher G. Parkin, MS
Lewis E. Braverman, MD; Samuel Dagogo-Jack, MD, FACE; Vivian A. Fonseca, MD, FACE; Martin M. Grajower, MD, FACP, FACE; Virginia A. LiVolsi, MD; Fernando Ovalle, MD, FACE; Herbert I. Rettinger, MD, FACE; Talla P. Shankar, MD, FACE; Joseph J. Torre, MD, FACP, FACE; Dace L. Trence, MD, FACE We would like to recognize Elliot Sternthal, MD, FACE, and Joseph Vassalotti, MD, for their review of these guidelines and thoughtful comments.
Reviewers
Acknowledgments
ENDOCRINE PRACTICE Vol 13 (Suppl 1) May/June 2007 3
AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13(Suppl 1) 2007
AACE Guidelines
AMERICAN ASSOCIATION OF CLINCAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE MANAGEMENT OF DIABETES MELLITUS
AACE Diabetes Mellitus Clinical Practice Guidelines Task Force
Abbreviations: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; CI = confidence interval; GDM = gestational diabetes mellitus; HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LOE = level-ofevidence; NPH = neutral protamine Hagedorn; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; VLDL-C = very low-density lipoprotein cholesterol 1. INTRODUCTION 1.1. Forward In 2001, the American College of Endocrinology (ACE) launched the first in a series of conferences to address the important and growing epidemic of diabetes mellitus in the United States and worldwide. The position statements and recommendations resulting from these conferences have articulated the need and laid the groundwork for more intensive inpatient and outpatient management of diabetes mellitus (1,2). Other consensus conferences have addressed the need for improved patient safety and early identification and treatment of the insulin resistance syndrome, a precursor for diabetes mellitus and cardiovascular disease (3,4). 1.2. Specific Mission and Methods Given the complex and diverse nature of diabetes management, evidence-based clinical practice guidelines are vital to a clinician’s ability to effectively treat this disease. The purpose of the recommendations herein is to provide clinicians with clear and accessible guidelines to care for patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). To facilitate ease of use and to enhance clinical utility, this clinical practice guideline is organized by topic; each topic section contains: (a) a general overview of information necessary to interpret the specific recommendations; (b) a succinct executive summary of graded recommendations based on clinical
ENDOCRINE PRACTICE Vol 13 (Suppl 1) May/June 2007
evidence and various subjective factors; and (c) evidence base and clinical considerations that include detailed discussion of the supportive clinical evidence and specific subjective factors (5). Ratings of the clinical evidence derived from each reference are noted next to the citations at the end of each topic section. Target audiences for this clinical practice guideline include: (a) endocrinologists; (b) cardiologists; (c) physicians who specialize in caring for patients with diabetes mellitus or who encounter patients with diabetes mellitus in their practice; and (d) other health care practitioners who wish to learn about diabetes care in the context of endocrinology, metabolism, and nutrition. The American Association of Clinical Endocrinologists (AACE) Diabetes Mellitus Clinical Practice Guidelines Task Force is composed of endocrinologists who are experts and practitioners in the field of diabetes. The task force members spend more than 50% of their practice in the area of diabetes, and they are active members of AACE. Each contributor has published in the field of diabetes and is active in one or more of the main medical societies committed to diabetes care in the United States and internationally. Task force members reviewed selected reports and studies and rated the clinical evidence from these sources. A summary of the methods used to prepare these guidelines is presented in Figure 1.1. A separate panel composed of AACE members with expertise in diabetes reviewed the compiled report. Final recommendations included in this clinical practice guideline represent a consensus among the task force members and have been approved by reviewers, the AACE Publications and Executive Committees, and the AACE Board of Directors. Comments and recommendations regarding physician-patient communication are based on expert judgment of task force members. The available scientific literature cited in these guidelines was reviewed and evaluated for strength of evidence based on 4 level-of-evidence (LOE) categories described in Table 1.1. The evidence categories were adapted from the American Association of Clinical Endocrinologists Protocol for the Standardized Production of Clinical Practice Guidelines (5). References with clinical evidence are accompanied by a LOE assignment following citation in the reference list. References were obtained by performing a computerized search of the literature using PubMed and other search engines; scanning incoming
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AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13(Suppl 1) 2007 AACE D iabetes Me llitus C linical P ractice Guidelines Task Force is created and instructions for guideline development are distributed Topics are a ssi gned to task f orce me mbers Medical literature is se arched Prim ary wr iting is comp leted Levels of scientific substantiation for clinical evidence are a ssigned Specific recomm endations b ased on g rading system are deve loped General review of g uidelines is comp leted by task f orce mem bers Guidelines are revised by task force chairperso n Guidelines are reviewed by s elected A ACE memb ers and a special reviewer Guidelines are revised by task force chairperso n Final review is com pleted by A ACE Publications Comm ittee and Board of Directors Guidelines are revised by task force chairperso n Final draft of the guidelines is su bmi tted
ß ß ß ß ß ß ß ß ß ß ß ß ß
Figure 1.1. Methods used to prepare the American Association of Clinical Endocrinologists (AACE) Medical Guidelines for the Management of Diabetes Mellitus.
journals in the medical library; and reviewing references in publications relevant to diabetes including review articles, leading textbooks, and syllabi from national and international meetings. LOE 1 data are defined as conclusive results from prospective, randomized controlled trials that have large subject populations representative of the target population and results that are easily generalized to the target population (5). LOE 1 data also include results from metaanalyses of randomized controlled trials, results from multicenter trials, and “all or none” evidence. LOE 2 data include conclusive results from individual randomized controlled trials that have limited subject numbers or target population representation. LOE 3 data include all other conclusive clinical findings from nonrandomized studies, studies without controls, and nonexperimental or observational studies (eg, well-documented case reports). Although LOE 3 data may be predicated on sound theory, these data require interpretation and, by themselves, are not compelling. LOE 4 data are defined as information based solely on experience or expert opinion and are not necessarily substantiated by any conclusive scientific data. Frequently, only LOE 4 data are available. When possible, clinical recommendations put forth in this clinical practice guideline have been assigned a letter grade (A-D) based on the level of scientific substantiation (Table 1.2). However, when task force members determined that clinical judgment regarding a recommendation outweighed study findings or a recommendation lacked supporting studies, they assigned the final grade based on their extensive clinical experience and expertise in diabetes management. An A grade is the strongest recommendation, and a D grade is the weakest recommendation. These
recommendations include subjective components such as: (a) judgment regarding whether results from a particular study are conclusive; (b) the relative weighing of positive and negative conclusive study results; (c) assignment of evidence rating when certain study methodologies are controversial; (d) the impact of risk-benefit analysis; (e) the impact of cost-effectiveness; (f) assessment of geographical differences in practice standards and availability of certain technologies; (g) assessment of ethnic, racial, and genetic differences in pathophysiology; (h) incorporation of patient preferences; and (i) incorporation of physician preferences. Criticism that purely evidence-based clinical practice guidelines do not reflect real life because subjective input is stifled or precluded is addressed to some extent by the AACE methodology for developing the guidelines. When the task force members judged that subjective factors influenced the grade of a recommendation to an extent that outweighed the available best evidence, this logic was explicitly described in the detailed discussion that follows each topic section’s executive summary. Thus, the process of developing evidence-based recommendations and the incorporation of subjective components are transparent to the reader. These methods, nevertheless, have the following shortcomings: (a) reliance on some subjective measures, which compromises reproducibility; (b) dependence on the best available evidence, even if only one study is used to formulate a recommendation grade; and (c) dependence on task force primary authors to perform a comprehensive literature search. Multiple levels of review by both AACEcredentialed and non–AACE-credentialed experts from academia and clinical practice backgrounds serve to address these predicted shortcomings.
level-of-evidence category 4 indicates unproven claims.3. and perioperative periods. 2. Background 1. Nathan and colleagues (11) report that early and aggressive glycemic control in patients with T1DM lowers the risk for cardiovascular disease by 50%.13(Suppl 1) 2007 Table 1. thus indicating a clear need to . There is no glycemic threshold for the reduction of complications. 1. use of insulin in diabetic ketoacidosis). Rationale for Aggressive Diabetes Management Diabetes mellitus is a worldwide epidemic that has created a crisis for the health care system and society. well-controlled trials at 1 or more medical centers Data derived from a substantial number of trials with adequate power. Endocr Pract. Recent findings from large randomized controlled trials provide clear and compelling evidence that intensive treatment of diabetes mellitus and conditions known to be risk factors can significantly decrease the development and/ or progression of chronic complications (6-10). 2007. Levels of Substantiation in Evidence-Based Medicinea Level-ofEvidence Categoryb 1 Study Design or Information Type Randomized controlled trials Multicenter trials Large meta-analyses with quality ratings Comments Well-conducted. or 3.1. “all or none” evidence Limited number of trials. AACE Diabetes Mellitus Guidelines. substantial number of subjects and outcome data Consistent pattern of findings in the population for which the recommendation is made—generalizable results Compelling nonexperimental.1. small number of subjects Well-conducted studies Inconsistent findings or results not representative for the target population Trials with 1 or more major or 3 or more minor methodologic flaws Uncontrolled or poorly controlled trials Retrospective or observational data Conflicting data with weight of evidence unable to support a final recommendation Inadequate data for inclusion in level-of-evidence categories 1. the better the control. clinically obvious evidence (eg.3. data necessitates an expert panel’s synthesis of the literature and a consensus 2 Randomized controlled trials Prospective cohort studies Meta-analyses of cohort studies Case-control studies Methodologically flawed randomized controlled trials Nonrandomized controlled trials Observational studies Case series or case reports Expert consensus Expert opinion based on experience Theory-driven conclusions Unproven claims Experience-based information 3 4 aAdapted from the American Association of Clinical Endocrinologists Protocol for the Standardized Production of Clinical Practice Guidelines (5). bLevel-of-evidence categories 1 through 3 indicate scientific substantiation or proof. cerebral ischemia. Results from numerous studies have demonstrated the importance of maintaining normoglycemia during severe infections. the lower the risk (9).
earlier and more aggressive application of available treatments and technologies is needed. a condition that may progress to clinical diabetes if not detected and treated early (29).3. cohort or casecontrolled analytic study. ≥1 conclusive level-ofevidence category 2 publications demonstrating benefit>>risk Evidence based on clinical experience. descriptive studies. See Table 1. and blood pressure (28). only 7% of patients with T1DM or T2DM achieve the 3 recommended goals for glycemia. 2007. These new medications. In addition to new rapid-acting and longacting insulin analogs. and similar therapies in development.1 for descriptions of level-of-evidence categories. or expert consensus opinion No conclusive level-of-evidence category 1 or 2 publication. Recommendation Grades in Evidence-Based Medicinea Grade A Description Homogeneous evidence from multiple well-designed randomized controlled trials with sufficient statistical power Homogeneous evidence from multiple well-designed cohort controlled trials with sufficient statistical power ≥1 conclusive level-of-evidence category 1 publications demonstrating benefit>>risk Evidence from at least one large well-designed clinical trial.2. Endocr Pract. Approximately 41 million Americans have prediabetes mellitus.13(Suppl 1) 2007 7 Table 1. or 3 publication demonstrating benefit>>risk Conclusive level-of-evidence category 1. Koro et al (27) report that the percentage of patients with T2DM with HbA1c levels of less than 7% decreased by approximately 20% from 1988 to 2000.8 million Americans (7% of the US population) have diabetes mellitus (29). and 6. Advances in blood glucose monitoring and continuous monitoring of interstitial glucose.2. Clearly. 1. initiate better management of diabetes and hyperglycemia in patients who are hospitalized (12-20). provide clinicians and patients with powerful tools to monitor and adjust treatment regimens (23-26).22). lipids. new medications have been introduced to address recently identified pancreatichormone and incretin-hormone deficiencies. effectively lower hemoglobin A1c (HbA1c) levels. Approximately 14. 2. or meta-analysis No conclusive level-of-evidence category 1 publication. ≥1 conclusive levelof-evidence category 3 publications demonstrating benefit>>risk No conclusive risk at all and no conclusive benefit demonstrated by evidence Not rated No conclusive level-of-evidence category 1. Epidemiology of Diabetes Mellitus An estimated 20.2 million remain undiagnosed. thereby reducing intraday glycemic variability and reducing weight (21. In academic-based health care settings. The age-adjusted prevalence of diagnosed diabetes mellitus increased among both sexes and all racial groups examined from 1980 through 2004 . Despite these new treatments and a broader understanding of the importance of effective disease management. diabetes control in US patients has deteriorated over the past decade. 2.AACE Diabetes Mellitus Guidelines. New pharmacologic therapies and treatment technologies safely and effectively lower glycemia to nearnormal levels.6 million people have been diagnosed with the disease. along with the introduction of “smart” insulin pumps. or 3 publication demonstrating risk>>benefit B C D aAdapted from the American Association of Clinical Endocrinologists Protocol for the Standardized Production of Clinical Practice Guidelines (5).
Because they were not always able to obtain routine medical care. (LOE 4) Bates D. Bransome ED Jr. Although the reason for this association remains unclear. the diagnosis of diabetes was frequently delayed. American College of Endocrinology. et al.7) Non–Hispanic black 3 200 000 (13. the age-adjusted prevalence among men and women was higher in 2004 than in 1997 (29). Native Hawaiian.3 million (20. For patients diagnosed before age 40 years. For example.9% (from 69. more likely to have diabetes than non–Hispanic white individuals (29). American College of Endocrinology position statement on inpatient diabetes and metabolic control.1) Although the age-adjusted prevalence of diagnosed diabetes mellitus increased among both sexes and all racial groups examined from 1980 through 2004. Of all individuals 20 years or older. Cobin RH. (%) With Diabetes Mellitus Non–white Hispanic 13 100 000 (8. For individuals born in the year 2000. 3.7 times. data show that minority populations are disproportionately affected by diabetes (29). The prevalence of obesity was greater among black individuals than among white and Hispanic individuals (29).7% to 80. et al.9:237-252. 2003.5%) and 9. the etiology of diabetes in patients with schizophrenia is probably multifactorial. Endocr Pract. 2004. the state of being overweight or obese increased 10. Cook RI. non–Hispanic black individuals and Mexican American individuals are 1. American College of Endocrinology Consensus Statement on Guidelines for Glycemic Control. Clark NG. Diabetes mellitus prevalence data for individuals 20 years or older from selected US ethnic populations are listed in the following tabulation (29): Ethnicity No. 10. The percentage of young Americans who are overweight has more than tripled since 1980. American College of Endocrinology and American Association of Clinical Endocrinologists position statement on patient safety and medical system errors in diabetes and endocrinology. et al. AACE Diabetes Mellitus Guidelines.13(Suppl 1) 2007 (29). and other Pacific Islander ancestry who are 20 years or older are more than twice as likely as non–Hispanic white individuals to have diagnosed diabetes (29). and the medication used to treat schizophrenia. 2002. Endocr Pract. Of individuals 60 years or older in the United States.3) Hispanic/Latino American 2 500 000 (9.9 million men (10.11:197-202. impaired lifestyle.1%). The latest data (2005) from the Centers for Disease Control and Prevention show a dramatic increase in the prevalence of diabetes mellitus in the United States. age-adjusted rates of obesity increased 15. American Indian and Alaska Native individuals are 2.2% (from 34. Moghissi ES.2 times more likely to have diabetes than non–Hispanic white individuals (29). (LOE 4) Einhorn D. age-adjusted prevalence of diagnosed diabetes was higher among black individuals than white individuals and was the highest among black women (29). Until recently. 68% for black men. Among individuals with known diabetes. it is much higher in certain ethnic populations (29). The prevalence of obesity among adults has risen notably in the United States during the past 20 years.9% of this age group) have diabetes mellitus. Age-adjusted prevalence increased 76% for white men. 2005. patients with schizophrenia were not routinely screened for diabetes.7 million women (8. 4. During that time. Among Hispanic individuals. Based on available data.8 times and 1. approximately 9 million (16%) children. The latest data from the National Center for Health Statistics show that more than 60 million Americans (30%) 20 years or older are obese (29). unfavorable upward trends in age-adjusted rates of being overweight or obese were observed between 1994 and 2003 (29).10(suppl 2):4-9. Endocr Pract. Endocr Pract. 65% for white women. and young adults 6 to 19 years of age are considered overweight (29). During this time period. Findings from recent reports indicate that up to 45% of newly diagnosed cases of diabetes among US children and adolescents are classified as T2DM (31). respectively. adolescents. Reaven GM.5) American Indian and Alaskan Native 118 000 (15. Sufficient data are not yet available to calculate more precise estimates of the total prevalence of diabetes (both diagnosed and undiagnosed) for Hispanic and Latino populations other than Mexican American. the estimated lifetime risk for developing diabetes (T1DM or T2DM) is 33% for males and 39% for females (29). American College of Endocrinology position statement on the insulin resistance syndrome. and 37% for black women (29). The association of schizophrenia and diabetes mellitus has been recognized since the turn of the last century (33). Increased visceral adiposity and hyperinsulinemia in the presence of elevated serum cortisol levels have been noted in a small group of treatment-naïve patients with schizophrenia (34). the average reduction in life expectancy is 12 years for men and 19 years for women (30). The prevalence of T2DM among American children is expected to continue to increase and exceed that of T1DM over the next 10 years (32). The risk for death among individuals with diabetes mellitus is almost twice that of individuals without diabetes of similar age (29). individuals of Asian. Ongoing epidemiologic and pathophysiologic studies may help delineate the causes for this relationship and for the reported association of antipsychotic therapy and diabetes mellitus. 2007.8(suppl 1):5-11.6%) (29). REFERENCES 1. (LOE 4) Garber AJ. contributing factors may include weight gain. Endocr Pract. Adults aged 65 to 74 years have the highest prevalence of diabetes mellitus—approximately 12 times the prevalence of that seen in adults younger than 45 years (29).8%) have diabetes mellitus (29).9% to 50. 10. . (LOE 4) 2.
13(Suppl 1) 2007 5. 2000. 25. Intensive insulin therapy in the critically ill patients. JAMA. Apstein CS. Gross K. Endocr Pract.S. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.290:1884-1890. 33. Chen YD. 29. Endocr Pract. 2006. Landon C. charges. with special emphasis on American Indian and Alaska Native children. (LOE 4) Bode BW. Diabetes Care. Grunkemeier GL. Weekers F. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. (LOE 1) UK Prospective Diabetes Study (UKPDS) Group. Endocr Pract. Clinical utility of the continuous glucose monitoring system. (LOE 3) National Diabetes Fact Sheet: United States 2005. Wedel H.10(suppl 2):21-33. Adler AI. Riddle MC. Cost-effectiveness of intense insulin treatment after acute myocardial infarction in patients with diabetes mellitus. (LOE 1) Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. 2003. Bowlin SJ. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.352:837853. (LOE 2) Bode B. 2005. Zerr KJ. Lifetime risk for diabetes mellitus in the United States. Ann Thorac Surg.109:1497-1502. Accessed August 1.28:103-117. 34. Intensive insulin therapy in the medical ICU. Fredrickson LP. 21. 2003. Starr A. 2002.21:80-86. Diabetes Res Clin Pract. 2003. et al. (LOE 2) Kendall DM. Backlund JY. et al. (LOE 1) Nathan DM. Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project.AACE Diabetes Mellitus Guidelines. selectively delays gastric emptying: potential role of vagal inhibition. Quality of diabetes care in U.354:449-461.65(suppl 7):4-18. van den Berghe G. 2004. (LOE 3) Grant RW. 2004. Buse JB. Excess length of stay. 14. J Clin Psychiatry. Sjostrand B. Diabetes Metab Res Rev. Johannesson M. 28. et al. 2000. Camilleri M. 2006. Ryden L. Meigs JB. American Academy of Pediatrics Committee on Native American Child Health. Grunkemeier GL. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Impaired fasting glucose tolerance in first-episode. 1999. 23. (LOE 2) Furnary AP. Bookin SO. 1993. 16. (LOE 2) 18. 345:1359-1367. 24.278:G946G951. Am J Physiol Gastrointest Liver Physiol.99:2626-2632. (LOE 1 1) Stratton IM. 32. Vella A. Malmberg K. Chipkin SR. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. Rizza RA. Am J Psychiatry. N Engl J Med. Norhammar A. 1999. 1995. Vadheim CM. (LOE 1) Almbrand B. 2000. Cabral H. 2004. (LOE 1) Zhan C. BMJ. Pediatrics. an amylin analog. Newcomer JW. 2005. 2000. JAMA. 11. . JAMA. Ryden L. 19. Pramlintide. N Engl J Med.353:2643-2653. Gao G. Diabetes Care. 2003. N Engl J Med.112:e328. academic medical centers: low rates of medical regimen change. Kishikawa H. Sabbah HT. Hermans G. 30.28:1083-1091. Rikalo N.125:1007-1021. (LOE 3) Casey DE. 321:405-412.ndep. Diabetes Technol Ther. Cleary PA. Miller MR. 22.10:353361. Fitzgerald CA. Haupt DW. 31. et al. et al. J Thorac Cardiovasc Surg. 1998. 12. Centers for Disease Control and Prevention Web site. Alarms based on real-time sensor glucose values alert patients to hypoand hyperglycemia: the guardian continuous monitoring system. Silverstein J. Wilmer A. American Association of Clinical Endocrinologists protocol for standardized production of clinical practice guidelines. (LOE 2) Furnary AP. 13. et al. Sorensen SW. Davidson PC.S. 20. (LOE 1) Koro CE. real-time continuous glucose sensor: a randomized controlled trial. (LOE 2) Garg S. 26. et al. (LOE 1) Samsom M. (LOE 3) van den Berghe G. Eur Heart J. and mortality attributable to medical injuries during hospitalization. (LOE 4) Diabetes Control and Complications Trial Research Group. Collins P. 27.28:337-442.67:352-360. adults diagnosed with type 2 diabetes: a preliminary report. (LOE 1) Ohkubo Y.gov/diabetes/pubs/2005_National_ Diabetes_Fact_Sheet. (LOE 1) Narayan KM. Glycemic control from 1988 to 2000 among U. 8. Circulation.354:602�. Early presentation of type 2 diabetes in MexicanAmerican youth. 15. 2003.6:105-113. (LOE 2) Furnary AP. Wu Y. Available at: www. Improvement in glycemic excursions with a transcutaneous. 2004. 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early detection and treatment is imperative to addressing the diabetes epidemic.6 lists diabetes mellitus classifications. or Pacific Islander ethnicity Previously identified impaired glucose tolerance or impaired fasting glucose Hypertension Increased levels of triglycerides. Clinical Interpretations of Plasma Glucose Concentrations (2) Glucose Concentration.4 for GDM risk factors and Table 2. Risk Factors for Prediabetes and Diabetes Mellitus (1) Risk Factors Family history of diabetes Cardiovascular disease Overweight or obese state Sedentary lifestyle Latino/Hispanic. 2007.1.3 to diagnose diabetes mellitus (grade B) ACE/AACE does not recommend using HbA1c measurement to diagnose diabetes mellitus (grade C) Screen all pregnant women for gestational diabetes mellitus (GDM) (grade A).10 AACE Diabetes Mellitus Guidelines.1. Asian American. Table 2.13(Suppl 1) 2007 2. SCREENING AND DIAGNOSIS 2.2. mg/dL Fasting <100 ≥126 126 100-125 Within the reference range Overt diabetes mellitus Impaired fasting glucose/prediabetes mellitus Clinical Interpretation 2-hour postchallenge load (75-g oral glucose tolerance test) <140 ≥200 140-199 Within the reference range Overt diabetes mellitus Impaired glucose tolerance/prediabetes mellitus . Endocr Pract. Evidence Base Given the large number of Americans with undiagnosed diabetes mellitus and prediabetes mellitus. ACE/AACE endorses the diagnostic criteria for prediabetes mellitus as established by the American Diabetes Association (2). Executive Summary • Annually screen all individuals 30 years or older who are at risk for having or developing T2DM (grade B) (See Table 2. women at high risk should be screened at 20 weeks’ gestation (grade B) (See Table 2.1 for a list of risk factors and Table 2. • • • Table 2. low concentrations of high-density lipoprotein cholesterol.2. women at low risk should be screened at 24 to 28 weeks’ gestation. Native American. or both History of gestational diabetes History of delivery of an infant with a birth weight >9 pounds Polycystic ovary syndrome Psychiatric illness Table 2.5 for diagnostic criteria using a 75-g oral glucose tolerance test) 2.2 for clinical interpretations of plasma glucose concentrations) Use 1 of the 3 diagnostic criteria presented in Table 2. Non–Hispanic black. ACE/AACE endorses the diagnostic criteria for diabetes mellitus and GDM as established by the World Health Organization (3).
. These assessments should be confirmed by repeated testing on a subsequent day in the absence of unequivocal hyperglycemia. Diagnostic Criteria for Diabetes Mellitusa (3) Diagnostic Criteria Symptoms of diabetes (polyuria. Asian American.4. non–Hispanic black. Risk Factors for Gestational Diabetes Mellitus Risk Factors >25 years of age Overweight or obese state Family history of diabetes mellitus (ie.5. or Pacific Islander ethnicity Fasting (no energy intake for at least 8 hours) plasma glucose concentration >85 mg/dL or 2-hour postprandial glucose concentration >140 mg/dL (indicates need to perform a 75-g oral glucose tolerance test) (4. polydipsia.AACE Diabetes Mellitus Guidelines. Endocr Pract. unexplained weight loss) plus casual plasma glucose concentration ≥200 mg/dL Fasting plasma glucose concentration ≥126 mg/dL or or 2-hour postchallenge glucose concentration ≥200 mg/dL during a 75-g oral glucose tolerance test aOne of the 3 criteria listed is sufficient to establish the diagnosis of diabetes mellitus. 2007.3. Table 2. in a first-degree relative) History of abnormal glucose metabolism History of poor obstetric outcome History of delivery of an infant with a birth weight >9 pounds History of polycystic ovary syndrome Latino/Hispanic. ≥150 g carbohydrate per day) and unlimited physical activity. Native American.13(Suppl 1) 2007 11 Table 2. Diagnostic Criteria for Gestational Diabetes Mellitus Using a 75-g Oral Glucose Tolerance Testa (2) State at Plasma Glucose Measurement Fasting 1-hour postglucose administration 2-hour postglucose administration aTwo Plasma Glucose Concentration.5) Table 2. mg/dL >95 >180 >155 or more of the listed venous plasma glucose concentrations must be met or exceeded for a positive diagnosis. The test should be performed after an overnight fast of 8 to 14 hours and after at least 3 days of unrestricted diet (ie.
(LOE 4) Reichelt AJ. (LOE 4) American Diabetes Association.13(Suppl 1) 2007 Table 2. rate of destruction is usually slower in adults Individuals at increased risk can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islet cells and by genetic markers Type 2 Diabetes Mellitus Accounts for 90% to 95% of all diabetes mellitus cases Caused by a combination of complex metabolic disorders that result from coexisting defects of multiple organ sites such as insulin resistance in muscle and adipose tissue. 3. adenovirus. Schmidt MI. Definition and Diagnosis of Diabetes Mellitus 4. ACE/AACE consensus conference on the implementation of outpatient diabetes mellitus: consensus conference recommendations.29(suppl 1):S43S48. 1998. 2006. 5. Branchtein L. Switzerland: WHO Document Production Services. de Lima L. Nucci LB. et al. unrestrained hepatic glucose production. definition applies regardless of the therapy used to treat the condition and Intermediate Hyperglycemia: report of a World Health Organization/International Diabetes Foundation Consultation. affected individuals who are not obese may have an increased percentage of visceral fat.6. 2. . (LOE 3) Schmidt MI. Diabetes Care. causing pathologic and functional changes in various target tissues Most affected individuals are obese and. cytomegalovirus. a progressive decline in pancreatic insulin secretion. 2007. have variable degrees of insulin resistance. Geneva. Forti AC.12 AACE Diabetes Mellitus Guidelines. therefore. Franco LJ. Spichler ER. Austin MM. Duncan BB. Matos MC. autoantibodies to glutamic acid decarboxylase (GAD65). Diabet Med. Reichelt AJ. Fasting plasma glucose is a useful test for the detection of gestational diabetes. (LOE 4) World Health Organization/International Diabetes Foundation. (LOE 2) REFERENCES 1. Diagnosis and classification of diabetes mellitus. a degree of hyperglycemia may be present. Blonde L. and other hormonal deficiencies Before the appearance of clinical symptoms. and mumps Markers of β-cell destruction include islet cell autoantibodies.21:1246-1249. and ACE/ AACE Diabetes Recommendations Implementation Writing Committee. Summary of Diabetes Mellitus Classifications (2) Type 1 Diabetes Mellitus Accounts for only 5% to 10% of all diabetes mellitus cases Caused by an absolute deficiency of insulin secretion due to a cellular-mediated autoimmune destruction of the pancreatic β-cells Viruses associated with initiation of β-cell destruction include congenital rubella. which can cause insulin resistance Other risk factors include increasing age and sedentary lifestyle Occurs more frequently in women with previous gestational diabetes and in individuals with hypertension or dyslipidemia Associated with a strong genetic predisposition Gestational Diabetes Mellitus Defined as any degree of glucose intolerance identified during pregnancy. Endocr Pract. Lebovitz HE. 2006. Endocr Pract. Brazilian Study of Gestational Diabetes (EBDG) Working Group. Prevalence of gestational diabetes mellitusdo the new WHO criteria make a difference? Brazilian Gestational Diabetes Study Group.12(suppl 1)6-12.17:376380. and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β Rate of β-cell destruction varies—infants and children often experience rapid β-cell destruction. autoantibodies to insulin.2006:1-46. 2000. Diabetes Care. coxsackievirus B.
for example.6.2). Supporting Studies Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medications Trial The aim of the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) trial (10) was to prospectively assess the ability of rosiglitazone to prevent T2DM in high-risk individuals.2). and dyslipidemia (grade A) Treat hypertension and dyslipidemia aggressively. Subjects were followed up for a median of 3 years.2). The primary outcome was a composite of the development of diabetes mellitus or the occurrence of death. The development of T2DM can be delayed or prevented by modest weight loss (5% to 7% of total body weight) and regular physical activity (eg. PREVENTION OF TYPE 2 DIABETES MELLITUS 3.1 for risk factors indicating who should be screened) Initiate interventions that include lifestyle modifications (grade C): o Refer patients to a registered dietitian or credible weight loss program/service for counseling in energy intake reduction and nutritional strategies. and the patient gains residual long-term benefits in reducing vascular complications (7). However. Overview Prediabetes is the term that describes those metabolic states that occur when blood glucose levels are elevated but remain below levels that are established for the clinical diagnosis of diabetes mellitus. β-cell function is preserved (6). Clinically significant cardiovascular disease may develop years before the clinical onset of diabetes mellitus (3-5). 30 minutes of walking.13(Suppl 1) 2007 13 3. Results from large randomized controlled trials demonstrate the effectiveness of lifestyle interventions (with and without pharmacologic therapy) in preventing the progression of impaired glucose tolerance to T2DM (1. 5 days a week) (1. Ethnic minorities in the United States are disproportionately affected by diabetes mellitus. ethnic background does not contribute further to the progression of diabetes (1). reduce saturated fat intake to less than 10% of total energy intake. In the absence of intervention. such as rosiglitazone. and 46 subjects had dropped . these conditions are responsive to lifestyle modification and to pharmacologic therapy (grade A) • • • • 3.2. have been studied (10). At the end of the study. Some patients with glucose intolerance will be missed by the fasting plasma glucose test because it is less sensitive than the 2-hour oral glucose tolerance test. study results suggest that reducing postprandial blood glucose concentrations may decrease cardiovascular events in patients with both impaired glucose tolerance and diabetes mellitus (7). 59 subjects had dropped out from the rosiglitazone treatment group. goals include: § Weight reduction goal: 5% to10% of total body weight (grade A) § Nutrition goals: reduce fat intake to less than 30% of total energy intake. 2007. because performing the oral glucose tolerance test is not always practical in an ambulatory care setting.AACE Diabetes Mellitus Guidelines. placebo-controlled. and increase fiber intake to 15 g/1000 kcal or more (grade A) Prescribe regular physical activity (approximately 150 minutes per week) (grade A) Counsel patients with prediabetes mellitus about cardiovascular risk factors such as tobacco use. and troglitazone (6).10-16). Evidence Base 3. and it is the recommended screening method for this condition (9).2. ACE/AACE does not advocate initiation of nonapproved pharmacologic therapy in patients with impaired glucose tolerance.1. This randomized. hypertension. When current glycemic goals are achieved early in the progression of the disease. acarbose (11). Prediabetes includes states of impaired fasting glucose or impaired glucose tolerance. However. other thiazolidinediones with similar properties. Some of these agents include metformin (1).2. Endocr Pract. orlistat (12). however. The 2-hour oral glucose tolerance test is more sensitive for diagnosing prediabetes than the fasting plasma glucose test (8). Results from epidemiologic studies also show that postprandial hyperglycemia is a strong independent risk factor for cardiovascular disease (3). once impaired glucose tolerance develops. Age-related differences in response to therapy are important factors to consider because weight loss in elderly patients. the fasting plasma glucose test may be used to identify patients with impaired fasting glucose.2. prediabetes often progresses to T2DM (1. Executive Summary • Perform screening with either the 2-hour oral glucose tolerance test or fasting plasma glucose test to establish a diagnosis of diabetes mellitus or to identify prediabetes mellitus (grade A) (See Table 2. may be deleterious. Although troglitazone is no longer available. Results from epidemiologic studies show that hyperglycemia is strongly associated with the subsequent development of cardiovascular disease and that patients with impaired glucose tolerance frequently have increased cardiovascular risk factors (3-5). Results from clinical trials also show several pharmacologic agents to effectively reduce progression from impaired glucose tolerance to T2DM (1.1. multicenter study included 5269 adults 30 years or older who had impaired fasting glucose and/or impaired glucose tolerance and no previous cardiovascular disease. 3.
6%) of the 2635 subjects given rosiglitazone and in 686 (26%) of the 2634 subjects given placebo. Study to Prevent Non–Insulin-Dependent Diabetes Mellitus In the double-blind Study to Prevent Non–InsulinDependent Diabetes Mellitus (STOP-NIDDM) trial (11).1% in the exercise-only group.1%) of 2634 participants in the placebo group developed heart failure.5%) of the 2635 subjects given rosiglitazone and in 798 (30. After a mean follow-up of 3. (b) exercise only. After adjusting for differences in baseline body mass index and fasting glucose concentration.0005). The ability to stop the progression to diabetes was strongly correlated with the degree to which subjects were able to achieve 1 or more of the following goals: (a) weight loss of more than 5% total body weight. 577 men and women with impaired glucose tolerance were randomly assigned to a control group or to 1 of 3 active treatment groups: (a) diet only.13(Suppl 1) 2007 out from the placebo group. The cumulative incidence of diabetes mellitus after 6 years of follow-up was 67. Finnish Diabetes Prevention Study In the large-scale Finnish Diabetes Prevention study of lifestyle intervention (2). The relative decrease in the rate of diabetes development in the active treatment groups was similar when subjects were stratified as lean (body mass index <25 kg/m2) or as overweight (body mass index ≥25 kg/m2). exercise-only. and both sexes. Regression to normoglycemia occurred in 1330 (50. 46% (P<. or (c) control group—placebo and standard diet and exercise. 1429 overweight and obese participants with impaired glucose tolerance were randomly assigned to receive either acarbose or placebo. the diet-only. (c) less than 10% of energy intake from saturated fat. The effect of acarbose treatment was consistent among all age groups. respectively.8% in the diet-only group. Da Qing Impaired Glucose Tolerance and Diabetes Study In the Da Qing Impaired Glucose Tolerance and Diabetes trial (17). 2007.05). a 58% relative reduction in the incidence of diabetes mellitus was observed in the intervention group compared with the control group. and the development of diabetes mellitus was reduced by 71% in these participants. When the diabetes diagnosis was confirmed by results of a second oral glucose tolerance test. 3234 subjects with impaired glucose tolerance were randomly assigned to 1 of 3 groups: (a) lifestyle group—intensive nutritional and exercise counseling. and a 31% relative reduction was observed in the metformin treatment group. and diet-plus-exercise interventions were associated with 31% (P<. a 36% relative risk reduction was seen in the acarbose treatment group. (b) metformin treatment group—medication and standard diet and exercise. Diabetes Prevention Program Study In the Diabetes Prevention Program (DPP) study (1). the annual incidence of T2DM was 5. a 25% relative risk reduction in progression to diabetes mellitus—based on results of a single oral glucose tolerance test—was observed in the acarbose treatment group compared with the placebo group. Approximately 50% of subjects in the lifestyle group achieved a 7% or greater weight reduction in the first year and sustained a 5% total weight loss for the study's duration.2 years. After adjusting for the main cardiovascular disease risk factors.8 years. heavier subjects—those participants aged 25 to 40 years with a body mass index of 36 kg/m2 or higher. 522 middle-aged obese subjects with impaired glucose tolerance were randomly assigned to receive either brief diet and exercise counseling (control group) or intensive personalized instruction on weight reduction and food intake and guidance on increasing physical activity (intervention group). 41. This translated to a 56% relative reduction in progression to diabetes mellitus in subjects treated with . (b) less than 30% of energy intake from fat. and 46% in the diet-plus-exercise group (P<. Endocr Pract.1% in the placebo group. in preventing T2DM was demonstrated by the findings of the Troglitazone in Prevention of Diabetes Study (TRIPOD) (6). 400 mg/daily. and 42% (P<. Compared with the control group after an average follow-up of 2. Lifestyle modifications were most effective in subjects 60 years and older. After a mean followup of 3. (d) fiber intake of 15 g/1000 kcal or more. The ethnicity of participants had no influence on the efficacy of the interventions. a thiazolidinedione.3 years.5%) of 2635 participants in the rosiglitazone treatment group and 2 (0. The findings from this trial demonstrate the importance of improving postprandial hyperglycemia. 14 (0. The primary composite outcome developed in 306 (11.03). A population of 235 Hispanic women with previous GDM was randomly assigned to receive placebo or troglitazone. The rate of cardiovascular events was similar in both subject groups.4% in the troglitazone treatment group and 12. Moderately intense activity of 150 minutes per week was maintained in 74% of subjects in the lifestyle group.7% in the control group compared with 43. A secondary analysis of the STOP-NIDDM data was performed to assess reductions in cardiovascular disease outcomes. Troglitazone in Prevention of Diabetes Study The efficacy of troglitazone. all ranges of body mass index values. or (c) diet plus exercise. and (e) more than 150 minutes of exercise per week. The effect of metformin treatment in reducing the risk for diabetes was most pronounced in younger.3%) of the 2634 subjects given placebo.1 AACE Diabetes Mellitus Guidelines. a 53% relative risk reduction in cardiovascular events was observed in subjects treated with acarbose.005) reductions in risk of developing diabetes. After a median follow-up of 30 months. a 58% relative reduction in the progression to diabetes mellitus was observed in the lifestyle group.
which corresponds to a relative risk reduction of 37. the development of new therapies that preserve β-cell function is desirable. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. 3305 subjects were randomly assigned to 1 of 2 groups: (a) lifestyle changes plus orlistat treatment. assessing for diabetes development was a post hoc analysis. Findings from the Heart Outcomes Prevention Evaluation (HOPE) trial (14) showed a 34% (P<. In this study. Gerstein HC.26:688-696. Lindstrom J. the preventive effects of the drug were still present. Although troglitazone was subsequently withdrawn from the market. 2 additional drugs in this class (pioglitazone and rosiglitazone) are available. a monosulfamyl diuretic. (LOE 1) 2. 2001. 2001. Coutinho M.4 years. 2004. Bowlin SJ. Fedder DO. and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk). Knowler WC. XENical in the Prevention of Diabetes in Obese Subjects Study The purpose of the XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) study (12) was to determine whether adding a weight-reducing agent to lifestyle modifications may lead to even greater weight loss.368:1770�. et al. et al. Yusuf S.27:17-20. is in progress. Primary end points were time to T2DM onset and change in body weight. A metaregression analysis of published data from 20 studies of 95.2% in the orlistat treatment group. (LOE 1) 9. Fowler SE.3% (P = . Participants had a body mass index of 30 kg/m2 or higher. 2003. Geneva. Bourgeois N.S. Koro CE. 2007. Khaw KT. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. Glycated haemoglobin. Walker EA. 2005. (LOE 1) 8. and thus further decrease the incidence of T2DM in obese patients. World Health Organization/International Diabetes Foundation. Lachin JM. The Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia: report of a World Health Organization/International Diabetes Foundation Consultation. (LOE 2) 4. an angiotensinconverting enzyme inhibitor.13(Suppl 1) 2007 1 troglitazone. (LOE 1) 7. 2006.368:1096-1105. et al.344:1343-1350. Wang Y. Buchanan TA. (LOE 1) 3. the cumulative incidence of diabetes mellitus was 9% in the placebo group and 6. Switzerland: WHO Document Production Services. may eventually prove to be effective in this capacity (18). et al. (LOE 1) .2006:1-46. 2002. Glycemic control from 1988 to 2000 among U.001) reduction in the development of diabetes mellitus in subjects treated with losartan. Gerstein HC. compared with subjects treated with chlorthalidone.22:233-240. Endocr Pract. an angiotensin-converting enzyme inhibitor.001) reduction in the development of diabetes mellitus in subjects treated with lisinopril. compared with subjects treated with a thiazide diuretic or a β1-adrenoceptor antagonist. DECODE Study Group. an angiotensin receptor blocker. The Losartan Intervention for End point Reduction in Hypertension study (LIFE) (16) showed a 25% (P<.034) reduction in the development of diabetes mellitus in subjects treated with captopril. Tuomilehto J. (LOE 2) 5. diabetes. REFERENCES 1. After 4 years of follow-up. Bosch J. prospective study. Backlund JY. double-blind.346:393-403.51:2796-2803.AACE Diabetes Mellitus Guidelines. N Engl J Med.0032). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. a large prospective randomized controlled trial with prevention of T2DM as the primary outcome. Xiang AH. Luben R. et al (DREAM [Diabetes REduction Assessment with ramipril and rosiglitazone Medication] Trial Investigators). Cleary PA. N Engl J Med. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial [erratum in Lancet. compared with subjects treated with atenolol. 2002. and 21% had impaired glucose tolerance. adults diagnosed with type 2 diabetes: a preliminary report. The findings from the TRIPOD study suggest that thiazolidinediones may prevent diabetes mellitus rather than delay its onset.783 individuals followed for 12. 79% had blood glucose concentrations in the reference range.353:2643-2653. Results from the Captopril Prevention Project (CAPPP Trial) (13) showed an average 14% (P = . Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care. Clearly. three times daily. (LOE 4) 10. N Engl J Med. European Diabetes Epidemiology Group. Diabetes Care. a β-adrenergic blocker. BMJ. Troglitazone improved insulin sensitivity and pancreatic β-cell function. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. (LOE 1) 6. 1999. Nathan DM.001) reduction in the development of diabetes mellitus in subjects treated with ramipril. Yusuf S. Peters RK. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (15) showed a 30% (P<. Eriksson JG. 2006. Diabetes. Results from analyses indicated that the preventive effect was demonstrated only in the subjects with impaired glucose tolerance. an angiotensin-converting enzyme inhibitor.322:15-18. Other Studies Other studies of antihypertensive and lipid therapies in which the development of diabetes mellitus was a secondary end point have been conducted. The relationship between glucose and incident cardiovascular events. The incretin mimetics and dipeptidyl-peptidase 4 inhibitors. 120 mg/daily or (b) lifestyle changes plus placebo. In this 4-year. Wareham N. Diabetes Care. After a washout period of more than 8 months. Hamman RF. Lancet. compared with subjects given a placebo. Barrett-Connor E. new classes of drugs.
28:187218. (LOE 1) Lindholm LH.289:178 and JAMA. Endocr Pract. 4. Josse RG. et al. (LOE 1) Pan XR. Laakso M (the STOP-NIDDM Trial Research Group). hypertension and cardiovascular disease in subjects with impaired glucose tolerance: facts and interpretations concerning the critical analysis of the STOP-NIDDM Trial data.27:856�. and retinopathy § Patients taking multiple daily injections who have demonstrated willingness and ability to comply with prescribed diabetes self-care behavior including frequent glucose monitoring. 17.359:1004-1010. 15. et al. Boldrin MN. 13. (LOE 1) Yusuf S. Karasik A. 1999. using a long-acting insulin analog in combination with a rapid-acting insulin analog or inhaled insulin at meals o Continuous subcutaneous insulin infusion with an insulin pump. 2002. Lancet. Ibsen H.286:1882-1885.5% (grade B) o Fasting plasma glucose concentration <110 mg/dL (grade B) o 2-hour postprandial glucose concentration <140 mg/dL (grade B) • Refer patients for comprehensive. Hauptman J. (LOE 1) ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. 2002. 2004. Dahlof B. 2007.353:611-616. Endocr Rev.1 AACE Diabetes Mellitus Guidelines.1. The Da Qing IGT and Diabetes Study. Sjostrom L. nephropathy. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [erratum in JAMA.1 describes the pharmacokinetics of available insulin preparations).20:537-544. (LOE 1) Hansson L. 2001. insulin pump therapy is indicated for: § Patients who are unable to achieve acceptable control using a regimen of multiple daily injections § Patients with histories of frequent hypoglycemia and/or hypoglycemia unawareness § Patients who are pregnant § Patients with extreme insulin sensitivity (pump therapy facilitates better precision than subcutaneous injections) § Patients with a history of dawn phenomenon (these patients can program a higher basal rate for the early morning hours to counteract the rise in blood glucose concentration) § Patients who require more intensive diabetes management because of complications including neuropathy. 2004. Hoogwerf B. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Patients With Type 1 Diabetes Mellitus • Initiate intensive insulin therapy (grade A) (Table 4. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients [erratum in Diabetes Care. Diabetes Care. regimen options include: o Basal-bolus therapy. Gerstein H. education should: 4. Niskanen L. Beta-cell failure in diabetes and preservation by clinical treatment. and insulin adjustment • Consider adding pramlintide to intensive insulin therapy to enhance glycemic control and to assist with weight management (grade D) . 2004.291:2196�.47:969-975. Li GW. 1997. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. • Be provided by a qualified health care professional o Focus on all aspects of diabetes selfmanagement relevant to each patient’s treatment plan o Promote behavioral changes to support effective and consistent application of the prescribed diabetes treatment plan and an overall healthy lifestyle o Be continued as an ongoing intervention to accommodate changes in the treatment plan and patient status Initiate self-monitoring of blood glucose levels (grade A) o 14. Gomis R. JAMA. et al. glycemic targets include: o HbA1c ≤6.27:155-161. Diabetologia.1.1. carbohydrate counting. Acarbose for the prevention of Type 2 diabetes. Executive Summary 4.288:2981-2997. Lindholm LH. et al. 2007. (LOE 1) Torgerson JS. ongoing education in diabetes self-management skills and nutrition therapy (grade A). 18.1. All Patients With Diabetes Mellitus • Encourage patients to achieve glycemic levels as near normal as possible without inducing clinically significant hypoglycemia (grade A). Hu YH. (LOE 1) Wajchenberg BL. 2004. Lancet. GLYCEMIC MANAGEMENT 4. Hanefeld M. 16. Chiasson JL.2. JAMA. (LOE 4) 12. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.13(Suppl 1) 2007 11. Diabetes Care. 2003. Ramipril and the development of diabetes.
AACE Diabetes Mellitus Guidelines. neutral protamine Hagedorn aMay require 2 daily injections in patients with type 1 diabetes mellitus. exercise caution because of the potential for increased fluid retention when thiazolidinediones are used with insulin Instruct patients whose glycemic levels are at or above target while receiving multiple daily injections or using an insulin pump to monitor glucose levels at least 3 times daily (grade A) Instruct patients whose glycemic levels are above target or who experience frequent hypoglycemia to monitor glucose levels more frequently.2 U/kg per injection. bAssumes 0. basal Long-acting.3. physical activity.1.1-0.13(Suppl 1) 2007 17 Table 4. • • • • Consider adding an insulin sensitizer to address insulin resistance as needed (grade C). diabetes self-management education) at the time of diagnosis (grade A) .7-23. Generic Name (Brand) Onset 5-15 min 5-15 min 5-15 min 5-15 min Peak 30-90 min 30-90 min 30-90 min 30-90 min Effective Duration <5 h <5 h <5 h 5-8 h Rapid-acting Insulin aspart injection (NovoLog) Insulin lispro injection (Humalog) Insulin glulisine injection (Apidra) Short-acting Regular NPH Insulin human (rDNA origin) Inhalation Powder (Exubera) (2) Intermediate.1. Endocr Pract. Onset and duration may vary significantly greatly by injection site. Patients With Type 2 Diabetes Mellitus • Aggressively implement all appropriate components of care (medical nutrition therapy. cTime to steady state. 2007.2 h 10-16 h 10-16 h 10-16 h 10-16 h 75% insulin lispro protamine suspension/25% insulin lispro injection (Humalog Mix 75/25) 50% insulin lispro protamine suspension/50% insulin lispro injection (Humalog Mix 50/50) (4) 5-15 min 5-15 min 5-15 min 30-60 min 70% insulin aspart protamine suspension/30% insulin aspart injection (NovoLog Mix 70/30) 70% NPH/30% regular Abbreviation: NPH. Pharmacokinetics of Available Insulin Preparations (1) Insulin. pharmacologic interventions. monitoring should include both preprandial and 2-hour postprandial glucose levels and occasional 2:00 AM to 3:00 AM glucose levels (grade C) Instruct insulin-treated patients to always check glucose levels before administering a dose of insulin • • by injection or changing the rate of insulin infusion delivered by an insulin pump (grade A) Instruct patients to monitor glucose levels anytime there is a suspected (or risk of) low glucose level and/or before driving (grade A) Instruct patients to monitor glucose levels more frequently during illness and to perform a ketone test each time a measured glucose concentration is greater than 250 mg/dL (grade C) 4. basal Insulin glargine injection (Lantus)ab Premixed Insulin detemir injection (Levemir)ab (3) 30-60 min 2-4 h 2-4 hc 3-8 h 2-3 h 4-10 h No peak No peak Dual Dual Dual Dual 5-8 h 10-16 h 20-24 h 5. weight management regimen.
6 present information about new medications and currently available oral therapies. unrestrained hepatic glucose production. or once-daily insulin alone to monitor glucose levels at least 2 times daily (grade C). oral agents plus once-daily insulin.67). a progressive decline in pancreatic insulin secretion. fasting/preprandial glycemic profile. 2007.3.2. there is no supporting evidence regarding optimal frequency of glucose monitoring in these patients Instruct patients who are meeting target glycemic levels (including those treated nonpharmacologically) to monitor glucose levels at least once daily (grade D) Instruct patients whose glycemic levels are above target or who experience frequent hypoglycemia to monitor glucose levels more frequently. this will require the patient to obtain comprehensive fasting. Overview T1DM is characterized by an absolute deficiency in insulin secretion (61). persistently monitor and titrate therapy over the next 2 to 3 months until all ACE/AACE glycemic goals are achieved (grade A) (Table 4.63. monitoring should include both preprandial and 2-hour postprandial glucose levels and occasional 2:00 AM to 3:00 AM glucose levels (grade B) Instruct patients to obtain comprehensive preprandial and 2-hour postprandial glucose measurements to create a weekly profile periodically and before clinician visits to guide nutrition and physical activity. and 4. T2DM is a progressive. . and 2-hour postprandial glycemic profile to evaluate the level of control and to identify patterns. and other hormonal deficiencies (62.13(Suppl 1) 2007 • • Persistently monitor and titrate pharmacologic therapy until all glycemic goals are achieved (grade A) o First assess the patient’s current HbA1c level. 4.1 AACE Diabetes Mellitus Guidelines. Evidence Base 4. initiate a more intensive regimen and persistently monitor and titrate therapy over the next 2 to 3 months until all ACE/AACE glycemic goals are achieved (grade A) o Recognize that patients currently treated with monotherapy or combination therapy who have not achieved glycemic goals will require either increased dosages of their current medications or the addition of a second or third medication (grade A) o Consider insulin therapy in patients with HbA1c levels greater than 8% and symptomatic hyperglycemia and in patients with elevated fasting blood glucose levels or exaggerated postprandial glucose excursions regardless of HbA1c levels (grade A) o Initiate insulin therapy to control hyperglycemia and to reverse glucose toxicity when the HbA1c level is greater than 10%.1. and to prevent hypoglycemia (grade B) Instruct patients to monitor glucose levels anytime there is a suspected (or risk of) low glucose level and/or before driving (grade A) Instruct patients to monitor glucose levels more frequently during illness and to perform a ketone test each time a measured glucose concentration is greater than 250 mg/dL (grade C) 4. there is no supporting evidence regarding optimal frequency of glucose monitoring with or without insulin pump therapy Instruct insulin-treated patients to always check glucose levels before administering a dose of insulin by injection or changing the rate of insulin infusion delivered by an insulin pump (grade B) Instruct patients whose glycemic levels are above target while being treated with oral agents alone. although monitoring • • • • • • • glucose levels at least 3 times daily is recommended.2. and postprandial glucose readings over a 7-day period (grade A) o After initiating pharmacologic therapy based on the patterns identified in the profile.2 shows examples of pharmacologic regimens that are intended to serve as starting points for selecting appropriate therapies. Patients often develop T2DM 9 to 12 years before the disease is diagnosed (64). preprandial. Tables 4.5.) o If glycemic goals are not achieved at the end of 2 to 3 months of therapy.4. complex metabolic disorder characterized by coexisting defects of multiple organ sites including insulin resistance in muscle and adipose tissue. Findings from the United Kingdom Prospective Diabetes Study (UKPDS) show that affected individuals have already lost 50% of β-cell function at the time T2DM is diagnosed (65). insulin treatment can then be modified or discontinued once glucose toxicity is reversed (grade A) o Consider use of continuous subcutaneous insulin infusion in insulin-treated patients (grade C) Instruct patients whose glycemic levels are at or above target while receiving multiple daily injections or using an insulin pump to monitor glucose levels at least 3 times daily (grade B). Effective management of T2DM requires persistent monitoring and adjustment of therapy (66). to detect postprandial hyperglycemia. 4. Endocr Pract.
6) Thiazolidinediones (7.15) Monitor and titrate medication for 2-3 months Consider combination therapy if glycemic goals are not met at the end of 2-3 months Patients With Type 2 Diabetes Mellitus Naïve to Pharmacologic Therapy Initiate combination therapy when HbA1c levels are 7%-8% Options include: Secretagogue + metformin (16. NPH.25) Fixed-dose (single pill) therapy Thiazolidinedione (pioglitazone) + metformin (26) Thiazolidinedione (rosiglitazone) + metformin (27) Thiazolidinedione (rosiglitazone) + secretagogue (glimepiride) (28) Thiazolidinedione (pioglitazone) + secretagogue (glimepiride) (29) Secretagogue (glyburide) + metformin (30) Rapid-acting insulin analogs or premixed insulin analogs may be used in special situations (31) Inhaled insulin may be used as monotherapy or in combination with oral agents and long-acting insulin analogs Insulin-oral medications.34) The therapeutic options for combination therapy listed for patients naïve to therapy are appropriate for patients being treated pharmacologically Exenatide may be combined with oral therapy in patients who have not achieved glycemic goals Approved exenatide + oral combinations: Exenatide + secretagogue (sulfonylurea) (36) Exenatide + metformin (37) Exenatide + secretagogue (sulfonylurea) + metformin (38) Exenatide + thiazolidinedione Pramlintide may be used in combination with prandial insulin Add insulin therapy in patients on maximum combination therapy (oral-oral.5% (35) Consider initiating basal-bolus insulin therapy for patients with HbA1c levels >8. hemoglobin A1c.17) Secretagogue + thiazolidinedione (18. oral-exenatide) whose HbA1c levels are 6. neutral protamine Hagedorn. Patients with Type 2 Diabetes Mellitus Currently Treated Pharmacologically .33) Premixed insulin analogs (31.5%-8. therapy combinations should be selected based on the patient's self-monitoring of blood glucose profiles Initiate/intensify combination therapy using options listed above when HbA1c levels are 8%-10% to address fasting and postprandial glucose levels Initiate/intensify insulin therapy when HbA1c levels are >10% Options include: Rapid-acting insulin analog or inhaled insulin with long-acting insulin analog or NPH (32.8) Secretagogues (9-12) Dipeptidyl-peptidase 4 inhibitors (13) α-Glucosidase inhibitors (14. 2007.13(Suppl 1) 2007 1 Table 4.5% Abbreviations: HbA1c.AACE Diabetes Mellitus Guidelines.2.22) Dipeptidyl-peptidase 4 inhibitor + metformin (23) Dipeptidyl-peptidase 4 inhibitor + thiazolidinedione (23) Secretagogue + metformin + thiazolidinedione (24.19) Secretagogue + α-glucosidase inhibitor (20) Thiazolidinedione + metformin (21. Examples of Pharmacologic Regimens for Treating Type 2 Diabetes Mellitusa Initiate monotherapy when HbA1c levels are 6%-7% Options include: Metformin (5. aThe options listed are in no order of preference. all oral medications may be used in combination with insulin. Endocr Pract.
Findings from a more recent study by Monnier and colleagues (101) show that postbreakfast glucose levels tend to be negatively affected first during the course of diabetes.91. education. impaired glucose tolerance. lispro. Given the emerging relationship between postprandial hyperglycemia and the development of macrovascular disease. Managing diabetes mellitus requires a team approach to patient care. For example. 2007. self-monitoring of urine glucose levels has not been as closely linked to improved outcomes (112). Endocr Pract. have fewer hypoglycemic episodes than patients using traditional insulins (eg. As demonstrated by Monnier and colleagues (100). However. effective management of postprandial glucose levels can reduce the risk of macrovascular disease (79-81). has been linked to the development of macrovascular disease (68. Early and aggressive management of glycemia by addressing mean glucose levels and glucose level variability. Patients using insulin analogs (eg. However. reduce morning hyperglycemia due to the dawn phenomenon.4% (100).2%. Insulin pump therapy is an effective alternative to multiple insulin injections in patients with diabetes mellitus (91). the relative contribution of fasting glucose levels to overall glycemia is approximately 70% in patients with HbA1c levels greater than 10. including patients with hypoglycemia unawareness. thus suggesting that treatment efforts should initially target fasting glucose concentrations and then focus on reducing postmeal glucose concentrations. improve endothelial function (82). inflammation. Near-normalization of blood glucose concentrations in patients with T1DM can be achieved safely by intensive insulin therapy (89). Initial and ongoing self-management education must be made available to all patients with diabetes mellitus (114.3% and 8.13(Suppl 1) 2007 Postprandial hyperglycemia. exercise. is vital to preventing or delaying the development of diabetic complications (79. Patients with T2DM can be taught as outpatients to use continuous subcutaneous insulin infusion and prefer this treatment modality over injections (99). the HbA1c reduction more than doubles when regular feedback is provided to patients (112).40% compared with interventions that do not include self-monitoring of blood glucose levels.74-78). and increased contact time with educators enhances the positive . findings from a recent meta-analysis show that interventions that include self-monitoring of blood glucose levels result in an HbA1c level reduction of 0. Therapeutic management programs that include structured self-monitoring of blood glucose levels result in greater HbA1c reduction in non–insulin-requiring patients with T2DM compared with programs that do not include self-monitoring of blood glucose levels (109-112). The recommendations for how frequently patients should perform self-monitoring of blood glucose levels are adopted from the consensus statements created by an international panel of diabetes experts who conducted a conference to address the use of this management tool (113). The therapeutic cornerstones to treat T1DM and T2DM are proper nutrition. Self-management education improves HbA1c levels.20 AACE Diabetes Mellitus Guidelines. and appropriate pharmacologic therapy (84).8588).3%. and diabetes mellitus (70-73). reduce hypoglycemia. The contribution of fasting glucose to overall glycemia decreases to approximately 30% when HbA1c levels are less than 7. Children and adolescents have been successfully treated with insulin pump therapy (94). Results from several studies demonstrate the value of self-monitoring of blood glucose levels in the management of T1DM. and reduce levels of methylglyoxal and 3deoxyglucosone (83).92). The efficacy and safety of continuous subcutaneous insulin infusion with an insulin pump are comparable to multiple daily injection insulin therapy for patients with T2DM. Conversely. Near-normalization of blood glucose levels in patients with T2DM can be achieved safely by intensive combination therapy—either dual-oral or tripleoral combinations and/or oral-insulin combinations (9598). and GDM (85. urine glucose monitoring is not an appropriate method to assess glycemic control. reduce hypoglycemia unawareness. Causal relationships between postmeal hyperglycemia and known markers of cardiovascular disease (eg.69). it may be more prudent to address both fasting and postprandial abnormalities simultaneously with the understanding that therapies targeting postmeal glucose concentrations will become more effective as HbA1c levels are reduced. Results from studies have demonstrated that pump therapy can improve overall glucose control.115). independent of HbA1c levels. The rationale for the proposed use of the treatment regimens presented in Table 4. The contributions of fasting and postprandial glucose levels are approximately equal when HbA1c levels are between 7. glargine) in physiologic regimens. A strong association has also been shown between postmeal and postchallenge glycemia and cardiovascular risk and outcomes in individuals with normal glucose tolerance. aspart. oxidative stress. and increase lifestyle flexibility (91-93).2 is derived from a new understanding of the variable relationship between fasting and postprandial glucose levels based on HbA1c levels. Therefore.102-108). Therapy should be tailored to the individual to maximize the likelihood of attaining and maintaining appropriate glycemic goals and to reduce the frequency of adverse effects (84). Intensive insulin therapy may reverse hypoglycemia unawareness in patients with T1DM (89) and can substantially prevent hypoglycemia and maintain target glycemic levels (89. endothelial dysfunction) have also been demonstrated (68. education in self-management skills is essential in implementing interventions (84). because diabetes is primarily a self-managed disease. T2DM. intima-media thickness.90). regular and neutral protamine Hagedorn [NPH�) (32.
reduce dosage to 50 mg daily If creatinine clearance is <30 mL/min/1. 2007. or a combination of metformin and a sulfonylurea. Endocr Pract. New Drugs to Treat Diabetes Mellitus Drug Name.3.2. and other hormonal deficiencies (62-64).73m2. Pathophysiology of Type 2 Diabetes Mellitus T2DM is a complex metabolic disorder that results from coexisting defects at multiple organ sites including insulin resistance in muscle and adipose tissue. rapid-acting or shortacting insulin. diminished production of gastrointestinal incretins. unrestrained hepatic glucose production. Group-based teaching of patients with T2DM for self-management strategies improves fasting glucose and HbA1c levels and increases knowledge of the disease.2. inappropriate glucagon secretion. reduce dosage to 25 mg daily Maximum dosage: 100 mg once daily in the morning Initial dosage: 50 mg/500 mg twice daily Maximum dosage: 50 mg/1000 mg twice daily Administer with or without food Administer with meals Not recommended for patients with severe renal disease effect (116).73m2. Insulin resistance in normoglycemic individuals predicts the development of T2DM (64. by 50% Type 2 Diabetes Mellitus Initiated at 60 µg and increased to a dosage of 120 µg as tolerated Reduce preprandial. a progressive decline in pancreatic insulin secretion. these improvements reduce the requirement for glucoselowering medication (117-120). but who have not achieved adequate glycemic control Initiated at 5 µg per dose administered twice daily any time within 60 minutes before morning and evening meals Dosage can be increased to 10 µg twice daily after 1 month of therapy Indicated as an adjunct treatment in patients taking prandial insulin who have not achieved desired glucose control Frequent monitoring of blood glucose levels is required to titrate dosage Contraindicated in patients with hypoglycemia unawareness or a diagnosis of gastroparesis Not a substitute for insulin in insulinrequiring patients Should not be used in patients with type 1 diabetes mellitus or to treat diabetic ketoacidosis Not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min/1. Generic (Brand) Dosage Comments Pramlintide (Symlin) (39) Exenatide (Byetta) (40) Type 1 Diabetes Mellitus Initiated at 15 µg and titrated at 15 µg increments to a maintenance dosage of 30 µg or 60 µg as tolerated Reduce preprandial. a sulfonylurea.121) and is influenced by both genetic factors (122. Insulin resistance initially occurs in skeletal muscle where greater concentrations of insulin are needed to transport glucose into cells.123) and environmental factors such as obesity . rapid-acting.13(Suppl 1) 2007 21 Table 4. including fixed-mix insulins. including fixed-mix insulins. 4. by 50% Indicated as adjunct treatment to improve glycemic control in patients with type 2 diabetes mellitus who take metformin. or shortacting insulins.AACE Diabetes Mellitus Guidelines.73m2) Sitagliptin (Januvia) (23) Sitagliptin plus Metformin (Janumet) Initial dosage: 100 mg once daily in the morning If creatinine clearance is 30 to 50 mL/min/1.
2.6). the glucose-lowering effect usually plateaus at approximately one half of the maximum recommended dose (10. they are not approved for use in combination with glinides. By binding to sulfonylurea receptors on the surface of pancreatic βcells. these agents attenuate postprandial glucose excursions and decrease the risk of hypoglycemia during the late postprandial phase because less insulin is secreted several hours after the meal (11. fasting hyperglycemia results (126). congestive heart failure. Medications The following text describes the oral medications currently available. Data from the United Kingdom Prospective Diabetes Study (UKPDS) show that patients treated with metformin experience less hypoglycemia and weight gain than those treated with sulfonylureas (137).12). metabolic acidosis. Sulfonylurea therapy reduces HbA1c levels by 1% to 2% (9. Glinides stimulate a rapid but short-lived release of insulin from pancreatic β-cells that lasts 1 to 2 hours (75). it is now understood that several hormones have roles in maintaining glucose homeostasis. nateglinide appears to be somewhat less potent (133. they have a much shorter metabolic half-life. dehydration. as the disease progresses. which facilitates cell-membrane depolarization. other hormonal deficiencies occur as T2DM progresses. Amylin and incretin hormones (ie.128) and β-cell function while prompting increased hepatic glucose production (129).55-57.124. these agents cause the voltage-dependent potassium adenosine triphosphate channels to close. In addition to decreasing β-cell function. Metformin is approved for use as a monotherapy and in combination with . however. pancreatic β-cell function gradually diminishes. therefore. However.3. repaglinide is only minimally cleared by the kidney and can. When hepatic glucose output exceeds glucose use. use of glinides should target postprandial blood glucose levels rather than fasting blood glucose levels. its primary effect is to reduce hepatic glucose production in the presence of insulin (5. In addition. The ensuing glucose toxicity that results from unrestrained hyperglycemia further reduces insulin sensitivity and pancreatic insulin secretion. However. Glinides are metabolized by the liver and cleared by the kidney and should be used with caution in patients with hepatic or renal impairment. Endocr Pract. and insulin secretion (130). Because most sulfonylurea agents are metabolized by the liver and cleared by the kidney. Table 4. With the discovery of the incretin hormones in the 1970s and the pancreatic hormone amylin in the 1980s. Results from studies show the efficacy of repaglinide to be similar to that of sulfonylureas (11.13(Suppl 1) 2007 and sedentary lifestyle. nausea. As insulin resistance increases. Glinides Glinides employ a mechanism of action similar to sulfonylureas to facilitate glycemic control. These effects occur in up to 50% of patients.136. 2007. glucagon-like peptide 1. in turn. Insulin resistance at the adipocyte level leads to unrestrained lipolysis and elevation of circulating free fatty acids. Although optimal dosing of sulfonylureas varies by agent. Metformin confers other nonglycemic benefits such as decreasing low-density lipoprotein cholesterol (LDL-C) levels. be used safely in patients with even severe renal impairment. Glucose abnormalities are first demonstrated by postprandial hyperglycemia. further diminishes the skeletal muscle insulin response (127.22 AACE Diabetes Mellitus Guidelines. Metformin has been shown to lower HbA1c levels by 1% to 2% (16. metformin should be temporarily withheld in patients with acute illness or those undergoing radiocontrast studies or surgery. Secretagogues Sulfonylureas Sulfonylureas lower blood glucose levels by increasing insulin secretion from the pancreatic β-cells.135). Sulfonylureas are approved for use as monotherapy and in combination with most other oral drug classes and insulin.132). however. a compensatory increase in pancreatic insulin secretion allows the body to maintain normal glucose concentrations for a period of time. When taken at meals. Metformin use should also be avoided in patients with hepatic dysfunction. Two glinides are commercially available: nateglinide and repaglinide.125).54). calcium entry into the cell. and the antifibrinolytic factor plasminogen activator inhibitor 1 levels (16.134). Adipose tissue also has an important role in the pathogenesis of T2DM. and alcoholism. Metformin should not be used in patients who are at increased risk for lactic acidosis because of renal impairment. which is caused by the loss of first-phase insulin secretion and reduced suppression of hepatic glucose output after meals due to insulin deficiency and glucagon excess (126). their frequency can be minimized with slow titration of therapy and food consumption (139).129.137). however. and diarrhea. Monotherapy with metformin is associated with weight loss (or no weight gain) and much less hypoglycemia than sulfonylurea therapy (5.10).138). Therefore. Adverse effects of metformin include gastrointestinal distress such as abdominal pain. This increase in free fatty acids. Biguanides Metformin The precise mode of action of metformin is not fully understood. 4. glucose-dependant insulinotropic polypeptide) are now recognized as influential factors in maintaining glucose homeostasis (62. they should be used cautiously in patients with hepatic or renal impairment. triglyceride levels.6 presents information about the effect of oral medications on HbA1c levels when used as monotherapy and in various combinations.
α-Glucosidase Inhibitorsd 100 mg three times daily 100 mg three times daily 120 mg three times daily Administer 15 to 30 min before each meal Administer with first bite of each main meal Dosage should be gradually increased as tolerated over several weeks Administer with first bite of each main meal Dosage may be gradually increased as tolerated over several weeks liver function tests at baseline followed by periodic monitoring. 2007. Endocr Pract. Generic (Brand) Pioglitazone (Actos) (41) Pioglitazone + Metformin (ActoPlus Met) (26) Initial Dosage 15 or 30 mg once daily If inadequately controlled on metformin monotherapy: Either 15 mg/500 mg or 15 mg/850 mg once daily or twice daily If initially responsive to pioglitazone monotherapy or switching from combination therapy of pioglitazone + metformin as separate tablets: Either 15 mg/500 mg twice daily or 15 mg/850 mg once daily or twice daily 4 mg once daily or 2 mg twice daily 2 mg/500 mg twice daily 4 mg/1 mg or 4 mg/2 mg once daily Maximum Dosage Thiazolidinedionesa 45 mg once daily Comments Administer with or without food Indicated for patients: (a) with type 2 diabetes mellitus treated with combination pioglitazone + metformin.AACE Diabetes Mellitus Guidelines.25 to 5 mg once daily 5 mg once daily. switch to twice daily regimen May have better gastrointestinal tolerance than immediate-release metformin Starting doses should not exceed daily doses of glyburide or metformin already taken. dStart with low dose and titrate up slowly.5 mg three times daily Patients previously treated with hypoglycemic agents or those with hemoglobin A1c >8%: Give 1 to 2 mg three times daily 120 mg three times daily. 2.13(Suppl 1) 2007 23 Table 4. (b) with glycemia not adequately controlled with metformin alone. (c) initially responsive to pioglitazone alone but require additional glycemic control Dosage schedule based on current dose of each component Consider administering in divided daily doses with meals to reduce the gastrointestinal adverse effects associated with metformin Rosiglitazone (Avandia) (42) Rosiglitazone + Metformin (Avandamet) (27) Rosiglitazone + glimepiride (Avandaryl) (28) Metformin (Glucophage) (43) Metformin extended release (Glucophage XR) (44) Glyburide + Metformin (Glucovance) (30) Glyburide (DiaBeta) (45) (Micronase) (46) Glipizide (Glucotrol) (47) Glimepiride (Amaryl) (48) Repaglinide (Prandin) (49) 8 mg once daily or 4 mg twice daily 4 mg/1000 mg twice daily 8 mg rosiglitazone and 4 mg glimepiride Administer with or without food Dosage schedule based on current dose of each component Administer with meals Administer with first meal of the day 500 mg twice daily or 850 mg once daily in the morning 500 mg once daily in the evening 2550 mg in 3 divided doses 2000 mg once daily Biguanidesb 1.5 mg once daily in elderly patients 1 to 2 mg once daily Second Generation Sulfonylureasc 20 mg in 1 or 2 divided doses once daily or twice daily 40 mg in 2 divided doses 8 mg once daily Administer with meals Maximum effective dose is 2000 mg/d Increase dosage by 500 mg/d weekly If glycemic control not tightened. . Oral Hypoglycemic Agents Drug Name. contraindicated in patients with New York Heart Association class III or IV cardiac disease and functional capacity. bStart with initial dose and titrate up slowly. dose increases can be made at 2-week intervals Administer once daily doses with breakfast or first main meal Doses >10 mg/d should be divided and given twice daily Administer once daily doses 30 min before breakfast or after first main meal Doses >15 mg/d should be divided and given twice daily Administer with breakfast or first main meal Nateglinide (Starlix) (50) Acarbose (Precose) (51) Miglitol (Glyset) (52) aPerform Elderly patients and patients not previously treated with hypoglycemic agents or patients with hemoglobin A1c <8%: Give 0. cHalf maximum dose typically provides most of the benefit. 60 mg three times daily in elderly patients 25 mg three times daily 25 mg three times daily Glinides (Short-Acting Secretagogues) 16 mg/d Administer 15 to 30 min before each meal.25 mg/250 mg once daily or twice daily 20 mg/2000 mg divided daily 1. monitor for edema.4.
Thiazolidinediones should not be used in patients with congestive heart failure (New York Heart Association class III or IV cardiac disease and functional capacity) or hepatic impairment. sulfonylureas. In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study (148). cardiac intervention. An accompanying editorial in the New England Journal of Medicine implies that thiazolidinediones should not be used (156). Weight gain and edema are more commonly seen in patients treated with thiazolidinediones and insulin. nonfatal myocardial infarction. Additionally. α-Glucosidase Inhibitors α-Glucosidase inhibitors provide postprandial glucose control by decreasing the absorption of carbohydrates from the gastrointestinal tract. edema. Preliminary data from high-risk patient studies and in vitro rodent studies also suggest that thiazolidinediones may prevent β-cell apoptosis (150.137. seem to have similar efficacy on glycemic control (7. thus attenuating postprandial glucose excursions (8. thiazolidinediones increase insulinstimulated glucose uptake in skeletal muscle cells (141143). this intervention did not show a significant relative risk reduction in the primary end point.15). Adverse effects of thiazolidinediones include weight gain. and insulin (154). P<. Through this process.2 AACE Diabetes Mellitus Guidelines. The combination of glyburide and metformin is more effective than either glyburide or metformin alone (16). Definitive resolution regarding the magnitude and statistical and clinical significance of these findings will require a more sensitive "time-to-event" (life-table) analysis and the final results of the ongoing phase 3 trial (RECORD) to evaluate cardiovascular outcomes in patients receiving rosiglitazone. P = . Adverse effects of . Thiazolidinediones are pharmacological ligands for a nuclear receptor known as peroxisome proliferator-activated receptor γ. The 2 thiazolidinediones currently available. anemia. the drugs’ greatest effect is on postprandial glucose excursions (14. cardiac death.145). and to a greater degree than α-glucosidase inhibitors (7. and improve endothelial function. pioglitazone demonstrated modest improvement in the composite outcome of all-cause mortality.160). enhance fibrinolysis (147).75 years of follow-up shows no statistically significant increased risk of myocardial infarction. 1.4% (17). Findings from the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) trial (152) demonstrate a significant (62%) reduction in the progression to diabetes mellitus in high-risk patients treated with rosiglitazone.98. In addition to lowering glycemia. Nissen and Wolski (155) report an increased risk for myocardial infarction in patients taking rosiglitazone compared with control patients (odds ratio.03-1. rosiglitazone and pioglitazone. 95% CI [confidence interval� 1.0% compared with HbA1c levels of placebo-treated patients.13(Suppl 1) 2007 sulfonylureas and other secretagogues. and peripheral fractures in women. Endocr Pract.5% to 1. The Food and Drug Administration still recommends periodic measurement of hepatic function in patients treated with thiazolidinediones. The odds ratio for cardiovascular death was 1. which are integrally involved in glucose production and uptake. In a recent meta-analysis of 42 studies.8).98-2. Interim analysis of the results of the RECORD trial with 4447 patients after 3. When activated. Both medications also confer benefits in increasing high-density lipoprotein cholesterol (HDL-C) concentrations and decreasing triglyceride concentrations (7. results from the A Diabetes Outcome Progression Trial (ADOPT) (153) show that treatment with rosiglitazone slows the rate of loss of β-cell function and improves insulin sensitivity to a greater extent than either metformin or glyburide. and insulin. while an editorial in the Lancet (157) recommends a balanced perspective until results from more studies become available. However. thiazolidinediones.151).43. the latter is expected in 2009 (158). major leg amputation.74. Most recently. Thiazolidinediones The mechanism of action of thiazolidinediones is not fully understood. acute coronary syndrome.03). combining 2 sensitizers from different drug classes (pioglitazone and metformin or rosiglitazone and metformin) produces an additive effect (21). or all-cause mortality in individuals receiving rosiglitazone (159). adding repaglinide to metformin therapy produces additional lowering of fasting plasma glucose levels by 40 mg/dL and HbA1c levels by 1. which was a composite of all-cause mortality. 2007. Thiazolidinediones are indicated as monotherapy and in combination with metformin. and stroke in patients with T2DM. These agents work by inhibiting α-glucosidase. α-glucosidase inhibitors delay intestinal carbohydrate absorption.144). these drugs are known to exert direct effects on the liver and peripheral tissues. Thiazolidinediones generally lower HbA1c levels the same degree as metformin and sulfonylureas. these agents modestly reduce blood pressure (145. and leg revascularization. It also remains to be seen whether other thiazolidinediones are associated with increased cardiovascular risks. nonfatal myocardial infarction. an enzyme located in the proximal small-intestinal epithelium that breaks down disaccharides and more complex carbohydrates. this receptor binds to response elements on DNA and alters transcription of various genes that regulate carbohydrate and lipid metabolism (140). 0. Similarly. αGlucosidase inhibitor therapy reduces HbA1c levels by approximately 0.64 (95% CI.146). stroke. However. Findings from the Carotid Intimal-Medial Thickness in Athersclerosis Using Pioglitazone (CHICAGO) trial (149) show that carotid artery intima-media thickness was significantly reduced in pioglitazone-treated patients compared with glimepiride-treated patients. Nissen and Wolski note several important limitations to their meta-analysis (155). Through competitive inhibition of this enzyme. This has been called an inconclusive study due to the limited number of cardiac events observed to date (159).06).
this has not yet been demonstrated in humans treated with glucagon-like peptide 1 or exenatide. Exenatide was approved by the Food and Drug Administration for the treatment of T2DM in patients who have not achieved glycemic goals using metformin. Sitagliptin treatment results in significant weight loss. is currently under review by the Food and Drug Administration (175). or both (168). and abdominal discomfort. Dipeptidyl-peptidase 4 inhibitors preferentially target postprandial glucose excursions. Dipeptidyl-peptidase 4 inhibitors have few adverse reactions (23). however. The occurence of hypoglycemia in subjects treated with sitagliptin plus metformin is less than one sixth as frequent as that in subjects treated with glipizide plus metformin (174). incretin mimetics. suppress glucagon release. inhibiting the release of glucagon after meals. 2007. Glucagon-like peptide 1. patients in these studies required less prandial insulin and also had a reduction in body weight compared with patients taking insulin alone (161. These actions include stimulating insulin production and response to elevated levels of blood glucose. vildagliptin. in contrast to the weight gain associated with glipizide treatment. Inhaled Insulin The first commercial preparation of inhaled insulin was introduced in 2006 as an alternative to traditional insulin injection and continuous subcutaneous insulin infusion. stimulate glucose-dependent insulin secretion.13(Suppl 1) 2007 2 α-glucosidase inhibitors include flatulence. Inhaled insulin can be used in combination with long-acting analogs to treat hyperglycemia in patients with T1DM and can be used as monotherapy or in combination with oral agents and long-acting insulin analogs to treat patients with T2DM. Frequent monitoring of blood glucose levels is needed. and a potential effect on feeding behavior and weight control (161). and a thiazolidinedione with or without metformin. This preparation consists of human insulin inhalation power. Sitagliptin Sitagliptin has been approved for use as monotherapy (13) and in combination with metformin (171) or a thiazolidinedione (173). slow titration may attenuate these gastrointestinal adverse effects over time. has multiple effects on the stomach. Dipeptidyl-Peptidase 4 Inhibitors Dipeptidyl-peptidase 4 inhibitors exert their action in part by slowing the inactivation of incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide by dipeptidyl-peptidase 4. for the treatment of T2DM. α-Glucosidase inhibitors are approved for use as monotherapy and in combination with sulfonylureas. which leads to less glycemic fluctuations during the day. Results from a randomized. multicenter study of 1172 patients who had failed to achieve satisfactory glycemic control being treated with metformin alone show that sitagliptin is comparable to glipizide in reducing HbA1c levels over 52 weeks of follow-up (174). secreted in response to food intake. diarrhea. Pramlintide is contraindicated in patients with hypoglycemia unawareness or a diagnosis of gastroparesis. and increasing satiety (167). pancreas. Endocr Pract. Incretin hormones increase insulin synthesis. Patients treated with pramlintide should reduce rapid-acting or short-acting insulin dosages (including fixed-mix insulins) by 50%.169). The inhaled insulin preparation has an onset of action similar to rapid-acting insulin analogs with a duration of glucose-lowering activity comparable to subcutaneously administered regular human insulin (176). Another dipeptidyl-peptidase 4 inhibitor. and brain that work in concert to regulate blood glucose (125). a self-administered injection given before meals. metformin (37). Inhaled insulin is contraindicated in patients who . liver. but have also been shown to decrease fasting plasma glucose levels. In vitro and in vivo animal models suggest that glucagonlike peptide 1 promotes proliferation and neogenesis from precursor β-cells (167. helps patients achieve lower blood glucose levels after meals. Exenatide is indicated for combination therapy with a secretagogue (sulfonylurea) (36). which increases the concentrations of these intestinally produced hormones that are decreased in patients with T2DM (170). Amylin has neuroendocrine actions that regulate glucose influx including suppression of glucagon. slowing the rate at which nutrients are absorbed.166).AACE Diabetes Mellitus Guidelines. Pramlintide is an antihyperglycemic drug used as an adjunct therapy in patients with diabetes mellitus who use prandial insulin and who have failed to achieve desired glycemic control. improved weight control. which is administered using an inhaler. a sulfonylurea. and it exhibits many of the same effects as the human incretin hormone glucagon-like peptide 1 (167). a secretagogue (sulfonylurea) plus metformin (38). and better long-term glucose control (HbA1c levels) compared with patients taking insulin alone (162-165). Incretin mimetics mimic the antidiabetic or glucoselowering actions of naturally occurring human hormones called incretins. Incretin Mimetics Exenatide Exenatide is the first in a new class of drugs. Amylin Analog Pramlintide Pramlintide is a synthetic analog of human amylin. On average. and increase satiety (171). a naturally occurring hormone that is cosecreted with insulin by the pancreatic β-cells (124). slowing of gastric emptying. and the dosage must be titrated. Findings from clinical studies demonstrate that pramlintide. delay gastric emptying.
2 AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13(Suppl 1) 2007
Table 4.5. Considerations for Oral Therapy in Patients With Type 2 Diabetes Mellitus (53)
Drug Class Primary Mechanism Possible Adverse Effects Monitoringa Comments
Sulfonylureas
Stimulates insulin release Inhibits hepatic glucose output
Hypoglycemia Weight gain
Biguanides
Dose-related diarrhea (usually self-limiting in 7-10 days) Lactic acidosis in patients with renal compromise
Fasting plasma glucose at 2 weeks HbA1c at 3 months
Serum creatinine at initiation Fasting plasma glucose at 2 weeks HbA1c at 3 months
Response plateaus after half maximum dose Glipizide and glimepiride may be preferred in elderly patients Less associated weight gain than with sulfonylureas and thiazolidinediones; weight loss may occur; helps limit weight gain in combination therapy Maximum effective dosage is 2 g/d Contraindications: Serum creatinine >1.5 mg/dL (men), >1.4 mg/dL (women) Congestive heart failure drug therapy Hepatic disease Alcohol abuse Administer with first bite of each meal Use slow titration to avoid gastrointestinal adverse effects (eg, 25 mg once daily for 2 weeks; then 25 twice daily for 2 weeks; then 25 mg three times daily for 8 weeks; maximum dosage is 100 mg three times daily) Must use glucose if hypoglycemia occurs
α-Glucosidase Inhibitors
Delays carbohydrate absorption to decrease postprandial hyperglycemia
Dose-related diarrhea, abdominal pain, flatulence
PPG at initiation HbA1c at 3 months
Thiazolidinediones
Enhances insulin sensitivity
Edema Weight gain Congestive heart failure
AST and ALT at baseline Monitor for signs of fluid overload
Glinides
Stimulates insulin secretion Restores GLP-1 and GIP levels
Hypoglycemia
DPP-4 Inhibitors
Not clinically significant
Fasting plasma glucose at 2 weeks HbA1c at 3 months PPG at initiation PPG at initiation Fasting plasma glucose at 2 weeks HbA1c at 3 months
Decrease in glucose may not be apparent for 4 weeks Maximum efficacy of dose may not be observed for 4-6 months Contraindications: ALT >2.5 times the upper limit of normal Hepatic disease Alcohol abuse NYHA class III or IV Commonly used for basalbolus dosing schedules
Reduce dosage in patients with renal insufficiency No weight gain or markedly reduced incidence of hypoglycemia
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DPP-4 inhibitors, dipeptidyl-peptidase 4 inhibitors; GIP, glucosedependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; HbA1c, hemoglobin A1c; PPG, postprandial glucose; NYHA, New York Heart Association cardiac disease and functional capacity. aAll measurements should be performed at the time noted after initiation of therapy and thereafter as directed by the patient’s physician.
AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13(Suppl 1) 2007 27
Table 4.6. Effect of Oral Therapies on Hemoglobin A1c Levels in Patients With Diabetes Mellitus Drug Therapy Monotherapy Sulfonylureas Biguanide (metformin) Thiazolidinediones α-Glucosidase inhibitors Dipeptidyl-peptidase 4 inhibitors Pramlintide Exenatide Noninsulin Injectables Hemoglobin A1c Reduction, % 0.9 to 2.5 (10,54) 1.1 to 3.0 (16,55-58) 1.5 to 1.6 (7,8,59) 0.6 to 1.3 (57,14,60) 0.8 (23) 0.43 to 0.56 (39) 0.8 to 0.9 (40) 1.7 (16) 1.4 (18) 1.2 (19) 1.3 (20) 1.4 (17) 0.7 (21) 0.8 (22) 0.7 (23) 0.7 (23)
Combination Therapy Sulfonylurea + metformin Sulfonylurea + rosiglitazone Sulfonylurea + pioglitazone Sulfonylurea + acarbose Repaglinide + metformin Pioglitazone + metformin Rosiglitazone + metformin Dipeptidyl-peptidase 4 inhibitor + metformin Dipeptidyl-peptidase 4 inhibitor + pioglitazone
have smoked within the previous 6 months or who have unstable or poorly controlled pulmonary disease. Although hypoglycemia is the most common adverse event reported in all insulin therapy, the most common respiratory event experienced by patients in clinical trials of inhaled insulin was cough, which was predominantly mild in severity and decreased with continued use of the inhaled insulin preparation. The Food and Drug Administration mandates pulmonary function testing before initiation of therapy, 6 months after initiation of therapy, and on an annual basis thereafter. 4.3. Clinical Support The following information is intended as assist clinicians in developing and implementing treatment strategies. The information is based on clinical experience and is not necessarily supported by the literature. 4.3.1. Initiating Insulin Therapy in Patients With Type 2 Diabetes Mellitus A basal-bolus regimen (long-acting insulin analog with rapid-acting insulin analog or inhaled insulin at meals) is the
most physiologic insulin regimen; however, many patients are reluctant to begin insulin therapy with this intensive approach (177). Instead, clinicians may consider starting with less intensive regimens and then adjust as needed. Common initial insulin regimens include: • Long-acting insulin analog • Long-acting insulin analog with rapid-acting insulin analog or inhaled insulin at largest meal of the day • Once daily premixed insulin analog (intermediateacting/rapid-acting insulin analog) at largest meal of the day • Long-acting insulin analog with rapid-acting insulin analog or inhaled insulin twice daily (breakfast and supper) • Premixed insulin analog or inhaled insulin twice daily (breakfast and supper) An initial dose of 10 units per injection is a safe starting dose for once daily and twice daily subcutaneously administered insulin regimens. Clinicians should refer to prescribing information for inhaled insulin starting doses and titration. More than 90% of patients with T2DM are insulin resistant (178); therefore, much higher doses are often required to achieve glycemic targets (97).
2 AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13(Suppl 1) 2007
When initiating insulin therapy, patients should measure blood glucose levels at least twice daily and provide selfmonitoring of blood glucose data to the clinician weekly (more frequently, if needed); stepwise adjustments can then be made in response to glucose values. For intermediateacting insulins: • Adjustments in prebreakfast dosages are based on presupper glucose levels • Adjustments in presupper dosage adjustments are based on prebreakfast glucose levels Two-hour postprandial glucose should be measured and addressed if the HbA1c level is elevated but premeal glucose levels are at target. Patients should also assess postprandial glucose levels periodically—even with favorable HbA1c levels—to detect unrecognized exaggerated postprandial glucose excursions. If a patient has not achieved glycemic goals after 2 to 3 months of therapy, or if recurrent hypoglycemia limits titration, the clinician should consider changing the regimen. The following recommendations are intended as guidelines for transitioning from less intensive to more intensive insulin regimens (177): • Transition from a long-acting insulin analog to a premixed insulin analog twice daily: o Divide the total daily dose in half by giving one half before breakfast, the other half before supper; this new regimen should be started 18 to 24 hours after the last basal dose was given o Titrate to goal based on self-monitoring of blood glucose data and diet history; the largest meal will require a larger proportion of insulin o Reduce the total dose by 20% if the patient experiences recurrent hypoglycemia • Transition from a once daily premixed insulin analog to a premixed insulin analog twice daily: o Divide the total daily dose in half by giving one half before breakfast, the other half before supper o Titrate to goal based on self-monitoring of blood glucose data and diet history; the largest meal will require a larger proportion of insulin o Reduce the total dose by 20% if the patient experiences recurrent hypoglycemia • Transition from a long-acting insulin analog to addition of a rapid-acting insulin analog at largest meal: o Give 10% of the total daily dose as a rapid-acting analog at largest meal o Reduce the basal dose by 10% • Transition from a premixed insulin analog twice daily to basal-bolus therapy (a long-acting insulin analog with a rapid-acting insulin analog at meals):
o o o
Divide the total daily dose in half Initial basal insulin dose = (total daily dose / 2) × 80% Initial prandial insulin dose = (total daily dose / 2) × percentage of estimated carbohydrates for each meal
4.3.2. Clinical Considerations Type 1 Diabetes Mellitus • Instruct patients to administer preprandial rapidacting analog insulin 20 to 30 minutes before the meal when the premeal blood glucose level is high and after the meal has begun when the premeal blood glucose level is below the reference range • Measure 2:00 AM to 3:00 AM blood glucose periodically in all patients with diabetes to assess for nocturnal hypoglycemia, especially when the morning blood glucose level is elevated • Consider using regular insulin instead of rapidacting insulin analogs to obtain better control of postprandial and premeal glucose levels in patients with gastroparesis; insulin pump therapy may also be advantageous in these patients • Some patients with T1DM treated with basal insulin may require 2, not 1, daily injections of basal insulin for greater stability • Carefully assess postprandial glucose levels when the HbA1c level is elevated and premeal glucose measurements are at target levels • Instruct patients to assess postprandial glucose levels periodically to detect unrecognized exaggerated postprandial glucose excursions even when the HbA1c level is at or near target • Arrange for continuous glucose monitoring for patients with T1DM with unstable glucose control and for patients unable to achieve an acceptable HbA1c level; continuous glucose monitoring is particularly valuable in detecting both unrecognized nocturnal hypoglycemia and postprandial hyperglycemia • Some patients using pramlintide may achieve better postprandial and premeal glucose control by combining it with regular insulin rather than rapidacting analogs • Individualize insulin regimens to accommodate patient exercise patterns • Treat hypoglycemic reactions with simple carbohydrates Type 2 Diabetes Mellitus • Combining therapeutic agents with different modes of action may be advantageous • Use insulin sensitizers such as metformin and/or thiazolidinediones as part of the therapeutic regimen in most patients unless contraindicated or intolerance to these agents has been demonstrated
Hirsch IB. Inc. Rosenstock J. Rosiglitazone monotherapy is effective in patients with type 2 diabetes [erratum in J Clin Endocrinol Metab.48:A106 (not rated) 20. and incretin mimetics do not cause hypoglycemia. Gomis R. Egan JW. Combination therapy with pioglitazone and sulfonylurea in patients with type 2 diabetes [abstract]. 2000. Schade DS.338:867-872. J Clin Endocrinol Metab. 2006. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. (LOE 1) 13.23:1605-1611. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Boyages S. 1991. Diabetes Care. Exubera (insulin human [rDNA origin]) Inhalation Powder [package insert]. Rendell M.22:33-37. (LOE 1) 14. Jovanovic L. Acta Diabetol. Goodman AM. Spengler M. (LOE 1) 18. Efficacy of metformin in the treatment of NIDDM.2:iv]. Houser V. Dole JF. Temelkova-Kurktschiev T. 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Hales CN. Frias JP. double-blind. Mechanism by which metformin reduces glucose production in type 2 diabetes. 2001. et al. Gary TL. 1999. 2007. (LOE 2) 125. Peters RK. Horm Metab Res. (LOE 1) 139. Effects of a new oral hypoglycaemic agent. Ader M. (LOE 2) . Brancati FL. Bogardus C. Whittemore R. 1993. The glucose fatty-acid cycle. Kruszynska YT.23:64-69. Diabetes Care. et al. 2000. 2000.47:788-792.1:785-789.49:2094-2101. Hirschberg Y.7:162-169. (LOE 1) 135. Whitcomb RW. Meyer PM. Annu Rev Med. 2000. Gerich JE. 1996. 2000. Vella A. Yu JG. Xiang AH. Mallows S. Hanefeld M. Tataranni PA. Buchanan TA.13(Suppl 1) 2007 33 119. Kruseman AC. Peck GM.278:G946G951. 1998. Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. 2000. Szarka LA. Dormandy JA. Diabetes Care. Guallar E. Dickinson S. 1996. Garland PB. Diabetes. Bailey CJ. 1998. Ishikawa M. placebo-controlled trial. 2000.46:1001-1009. (LOE 2) ( 124. Krssak M. Karara AH. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. et al. Genkinger JM. A randomized. Eckland DJ. Pramlintide. Metformin. Price TB. Effect of pioglitazone compared with glimepiride on carotid intimamedia thickness in type 2 diabetes: a randomized trial. Sung BH. (LOE 2) 144. (LOE 2) 133. controlled study. and lean normal subjects. Gerow K. Zinsmeister AR. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. Hanson RL.7:1399-1412. Gatlin M. Peyrot M.49:2063-2069. 2000. Development of glucagon-like peptide1-based pharmaceuticals as therapeutic agents for the treatment of diabetes. UK Prospective Diabetes Study (UKPDS) Group. 1991.7:222-223]. Zimmerman BR. Comparison of effects of thiazolidinediones on cardiovascular risk factors: observations from a clinical practice [erratum in Endocr Pract. 2000. Curr Pharm Des. 2003. Turner RC. 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5. endothelin. inhibit phosphatidylinositol-3. Comorbidities. Metabolic abnormalities associated with diabetes mellitus contribute to endothelial dysfunction. Angiotensin-Converting Enzyme Inhibitors Angiotensin-converting enzyme inhibitors suppress the biosynthesis of angiotensin II from its precursor. 5. Endothelial cells synthesize several potent bioactive substances that regulate blood vessel structure .2. The results of multiple large randomized controlled trials indicate that blood pressure control reduces morbidity and mortality (1). These substances include nitric oxide.14). and angiotensin II (21).1. nitric oxide helps to inhibit atherogenesis and to protect blood vessels.3. In individuals without diabetes. 2007. Detection. which causes excess release of free fatty acids from adipose tissue (24). HYPERTENSION MANAGEMENT 5.AACE Diabetes Mellitus Guidelines. and certain characteristics. Cardiovascular disease is the main cause of morbidity and mortality in patients with diabetes mellitus (2). to adequately control blood pressure (28). Pharmacology and Mechanisms of Action of Antihypertensive Agents The use of specific antihypertensive agents may benefit patients with diabetes mellitus by providing renal protection as well as stabilizing the endothelium and reducing the risk of coronary artery disease. and increase reactive oxygen species production. which result in vascular and metabolic consequences that contribute to morbidity. angiotensin I.13(Suppl 1) 2007 3 5. a reactive oxygen species that impairs nitric oxide formation (23). up to 14% of adults have T2DM associated with hypertension (2). prostaglandins. Executive Summary • • Aim for target blood pressure goals less than 130/80 mm Hg for management of hypertension in patients with diabetes mellitus (grade A) Use the following as first-line therapy for patients with diabetes mellitus: an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in combination with a low-dose diuretic. Evidence Base 5. all of these mechanisms directly affect nitric oxide production or decrease its bioavailability (25). calcium channel blocker. in turn. These agents in combination with diuretics may be required in some patients.1.2. stroke. Because angiotensinconverting enzyme inhibitors reduce the aldosterone response to sodium loss. Angiotensin-converting enzyme inhibitors and. may influence the choice of antihypertensive agents. Summaries of clinical trial findings are presented in Tables 5. The deleterious effects caused by excessive activation of the renin-angiotensin system at the molecular level and the benefit of regulating this system to reduce insulin resistance and to improve renal and cardiovascular outcomes is well demonstrated (7. Pathophysiology In people with diabetes mellitus. Hyperkalemia and a decline in renal function in patients with renal artery stenosis are concerns. The literature is rich with large randomized controlled trials that assess outcomes of different pharmacologic interventions for treating hypertension.19.26).2. other reactive species.2. activate protein kinase C. Approximately 25% of individuals with T1DM and more than 50% of individuals with T2DM have hypertension. 5. such as ethnicity and drug tolerance. angiotensin receptor blockers improve cardiovascular and renal outcomes via an effect that is independent of blood pressure reduction (7. and renal failure. Study findings consistently indicate that combination therapy is generally required to achieve adequate blood pressure control and to improve clinical outcomes (7). Endocr Pract. the bioavailability of endothelium-derived nitric oxide is reduced in individuals with diabetes mellitus (22).2. such as congestive heart failure. Overview Hypertension represents a serious risk for developing the complications of diabetes mellitus because it amplifies the effects of hyperglycemia in producing microvascular complications.1 and 5. Treating all middle-aged patients with T2DM who are able to tolerate angiotensinconverting enzyme inhibitors has been proposed to be cost effective (27). Hypertension is possibly a more clinically significant risk factor for macrovascular complications than hyperglycemia itself (1). Nitric-oxide production is further impeded by insulin resistance. and/or third generation β-adrenergic blocker in addition to lifestyle modification (grade A) Individualize hypertension therapy for patients with diabetes mellitus according to the specific comorbidities and individual needs of the patient in consultation with the patient’s physician (grade A) • and function. Hyperglycemia inhibits production of endotheliumderived nitric oxide synthase activation and increases the production of superoxide anion. Free fatty acids. However. hypertension is associated with insulin resistance and abnormalities in both the renin-angiotensin system and sympathetic tone. they have an excellent synergistic effect with diuretics and are also effective as monotherapy. controlling hypertension is critical in preventing myocardial infarction. and Treatment of High Blood Pressure (3) and the National Kidney Foundation (4). in some cases.2. particularly in elderly African American patients. In the African American population. ACE/AACE concurs with the target blood pressure goals of the seventh report of the Joint National Committee on Prevention. Therefore. Evaluation.
0.36). aP>. UKPDS. and neuropathy progression. Systolic Hypertension in Europe. 0.70 (95% CI. retinopathy progression. 2007. % Not reported Not reported 16 21c 70d Not reported Trial SHEP (5) Syst-Eur (6) HOPE (7) RENAAL (8) IPDM (9) HOT (10) Intervention and Primary Agents Thiazide diuretic vs usual care Calcium channel blocker vs placebo Angiotensin-converting enzyme inhibitor vs placebo Angiotensin II receptor blocker vs placebo Angiotensin II receptor blocker vs placebo Analysis Type Subgroup Subgroup Subgroup Primary Primary Subgroup UKPDS (11) Target diastolic blood pressure: <80 mm Hg or <90 mm Hg Agents: felodipine. HOPE. Heart Outcomes and Prevention Evaluation study. bNot significant.84-2. progression from microalbuminuria to overt albuminuria. then angiotensin-converting enzyme inhibitor or βadrenergic blocker ABCD (12) Target blood pressure: <180/105 mm Hg vs <150/85 mm Hg Agent: captopril or atenolol Primary 34e 18 37 Target diastolic blood pressure: 75 mm Hg vs 80 to 89 mm Hg Agent: nisoldipine or enalapril Primary No difference 49 No differencef Abbreviations: ABCD. . 0. Endocr Pract. cRenal outcomes (doubling of serum creatinine concentration and risk for end-stage renal disease).15). 1. dComparison for 300-mg dose of irbesartan.13(Suppl 1) 2007 Table 5. eP =0. 150-mg dose did not significantly reduce risk. Systolic Hypertension in the Elderly Program. IPDM.019. 0.36-1. Appropriate Blood Pressure Control in Diabetes.1. Irbesartan in Patients with Type 2 Diabetes Mellitus and Microalbuminuria. 1. United Kingdom Prospective Diabetes Study. 0. risk is for progression of nephropathy.38 (95% confidence interval [CI�. % 26 41 24 -2b Not reported 44 Relative Risk Reduction of Microvascular End Points. Hypertension Optimal Treatment. % 34 62 25 10a Not reported 51 Relative Risk Reduction of Total Mortality. Primary Trials of Drug Efficacy in Hypertension Control in Patients With Diabetes Mellitus Relative Risk Reduction of Total Cardiovascular Events. fNo combined end point reported.68-1. RENAAL.01-1. HOT. Syst-Eur. Relative risks for individual end points comparing intensive blood pressure control with moderate blood pressure control: progression from normoalbuminuria to microalbuminuria. SHEP.88 (95% CI.30 (95% CI.27). Reduction of End Points in Non–Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan.3 AACE Diabetes Mellitus Guidelines.66). 1.2.
gastrointestinal therapeutic system.61 20c -1c 23c Risk for microalbuminuria lower in the losartan group. Effects of Different Drug Classes in Patients With Diabetes Mellitus Treated for Hypertension Relative Risk Reduction of Total Cardiovascular Events. ALLHAT. IDNT. Irbesartan Diabetic Nephropathy Trial. Losartan Intervention for End Point Reduction in hypertension study. aNot significant.AACE Diabetes Mellitus Guidelines.2.28-0. NORDIL.13(Suppl 1) 2007 37 Table 5. . Captopril Prevention Project. International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment. (P = .51 (95% confidence interval. only doubling of the serum creatinine concentration was significantly lower with irbesartan treatment compared with either placebo or amlodipine treatment. Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial. GITS. LIFE.002) Not reported Not reported Secondary ALLHAT (20) Lisinopril vs chlorthalidone Amlodipine vs chlorthalidone Secondary -8a -6a -2a 4 Abbreviations: ABCD. 2007. STOP-2. % Not reported Not reported Not reported -29a Not reported Not reported Not reported Trial ABCD (12) FACET (13) CAPPP (14) UKPDS (11) NORDIL (15) INSIGHT (16) STOP-2 (17) IDNT (18) LIFE (19) Intervention and Primary Agents Enalapril vs nisoldipine Fosinopril vs amlodipine Captopril vs thiazide diuretic or βadrenergic blocker Captopril vs atenolol Diltiazem vs βadrenergic blocker or diuretics Nifedipine GITS vs coamilozide Calcium channel blocker vs diuretics or β-adrenergic blocker Angiotensin-converting enzyme inhibitor vs diuretics or βadrenergic blocker Angiotensin-converting enzyme inhibitor vs calcium channel blocker Irbesartan vs placebo Amlodipine vs placebo Irbesartan vs amlodipine Losartan vs atenolol Analysis Type Primary Primary Subgroup Primary Subgroup Subgroup Subgroup 15 12 Not reported 6b -14a Not reported Primary 9 12 -3a 24 8 12 -4a 0. Swedish Trial in Old Patients with Hypertension-2. INSIGHT. doubling of serum creatinine concentration plus development of end-stage renal disease equals all-cause mortality. Nordic Diltiazem study. bThe risk for myocardial infarction in the angiotensin-converting enzyme inhibitor treatment group was 0. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. UKPDS. % 67 51 41 -29a -1a 1 9 Relative Risk Reduction of Total Mortality. % 33 19 46 -14a -7a 0. Appropriate Blood Pressure Control in Diabetes. when assessed individually. Endocr Pract. United Kingdom Prospective Diabetes Study. cComposite microvascular end point.92) compared with the calcium channel blocker treatment group. 0.75 21 Relative Risk Reduction of Microvascular End Points. CAPPP. FACET.
Findings from the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) (39). National Diabetes Fact Sheet: Unites States 2005. and stroke compared with patients treated with a β-adrenergic blocker and a diuretic. Diuretics Thiazide diuretics more effectively lower blood pressure than loop diuretics in patients with normal renal function. angiotensin receptor blockers promote smooth-muscle relaxation. Endocr Pract. 2007. Deterioration of lipid parameters has not been reported with use of carvedilol (37). Results from long-term. Accessed August 1. this concept has recently been challenged by an extensive review of the literature (35). and increased HDL-C levels. endothelial dysfunction. β-Adrenergic blockers decrease myocardial oxygen consumption and myocardial use of free fatty acids (32). However. REFERENCES 1. Peripheral vascular resistance is reduced by these agents because they reduce interstitial fluid volume and smoothmuscle sodium concentration (29). control of peripheral adrenergic neuron function. β-Adrenergic Blockers β-Adrenergic blockers reduce myocardial contractility. Patients taking α-adrenergic blockers have a marked risk of orthostatic hypotension and an increased risk of congestive heart failure (24). Dihydropyridine agents increase proteinuria. increased insulin resistance. hypertension.13(Suppl 1) 2007 Angiotensin Receptor Blockers By blocking the effects of angiotensin II. Reflex sympathetically mediated tachycardia may occur in patients treated with calcium channel blockers.nih. 2006 (LOE 1) . renal salt and water loss. nondihydropyridines are less likely to have this effect (29). www. diuretics have been considered superior first-line agents in African American patients. are prevented by blockade of its receptor (30). α-Adrenergic blockers are generally reserved for combination therapy when other forms of treatment have failed (16). Favorable effects on lipids include reduced total and LDL-C levels. show that patients treated with an angiotensin-converting enzyme inhibitor (perindopril) and a calcium channel blocker (amlodipine) experience significant reductions in cardiovascular mortality. however. and increase insulin resistance. 2000. vasodilatation.pdf. Calcium Channel Blockers Calcium channel blockers decrease peripheral resistance by inhibiting transmembrane movement of calcium ions. the use of β-adrenergic blockers conferred a level of protection comparable to that of angiotensin-converting enzyme inhibitors (34). Centers for Disease Control and Prevention Web site. Historically. and an increase in prostacyclin biosynthesis (29). Carvedilol Carvedilol has nonselective β-blocking and α1blocking activity. decrease pancreatic insulin release. Other deleterious actions of angiotensin II. however. and decreased cellular hypertrophy (29). In the United Kingdom Prospective Diabetes Study (UKPDS). reduced triglyceride levels.321:412419. These agents also interfere with the recognition of and recovery from hypoglycemia. It improves insulin resistance and lowers blood glucose concentrations.gov/diabetes/pubs/2005_National_Diabetes_ Fact_Sheet. and no previous history of microalbuminuria when compared with an angiotensin-converting enzyme inhibitor (38). all-cause mortality. and increased oxidative stress. the reduction in blood pressure is effected via control of the central sympathetic nervous system. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. a change in baroreceptor sensitivity. the benefits of β-adrenergic blockers in reducing cardiac mortality in patients with diabetes mellitus usually outweigh their potential limitations (33). such as insulin resistance. and renin output.ndep. However. which followed 19 257 patients.3 AACE Diabetes Mellitus Guidelines. (LOE 3) 2. Stratton IM. diuretics may be particularly useful in patients with congestive heart failure. BMJ. Renal and cardiovascular outcomes are significantly improved by angiotensin receptor blockers as monotherapy (8) and in combination with angiotensin-converting enzyme inhibitors (31). randomized clinical outcome studies of carvedilol treatment in patients with hypertension and diabetes mellitus are not yet available. cardiac output. α-Adrenergic Blockers Arteriolar resistance and venous capacitance are reduced with the vasodilatation produced by α-adrenergic blockers. The significant reduction in cardiovascular mortality and morbidity prompted an early discontinuation of the trial (39). Adler AI. Available at:. Neil HA. At higher doses. Angiotensin-Converting Enzyme Inhibitors and Calcium Channel Blockers Combination therapy with angiotensin-converting enzyme inhibitors and calcium channel blockers is superior in efficacy compared with β-adrenergic blockers and diuretics. and elevations of LDL-C may occur. myocardial infarction. Although worsening hyperglycemia. reduction in plasma volume. but this finding is absent with verapamil and diltiazem because of their direct negative chronotropic effects. accumulating literature strongly argues against using β-adrenergic blockers as first-line antihypertensive therapy. the nondihydropyridine verapamil confers no protection in patients with diabetes mellitus. This agent is also beneficial in reducing the risk of microalbuminuria in the presence of renin-angiotensin system blockade. et al.
(LOE 1) 9. N Engl J Med. (LOE 2) Inoguchi T. JAMA. Brenner BM. et al. 2003. Hansson L. Katusic Z.317:703-713. Insulin-resistant lipolysis in abdominally obese hypertensive individuals. 2000. 2002. Detection. Lancet. Diabetes Care. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. (LOE 4) Milstien S. 2002. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. 2001. Kelly TM. et al. et al (the National Heart.18:16711675. Preserving renal function in adults with hypertension and diabetes: a consensus approach. and Blood Institute Joint National Committee on Prevention. Lehnert H. Hansson L.359:1004-1010. A summary of the effects of antihypertensive medications on measured blood pressure. Gifford N. (LOE 4) Hennes MM. Pressel SL. (LOE 1) Golan L. (LOE 3) Wu J. and Treatment of High Blood Pressure: the JNC 7 report [erratum in JAMA. 1996. Dahlof B. (LOE 1) Lindholm LH. Black HR. Kissebah AH. 2001. 20.18:935-942. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. 2007. 1998. (LOE 4) Beckman JA. 2000. and management. (LOE 1) 11. Creager MA. J Hypertens. (LOE 1) 14. Systolic Hypertension in Europe Trial Investigators. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. National High Blood Pressure Education Program). Biochem Biophys Res Commun. Bakris GL. Dworkin L. 1999. JAMA. Evaluation. (LOE 1) Lewis EJ.358:1556 and Lancet. O'Shaughnessy IM. et al. 17. and Treatment of High Blood Pressure.358:1033-1041. Welch HG. STOP Hypertension-2 Study Group. Endocr Pract. N Engl J Med.345:851-860. (LOE 4) 5. 2001. .356:366-372. (LOE 1 1) ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. 2000.291:2196�. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Palmer CR. 1998.28:120-126. Lancet.356:514�. Ugeskr Laeger. Ekbom T. Hypertension. Role of the renin-angiotensin system. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Parving HH. Umeda F. Brochner-Mortensen J. de Zeeuw D. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. UK Prospective Diabetes Study (UKPDS) Group. The Seventh Report of the Joint National Committee on Prevention. Hansson L. et al. Byington RP. et al. 24. 1999. (LOE 1) 13. Major outcomes in highrisk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [erratum in JAMA.36:646-661. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Ann Intern Med. (LOE 1) Cines DB. 2000. Diabetes and atherosclerosis: epidemiology. Evaluation. 1999. Lindholm LH. Hedner T. (LOE 1) 15. et al. 2005. 2002. 22. LaBelle P. (LOE 1) Lindholm LH.345:861-869. Comparison of antihypertensive treatments in preventing cardiovascular events in elderly diabetic patients: results from the Swedish Trial in Old Patients with Hypertension-2. Am J Hypertens. 1998. Hiatt WR. (LOE 3) PROGRESS Collaborative Group. Clarke WR. Cutler JA. 27. Tuomilehto J. 2001. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 [erratum in BMJ.355:253259. Bakris GL. BMJ. Pollak ES. Buck CA.AACE Diabetes Mellitus Guidelines.131:660-667.276:1886-1892. 21. (LOE 1) 4.91:3527-3561. 2003. et al. 2000. (LOE 1) 8. 2002. Lancet. 1998. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Chobanian AV. 2003. 26.353:611-616.359:2120�. 1996. The costeffectiveness of treating all patients with type 2 diabetes with angiotensin-converting enzyme inhibitors. Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function. Anderson S. N Engl J Med. Effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.318:29�. pathophysiology. 2000. Libby P. Carruthers SG. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) [erratum in Lancet. Zanchetti A. Tatti P.13(Suppl 1) 2007 3 3.356:359-365.21:597-603.287:2570-2581. Li P. (LOE 1 1) 10. Lung. Birkenhager WH. et al. Lancet. Lancet.356:860�. et al. 2004. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy [erratum in Lancet. et al.163:5519-5524.351:1755-1762. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 28. 23. Schrier RW. JAMA. JAMA. Am J Kidney Dis. Birkmeyer JD. Williams M. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. (LOE 1) 12. Amer P. (LOE 1) 6. 2000. Niskanen L.263:681-684.289:2560-2572. 2001. Jeffers BW. Detection. (LOE 1) 7. Hunsicker LG. et al. et al. N Engl J Med.289:178 and JAMA. 25. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6. Egan BM. Systolic Hypertension in the Elderly Program Cooperative Research Group. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study.49:19391945. Rastenyte D. Oberman A.340:677684. Hansson L. et al.288:2981-2997.289:2560-2572�. 19. (LOE 1) 16. Lund-Johansen P. 2000. HOT Study Group. 1999. Biggerstaff SL. Gomis R. Curb JD. 1999.338:645-652. Blood. Effect of diureticbased antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. 18. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Cooper ME. et al. et al. (LOE 1) Brown MJ. Pahor M. Diabetes. Ibsen H. 1998. Estacio RO.105 individuals with previous stroke or transient ischaemic attack [erratum in Lancet. Kraja AT. Castaigne A.
In patients with T1DM and T2DM. Kidney Int.0 AACE Diabetes Mellitus Guidelines. and small.361:1149-1158.2. Ritz E. 1997. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Waldenstrom A. A primary goal is to reduce the LDL-C level to less than 100 mg/dL. Evidence Base 6. 1997. Combined hypertension and orthostatic hypotension in older patients: a treatment dilemma for clinicians. low HDL-C levels. Preventive pharmacologic interventions have proved beneficial (eg. 2005. Fonseca V. ACE/AACE also endorses the more aggressive option of the National Cholesterol Education Program Adult Treatment Program III update—targeting the LDL-C goal of less than 70 mg/dL in high-risk individuals (4).317:713-720. however. Aggressive lipid management is critical to reduce morbidity and mortality. Ann Intern Med. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations. Ilieva AP. Ryden L. BMJ.292:2227-2236. patients with diabetes mellitus older than 40 years who were treated with simvastatin (with the goal of reducing the LDL-C level by 30% from a baseline measurement) showed a 25% reduction in the first-event rate for major coronary artery events. van Montfrans GA.2. dense LDL-C particles are highly atherogenic because of their enhanced susceptibility to oxidation and increased uptake by the arterial wall (6). 36. Katholi RE. Endocr Pract. NY: McGraw-Hill. in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Beta-adrenergic blocking agents in patients with diabetes--friend and foe. • • 35. (LOE 1) Sever PS. (LOE 2) Sowers JR. et al (Bergamo Nephrologic Diabetes Complications Trial [BENEDICT] Investigators). Atherosclerosis occurs earlier in life. 2004. Hamsten A. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. JAMA. 2004. In the Heart Protection Study (5).141:614-627. and statin plus omega-3 fatty acids (grade C) Use fibrates as primary therapy for patients with triglyceride levels greater than 400 mg/dL (grade C) Use fibrates cautiously in combination with statins because of the risk of rhabdomyolysis. Herlitz J. 2004. Executive Summary • Aggressive management of dyslipidemia in patients with diabetes mellitus is critical. the condition increases the occurrence of and accelerates the progression of coronary events. Limbird LE. Expert Rev Cardiovasc Ther. LIPID MANAGEMENT 6. 38. Poulter NR. Hardman JG. 39.1. Lancet. 34. 6. et al (ASCOT Investigators). (LOE 1 1) • • • 32. and findings from randomized controlled 37. Cardiovasc Res. note that benefits may differ between women and men (grade A) 6. Dahlof B.67:799-812. is more diffuse.1. New York. Endocr Pract. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. (LOE 1 1) Malmberg K. (LOE 2) Lee T. Systematic review: antihypertensive drug therapy in black patients. Women with T1DM are more likely to die of coronary artery disease than women without diabetes (3). 10th ed. (LOE 2) Wolf G. 1998. These small. Gilman AG. aspirin). Mortality prediction in diabetic patients with myocardial infarction: experiences from the DIGAMI study [erratum in Cardiovasc Res. Kleijnen J. statin plus niacin.351:1941-1951. 1999. dense LDL-C particles. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. (LOE 1) Brewster LM. Fassi A. 31. Moore A. 2001. treat patients to achieve the following goals (grade A): o LDL-C <100 mg/dL (<70 mg/dL is recommended for patients with diabetes mellitus and coronary artery disease) o HDL-C >40 mg/dL in men and >50 mg/ dL in women o Triglycerides <150 mg/dL Lifestyle modifications are essential (grade D) Statins are the pharmacologic treatment of choice (grade A) • • . Wedel H.286:H1597-H1602. The lipoprotein pattern in patients with diabetes mellitus is typically characterized by moderate elevation of triglyceride levels.13(Suppl 1) 2007 29. Donegan C.34:248-253. N Engl J Med. statin plus bile-acid sequestrant. and peripheral arterial disease (2). and is associated with higher mortality rates in individuals with T1DM compared with the general population. 2004. Overview Diabetes mellitus is a cardiovascular risk equivalent (1). statin plus ezetimibe. 30.36:460� . 2003. (LOE 3) UK Prospective Diabetes Study (UKPDS) Group. 2005.5:51-53. (LOE 1) Bell DS. • • 33. et al. strokes. independent of the baseline LDL-C levels. this risk is markedly lower for fenofibrate than for gemfibrozil (grade C) Niacin may be a useful adjuvant when the primary abnormality is a low HDL-C level (grade D) Use low-dose aspirin prophylaxis routinely unless a specific contraindication is present. (LOE 1) Ruggenenti P.3:433-440. Am J Physiol Heart Circ Physiol. Use ezetimibe in patients who are intolerant of statins or in combination with statin therapy and other lipidmodifying agents (grade B) Combination therapy is indicated in patients who have not achieved the desired goals with monotherapy (grade C) Multiple options are available for combination therapy including statin plus fibrate. Preventing microalbuminuria in type 2 diabetes. (LOE 4) Bakris GL. Insulin resistance and hypertension. lipid-modifying agents. 2007.
9). there is a relationship between the LDL-C level and the risk of cardiovascular events (11). and vasoconstriction (28). and a preponderance of small. Markers The management of patients with diabetes mellitus involves estimating the risk of coronary artery disease and implementing appropriate risk reduction strategies. Ethnic differences in the risk of clinical coronary artery disease may exist in individuals with diabetes mellitus (10).2. and peripheral arterial disease. Data suggest that large variability in glucose excursions causes oxidative stress (30. intercellular adhesion molecule 1. Use of biochemical markers associated with increased cardiovascular disease risk has been advocated (11. Compared with individuals without diabetes. C-Reactive Protein C-reactive protein is considered an independent predictor of cardiovascular events. enhanced platelet aggregation. and risk of coronary disease is directly related to duration of diabetes (8. Certain lipid-modifying agents may be preferred in patients with diabetes mellitus because of the underlying pathophysiology and comorbidities. activation of vascular angiotensin-converting enzyme. Compared with individuals without diabetes. Hyperglycemia results in generation of reactive oxygen species that lead to increased oxidative stress and subsequent decreased nitric oxide bioavailability. the longterm and short-term prognoses following a coronary event are worse in patients with diabetes mellitus. regardless of weight. leading to the activation of the transcription factor designated as nuclear factor–κB. These end-products bind to their receptors.2. which evaluated 2316 men with diabetes mellitus who had no history of cardiovascular disease (14). After sustaining a cardiovascular event. Cardiovascular fitness is associated with a lower risk for cardiovascular disease mortality in overweight and obese people with diabetes mellitus. it is the most widely studied inflammatory marker (33.3.16). Hyperglycemia has been associated with increased oxidative stress. 6. individuals with T2DM have a 2-fold to 4-fold higher incidence of coronary artery disease (16) and a 3fold higher incidence of stroke (16-18). and death are increased compared with the general population.2. Cardiovascular markers such as C-reactive protein and lipoprotein-associated phospholipase A2 may potentially assist in identifying high-risk patients and in instituting preventive measures (11-13). leading to the formation of advanced glycation end-products (29). Pathophysiology Cardiovascular disease is the leading cause of morbidity and mortality in individuals with diabetes mellitus. Homocysteine The mechanisms by which homocysteine potentially contributes to cardiovascular risk include increased oxidative stress. dense LDL-C particles that are highly atherogenic (6.9). stroke.32). vascular smooth muscle proliferation. decreased HDL-C levels. Lifestyle modifications including diet. revascularization procedures and particularly percutaneous coronary intervention are less effective in patients with diabetes than in the nondiabetic population (22). 6. and it is as strong as the relationship observed between LDL-C levels and risk of cardiovascular events (11). increases in homocysteine levels have also been noted with .34). Mild to moderate elevation of homocysteine may contribute to the atherosclerotic process (36). Rationale for Therapy The characteristic dyslipidemia of T2DM includes elevated triglyceride levels.13(Suppl 1) 2007 1 trials support the therapeutic recommendations as discussed in the following section. Endothelial dysfunction is an early manifestation of atherosclerosis. Diabetes blunts the beneficial effects of female sex.4. weight management. patients with diabetes have worse short-term and long-term prognoses compared with patients without diabetes (19-21). In addition. congestive heart failure. and tobacco avoidance are of utmost importance. In patients taking statins. The rates of reinfarction. Prospective observational data was obtained from the Aerobics Center Longitudinal Study. The main outcome measure was cardiovascular disease mortality across levels of fitness with stratification by body mass index. 6.31). Types of cardiovascular disease include coronary. Endocr Pract. Revascularization procedures are less successful in patients with diabetes mellitus than in patients without diabetes (9).24). and activation of nuclear factor–κB. A significantly higher mortality rate was observed in men with a low fitness level. and venous thromboembolism (35). and the prognosis following an acute cardiovascular event is worse in women than in men (7). Findings from a meta-analysis of 27 studies indicate that elevated levels of homocysteine are associated with an increased risk of coronary artery disease. 2007. Plaque morphology has an important role in diabetic atherothrombosis (25-27). and it is eventually associated with plaque instability leading to cardiovascular events. Atherosclerosis is an inflammatory disease (23. Diabetes is associated with an accelerated and diffuse process of atherosclerosis.2.AACE Diabetes Mellitus Guidelines. Increased monocyte adhesion and migration into the vessel walls occurs by increasing endothelial expression of monocyte chemoattractant protein-1. However. and it accounts for approximately 80% of deaths in this population (15. exercise (7). and vascular cell adhesion molecule 1. There is also a relationship between higher C-reactive protein levels and increased risk of a cardiovascular event—this relationship is present regardless of the LDL-C level. cerebrovascular. peripheral arterial disease.
This reduces hepatic cholesterol stores and increases clearance of cholesterol from plasma. 6. Nicotinic Acid Nicotinic acid (niacin) inhibits the hepatic synthesis of triglycerides and the secretion of VLDL-C by hindering the mobilization of free fatty acids.41). monocytes.5. Fibrinogen Fibrinogen is an important component of the coagulation pathway. These agents are contraindicated in patients with hypertriglyceridemia. and hepatotoxicity. Adverse effects from fibrates may include dyspepsia.5%. upper-gastrointestinal distress. Bile-Acid Sequestrants Bile-acid sequestrants lower cholesterol levels by forming complexes with the cholesterol-containing bile acids in the gastrointestinal tract. gallstones. which then reduces very low-density lipoprotein cholesterol (VLDL-C) secretion.13(Suppl 1) 2007 aging. Cholesterol-Lowering Agents Statins Statins act as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A reductase and thereby interfere with the hepatic biosynthesis of mevalonate. . mild hyperglycemia. and that both effects are independent predictors of the reduction in atheroma volume if the LDL-C level is reduced below 87. Lipoprotein(a) Lipoprotein(a) is associated with impaired fibrinolysis (43). Elevated plasma fibrinogen levels are predictive of stroke and myocardial infarctions (42). cyclosporins. and chronic kidney disease.39). Elevated levels of cell adhesion molecules have been associated with diabetes mellitus and noted in people at increased risk for diabetes. interrupting the enterohepatic circulation of bile acids. and increased expression of intercellular adhesion molecule 1 in endothelial cells (45). niacin therapy is safe and effective in this patient population (51). Concomitant use of certain drugs are contraindicated (eg. Niacin increases HDL-C levels and reduces cardiovascular morbidity and mortality (50). Endocr Pract. a precursor of cholesterol. They found that statins result in favorable changes in both LDL-C and HDL-C levels. Lipoprotein-associated phospholipase A2 is bound primarily to LDL-C and preferentially cleaves oxidized LDL-C.5 mg/dL and the HDL-C level is increased by more than 7. Other Markers Other potential markers include E selectin.2. This enzyme is secreted by inflammatory cells (eg. Although use of niacin in patients with diabetes mellitus has been limited because of associated increased hyperglycemia. erythromycin) because of increased risk of myopathy.2 summarizes the findings from major clinical trials with fibrates. low levels of vitamin B6 and B12. Adverse effects of niacin therapy include flushing. folate deficiency.13. hyperuricemia. An up-regulation of low-density lipoprotein receptors increases the clearance of LDL-C.38). Administration of supplements containing folic acid and vitamins B6 and B12 is not cardioprotective (37. Nicholls and colleagues (48) conducted a meta-analysis of 4 studies using the intravascular ultrasound technique to examine the relationship between changes in lipoprotein levels and coronary artery atheroma volume. menopause. Table 6. during advancing age or menopause. 2007. vascular smooth muscle cell proliferation (44). Table 6. Recently. Fibrates and niacin can be used with caution in combination therapy (47).1 summarizes the findings from major clinical trials with statins. and myopathy. a common condition in people with diabetes mellitus. vascular cell adhesion molecule. macrophages. and tumor necrosis factor α. and increasing hepatic conversion of cholesterol into bile acids. T lymphocytes) and may play a role in the progression of atherosclerosis (12.13. Statins are associated with a low incidence of myopathy and elevation of liver enzymes. These products exert an atherogenic effect by attracting monocytes and T lymphocytes to the atherosclerotic plaque and enhancing the expression of vascular cell adhesion molecules (12. They decrease endothelial cell activation by proinflammatory cytokines and reduce tissue factor production by human macrophages (49). and in patients who smoke. hypothyroidism.39). Lipoprotein(a) is also associated with increased risk of cardiovascular events when plasma levels exceed 20 to 30 mg/dL (46).2 AACE Diabetes Mellitus Guidelines. Fibrinogen levels have been associated with several risk factors for coronary heart disease and peripheral arterial disease (40. Lipoprotein-Associated Phospholipase A2 Lipoprotein-associated phospholipase A2 is an emerging independent specific risk marker for cardiovascular disease. Ezetimibe Ezetimibe selectively inhibits the absorption of dietary cholesterol from the gastrointestinal tract by action at the brush border of the small intestine. Plasma levels of fibrinogen typically increase in patients with diabetes mellitus or adiposity. Fibric Acids Fibric acids (fibrates) accelerate the degradation of lipoproteins by activating lipoprotein lipase and reducing hepatic apoprotein synthesis. resulting in the formation of 2 inflammatory products— lysophosphatidylcholine and free oxidized fatty acids.
A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden. low-density . median reduction) Abbreviations: 4S. CARE. Treating to New Targets. HPS. Major Clinical Trials Using Statins in Patients with Diabetes Mellitus Mean Baseline LDL-C. ASCOT-LLA. Subjects 202 586 5963 2838 2532 4162 (diabetic and nondiabetic subjects) Outcome (Relative Risk Reduction) Total mortality (43%) Major coronary heart disease event (55%) Major coronary heart disease event (13%) Expanded end point (25%) Major coronary heart disease event (27%) Any major cardiovascular event (22%) Acute coronary heart disease event (36%) Any major cardiovascular event (48%) Major coronary heart disease event (16%) Total cardiovascular events and procedures (23%) Primary end point: death from any cause. Reversal of Atherosclerosis with Aggressive Lipid Lowering. lipoprotein cholesterol. acute myocardial infarction. IDEAL. defined as death from coronary heart disease. Incremental Decrease in End Points Through Aggressive Lipid Lowering. or fatal or nonfatal stroke (22%. REVERSAL. ASTEROID. PROVE-IT. documented unstable angina requiring rehospitalization. cardiac arrest with resuscitation (11%.8%.13(Suppl 1) 2007 3 Table 6. Pravastatin or Atorvastatin Evaluation and Infection Therapy. . revascularization (performed at least 30 days after randomization). TNT. revascularization (25%) First major cardiovascular event. resuscitation after cardiac arrest. whereas moderately treated patients showed progression ASTEROID (68) 130 Regression of coronary atherosclerosis determined by intravascular ultrasound (6. Endocr Pract.AACE Diabetes Mellitus Guidelines. Heart Protection Study. Collaborative Atorvastatin Diabetes Study. Scandinavian Simvastatin Survival Study. LDL-C. and stroke (16%) Secondary end point: death due to coronary heart disease. CARDS. mg/dL 186 136 124 117 128 … Trial 4S (60) CARE (5) HPS (61) CARDS (62) ASCOT-LLA (63) PROVE-IT (64) Medication (Dosage) Simvastatin (10-40 mg once daily by mouth) Pravastatin (40 mg once daily by mouth) Simvastatin (40 mg once daily by mouth) Atorvastatin (10 mg once daily by mouth) Atorvastatin (10 mg once daily by mouth) Pravastatin (40 mg once daily by mouth) vs atorvastatin (80 mg once 80 daily by mouth) Atorvastatin (10 mg once daily by mouth vs 80 mg once daily by mouth) Atorvastatin (80 mg once daily by mouth) vs simvastatin (20 mg once daily by mouth) ) Atorvastatin (80 mg once daily by mouth) vs pravastatin (40 mg once daily by mouth) Rosuvastatin (40 mg once daily by mouth) No. Cholesterol and Recurrent Events Trial. myocardial infarction. myocardial infarction. diabetic and nondiabetic subjects) TNT (65) <130 10 001 (diabetic and nondiabetic subjects) 1069 diabetic subjects (8888 total) 654 (diabetic and nondiabetic subjects) 28 diabetic subjects (191 total) IDEAL (66) 121 REVERSAL (67) 150 Intensively treated patients had no change in atheroma burden. nonfatal non– procedure-related myocardial infarction.1. 2007. diabetic and nondiabetic subjects) Coronary death. Anglo-Scandinavian Cardiac Outcomes Trial—LipidLowering Arm.
6. leading to increased risk of myopathy. Diabetes Atherosclerosis Intervention Study. (b) statins appear to have pleiotropic effects. Gemfibrozil interferes with the glucuronidation of statins. Simvastatin has been evaluated in combination with fenofibrate. HDL-C. LDLC. and (c) patients often still have significant residual risks of atherogenesis and cardiovascular morbidity and mortality despite maximal dosage and effect of any one agent.2. Fenofibrate Intervention and Event Lowering in Diabetes. Major Clinical Trials Using Fibrates in Patients with Diabetes Mellitus Trial Medication (Dosage) No. triglycerides. FIELD. Plant Sterols and Stanols Plant sterols and stanols displace cholesterol from bile-salt micelles. Hepatotoxicity from high-dose niacin may cause decreased clearance of the statin. The fibrates beneficially affect inflammation and thrombotic processes. some evidence suggests that these fatty acids have direct cardioprotective effects. Veterans Affairs HDL Intervention Trial. Thiazolidinediones Thiazolidinediones may decrease the concentration of small. and it shows greater reduction of triglyceride levels and greater increase in HDL-C levels than either agent alone (55).5 g/d) has been reported. dense LDL-C and increase the resistance of LDL-C to oxidation (54). Ezetimibe is effective when used alone. Combination Therapy Using combination therapy to lower cholesterol is logical for several reasons: (a) the various lipid-lowering medications have different mechanisms of action and differentially affect the lipid classes (ie. and findings from clinical trials . AACE Diabetes Mellitus Guidelines. Fenofibrate is associated with lower risk of myopathy than gemfibrozil. A meta-analysis of 97 studies involving more than 100 000 subjects found that cardiac mortality was reduced by 32% in subjects treated with omega-3 fatty acids (53). omega-3 fatty acids reduce triglyceride levels.13(Suppl 1) 2007 Table 6. thereby reducing intestinal cholesterol absorption (52). Omega-3 Fatty Acids In high doses. The clinician must titrate niacin gradually to minimize the undesirable effects of flushing and to monitor blood glucose levels to ensure that the niacin does not deteriorate glycemic control. VA-HIT. Myopathy occurring with the use of lovastatin and high doses of niacin (≥2. This drug class is discussed in greater detail in Section 4. 2007. In addition. Statin + Ezetimibe The combination of a statin and ezetimibe is convenient because a combination pill is available.6. Subjects 633 diabetic subjects (2531 total) 713 Outcome (Relative Risk Reduction) VA-HIT (69) Gemfibrozil (600 mg twice daily by mouth) Fenofibrate (200 mg/d) Acute coronary heart disease events (22%) Stroke (31%) Acute coronary heart disease events (23%) Acute coronary heart disease events (19%) Nonfatal myocardial infarction (24%) DAIS (70) FIELD (71) Fenofibrate (200 mg once daily by mouth) 9795 Abbreviations: DAIS. Findings from the High Density Lipoprotein Atherosclerosis Treatment Study (56) show a 90% reduction in composite cardiovascular end points for statin and niacin combination therapy compared with placebo. leading to increased serum levels of the agent and hence increased risk of myopathy and hepatotoxicity. and it consistently reduces LDL-C and triglyceride levels. VLDL-C. dense LDL).2. Statin + Fibrate The combination of a statin and a fibrate reduces LDLC and triglyceride levels and achieves a greater increase in HDL-C levels than either agent alone. small. Statin + Niacin The combination of a statin and niacin has additive effects on increasing the HDL-C level. particularly when used in combination with statins. Endocr Pract.
Lipsitz SR. et al (National Heart. N Engl J Med. Diabetes Care. The recommended dosage of omega-3 fatty acids is 3 to 4 g/d. Arch Intern Med. 2000. Lung. 12. Conclusions We have witnessed tremendous advances in the ability to reduce cardiovascular morbidity and mortality in patients with diabetes mellitus.153:483490. Haffner SM. (LOE 1) Natarajan S.27:704-708. (LOE 2) Ridker PM. (LOE 2) Goldberg RB. 5. exhibit antithrombotic and fibrinolytic activities.165:430-435. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines [erratum in Circulation. Arch Intern Med. which does not preclude its use. Langefeld CD. Endocr Pract. McGee DL. and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. 2005. D'Agostino RB Sr. 2004. 4. The significant effect of diabetes duration on coronary heart disease mortality: the Framingham Heart Study. Hsu FC. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without 2. reduce blood viscosity. Mellies MJ. dense LDL-C and increases the HDL-C level. Liao Y. reduce platelet aggregation. and patients still have notable residual risk for cardiovascular disease. To achieve still greater risk reduction. the average risk reduction is approximately 25% to 35%. Ezetimibe is also effective when combined with a bile-acid sequestrant (57). 2005. Diabetologia. Circulation. weight reduction. Report of the National Heart. Cannon CP. Merz CN. Veerkamp MJ. et al. particularly by lowering triglyceride levels and increasing HDL-C levels. Hoogeveen RC. 1998. Atherosclerosis. Circulation. and Blood Institute. Specifically. Intensive control of hypertension and glycemia is essential as addressed in other sections of this guideline. Bredie SJ. 6. 2005. 8. Niacin is indicated for increasing HDLC levels. high-sensitivity C-reactive protein. 10. 2001. et al (Prevastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22 [PROVE IT-TIMI 22] Investigators). 2004. and smoking cessation. The impact of ethnicity and sex on subclinical cardiovascular disease: the Diabetes Heart Study. Sullivan L. (LOE 1) Demacker PN. et al (National Heart Lung. 6. Statin + Omega-3 Fatty Acids The combination of a statin and omega-3 fatty acids is an important option. et al. Salomaa V. Cao G. Sex differences in the effect of diabetes duration on coronary heart disease mortality.2. 11. combination therapy with ezetimibe and simvastatin is well tolerated and more effectively lowers LDL-C levels than increasing the simvastatin dosage in patients with T2DM who are also taking thiazolidinediones (59). exercise. et al. triglyceride levels are essentially unchanged (57). Sinha D.13(Suppl 1) 2007 suggest a synergistic effect with simvastatin or atorvastatin. Lipoproteinassociated phospholipase A2.110:227-239. 1998. This treatment reduces the concentration of small.165:2479-2484. (LOE 1) Libby P. Aspirin should be included in the therapeutic regimen. Lehto S. exhibit antiinflammatory action. although it has been associated with a modest deterioration of glycemic control. and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. (LOE 1) Freedman BI. Nathan DM. C-reactive protein levels and outcomes after statin therapy. 7. 1998. This observation allows the clinician to use a lower statin dosage to maintain the same level of LDL-C. 2007. 3. Coadministration of ezetimibe with statins is well tolerated and effective in lowering LDL-C levels in patients with diabetes mellitus (58). Sacks FM. et al. Impact of diabetes on mortality after the first myocardial infarction. Wilson PW (Framingham Heart Study).110:763�. Comparison of the measurement of lipids and lipoproteins versus assay of apolipoprotein B for estimation of coronary heart disease risk: a study in familial combined hyperlipidemia. prior myocardial infarction. Arch Intern Med. Lung. (LOE 1) Hu FB. (LOE 1) Fox CS. more aggressive intervention at earlier stages in the disease process is necessary. Morrow D. The FINMONICA Myocardial Infarction Register Study Group. American College of Cardiology Foundation. de Graaf J. The combination of a statin and ezetimibe has an excellent safety profile.339:229234. N Engl J Med. Laakso M. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. Stampfer MJ. Marcovina SM. Lehto S. REFERENCES 1. Abraham K. especially in patients with hypertriglyceridemia. (LOE 1) Miettinen H. 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95:462-468. Betteridge DJ.354:778�.96:61F68F. Pedersen TR. (LOE 1) 64. Sipahi I. 2005. History and development of plant sterol and stanol esters for cholesterol-lowering purposes. et al. Rubins HB. Lewin A. 1997. Tuzcu EM. Briel M. Executive Summary • • • Medical nutrition therapy is an essential component of any comprehensive diabetes mellitus management program (grade A) Meal composition affects glycemic control and cardiovascular risk (grade A) Tailor a diet for individual patients based on current weight. (LOE 1) 61. (LOE 2) 53. N Engl J Med.284:1263-1270. 2005. Parish S. et al (CARDS Investigators). Bucher HC. (LOE 1) 59. PPAR-alpha activators inhibit tissue factor expression and activity in human monocytes. Thompson GR.297:499-508. Endocr Pract. Rationale for targeting multiple lipid pathways for optimal cardiovascular risk reduction. Lancet. Braunwald E. Faergeman O.26:1513-1517. 2003. Arterial Disease Multiple Intervention Trial. Diabetes Care. et al. Diabetes Obes Metab. 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Peto R (Heart Protection Collaborative Group). Grundy SM. Poulter NR. (LOE 2) 49. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: A randomized trial. Collins R. Effects of ezetimibe added to on-going statin therapy on the lipid profile of hypercholesterolemic patients with diabetes mellitus or metabolic syndrome. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Nicholls SJ. Glass TR. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S) [erratum in Diabetes Care.1. or the combination for the prevention of coronary disease.323:1289-1298.103:213-219. Masana L. Vega GL. Kastelein JJ. (LOE 1) 58. Simes RJ. JAMA. 2007. Effect of intensive lipid lowering on progression of coronary atherosclerosis: evidence for an early benefit from the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. Durrington PN. McCabe CH. et al (Prevastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators). et al (Treating to New Targets [TNT] Investigators).361:2005-2016. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Faas FH. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Zhao XQ. antioxidant vitamins. et al. lifestyle.28:1151-1157. 2006. Relationships between low-density lipoprotein particle size. and regression of coronary atherosclerosis. Troglitazone decreases the proportion of small. (LOE 1) 62. 2001. Curr Med Res Opin. (LOE 1) 70. Mackman N. Studer M. Marx N. Circulation. and lipid profile (grade A) . 1998. Yuan Z. (LOE 1) 67. Sleigh P. 1997. Grundy SM.107:1733-1737. (LOE 1) 68. et al (FIELD Study Investigators).364:685-696. (LOE 2) 50. 2005. JAMA. et al. 2005. et al (Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] Study Group). Reduction in cardiovascular events with atorvastatin in 2.352:1425-1435. 2005. Diabetes Care. 2003. Brown BG. plasma lipoproteins.AACE Diabetes Mellitus Guidelines. Statins.345:1583-1592. (LOE 1) 66. 2004. Am J Cardiol. (LOE 2) 52. Davis KB.350:14951504. (LOE 1) 69. Diabetes Care. Tonkon M. Simons L. et al. 2006. et al. 2005. Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT).20:1048�. Battisti WP. Vakkilainen J. (LOE 1) 65. dense LDL and increases the resistance of LDL to oxidation in obese subjects. Chait A. (LOE 1) 56. 2005. 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800 to 1000 mg/d (stages 3-5). Dietary saturated fat should be limited to less than 10% of total daily energy intake with fewer than 300 mg/d of cholesterol (2. Overview Fiber should be consumed in amounts of 25 to 50 g/ d or 15 to 25 g/1000 kcal ingested (1). phosphate. For example. Endocr Pract. Restricting cow’s milk during the first year of life (16) and avoiding vitamin D deficiency (17. consider additional micronutrients such as zinc and oral vitamins C and A depending on the severity of the wounds and the nutritional status of the patient (grade D) 7. and cholesterol should be limited to less than 200 mg/d (grade A) o Trans-fat intake should be minimized. Patients With Type 1 Diabetes Mellitus The key to successful medical nutrition therapy is synchronizing carbohydrate intake with insulin therapy. and blood pressure is a tertiary preventive strategy for the complications of diabetes mellitus (grade A) Restrict the following in patients with chronic kidney disease: sodium.6 g/d (stages 3-4). Terms such as simple sugars and complex carbohydrates have recently been abandoned since it is now recognized that their effects on blood glucose are similar (12).8 g/d (stages 1-2). Dietary monounsaturated fatty acids and n-3 polyunsaturated fatty acids have beneficial effects on the lipid profile and should comprise most fat intake (3-6). saturated fat should be limited to less than 7% of total energy intake. exercise. potassium. eliminated (grade D) Basal-bolus insulin therapy using insulin analogs or continuous subcutaneous insulin infusion in conjunction with carbohydrate counting is the most physiologic treatment and provides the greatest flexibility in terms of food choices and timing of meals (grade B) Basal-bolus therapy using a consistent carbohydrate meal plan can be equally effective for patients unable or unwilling to count carbohydrates (grade D) Instruct patients who choose to consume alcohol to limit intake to 1 drink per day for women and 2 drinks per day for men (grade D) Secondary prevention strategies for T2DM in individuals with impaired glucose regulation include a controlled-energy diet. 1. lipids. 2 to 3 g/d (stage 5 on hemodialysis) and 3 to 4 g/d (stage 5 on peritoneal dialysis). basal-bolus therapy using a consistent carbohydrate meal plan can be equally effective (15). Evidence Base 7. Considering the glycemic index and the glycemic load of foods is another tool that can be used to optimally time the mealtime insulin injection (12). fat (8. For patients unable or unwilling to count carbohydrates. consumption of saturated fat should be limited to less than 7% of daily energy intake.2. Early exposure to wheat gluten (19) as well as nitrates and nitrites (20) may increase the risk for T1DM. or preferably. 0.1. Currently.13(Suppl 1) 2007 • • • • • • • • • • • • No specific diet is endorsed by ACE/AACE for people with diabetes mellitus (grade D) Total dietary carbohydrates should represent 45% to 65% of daily energy intake unless otherwise indicated (grade D) Protein intake should be the same as for patients who do not have diabetes mellitus: 15% to 20% of daily energy intake (grade D) Fiber should be consumed in amounts of 25 to 50 g/d or 15 to 25 g/1000 kcal ingested (grade A) Total dietary fat should generally comprise less than 30% of daily energy intake (grade D): o Dietary monounsaturated fatty acids and n-3 polyunsaturated fatty acids have beneficial effects on the lipid profile and should comprise most fat intake (grade B) o Dietary saturated fat should be limited to less than 10% of daily energy intake with less than 300 mg/d of cholesterol (grade A) o If the patient’s LDL-C level is greater that 100 mg/dL.5 to 2.6). and cholesterol should be limited to less than 200 mg/d (2). Dietary saturated fat contributes to cardiovascular risk (2).14). no nutraceuticals are supported by strong enough evidence to be recommended as first-line treatment for diabetes mellitus or its related complications (7). and weight loss (grade A) Dietary modification to achieve target ranges for glucose. and 1.9) and fiber (10. prescribe 1 daily multivitamin and a diet with adequate protein for patients with diabetes mellitus who have nonhealing wounds. Clinical Considerations All Patients With Diabetes Mellitus Carbohydrate absorption may be altered by other foods in a mixed meal. Sucrose does not need to be avoided by patients with diabetes mellitus.3 g/d (stage 5 on peritoneal dialysis) (grade A) For optimal nitrogen retention.2.4 g/d. it should replace other carbohydrates in the diet (12).11) delay the absorption of carbohydrates and blunt the glycemic response. 1. The use of basal-bolus insulin therapy using insulin analogs or continuous subcutaneous insulin infusion in conjunction with carbohydrate counting is the most physiologic treatment and provides the greatest flexibility in terms of food choices and timing of meals (11. and protein. If the patient’s LDL-C level is greater than 100 mg/dL.2 g/d (stage 5 on hemodialysis). .18) in early life are associated with decreased risk of developing T1DM. AACE Diabetes Mellitus Guidelines. 2007.2. but when it is consumed.13. 7.2. 0.
(LOE 3) 11. Dietary modification to achieve target ranges for glucose. (LOE 3) 9. Garg A. Carbohydrate and fiber recommendations for individuals with diabetes: a quantitative assessment and meta-analysis of the evidence. Environmental factors in childhood IDDM. Ciardullo AV. Frayn KN. et al. Br J Nutr. Effects of meal carbohydrate content on insulin requirements in type 1 diabetic patients treated intensively with the basal-bolus (ultralente-regular) insulin regimen. Endocr Pract. can be considered depending on the severity of the wounds and the nutritional status of the patient.94:1-11. is helpful in managing hypertension (24). (LOE 3) 21. 2005.23:5-17. Irwig L. potassium (29). Bantle JP. (LOE 3 3) 19. (LOE 2) 5. National Cholesterol Education Program (NCEP) Expert Panel on Detection. Jarvelin MR. intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. A small dose of soluble alginate-fiber affects postprandial glycemia and gastric emptying in humans with diabetes. (LOE 2) 7. Ratner R. et al.271:1421-1428. Physical activity of 30 to 90 minutes per day lowers glucose levels and assists with weight loss or weight maintenance (23). Endocr Pract. and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).AACE Diabetes Mellitus Guidelines. Rasanen L. J Am Coll Nutr. Patch CS. 2004. Sheard NF. Jenkins DJ. (LOE 2) 4. Simpson JM. 2006. in association with increased intake of fresh fruits and vegetables.21:142-149. Kendall CW. and weight loss (26.28:888-894. Metabolism. (LOE 2) 6. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Englyst HN. Diabetes Care.290:1713-1720.11:656-662. Haffner S. phosphate (renal failure stages 3-5) (30). Tolli J. Goldberg R. Br J Nutr. Dietary carbohydrate (amount and type) in the prevention and management of diabetes: a statement by the American Diabetes Association. Klingensmith G. Mackerras D. Alpsten M. Torsdottir I. Nitrate and nitrite intake and the risk for type 1 diabetes in Finnish children. Louche-Pelissier C. Training in flexible. 1994. Virtanen SM. lipids. and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Diabetes Care. Batterham M. BMJ. Diabet Med. 1999.27:2266-2271. (LOE 4) 16.62:340-347. 2004. Reunanen A. 2003. (LOE 4) 13. Childhood Diabetes in Finland Study Group. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection. et al. 2001. 2005. olive oil-rich diet on the susceptibility of LDL to oxidative modification in subjects with Type 2 diabetes mellitus. Norris JM.5 g/d. (LOE 4) 18. Virtanen SM. Effects of varying carbohydrate content of diet in patients with non-insulindependent diabetes mellitus. Endocr Pract. Nutrition therapy for the hospitalized patient with diabetes.22:667-673. 2002. REFERENCES 1. Diabet Med. and blood pressure is a tertiary preventive strategy for the complications of diabetes mellitus (28). JAMA. Circulation. Increased intake of dietary saturated fat is associated with an increased risk for T2DM (25). 1991. Gillen LJ. Barriga K. (LOE 1) 2. If patients choose to consume alcohol. cardiovascular risk is lowest when the body mass index is less than 25 kg/m2 (22). et al.121:795-799. Hypponen E. Evaluation. JAMA. Lancet. 1992. Normand S.325:746. Diabetes Care. Rodriguez-Villar C. (LOE 1) . Englyst KN. American Association of Clinical Endocrinologists medical guidelines for the clinical use of dietary supplements and nutraceuticals. 1994. Comparison of a high-carbohydrate and a highmonounsaturated fat. 2005. Khalfallah Y. Rabasa-Lhoret R. Diabetes Care. Structured dietary advice incorporating walnuts achieves optimal fat and energy balance in patients with type 2 diabetes mellitus.105:1087-1096. 2001. Jaakkola L.86:3-11.12(suppl 3):6167. Casals E. Evaluation. exercise. Poisson D. American Association of Clinical Endocringologists. Sandberg AS. Randles KM. Silink M. Hypponen E. et al. et al. (LOE 2) 15. case-control study. including restrictions of sodium (29).358:1500-1503. (LOE 3) 20. Tapsell LC. Effects of fat on carbohydrate absorption: more is not necessarily better. DAFNE Study Group. Chiasson JL.41:1373-1378. Henry RR. Laara E. Carbohydrate bioavailability. Clark NG. et al. Rivellese AA. Ros E.86:1-2. Influence of dietary fat on postprandial glucose metabolism (exogenous and endogenous) using intrinsically (13)Cenriched durum wheat. 2007. Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. 2003. Swift CS. J Am Diet Assoc.17:1381-1389. and nicotinamide. (LOE 1) 3.27). Mercade I. Br J Nutr. Obesity is associated with decreased insulin sensitivity and increased risk for developing cardiovascular disease (22). Verge CF. A highmonounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients. Langelier H. Howard NJ. Boucher JL. (LOE 4) 8. Nutr Rev. Brand-Miller JC. Holm G. Perez-Heras A. such as zinc and oral vitamins C and A. Owen A. intake should be limited to 1 drink per day for women and 2 drinks per day for men. and protein (29). vitamin E. additional micronutrients. 2002. Patients with diabetes mellitus who have nonhealing wounds should take 1 daily multivitamin and adequate protein for optimal nitrogen retention. 2001. Garon J. 2004. A population-based. (LOE 4) 10.13(Suppl 1) 2007 Patients With Type 2 Diabetes Mellitus Weight control and a controlled-energy diet are essential components of diabetes mellitus management to lower glucose levels and to reduce the risk for cardiovascular disease (21). 2004. (LOE 3) 17. Salt restriction to less than 1. Parillo M.9:417-470. Secondary prevention strategies for T2DM in individuals with impaired glucose regulation include a controlled-energy diet. Special Populations Patients with chronic kidney disease require special attention to diet. (LOE 2) 14.106:3143-3421. 1994. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. Micronutrients and the risk of type 1 diabetes: vitamin D. J Nutr. Anderson JW. (LOE 4) 12.
(LOE 1) 27. Wylie-Rosett J.346:393403. Wasserman DH. N Engl J Med.6:464�. Am J Kidney Dis. et al (DASHSodium Collaborative Research Group). Nephropathy • Screen all patients with diabetes mellitus for chronic kidney disease annually. National Kidney Foundation. and Treatment of Overweight and Obesity in Adults--The Evidence Report.73 m2 or albumin-tocreatinine ratio ≥30 mg albumin/g creatinine § Microalbuminuria ≥30 mg albumin/ g creatinine § Macroalbuminuria ≥300 mg albumin/g creatinine • Prescribe an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker in the antihypertensive regimen in the absence of contraindications (grade A) • Consider prescribing non–dihydropyridine calcium channel blockers. N Engl J Med.6(suppl 2):51S209S. Sacks FM. Lindstrom J. Diabetes Care.142:313-322. et al (Finnish Diabetes Prevention Study Group). (LOE 1) 25.29:1433-1438. (LOE 4) • • Control other risk factors including (grade A): o Hypertension—treat blood pressure to the target of less than 130/80 mm Hg o Dyslipidemia—strive to achieve all lipid level goals o Smoking—refer patients to smoking cessation program as needed o Lifestyle—initiate weight reduction/control and individualized exercise regimen Select drug therapy with attention to cardiovascular risk (grade A) 8. 2007. 2002. Davey Smith G.26:3230-3236. Nutrition recommendations and interventions for diabetes--2006: a position statement of the American Diabetes Association. (LOE 1) 26. Kenny GP. Bracha Y.29:2140-2157. (LOE 4) 29. taking non–dihydropyridine calcium channel blockers may reduce albuminuria in patients with diabetes mellitus. (LOE 4) 30. Sigal RJ.0 AACE Diabetes Mellitus Guidelines. Louheranta A.1. Executive Summary 8. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation.8 to 1. Mannelin M. National Kidney Foundation. Vollmer WM. Am J Kidney Dis.42:S1-201.8 g/kg per day in patients who are in the later stages of chronic kidney disease (grade B) • The diagnosis of anemia is established if the hemoglobin level is less than 13. Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Association.73 m2.2. Obes Res. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. CastanedaSceppa C. evidence demonstrates that glycemic variability is an independent risk factor for microvascular disease (grade B) • Consider preprandial and postprandial self-monitoring of blood glucose readings separately. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. 2002. 1998. adjust therapy if 25% of measurements exceed glycemic targets (grade C) 8. Svetkey LP. Bantle JP. including those patients who are pregnant (grade C) • Reduce protein intake to 0. Testing includes: o Measurement of albumin-to-creatinine ratio in a spot urine specimen and measurement of the estimated glomerular filtration rate derived from serum creatinine o The following are diagnostic criteria for chronic kidney disease: § Estimated glomerular filtration rate <60 mL/min/1. Svendsen KH. (LOE 4) 23. or diuretics to manage blood pressure in the setting of albuminuria or nephropathy in patients unable to tolerate angiotensinconverting enzyme inhibitors and/or angiotensin receptor blockers. 2001. Diabetes Care. 2003. et al (Diabetes Prevention Program Research Group). Kuller LH (Multiple Risk Factor Intervention Trial Research Group). Albright AL.1. Fowler SE. Incidence of type 2 diabetes in the randomized multiple risk factor intervention trial. β-adrenergic blockers. 2006.1. The Finnish Diabetes Prevention Study (DPS): Lifestyle intervention and 3year results on diet and physical activity. and stratification. Evaluation. classification. Ann Intern Med. screening should begin 5 years after diagnosis in patients with T1DM and at the time of diagnosis in patients with T2DM (grade A). Knowler WC.1. Diabetes Care. Haffner SM. 1998. 2006. (LOE 4) 24.13(Suppl 1) 2007 22. refer patients for consultation and evaluation for renal replacement therapy by . White RD. et al.0 g/kg per day in patients who are in the earlier stages of chronic kidney disease and to 0. National Institutes of Health [erratum in Obes Res.5 g/dL in adult men and less than 12 g/dL in adult women (grade B) • When the estimated glomerular filtration rate is less than 30 mL/min/1.39: S1-266. Barrett-Connor E.344:3-10. Endocr Pract. All Patients With Diabetes Mellitus • Encourage all patients to strive to achieve glycemic goals (grade A) • Use results from postprandial glucose monitoring and the calculated standard deviation of downloaded meter results of self-monitoring of blood glucose when considering glycemic management strategies (grade B). Neaton JD. 2003. 2005. (LOE 1 1) 28. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. MICROVASCULAR COMPLICATIONS 8. Clinical Guidelines on the Identification. DASHSodium Collaborative Research Group.
or pressure using a monofilament Refer the patient to a qualified podiatrist. annual examinations should be performed thereafter in all patients. and neuropathy (1014). evaluate skin. and capillary basement membranes. assess sensory function by pinprick. To achieve the benefit of normoglycemia. Endocr Pract. pulses. such as the glial or neural elements of the retina and the axons or myelin sheath of nerve. temperature. if indicated. retina (2. but must be prescribed with knowledge of potential toxicities (grade C) Further study is required before botanical preparations and dietary supplements can be advocated to treat neuropathic symptoms (grade C) Maintain a referral network for podiatric and peripheral vascular studies and care (grade C) 8. a program of periodic preventive monitoring is necessary. Evidence Base 8. annual examinations should be performed thereafter (grade A) • Alternatively. The rationale for a screening program is based on the need to detect unsuspected asymptomatic disease that would be potentially responsive to specific therapy. gabapentin. both of which are indicated to treat diabetic neuropathy (grade C) When treating patients with cardiac autonomic neuropathy. and all patients with T1DM should be assessed 5 years after diagnosis (grade A). kidney transplantation. and lamotrigine may provide symptomatic relief. the treatment goal is to interrupt progression or achieve reversal of the abnormality (7-9). retinopathy. and hygiene (grade B) 8. Overview Control of hyperglycemia and nonglycemic risk factors for microvascular disease are essential for preventing and treating nephropathy. pericytes. and other strategies are specific to each affected organ. Screening may include: o History and examination eliciting signs of autonomic dysfunction o Testing for heart rate variability.4.3.2 Glycemic Control Tight glycemic control prevents the onset and progression of diabetic nephropathy. or 5 years after T1DM is diagnosed. the results from 7-field stereo color fundus photography or digital retinal imaging may be read by a qualified reading center. choose strategies appropriate for protection against cardiovascular disease (grade A) Tricyclic antidepressants. which may include expiration-to-inspiration ratio and response to the Valsalva maneuver and standing. • Inspect the patient’s feet at every visit. tissues affected by microvascular disease contain not only endothelium. evidence of pressure.AACE Diabetes Mellitus Guidelines. Neuropathy • All patients with T2DM should be assessed for neuropathy at the time of diagnosis.2. orthopedist. and peritoneal dialysis should be considered (grade B). topical capsaicin.73 m2 (grade D). temperature and vibration sensation using a tuning fork.2.3).1. Therefore. Monitor diuretic and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy with periodic electrolyte measurement and estimation of glomerular filtration rate (grade C) Monitor intact parathyroid hormone levels for secondary hyperparathyroidism if the glomerular filtration rate is less than 60 mL/min/1. and neuropathy. there is no .13(Suppl 1) 2007 1 • • • • • a nephrologist (grade B). 2007. home hemodialysis. but also nonvascular cells at risk. pregabalin. retinopathy.2. topiramate. and nerve (4-6) are 3 tissues that exhibit microvascular complications (microangiopathy) of diabetes mellitus. Retinopathy • Refer the patient to a trained examiner (ophthalmologist and/or retinal specialist) for annual dilated retinal examination at the time T2DM is diagnosed. and antiepileptic drugs such as carbamazepine.1. Some prevention and treatment strategies are general for all microvascular disease.1. as long as the center operates under the direction of a medical director who is a retinal specialist (grade B) • Promptly refer the patient to a retinal specialist if there is evidence that early retinopathy is progressing or if advanced retinopathy exists (grade A) 8. or neurologist if there is a lack sensation or mechanical foot changes (grade C) Consider treatment with duloxetine or pregabalin. consider treatment with paricalcitol (grade D) Monitor for anemia associated with chronic kidney disease (grade B) Use perioperative intravenous insulin infusion for glycemic control at the time of renal transplantation (grade B) ACE/AACE does not recommend pancreas-only transplantation for the isolated indications of retinopathy or neuropathy in patients without lifethreatening or disabling metabolic complications of diabetes mellitus who do not require renal replacement therapy (grade C) • • • • • • • Perform an annual comprehensive foot examination (grade B).2). Kidney (1. nails. 8. in-center hemodialysis. Manifestations of microvascular disease may be demonstrable to the examiner before the patient experiences any symptoms. Although these disorders are encompassed under a term that implies the presence of microvasculopathy.
smoking.31). systemic hypertension.44).27. Ruboxistaurin is an investigational protein kinase C inhibitor that is currently undergoing evaluation in clinical trials for retinopathy.3.28). and symptomatic neuropathy. Conventional macrovascular risk factors may increase the risk for neuropathy (34). 8. to evaluate need for iron therapy. however it has not yet received Food and Drug Administration approval (24. dyslipidemia. this observation would create a strong argument for perioperative use of insulin infusion at the time of kidney transplant. If confirmed. and to avoid exacerbation of hypertension or development of other therapeutic complications.52-55). The extent of glycemic variability may be discerned not only by reviewing the patient’s logbook data. These mechanisms include heritable variation in the angiotensin-converting enzyme gene. microalbuminuria. chronic sensorimotor. Duloxetine or pregabalin are safe and effective for treating diabetic neuropathic pain (3. Hypertension and dyslipidemia may exacerbate diabetic retinopathy (33). Interception of Downstream Metabolic Consequences of Hyperglycemia Pharmacologic interruption of downstream biochemical pathways in conjunction with tight glycemic control may hold promise for the future of preventing and treating microangiopathy (24. Endocr Pract.38. Simultaneous pancreas and kidney transplant. Protein restriction helps slow the progression of albuminuria. Painful neuropathy may occur in patients with impaired glucose tolerance. focal limb. All of these mechanisms may increase the risk of developing nephropathy (30. pancreasafter-kidney transplant.47). When hypertension is present in patients with T2DM.2. and high-protein diet. but also for normotensive patients with early stage nephropathy (8. and renal insufficiency (serum creatinine >1.5 mg/dL) (29. Observationally. hypertension.2 AACE Diabetes Mellitus Guidelines. As a normal HbA1c level is approached. nephropathy. Diabetic neuropathy can be classified in 2 categories: (a) generalized symmetric polyneuropathies including acute sensory. and all-cause mortality (1.18). stroke. 2007. and pancreas-alone transplant may help prevent progression of microangiopathy (20-22). Secondary hyperparathyroidism can be associated with chronic kidney disease in stage 3 and stage 4. Therefore. proximal motor.4). but also by analyzing the downloaded meter readings at the time of office or clinic visits (19). paricalcitol decreases parathyroid hormone levels with no effect on . particularly in patients whose nephropathy appears to be progressing despite optimal glucose and blood pressure control with use of an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker (51). glomerular filtration rate decline.45). Modifiable risk factors associated with regression of microalbuminuria include treatment of dyslipidemia and glycemic exposure (36). Vascular endothelial growth factors promote protein kinase C–β signaling in the retina (32). including an angiotensin-converting enzyme inhibitor in the antihypertensive treatment regimen is helpful for preventing or delaying the onset of nephropathy (35). intraglomerular capillary pressure. Treatment to achieve a hemoglobin concentration of 11 g/dL has been advocated for individuals with demonstrable deficiency of erythropoietin.37-39). truncal. such as the use of antagonists to vascular endothelial growth factor for retinopathy (26). Targeting Organ-Specific Nonglycemic Pathogenetic Mechanisms Organ-specific pathogenetic mechanisms and vulnerabilities to nonglycemic abnormalities can amplify the risk of developing or experiencing progression of microvascular disease (29). 8. there is a narrow window of time in the immediate hours after kidney transplantation during which adequacy of glycemic control may determine the future risk for acute rejection and postoperative infection (23). See Section 4 for details regarding therapies for glycemic control. and coexisting chronic inflammatory demyelinating polyneuropathy (17). or autonomic. Anemia due to erythropoietin deficiency may occur early in the course of diabetic nephropathy. The clinician can then calculate the standard deviation of glucose levels and compare it with normal values based on a larger patient population. It is the standard of care to use angiotensin-converting enzyme inhibitors or angiotensin receptor blockers not only for hypertensive patients.4.43. The potential indications for and complications of combination angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy deserve attention (40-42).39. postprandial glucose control becomes an increasingly dominant determinant of further improvement of the HbA1c level (16). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers slow the progression of microalbuminuria in patients with T2DM. Specific interventions may be envisioned to combat organ-specific pathogenetic mechanisms or vulnerabilities. The analysis of a spot urine sample to assess the albumin-to-creatinine ratio is strongly recommended by most authorities (46. glomerular hyperfiltration. and occurrence of end-stage renal disease (48-50). The outcomes of erythropoietin treatment are presently being studied in the Anaemia CORrection in Diabetes (ACORD) trial (56). Anemia has been associated with myocardial infarction or fatal cardiovascular heart disease. and (b) focal and multifocal neuropathies including cranial.25).13(Suppl 1) 2007 threshold above a normal HbA1c level (15). Orthostatic hypotension sometimes is benefited by treatment (53).2. Caution must be exercised to select patients who show a need for replacement. suggesting that postprandial hyperglycemia may be a pathogenetic mechanism of injury even in prediabetes mellitus (5. postprandial glucose excursions should be considered a target of therapy. Angiotensin-converting enzyme inhibitors delay the progression of nephropathy in patients with T1DM who have hypertension and any degree of albuminuria (8.
N Engl J Med. Colette C. Boulton AJ. 2000. 2001. In the predialytic stage of chronic kidney disease. Diabetes Control and Complications Trial Research Group. Plasma glucose levels throughout the day and HbA(1c) interrelationships in type 2 diabetes: implications for treatment and monitoring of metabolic control.AACE Diabetes Mellitus Guidelines. Klein R. Silveiro SP. Maser RE. The presence of neuropathy predicts the occurrence of foot ulcers. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. 2005. 1993. Singleton JR. may exhibit superior safety compared with calcitriol when used in stage 3 and stage 4 of chronic kidney disease with respect to hypercalcemic episodes (58). Lombardi S. (LOE 2) 8. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Zelmanovitz T. (LOE 2) 17. [erratum in Lancet. some patients with metabolic bone disease require treatment with vitamin D or its analogs. Wingard DL. Diabetic somatic neuropathies. Klein R. Frank RN. 2000. Malik RA. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.321:405-412. Vedel P. Diabetic retinopathy. For other patients. Symptomatic relief of neuropathic pain may be achieved by using tricyclic antidepressants and antiepileptics (27. Parving HH. prevention. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.352:837853. Sosenko JM. Pedersen O. 2000. 2005.342:1376�. (LOE 2) . [erratum in N Engl J Med. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Treating retinopathy entails using laser and vitrectomy for specific indications (61-63). N Engl J Med. N Engl J Med. and in collaboration with a vascular surgeon.354:602� Lancet. Bain RP. Diabetes. Arezzo JC. Calcaterra F. REFERENCES 1. 2000. For patients receiving dialysis. Monnier L.72). Arezzo JC. (LOE 1) 15. The Collaborative Study Group. (LOE 1) 9. such as paricalcitol. 1998. 2007. Fong DS. Mitchell BD. Diabetes Care. et al. (LOE 1) 14. Drugs must be prescribed with knowledge of potential toxicities (17). (LOE 4) 2. 350:48-58. Diabetes Control and Complications Trial Research Group. Neil HA. Barrett-Connor EL. Boulton AJ.342:381-389. Visual impairment and retinopathy in people with normal glucose tolerance. Diabetic neuropathies: a statement by the American Diabetes Association. and newly diagnosed NIDDM. Stratton IM. 2001. Lapinski H.24:14481453. Adler AI. de Azevedo MJ. 2004. Diabetes Care. Camori ML. 2004.342:1376� N Engl J Med. BMJ. 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Diabetes Care. 1995. analogs of vitamin D2. and the possibility of exacerbated vascular calcifications. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. however.27:1458-1486. (LOE 1) 12. (LOE 4) 4.353:617-622.45:1289-1298. and/or cinacalcet (59). Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy [erratum in N Engl J Med. Vinik AI. Other treatment modalities have been reviewed (17). A multifaceted intervention for prevention may include the following: (a) requesting that patients remove their footwear at the time of examinations. Freeman R. vitamin D analogs. Bromberg MB. and (c) providing foot-care education (71. 28:164-176. Diabetic nephropathy: diagnosis. Diabetes Care.13(Suppl 1) 2007 3 calcium and phosphorous levels (57). 2004. 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Bain SC. 2005. Am J Kidney Dis. Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial. et al (Collaborative Study Group). Pietraszek L. (LOE 2) 26.124:627-632. Bouter P. 2001. Coppelli A. 2005. Br J Diabetes Vasc Dis. 1994. Bakris GL. Gomis R. 2005. 48. de ZD. N Engl J Med. Hu K. Hostetter T. UK Prospective Diabetes Study (UKPDS) Group. Angiotensinreceptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy [erratum in N Engl J Med. N Engl J Med. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. 2004. 2001. [erratum in Endocr Rev. et al (Bergamo Nephrologic Diabetes Complications Trial [BENEDICT] Investigators). 2001. Preventing microalbuminuria in type 2 diabetes.25:859-864. Vistoli F. Adamis AP. 42. 2003. N Engl J Med.28:1366-1370. an anti-vascular endothelial growth factor aptamer. Chaturvedi N. (LOE 4) Laffel LM. 2005. (LOE 1) Rossing K.318:29�. 2001. (LOE 4) 20. (LOE 2) Palmer BF.112:1747-1757. 2007. Makita Z. Giannarelli R.25:1313-1319.317:703-713. Klein BE. (LOE 1) Bakris GL.42:617-622. North American Microalbuminuria Study Group. Ophthalmology. 2002. (LOE 1) 29.28:2686-2690. McGill JB.99:497-504. Ilieva AP. Rao MM. (LOE 2 2) Pedrini MT.54:2188-2197. 49. Moss SE. N Engl J Med. Ann Intern Med. Advanced glycosylation end products in patients with diabetic nephropathy. Diabetes. (LOE 4) 28. 2004.345:851-860. Diabetes Care.351:585-592. Parving HH. Lehnert H. Nephrol Dial Transplant. Andersen S. (LOE 1) 35. Chalmers TC. 2005. et al. Hunsicker LG. Gans DJ. (LOE 2) 22. Levey AS. Thomas MC. (LOE 2 2) Pijls LT. 1998.345:870-878. (LOE 4 4) Meigs JB. 41. (LOE 4) Kumar R. Transplantation.26:2268-2274. Finkelstein DM.351:1952-1961. et al. 38.331:1480-1487. Vascular risk factors and diabetic neuropathy. 2004. 2004. 37. 1999. 39. Early peri-operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. (LOE 1) Brenner BM. N Engl J Med. et al. et al (EURODIAB Prospective Complications Study Group). (LOE 1 1) 36. Diabetes.5:266-271. Larsen JL. Diabetes Care. de Vries H. Dual blockade of the renin angiotensin system in diabetes— rationale and risks. Silva KH. Mathew TH. Arrigg PG.13(Suppl 1) 2007 19. Rayfield EJ. 2005. The beneficial effects of pancreas transplant alone on diabetic nephropathy. Altaweel M. N Engl J Med. for diabetic macular edema. KrolewskiAS. Wang PH. J Clin Endocrinol Metab. et al. N Engl J Med. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 [erratum in BMJ. BMJ. Coronary artery calcification in type 2 diabetes and insulin resistance: the Framingham offspring study. (LOE 2) 24. 1999. Avery RL.352:341350. Endocr Pract. 46. 40. Giannarelli R. Toto RD. D'Agostino RB. N Engl J Med. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. (LOE 2) 33. Hougaard P. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Fassi A. 2004. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. 2000. N Engl J Med. et al. Mirea L. Clarke WR. Amer P (Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group). 1991. Hirsch IB. 2005. (LOE 2) 31. Jacobsen P.72:1321-1324. et al (RENAAL Study Investigators). Cooper ME.54:1238-1244. Surawicz TS.10:67-76. Coppelli A. Diabetes Care. (LOE 2) Barnett AH. Paterson AD. Blood glucose monitoring technology: translating data into practice. Radoff S.. Aiello LP. 2005. The effect of protein restriction on albuminuria in patients with type 2 diabetes mellitus: a randomized trial. et al. 2002. Larson MG. Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK). N Engl J Med.345:861-869. Jr. Am J Med. Eaton SE. Am J Kidney Dis. 2003. 1991. Brochner-Mortensen J. Early improvement of unstable diabetic retinopathy after solitary pancreas transplantation.325:836-842. (LOE 1) 27. (LOE 1) Eknoyan G. Dworkin L. et al. Sartini MS. Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. 2005. 1995. McGill JB. Anderson PW. Diabetes Care.36:646-661. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Winocour PH. Tuttle KR. (LOE 4) 23. 2004. Williams M.25:23582359. Ficociello LH. 2002. et al. Tesfaye S. Warram JH.98:1261-1265. Relationship of serum cholesterol to retinopathy and hard exudate. Parving HH. (LOE 1) Parving HH.25:919-946. PKC-DRS Study Group. (LOE 1) 30. Diabetes Care. (LOE 1) 25. Ophthalmology. AACE Diabetes Mellitus Guidelines.348:2285-2293.14:1445-1453. 2003. Russ GR. Moran J. et al (DCCT/EDIC Research Group). Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study. Ruggenenti P. Pancreas transplantation: indications and consequences. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. van Eijk JT. XIII.90:4936-4945. Donker AJ. Diabetes Care. (LOE 2) 34. Bakris GL.
Mtonga R. et al. Nussbaum JJ. (LOE 3 3) 61. if safely achievable. Diabetes Care. Haas W. Tighiouart H. Diabetes Care.85:82-106. Brinton EA. smoking cessation.AACE Diabetes Mellitus Guidelines.165:466-469. Diabetic Retinopathy Study Group. Jacobsen G. Halat KM. (LOE 2 2) 65. Lazarus JM. Martin KJ. The Operation Desert Foot experience. 2006. Mellstrom M.27:265-272. Diabetes Care. Martin KJ. Early Treatment Diabetic Retinopathy Study Research Group. Jensen BR. Louis TA. Ophthalmic Surg Lasers Imaging. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report no. (LOE 2 2) 51. J Am Soc Nephrol. (LOE 4 4) 54. Schiffman RM. Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease. Ofsthun N. 4. Gill GV. Lakatua JD. JAMA. et al. (LOE 1 1) 57. 1978. Hansen HP. (grade A) and blood glucose concentration between 60 mg/dL (fasting) and 120 mg/dL (1 hour after a meal) (grade A) o The need for optimal blood pressure control (<130/80 mm Hg) (grade A) o The importance of a healthy lifestyle.24:503-510. et al. Erythropoietin treatment of postural hypotension in anemic type 1 diabetic patients with autonomic neuropathy: a case study of four patients. Anemia with erythropoietin deficiency occurs early in diabetic nephropathy. Sachdeva A. Oliver DA.16:3403-3410. Singh N. Weiner DE. 2004. 2004. 2005.1. Qiu P. 1993. Lowrie E. Wolf M. Watkins PJ. Vitamin D insufficiency and deficiency in chronic kidney disease. (LOE 2 2) 67.119:3641. (LOE 3 3) 55. Sharma U. Diabetes Care. Acharya M. 2005. 1987.63:2104-2110. Litzelman DK. Block GA. MacIsaac R. J Am Board Fam Pract. (LOE 1) 60. 2005. 2007. Ma JZ. and alcohol use (grade B) • Discontinue oral glucose-lowering drugs and start insulin if needed (grade A) • Discontinue angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Ophthalmology. 1999. Thomas MC. or labetalol (grade A) . Executive Summary 9. (LOE 1 1) 52. nifedipine extended release.26:491-494. Laville M and Anaemia CORection in Diabetes Trial. Lesser H. Neurology. controlled trial. Comparison of a digital retinal imaging system and sevenfield stereo color fundus photography to detect diabetic retinopathy in the primary care environment. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. McGill M. Botanicals and dietary supplements in diabetic peripheral neuropathy.1. Langefeld CD. (LOE 4) 58. Slemenda CW. (LOE 2 2) 53. counseling should address: o Information and skills relevant to the management of pregnancy in a woman with diabetes mellitus (grade B) o The need for optimal control of the HbA1c level (<6%). (LOE 2 2) 68. Endocr Pract. (LOE 4) 9. Results of a randomized trial--Diabetic Retinopathy Vitrectomy Study Report 3. exercise. (LOE 2 2) 72.22:678-683. (LOE 2 2) 62. 2004. Teng M.62:220-228. Mason S. Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. provide contraceptive advice when appropriate (grade A) • Offer prepregnancy counseling to all women with diabetes mellitus who are considering pregnancy (grade A). Macdougall IC. Am J Kidney Dis. A metaanalysis of the effects of dietary protein restriction on the rate of decline in renal function. Which diabetic patients should receive podiatry care? An objective analysis. Amputation and mortality in new-onset diabetic foot ulcers stratified by etiology. Reduction of lower extremity clinical abnormalities in patients with non-insulin-dependent diabetes mellitus. (LOE 2 2) 66.47:263-276.13(Suppl 1) 2007 50. Provide Prepregnancy Counseling • Identify the possibility of pregnancy annually by directly questioning all fertile women of childbearing age with diabetes mellitus. Ann Intern Med. 2005. Tauber-Lassen E. et al. Molyneaux L. 2003.31:954961. Vlagopoulos PT. et al. Yue DK. 1988. Winkler AS. 2004. 2001. N Engl J Med. Diabetic Retinopathy Vitrectomy Study Research Group. DIABETES AND PREGNANCY 9. Thadhani R. Preventing foot ulcers in patients with diabetes. de Francisco AL. (LOE 1 1) 64. Gonzalez EA. 2001. Moulik PK. Coyne D. Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD.26:1691-1695. Dennehy CE. Wheeler LA. Acta Diabetol. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.350:1516-1525. hydralazine. use methyldopa. Diabetes Care.24:495499.35:451-456.16:47-57. et al. Anemia with impaired erythropoietin response in diabetic patients. Poole RM. A single center observational study. 2003. 2002. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Van Gils CC. A randomized.293:217-228. Arch Intern Med.41(suppl 1):S18-S22. Cooper ME. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. 2003. (LOE 2 2) 70. Am J Nephrol. (LOE 2 2) 69. Bosman DR.95:1307-1320. Kidney Int.36:46-56. (LOE 3 3) 56. Watkins PJ. Jerums G. Marsden JT. Landau S. (LOE 2 2) 63. Plank J. including advice on nutrition. LaMoreaux L. Ophthalmology. Winkler AS. Evaluation of the impact of chiropodist care in the secondary prevention of foot ulcerations in diabetic subjects. Tsalamandris C. New strategies in anaemia management: ACORD (Anaemia CORrection in Diabetes) trial. Kasiske BL. 2003. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. 1998. (LOE 2 2) 71. N Engl J Med. Int Ophthalmol Clin. Am J Kidney Dis. (LOE 1 1) 59. Armstrong DG. 349:446-456. Wheeler CG. Amputation prevention by vascular surgery and podiatry collaboration in high-risk diabetic and nondiabetic patients. Lipsky BA.24:1121-1123. Intern Med J. Parving HH. Rakovac I.1. 2005.
13(Suppl 1) 2007 • • • Discontinue statins and fibrates (grade A) Assess the patient for retinopathy. as a result. blood glucose concentrations should remain between 60 to 90 mg/dL (fasting) and less than 120 mg/dL (1 hour after the first bite of food at each meal) (grade A) o Monitor weight gain and blood pressure and advise and treat the patient accordingly. Diabetes Management Throughout Pregnancy • Frequently assess the status of diabetes control.5 mg/kg per min (grade C) . measure fasting glucose at the first prenatal visit (no later than week 20). risk for and presence of diabetic complications. before each meal to • determine insulin dosage correction and 1 hour after the first bite of food at each meal (grade A) o Accurate timing of glucose testing at meals is critical to accurately assess glucose control (grade B) o Expect insulin requirements to rise as pregnancy progresses. avoid using renin-angiotensin system blocking drugs (grade A) • Persistently monitor and adjust insulin therapy to achieve all glucose targets (grade A) o Initiate a basal-bolus insulin regimen if a patient cannot maintain glucose targets with diet alone. prebreakfast and 1 hour after the first bite of food at each meal (grade A) § Insulin therapy—instruct patients to assess blood glucose concentrations 6 times daily. Perform a 75-g oral glucose tolerance test if the fasting glucose concentration is greater than 85 mg/dL (grade A) o Initiate medical nutritional therapy immediately if the diagnosis of gestational diabetes is established (grade B) o Initiate insulin therapy if the patient is following an optimal diet but the selfmonitored glucose levels reveal fasting glucose concentrations greater than 90 mg/dL and/or if postprandial glucose concentrations are greater than 120 mg/dL 1 hour after the first bite of food at each meal (grade A) 9.1.4. AACE Diabetes Mellitus Guidelines.2 present protocols for adjusting intrapartum intravenous solutions and insulin administration during labor and the postpartum period in women with insulin-requiring diabetes mellitus.5 mg/kg per min (grade C) o Measure the capillary blood glucose concentration hourly (grade C) o Double the glucose infusion for the next hour if the blood glucose value is less than 60 mg/ dL (grade C) o Glucose values greater or equal to 120 mg/dL require the administration of regular insulin subcutaneously or intravenously until the blood glucose value falls to 70 to 90 mg/dL. nephropathy.1. now. and use of self-monitoring of blood glucose (timing and interpretation of test results and appropriate response) (grade B) 9. Table 9. if the patient is overweight. and thyroid function (grade A) Initiate folic acid supplementation to reduce the risk of neural tube defects (grade A) 9. current pharmacologic therapy. and the presence of other medical conditions (including weight gain) (grade B) o Strive for a HbA1c level less than 6%. therefore. insulin requirements may be decreased by hyperemesis. blood pressure should be maintained at less than 130/80 mm Hg.2. advise a diet suitable for someone of optimal weight and encourage moderate exercise such as armchair exercises (grade A) o Management by a health care team is needed to assess and reinforce patient understanding of diabetes management including dietary needs and considerations. intrapartum maintenance of maternal euglycemia is essential (grade B) • Insulin is still required before active labor and can be given subcutaneously or by intravenous infusion with a goal of maintaining blood glucose concentrations between 70 to 90 mg/dL (grade B) • As the mother enters active labor. Labor and Delivery • Maternal hyperglycemia is the main cause of neonatal hypoglycemia. 2007.1 and 9. insulin resistance rapidly decreases because of the energy expenditure of labor as a form of strenuous exercise.1. steroid therapy increases insulin requirements (grade B) Offer medical nutrition therapy and education. Screen for Undiagnosed or New (Gestational) Diabetes During Pregnancy • In all pregnant women. insulin requirements drop to zero (Tables 9. this regimen may include either NPH insulin (basal) and rapid-acting insulin at meals or subcutaneous insulin infusion with an insulin pump (grade B) o Patients should intensively monitor blood glucose levels (grade A): § Diet only—instruct patients to assess blood glucose concentration 4 times daily. Endocr Pract.3 lists sample glucose infusion rates in active labor) (grade B) • To prevent hypoglycemia: o Infuse glucose at a rate of 2. knowledge of glucose targets.3. the insulin dose is titrated to maintain normoglycemia while glucose is infused at a rate of 2.
and thus the need for more frequent glucose monitoring. thus.13(Suppl 1) 2007 7 Table 9. Although most studies have been performed in women with T1DM. l00 mL/h plus 6% of TDIR Abbreviation: TDIR. 10 cD normal saline is 5% dextrose in normal (isotonic) saline. the same risks resulting from hyperglycemia apply to those with T2DM (9). prepregnancy counseling and planning are essential in women of childbearing age who have diabetes mellitus. Endocr Pract. Therefore. The rationale for the recommended blood pressure target of less than 130/80 mm Hg stems from the increased risk of retinopathy. Hyperglycemia at conception (when the woman may not know she is pregnant) and during the first trimester increases the risk of fetal malformations. advise the patient of the high risk of future diabetes and educate the patient about preventative lifestyle measures. screen for diabetes in women who developed new diabetes in pregnancy. Women with T2DM are less likely than women with T1DM to have preconception care and counseling—often because the diagnosis of diabetes mellitus has not yet been made—and thus. Normalizing blood glucose concentrations before pregnancy or early in gestation can reduce the risks of spontaneous abortion and congenital malformations nearly to that of the general population (10). At term. and both preprandial and postprandial glucose measurements are recommended to guide therapy (14.15). the insulin requirement is 1. advise the patient to be examined for diabetes annually because women with GDM have a 50% risk of developing T2DM within 5 years (10% conversion per year) (grade A) o 9. l00 mL/h 101-120 121-140 >141 Normal saline plus regular insulin intravenously or bolus analog subcutaneously as percent of TDIR Normal saline. and fetal or neonatal acidosis (grade A) o Anticipate changed insulin requirements. Higher HbA1c values early in pregnancy are correlated with higher rates of spontaneous abortion and major congenital malformations (6-8). it increases the risk of macrosomia and metabolic complications at birth (2). 2007. 100 mL/h for 10 to 15 min D5 normal salinec.1. later in pregnancy. fetal hypoxia. if there is no evidence of diabetes. total daily insulin requirement. and this observation has subsequently been confirmed in several studies (12.4). Assessing fasting plasma glucose is a useful test for screening both subcategories of women with GDM (5). if the patient is continuing insulin therapy postpartum and during lactation (grade C) Provide appropriate care and facilities for the newborn (grade B) At 45 to 60 days after delivery. even mild background retinopathy . mg/dL Adjustment ≤70 71-100 >121 Dl0 normal salineb. The importance of normalizing the postprandial glucose levels to decrease macrosomia was first reported in 1991 (11). bD normal saline is 10% dextrose in normal (isotonic saline). l00 mL/h plus 3% of TDIR Normal saline. Protocol for Adjusting Intrapartum Intravenous Solutions and Insulin Administration During Labor and the Postpartum Period in Women With Insulin-Requiring Diabetes Mellitus Treated With Insulin Pump Therapya Blood Glucose Concentration.13). they are at even greater risk of bearing child with a birth defect than women with T1DM (3. aBasal insulin infusion rate to be reduced in half. 3% of this dose would be 3 units in a woman weighing 100 kg at term. Evidence Base Approximately 8% of all pregnancies in the United States are complicated by hyperglycemia (1). Self-monitoring of blood glucose during pregnancy is essential.AACE Diabetes Mellitus Guidelines.2. 5 • • Do not give bolus doses of glucose because they can raise maternal blood glucose concentrations and increase the risk of neonatal hypoglycemia. l00 mL/h Normal saline.0 units/kg/d.
This decline appears to reflect a transient increase in Table 9. bGlucose infusion rate is 2. From the physiologic point of view.55 mg/kg/min. Although a consistent hallmark of the diabetic pregnancy is an increased insulin requirement in late gestation (17). aDiscontinue neutral protamine Hagedorn (NPH) insulin administration. normal saline is 5% dextrose in normal (isotonic) saline. mg/dL ≤60 61-100 101-120 121-140 ≥141 Adjustment Twice the target rateb Target rateb or D5 normal salinec Normal saline.60 6.5 153.10 5.58 5.0 D5 Normal Salineb. there is a decline in the insulin requirement in patients with T1DM who are treated early in the first trimester of pregnancy (18). AACE Diabetes Mellitus Guidelines.0 178. mL/min 2. Endocr Pract.55 3.2.55 mg/kg of pregnant weight/min.12 rate of infusion is equal to dextrose 2. 5 . 100 mL/h plus 3% TDIR Normal saline. but can also be seen in pregnant women with very wellcontrolled diabetes who do not otherwise have pregnancy complications.56 4. Protocol for Adjusting Intrapartum Intravenous Solutions and Insulin Administration in Women With Insulin-Requiring Diabetes Mellitus Based on Hourly Blood Glucose Measurementa Blood Glucose Concentration. these clinical observations are consistent with the underlying pattern of declining glucose concentrations in the first trimester of normal pregnancy (19). mg/min 127. even a modest decrease in insulin requirement could increase the risk of hypoglycemia.5 204.08 4. Because mild degrees of retinopathy can be missed in women with undiagnosed T2DM the blood pressure criteria is a safety feature to prevent progression of retinopathy in all pregnant women with diabetes mellitus. cD normal saline is 5% dextrose in normal (isotonic) saline. 100 mL/h Normal saline.5 306. total daily insulin requirement.3. Particularly for women with good glycemic control. 5 can rapidly progress during pregnancy (16). Thus.13(Suppl 1) 2007 Table 9. Sample Glucose Infusion Rates for Women With Insulin-Requiring Diabetes Mellitus in Active Labora Weight. kg 50 60 70 80 90 100 110 120 aThe bD Glucose. The rise and fall in insulin requirement is most notable in patients with initially poorly controlled diabetes and in overweight and obese patients.5 255.0 229. 2007.0 280. 100 mL/h plus 6% TDIR Abbreviation: TDIR. all insulinrequiring women with diabetes mellitus and their caregivers should be taught to anticipate the possibility of a decrease in insulin requirement in the mid-late first trimester.06 3.
6:1-27. Kjos SL. Executive Summary 10. (LOE 3 3) 18. REFERENCES 1. Aula P. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. 1983. 1995. Hare JW. Guidetti D. Greene MF. Pregestational diabetes: insulin requirements throughout pregnancy. (LOE 2 2) 10. Ilic S. Bennett PH. Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study. Data Collection and Record Keeping • Measure the blood glucose concentration at hospital admission (grade A) • Record “diabetes mellitus” on the medical chart. 1998.39:225-231. Declining insulin requirement in the late first trimester of diabetic pregnancy. Intensified versus conventional management of gestational diabetes. (LOE 2 2) 17. Mills JL. Br Med J (Clin Res Ed). Khoury MJ.85:1-9.333:1237-1241. Langer O. Diabetes Care. Becerra JE.1. Towner D. et al. Morgan MA. Ylinen K. 1989. (LOE 2 2) 4. Jovanovic L. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy.21:1246-1249. Diabetes Care.170:1036-1046. Branchtein L.1. Am J Obstet Gynecol. Diabetes mellitus in the Pima Indians: incidence. (LOE 2 2) 10. 1995. et al. (LOE 2 2) 3. Damm P. Semmler K. Glockner E. 1988. Franklin B. (LOE 2 2) 2. if a history of diabetes mellitus exists. Reed GF. (LOE 1 1) 15. Cordero JF. (LOE 2 2) 19. Cloherty JP. Molsted-Pedersen L. Rodriguez DA. McFarland MB. Level of glycemia and perinatal outcome in pregestational diabetes. Leung B. Knowler WC. DIABETES MANAGEMENT IN THE HOSPITAL SETTING 10. Am J Obstet Gynecol. Anyaegbunam A. Goldberg JD. which in turn is rooted in the underlying maternal endocrine adaptations to pregnancy. Conway DL. Number 200— December 1994 (replaces No. Physiological reduction in fasting plasma glucose concentration in the first trimester of normal pregnancy: the diabetes in early pregnancy study. 1989. Jovanovic L. Diabetes Metab Rev. (LOE 2 2) 9.159:616-621. Levy J. Brazilian Study of Gestational Diabetes (EBDG) Working Group.48:331-339. et al. or if a HbA1c value (within the past 3 months) is not available for review (grade B) • Order point-of-care glucose monitoring in a pattern appropriate to the patient’s diagnoses and carbohydrate exposure if hyperglycemia is present at hospital admission or if conditions present high risk for developing hyperglycemia (grade A) . Diabetes Care. et al. Xenakis EM. Knopp R. et al. 92. develop a glycemic management plan with the patient before admission and share the plan with colleagues who will be involved in the patient’s care (grade C) 10. Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists. Jovanovic L.47:1140-1144.1. The National Institute of Child Health and Human Development--Diabetes in Early Pregnancy Study. 1990. Diabetes Care.2. Teratology. 1999.18:1446-1451. et al. (LOE 2 2) 5.24:1130-1136. Spichler ER. Int J Gynaecol Obstet. Am J Obstet Gynecol. Endocr Pract. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Mazze R. (LOE 2) 16. Arrendono F. et al (National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study Group).161:1163-1167. This trend is the opposite of the better known late rise in insulin requirement. 2007. J Matern Fetal Med.13(Suppl 1) 2007 insulin sensitivity in the latter half of the first trimester. et al. (LOE 2 2) 13.AACE Diabetes Mellitus Guidelines.289:345-346. Brown Z. Metabolism. 2000. Gestational diabetes: impact of home glucose monitoring on neonatal birth weight. (LOE 2 2) 8. These data provide a basis to anticipate a sometimes sudden and dramatic decrease in insulin requirement in the midlate first trimester of the diabetic pregnancy. Pediatrics. Pettitt DJ. Lasser D. Saad MF. Berkus MD. Mills JL.9:35-41. Risk of minor and major fetal malformations in diabetics with high haemoglobin A1c values in early pregnancy. Major CA. Congenital malformations in pregnancies complicated by NIDDM. Kesaniemi-Kuokkanen T. Pettitt DJ.6:219-223. which reflects a rise in maternal contra-insulin hormones in late pregnancy. 1990. Prevention of congenital malformations in infants of insulin-dependent diabetic mothers. Teramo K.18:631-637. Benacerraf BR. 1994. (LOE 2 2) 12. Am J Obstet Gynecol.1. (LOE 2 2) 14. Hospital Preadmission Planning • For elective hospital admissions. Soeldner JS. risk factors and pathogenesis.154:546-550. 1995. N Engl J Med.164:103-111. Fuhrmann K. First-trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy. Brustman L. Knopp RH. 1991. Jovanovic-Peterson L. Peterson CM. The Diabetes in Early Pregnancy Study. Stenman UH. Reichelt AJ. Fasting plasma glucose is a useful test for the detection of gestational diabetes. (LOE 3 3) 7. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study. Am J Obstet Gynecol. 1986. de Veciana M. Metzger BE. Chew EY. Significant decrease in congenital malformations in newborn infants of an unselected population of diabetic women.22:1422-1427. Erickson JD. (LOE 2 2) 11. Fisher F. 1984. Metabolic control and progression of retinopathy. 1995. Fisher M. Diabetes and pregnancy. May 1986). if the diagnosis of diabetes mellitus is known (grade C) • Measure the HbA1c level at hospital admission if hyperglycemia is present. (LOE 1) 6. Diabetes Care. ACOG technical bulletin. Reiher H. Langer O. 1998. Langer O. et al. 2001. Diabetes Care.
trauma (16). With study results demonstrating that glycemic control reduces mortality.6. less than 180 mg/dL (grade B) • Critically ill patients. progression to renal failure. permit the use of advanced carbohydrate counting and nurse-determination or patient self-determination of prandial insulin doses (grade C) 10. the occurrence of sepsis. Evidence Base 10. Standards for blood glucose monitoring and record keeping are necessary for clinicians to effectively prescribe and administer insulin therapy. Standards for intensive insulin management have been articulated by consensus (46-48).41). and the development of neuropathy (7).1.7. Hypoglycemia Prevention • Modify insulin therapy preventively if a downward trend in blood glucose concentrations is observed or there are other conditions that predispose to hypoglycemia (grade A) • For abrupt interruption of carbohydrate exposure within the time frame of action of previously administered nutritional insulin. Meal Plan • For hyperglycemic patients who are eating. and length of stay or costs (36-40). mortality related to endocarditis (23). hospital administration. Endocr Pract. morbidity. and others (grade B) 10. physical activity.1.1. Comanagement • Work collaboratively with diabetes care professionals from the disciplines of nursing.1. patient mortality.3. renal transplantation (17). Hospital Discharge Planning • Offer inpatient education to patients regarding medication administration (including subcutaneous insulin injections if appropriate). The usefulness of measuring HbA1c levels has been supported by its predictive value for outcomes (45). offer appropriate intensification of the patient’s preadmission management plan (grade B) At hospital discharge. 2007.1. duration of remission after induction chemotherapy for acute lymphocytic leukemia (18). either: (a) order a consistent carbohydrate diet or (b) for knowledgeable nurses or insulin-requiring patients. Results from randomized controlled trials using glucose-insulin-potassium infusions show benefit in the setting of myocardial infarction or cardiac surgery when blood glucose concentrations are lowered (42-44). less than 110 mg/dL (grade C) • Peak postprandial.1. international attention has now focused on intensive insulin management. nutrition. quality assurance. glucose monitoring. Standards have been developed for blood glucose targets and for the use of intravenous insulin and subcutaneous insulin as part of a comprehensive glycemic management plan.5.2. between 80 to 110 mg/dL (grade A) 10. order scheduled subcutaneous insulin (grade B) • For subcutaneous management. myocardial infarction (11. Insulin Management Plan • If appropriate for the patient. and criteria and strategies for using intravenous insulin infusion have been established (49-51). nosocomial infections (24-28). order amounts of insulin sufficient to cover basal and nutritional needs (grade B) • Plan the patterns of glucose monitoring and delivery of insulin to match carbohydrate exposure (grade B) • Revise the amounts of scheduled insulin daily or more frequently based on patient response (grade B) • For patients receiving scheduled insulin.13(Suppl 1) 2007 10. In one randomized controlled trial. labor and delivery (35). The outcomes studied include hospital or critical care unit mortality (1-8) and the outcome of strokes (9-15). treat the patient preemptively with intravenous concentrated dextrose before hypoglycemia occurs (grade B) 10. Sliding-scale insulin regimens used .19-22). Using intravenous insulin infusion in appropriately selected patients is cost-effective (40. specify the times or mealtimes to which the order applies (grade B) 10. order an as needed correction dose of subcutaneous insulin with dosing that is: (a) proportionate to blood glucose elevation and insulin sensitivity of the patient and (b) appropriate to time of day. Target Blood Glucose Levels • Preprandial. provide an explanation of circumstances that should prompt the patient to call the clinician for guidance (grade B) Plan follow-up visits to be conducted after hospital discharge to discuss glycemic control and to continue patient education (grade B) 10. • • • nutrition. Findings from observational studies and ongoing clinical trials comparing intensified regimens with historical controls show correlation between poor glycemic control and unfavorable outcomes. and other lifestyle factors (grade B) At hospital discharge.8. transfusion requirements. and length of stay have been linked to failure of glycemic control. the maintenance of normoglycemia using intravenous insulin infusion in patients being cared for in the surgical intensive care unit reduced the duration of ventilatory assistance. pharmacy.1. cardiac surgery (30-34).2. use intravenous insulin infusion (grade A) • If hyperglycemia is reproducibly present and intravenous insulin infusion is not necessary.0 AACE Diabetes Mellitus Guidelines. pneumococcal sepsis (29). Overview In the hospital setting.4.
Stroke. (LOE 1 1) Gentile NT.58). computerized order entry systems that guide and teach. 2004. (LOE 3 3) Levetan CS. to withhold. 2004. Gaughan J. 2002. Correction dose insulin orders should be tagged with additional directions to not withhold. or to reduce the insulin dose in the event that the patient has delayed or reduced carbohydrate exposure or point-of-care test results are obtained at an irregular time.64:1348-1353. Acad Emerg Med. Patients Without Confirmed Diabetes Mellitus Who Have Hyperglycemia While Hospitalized For patients without confirmed diabetes mellitus who experience hyperglycemia while hospitalized.AACE Diabetes Mellitus Guidelines. Isaacs SD. Elia A. 2002. 2003. (LOE 3 3) Krinsley JS. 14. Huynh T. when using subcutaneous insulin injection therapy. (LOE 3 3) Leigh R. All Patients With Diabetes Mellitus Using rapid-acting insulin analogs should be restricted to prandial and correction dose therapy. REFERENCES 1. Effect of hyperglycemia on stroke outcomes. (LOE 1 1) Baird TA. Patient self-management in the hospital is feasible and desirable for experienced patients when they are competent to continue self-management under the conditions of the hospital admission (59. (LOE 2 2) Bruno A. N Engl J Med.87:978-982. Call parameters should be ordered. protocols activated by a single signature. 2004. et al (NINDS rt-PA Stroke Study Group). 2003. A call order should be included to alert the clinician if the patient experiences a sudden change in carbohydrate exposure.13:174-180. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. et al.164:2005-2011.34:2208-2214. Kruus LK. 1995. Mortality in hospitalized patients with hypoglycemia and severe hyperglycemia. and policies (50. (LOE 3 3) Krinsley JS. Decreased mortality by normalizing blood glucose after acute ischemic stroke. 9. Lau J. Linekin PL. Intensive insulin therapy in the critically ill patients. and basal insulin should be ordered separately from nutritional coverage. Neurology. the use of long-acting insulin analogs should be restricted to basal requirements. scheduled or “standing” insulin regimens should be the standard of care (54-56). 4.345:1359-1367. 2007. . Clinical Considerations The following considerations are relevant for clinician involvement unless the need already is covered under policies of the hospital. Endocrinologists should participate as members of the health care team managing individual patient care and as agents promoting institutional changes by developing hospital order sets completed by check marks and numbers.2. JAMA. 11. In patients whose conditions are clinically unstable. Lancet. Mayo Clin Proc. Hunt D.59:669-674. Gerstein HC. the ward. and various guidelines. 12. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview.60).62:422-426. Patients With Type 2 Diabetes Mellitus For patients with T2DM. Patients With Type 1 Diabetes Mellitus For patients with T1DM.35:1903-1907. (LOE 3 3) Umpierrez GE.2. Frankel MR.13(Suppl 1) 2007 1 alone are ineffective and potentially harmful (52. Bruyninckx F.61-67). procedures. Phanh T. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. 2006. Becx P. (LOE 3) van den Berghe G. 10. to withhold.10(suppl 2):34-39. Seftchick MW. Endocr Pract.54. (LOE 1 1) Stagnaro-Green A. (LOE 1 1) van den Berghe. et al. 10. Thaler LM. 5. Insulin therapy for critically ill hospitalized patients: a meta-analysis of randomized controlled trials. Hypoglycemia is usually predictable and therefore preventable (57. Evans TW. Arch Intern Med.78:14711478. Roman SH. Zekveld C. Mayo Clin Proc. adjust carbohydrate exposure. deBeer K. Basal insulin orders should be tagged with the specification do not withhold insulin.You X. Insulin therapy protects the central and peripheral nervous system of intensive care patients. or other service entity. Schoonheydt K. J Clin Endocrinol Metab. 8. (LOE 4 4) 3. Mt Sinai J Med. Wouters PJ. Kitabchi AE. 2003. 2001. or respond to other factors resulting in destabilization based on blood glucose concentration thresholds. 6. 2000.355:773-778. basal insulin orders should be tagged with additional directions to not withhold. (LOE 2 2) Pittas AG.79:992-1000. Suri MF. Neurology.53). Bazargan N. Levine SR. Malmberg K. 2004. the presence or absence of diabetes should be established in outpatient follow-up using venous blood and plasma glucose concentration criteria. Endocr Pract. Finney SJ. Parsons MW. Corkery E. Stroke. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Wouters P. Barton MK. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. the basal insulin requirement should be identified in units per day. (LOE 1 1) Capes SE.290:20412047. Weekers F. Siegel RD. Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy. which describe when the clinician should be alerted to revise scheduled insulin therapy. 7. 13. Glucose control and mortality in critically ill patients. Zaidat OO. 2005. 2. or to reduce the insulin dose in the event that the patient has reduced carbohydrate exposure. Nutritional insulin orders should be tagged with directions that nurses can follow in case the patient has delayed or reduced carbohydrate exposure. et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial.
Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Chitwood WR Jr. Ann Thorac Surg. Grunkemeier GL. Lancaster AD.10(suppl 2):46-52. Malmberg K. Ann Thorac Surg. Diabetes Care. Kleybrink S. Szabo Z. Ann Thorac Surg.164:982-988. et al. Zerr KJ. III.10:112-118. Utility of HbA(1c) levels for diabetes case finding in hospitalized patients with hyperglycemia. (LOE 2 2) 34. (LOE 3 3) 22. Stroke. Dall T. Vora AC. Chang MC. (LOE 3 3) 24. Vriesendorp TM.22:1408-1414.74:712-719. Kailasam M. Early peri-operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study. Starr A. Diabetes and coronary artery bypass surgery: an examination of perioperative glycemic control and outcomes.75:1392-1399. J Am Coll Cardiol. 2004.100:1179-1185. Stranders I. Grunkemeier GL. Malkani S.109:1745-1749. Kosiborod M.26:57-65. Malmberg K. et al.13(Suppl 1) 2007 15. Relationship of early hyperglycemia to mortality in trauma patients. (level 3) 45.27:7076. Efendic S. Greci LS. Rao MM. results from the DIGAMI study. (LOE 2 2) 27.314:15121515. 2004. Circulation. (LOE 2 2) 32. Fitzgerald CA. Russ GR. 1997. 2000. Ryden L. Eur Heart J. (LOE 3 3) 21. Cabral H.56:1058-1062. Diabetes Care. (LOE 3 3) 35. (LOE 3 3) 29. 2004. Gao G. Diabetes and outcome of community-acquired pneumococcal bacteremia: a 10-year population-based cohort study. Lindsberg PJ. Hakanson E. Pomposelli JJ. JPEN J Parenter Enteral Nutr. Circulation. Furnary AP. et al. Diabetes Care.111:3078-3086. (LOE 3 3) 18. Lervang HH. Cabanillas ME. et al. Brancati FL. Reduction of hospital costs and length of stay by good control of blood glucose levels. Endocr Pract. Endocr Pract. Glucose and insulin requirements during labor and delivery: the case for normoglycemia in pregnancies complicated by diabetes. Malmberg K. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. et al. Pirolo JS. Almbrand B. Peart-Vigilance C. Kilgo PD. (LOE 4 4) 36. 1999. Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Endocr Pract. The association of diabetes and glucose control with surgical-site infections among cardiothoracic surgery patients. Svedjeholm R.109:1497-1502. and dexamethasone/methotrexate-cytarabine regimen. 2004. 2003. Diabetes Care. Baxter JK. Early postoperative outcome and medium-term survival in 540 diabetic and 2239 nondiabetic patients undergoing coronary artery bypass grafting. Amad H. Circulation. 2004. Outcomes and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting. Ann Thorac Surg. Weiser MA. Apstein CS.10(suppl 2):53-56. Inzucchi SE. Young JA. Schnell O. 2003. 2004. (LOE 2 2) 28.10(suppl 2):40-45. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. van Gelder RE. Schafer O. Transplantation. Grunkemeier GL. BMJ. Perdrizet GA. (LOE 1 1) 44.125:1007-1021. Ryden L. et al. 1995.10(suppl 2):21-33. Saleem TM.21:733-739. A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes. Moran J. 2004. J Trauma. Man J.26:917-932. Wu Y. 2003. Hyperglycemia in acute stroke. 2001. 1999. Morelis QJ. et al. 2001. Diabetes Care. Devries JH. Ahmann A. McAlister FA. Arch Intern Med. doxorubicin. et al. Early post-operative glucose levels are an independent risk factor for infection after peripheral vascular surgery. 1998.67:352-360. Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. 2007. Diamant M. Estrada CA. (LOE 1 1) 43. Jovanovic L. Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. 2004. (LOE 2 2) 20. Johannesson M. Furnary AP. (LOE 1 1) 38. 2003. Legemate DA. Grey NJ. Chu VH. et al. Roine RO. Heart.35:363-364. Bao Y. 2004. (LOE 4 4) 42. (LOE 3 3) 40. Intensification of therapeutic approaches reduces mortality in diabetic patients with acute myocardial infarction: the Munich registry. et al. Johnsen SP. Thomsen RW. Covington JF. (LOE 3 3) 30. Thomas MC. 1997. Konopleva M. Latham R. Improved perioperative glycemic control by continuous insulin infusion under supervision of an endocrinologist does not increase costs in patients with diabetes. 2005. Foo K. Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus. et al. (LOE 4 4) 37. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.27:455-460. A retrospective study. Diabetes Care. (LOE 3 3) 23.89:512516.26:1064-1068. Tandon P. 2004. Miller PR. Sjostrand B. J Thorac Cardiovasc Surg. 2004. Infect Control Hosp Epidemiol. 2002. (LOE 2) . 2003. Cancer. Economic costs of diabetes in the US in 2002. Deaner A. Rathore SS.22:77-81. Babineau TJ. Nifong LW. DIGAMI (Diabetes Mellitus. 2003. Eur J Vasc Endovasc Surg. Cooper J. (LOE 3 3) 39. Lazar HL. (LOE 2 2) 25.22:607-612. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. Hoekstra JB.26:1518-1524. Hundborg HH. Kao WH. Chipkin SR. Furnary AP. Early predictors of in-hospital death in infective endocarditis. Bistritz L. Thomas CS. Glucose control lowers the risk of wound infection in diabetics after open heart operations. (LOE 2 2) 26. (LOE 3 3) 19. (LOE 3 3) 33. Benjamin DK Jr. Bookin SO. Endocr Pract. Zerr KJ. Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes.28:520-525. 2004. Furnary AP. vincristine.72:1321-1324. Laird AM. Endocr Pract. 2004. Endocr Pract. Golden SH. Polomano RC. (LOE 2 2) 31. Hogan P. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Reduction of nosocomial infections in the surgical intensive-care unit by strict glycemic control. Meredith JW. 2004. et al.63:356-361. (LOE 3 3) 17. Nikolov P (American Diabetes Association). Schonheyder HC. Cabell CH. Mathew TH. (LOE 4 4) 16. Sorensen HT. Cost-effectiveness of intense insulin treatment after acute myocardial infarction in patients with diabetes mellitus.2 AACE Diabetes Mellitus Guidelines. (LOE 2 2) 41.
28(suppl 1):S4-S36. 2001. Braithwaite SS.27:856 and Diabetes Care. (LOE 3 3) 54. 2003.13(Suppl 1) 2007 3 46. Hypoglycemia in hospitalized patients. Newman JH. Lee SW.10(suppl 2):4-9. Braithwaite SS.8:10-18. et al. Causes and outcomes. 2004. Braithwaite SS. Replogle WH.1 Systems Issues • Medical errors are common and adversely affect important outcomes in diabetes care (grade A) • Most medical errors are not injurious because they are discovered and corrected by the health care team before they cause harm (grade A) • A high level of patient safety is not a predictable outcome of complex medical systems and is usually achievable only with considerable and continuous effort (grade C) • Create a nonpunitive environment to encourage learning from mistakes and involve all members of the health care team who are responsible for the care of the diabetic patient in the clinical setting (grade B) • Schedule regular health care team meetings to address patient safety as a priority and insert a line item into the annual budget to pay for needed changes (grade B) • Encourage voluntary sharing of error data and address them using an analytic method to improve the system of care and to reduce the frequency of injurious medical errors (grade B) • As part of diabetes care coordination. Forbes RC. a group of health care workers who function as a team to protect the patient from injurious medical errors (grade B) • Use algorithms to address complex medical procedures and provide ample time for relevant staff to learn and practice how to use the algorithms (grade B) • Always balance profitability with safety concerns (grade A) • Implement and use an electronic health record or information sharing system. 2005. (LOE 2 2) 53. Kington R. Ratner RE. Lees JA. Baldwin D.27:172-184. 2004. (LOE 4 4) 57. Sayre CA. Davidson PC. Im R. (LOE 4 4) 49. [erratum in Diabetes Care. Kearns LE. Steed RD. Campbell KB. Endocr Pract. Passaro MD. Endocr Pract. Brancati FL. Levetan CS.1 Executive Summary 11. Diabetes Care. Rogers W. Training in flexible. Achtmeyer CE.325:746. (LOE 3 3) 58. 2002. Trence DL.315:1245-1250. (LOE 3 3) 64. Quevedo SF. (LOE 4 4) 48. develop a culture of safety. 1994. Gearhart JG. Thompson CL. Diabetes Care.10(suppl 2):89-99. 2002. PATIENT SAFETY IN DIABETES CARE 11.157:545-552. Payne TH. Wilets IF. Endocr Pract. (LOE 4 4) 61. (LOE 2 2) 50. Crit Care Nurs Q. Braithwaite SS.10(suppl 2):100-108.14:226-233. Bransome ED Jr. 2004.22:81-88. Subcutaneous insulin therapy in the hospital setting: issues. Hospital hypoglycemia: not only treatment but also prevention. Buie MM. American College of Endocrinology position statement on inpatient diabetes and metabolic control. Management of diabetes and hyperglycemia in hospitals [erratum in Diabetes Care. (LOE 4 4) 66. Markovitz LJ. 2004. (LOE 4 4) 47. and transition to subcutaneous insulin therapy. (LOE 1 1) 56.41:277-281. Queale WS. American Diabetes Association. Fischer KF. BMJ. 2004. 1997. (LOE 2 2) 51.28:990� Diabetes Care. Endocr Pract. Fam Pract Res J. Walley EJ. and implementation.99:22-28. Magee MF. Ku SY. 1999. (LOE 2 2) 52. (LOE 4 4) 11. concerns. Kelly JL. 2005. Clement S. Wiechmann RJ. Magee MF. Zumoff B. Sullivan E. 2004. (LOE 4 4) 63. Hyperglycemia in the hospital. 2004.14:313-322. 2005. Glycemic control and sliding scale insulin use in medical inpatients with diabetes mellitus. McNutt R. (LOE 2 2) 60. Current perspectives on the use of continuous subcutaneous insulin infusion in the acute care setting and overview of therapy. Diabetes Spectr. Endocr Pract. Computer order entry system decreased use of sliding scale insulin regimens. DAFNE Study Group.18:20-27.22:1790-1795. Salas JR. Villanueva G. Bode BW. Moghissi ES. Hospital management of hyperglycemia. Hirsch IB. Menon MC. 2004.27:1255�.AACE Diabetes Mellitus Guidelines. Standards of medical care in diabetes. intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. Arch Intern Med.27:553-591. 2002. Methods Inf Med. Diabetes Spectr.10(suppl 2):71-80. Clin Diabetes. Braithwaite SS.31:141-147. Kelly JL. Dunn KC. New insulin infusion protocol improves blood glucose control in hospitalized patients without increasing hypoglycemia. III. Garber AJ. Bhatnagar S. Thompson CL. Am J Med. J Clin Endocrinol Metab. Intravenous insulin infusion therapy: indications. (LOE 4 4) 59. Magbual R. Levetan CS. methods. Anawalt BD. Endocr Pract. Diabetes Care. Jablonski KA. 2004. The rationale and management of hyperglycemia for in-patients with cardiovascular disease: time for change. Clement S. Effect of physician specialty on outcomes in diabetic ketoacidosis.88:2430-2437. a well-designed system may significantly reduce the frequency of medical errors (grade A) • Implement and use well-designed computerized physician order entry systems to reduce medication errors (grade A) . Endocr Pract. et al (American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control). 1986. 1995. Harris N.10(suppl 2):81-88. Description and evaluation of a glycemic management protocol for patients with diabetes undergoing heart surgery.28:1008-1011. Impact of endocrine and diabetes team consultation on hospital length of stay for patients with diabetes. Duncan JL. 2004. Seidler AJ. Jt Comm J Qual Patient Saf. et al. et al (American Diabetes in Hospitals Writing Committee). Hirsch IB. A systems approach to reducing errors in insulin therapy in the inpatient setting. 2005. (LOE 4 4) 62. Efficacy of sliding-scale insulin therapy: a comparison with prospective regimens.1. 2007. Hellman R. Improving diabetes care in the hospital using guideline-directed orders. (LOE 2 2) 55. N Engl J Med. (LOE 3 3) 65. 2005. (LOE 4 4) 67. Eliminating inpatient sliding-scale insulin: a reeducation project with medical house staff.
A systems approach to medical error reduction has a much greater chance of successfully improving patient safety because factors at the so-called blunt end of care—parts of the health care system that are not in direct contact with patients. complications. A culture of safety is designed to provide a system of care that will assist health care providers anticipate and prevent such events. when physicians order tests or medications. prevention. and patient preferences often cause necessary and appropriate variations in care practice. The most compelling data in the safety arena are from outcome studies that use clear clinical end points such as mortality or infection data. patients.1. clear insulin orders to anticipate each of the common or important situations that patients must confront (grade A) • Use written algorithms for insulin therapy. studied in the field of patient safety are complex. if possible.13(Suppl 1) 2007 • Although comorbid conditions.9).13). Endocr Pract. many of them cohort or observational studies. economic conditions. Findings from some outcome studies show striking reductions in infectious complications and death rates (10). such as hospitals. Most errors are not injurious and are discovered and corrected by the health care team. for example. even excellent physicians usually will be unable to notably improve overall care. but of morbidity. Evidence Base 11. Therefore. Nearly all medical errors are inadvertent or systematic. but which affect personnel and equipment—are much more powerful influences than factors at the so-called sharp end of care—parts of the health care system that care for patients directly (16). the error is inadvertent. have provided excellent outcome information and evidence that support the recommendations for methods to improve patient safety (2). linked interventions.2. and treatment (grade A) 11. improvement in safety is often difficult to achieve (15). Health care professionals are understandably reluctant to voluntarily disclose injurious errors they have made. 2007.2. without such an approach.2. the patient medical information they have access to is often incomplete (13). A culture of safety can be defined as a group of health care workers who work together to protect the patient from preventable. but before the patient eats. often iterated over a period of time (2. most data are not derived from randomized controlled trials. Modern patient safety programs focus on improving the system of care because the blunt end of care has a much greater effect on patient safety.14). For example. the architecture of such clinical research involves multiple simultaneous. AACE Diabetes Mellitus Guidelines. monitoring of desired clinical performance standards becomes easier (grade A) 11. It is necessary to adopt a nonpunitive approach when discussing medical errors. Results from several randomized controlled trials document the validity of recommendations related to safety (3-8). In an unsafe system of care. 11. and disability (13. reduce variations in care that are not evidencebased to decrease the occurrence of errors. Overview Although abundant evidence is available regarding proven strategies in patient safety efforts. As a result.1.2. but the organizational behavior is the focus (11). Because of ethical concerns. Patient Issues • Give explicit. or whose leisure time involves high-risk activities to participate in an education program with emphasis on hypoglycemia recognition. An error may be outside of a physician’s ability to correct because it was both unanticipated and unobserved. a randomized controlled trial is more conducive to assessing quality than safety. it is unethical to put subjects in harm’s way to prove that injurious medical errors are more common in the control group. Rationale Medical errors are common and adversely affect clinically important outcomes in diabetes care (12. Almost always. a common injury to a patient with diabetes mellitus is hypoglycemia that occurs when a patient is taken to radiology by a transportation worker after an insulin injection. they should be typed or printed (grade A) • Provide frequent glucose monitoring according to the medical needs of the patient (grade A) • Routinely recheck patient understanding of basic concepts of self-care at appropriate intervals (grade A) • Assess for coronary heart disease in patients with diabetes mellitus (grade A) • Evaluate all patients for their relative risk of hypoglycemia (grade A) • Use diabetes education programs that are evidencebased and focused on issues of patient safety (grade C) • Encourage all patients who drive motor vehicles. Some system data are also based on studies in other systems. an abundance of studies. Because the health care systems. despite their best efforts (16). Bates and others report that underreporting of errors is common even in hospitals known to provide outstanding medical care (1). injurious medical errors. Also. allow others (peers. wherever possible. and families of patients) to facilitate best practices. For example. coordination of care should include development of a culture of safety in the clinical diabetes care setting. Evidence shows that a high prevalence of injurious medical errors in diabetes care increases the frequency of not only death. Fortunately. who have high-risk occupations. allied health professionals.2. Such system . in a hospital setting.
if not exposed. Medication errors can be markedly reduced with the use of a well-designed computerized physician order entry system. these errors can be lethal (13). For example. a patient may be unaware of the new risks to the feet that result from neuropathy or peripheral vascular disease (14). diminished oral intake. 2007. clear insulin orders should be given to anticipate each of the common or important situations that patients encounter (13.18). A high index of suspicion for coronary heart disease in diabetic patients will reduce the risk of sudden death (2426).AACE Diabetes Mellitus Guidelines. Frequent glucose monitoring should be conducted according to the medical needs of the patient. An assessment of the frequency. patients. In hospitals. In contrast. The optimal form or content of such programs are not yet established but should be designed to aid in communication with the health care team and to increase the level of safety for the patient with diabetes mellitus (13). systems of care.2. The enlistment of the patient’s family or other support system may be needed to protect the patient from hypoglycemic .19). or a physician may be unaware of how much a patient’s visual loss has affected usual self-care activities such as drawing up insulin.3. Data from the Federal Aviation Administration and from the US Nuclear Regulatory Commission—high-safety level organizations with exemplary performance—show the necessity of providing safe harbor for those who report medical errors. To help reduce the risk of accidents. When many different people use only a few selected algorithms. nursing care is sufficient. and society (16.21). and clinicians should not assume that patients under longterm care understand instructions regarding their treatment regimen. However.22). Both the patient and the physician may be uniformed about the other’s knowledge regarding changes in the status of diabetes complications and the related increased risk for injury (27). 11. Inadequate screening for cardiac complications of diabetes mellitus is common because patients with neuropathy frequently have atypical chest pain or no chest pain. Patients With Type 1 Diabetes Mellitus Hypoglycemia is a common problem that causes accidents and serious injury. should be used to guide insulin therapy. Endocr Pract.15). Many patients forget what they once were taught. but it is a source of many serious medical errors of commission or omission by health care providers. The presence of autonomic neuropathy.13(Suppl 1) 2007 problems are best solved by effective communication among all members of the team who care for the patient (13). the ability to quickly review years of clinical data. which is currently available mostly in inpatient settings (1. The size and complexity of the group can be extremely varied. An electronic medical record can provide critically important clinical information to physicians when they most need it. it is important to preserve the capability of the system to provide safe medical care. the modern medical tort system encourages hiding errors. aggregate and display data before making a clinical decision. 14 to 60 steps—or more— may occur before a medication order is fulfilled and the medication is given to the patient. and many other factors should be noted as well as the frequency of glucose monitoring (27-29). silent ischemia is common in this population (23). Evidence-based patient education programs can potentially enhance the safety of the patient with diabetes mellitus. The complications of diabetes mellitus often affect the patient’s risk of injury. with prescriptions submitted using computerized physician order entry systems. Explicit. The common methods of resolution include backup checks and timely communication of medical information (14. With a few keystrokes. Computerized physician order entry systems greatly reduce the possibility of error or ambiguity. particularly errors with which they were involved (13). use of βadrenergic blockers. pharmacy staff do not need to decipher physicians’ handwritten scripts (1. and any recent exacerbation of hypoglycemia should be done when the patient presents for evaluation of hypoglycemia. training the entire group is easier (13). Clinical Considerations All Patients With Diabetes Mellitus Insulin is a potent and invaluable medication. Abundant data show the importance of taking a nonpunitive approach when discussing medical errors. Generally. This information will allow the dose to be matched more closely to the patient’s needs (13). Profitability must always be balanced by safety concerns. Implementing an electronic medical record or information-sharing system would reduce errors in medical care (9). which. In diabetes care settings. are often repeated inadvertently by others (17). Written algorithms. it is safest to assess the patient’s glucose level each time insulin is administered. severity. and proper technology is available when needed may cost more initially. For example. the clinician should periodically check in with the patient and strive for better communication. Some computer systems have decision aids or clinical reminders that can enhance performance (20). budgeting for safety is a valid short-term and long-term strategy that ultimately leads to better outcomes and more value for patients. and check for contraindications or for drug interactions make an electronic medical record a powerful tool to improve patient safety. Rechecking patients’ understanding of basic self-care concepts should be done routinely at appropriate intervals (13). and other caregivers such as family members. chronic kidney disease. preferably typed or printed. Providing the resources to ensure that patient education is effective. Such programs should be a part of the ongoing care of the patient.
2004. 2001. A controlled trial of smart infusion pumps to improve medication safety in critically ill patients. Regan J. Becher EC. (LOE 2 2) 4. Hellman R. 2000. Crit Care Med. Patients who repeatedly miss medical appointments may be at increased risk for medication noncompliance and may require diligent follow-up measures to resolve underlying issues. (LOE 1 1) 9. et al. An education program for all patients with T1DM who drive motor vehicles may be lifesaving (30. Frequent glucose monitoring is useful in nearly all circumstances. J Am Med Inform Assoc. Washington. 1998.283:1293�. Recent data show that as many as 30% of patients with health coverage by Medicare will not take at least 1 of their medications because of financial constraints (34). Crossing the Quality Chasm: A New Health System for the 21st Century. Patients who drive motor vehicles and become hypoglycemic are at particularly high risk of serious morbidity and death. Strategies to Reduce Medical Errors in the Management of Diabetes. Inc. Rosen H. Fauci AS. Cronin JW. 16th edition. (LOE 2 2) 2. Patient compliance with a prescribed medication regimen should not be assumed. The McGraw-Hill Companies. Landrigan CP. (LOE 4 4) 10. Intensive insulin therapy in the critically ill patients. Rothschild JM. Clark NG. A systems solution is required to monitor for potential drug interactions and to improve patient safety (13).11:197-202.33:533-540. 1990. Harrison’s Online available at http://www. Cullen DJ. Human Error. Cambridge. Effect of reducing interns' work hours on serious medical errors in intensive care units. Cognitive impairment is not limited to hypoglycemic episodes (32). REFERENCES 1. Bates D. (LOE 4 4) 3. and their sensory apparatus may also be severely impaired. Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. which would probably have been preventable with earlier diagnosis. van den Berghe G.345:1359-1367. but by itself. A systems approach to reducing errors in insulin therapy in the inpatient setting. Isselbacher KJ. 2001.12:431-437. J Am Med Inform Assoc. Hellman R. These patients often experience cognitive impairment. N Engl J Med.com.29). eds. Bates DW.351:1838-1848. Braunwald E. 2004. 2005. Improving quality. (LOE 1 1) 7. American College of Endocrinology and American Association of Clinical Endocrinologists position statement on patient safety and medical system errors in diabetes and endocrinology. 2007. minimizing error: making it happen. Improving response to critical laboratory results with automation: results of a randomized controlled trial. Tanasijevic MJ. 2001. Jameson L. Endocr Pract. (LOE 4 4) .20:258-264. et al.280:1311-1316.13(Suppl 1) 2007 episodes. Accessed July 15. 2005. Pharmacist participation on physician rounds and adverse drug events in the intensive care unit [erratum in JAMA. United Kingdom: Cambridge University Press.10(suppl 2):100-108. Hauser SL. Hyperglycemia. Institute of Medicine. In: Kasper DL. during which hypoglycemia could cause serious accidents. 1999. N Engl J Med. Leape LL. (LOE 1 1) 8. The same strategy should be used for patients with highrisk occupations or for patients whose leisure time involves activities such as climbing ladders or scuba diving. Cook RI. et al (Writing Committee on Patient Safety and Medical System Errors in Diabetes and Endocrinology). AACE Diabetes Mellitus Guidelines. 1999. Longo DL. JAMA. Gandhi TK. 2006.31). Their care should be customized to fit their needs. may present with central nervous system findings of coma or focal weakness. et al. if sufficiently severe. it may not be sufficient to prevent hypoglycemia. et al. 2005. (LOE 2 2) 6. Teich JM. Elderly and frail patients. Keohane CA. Reason JT. DC: National Academies Press. even in high-risk populations. (LOE 4 4) 12. The most commonly used tools to assess for drug interactions in real time are computers and PDAs. Rothschild JM. A patient recovering from mild ketosis or marked hyperglycemia (33) may also be temporarily impaired in their memory or judgment. Medications and other comorbid conditions may affect cognitive function in patients with diabetes mellitus. Adverse drug interactions are problematic. particularly those who are institutionalized. particularly in patients with T2DM who have multiple comorbidities that confer an added risk for mortality (10). et al. Endocr Pract. Wouters P. which is most often a system-derived problem because of the pressures to limit screening. More than 50% of patients diagnosed with T2DM have at least 1 complication at the time of diagnosis. Patients are often unaware that they may be impaired even 45 minutes after the onset of severe hypoglycemia.harrisonsonline. 1997. Sequist TD. Karson AS.282:267-270. et al. (level 2) 11. Committee on Quality of Health Care in America. A randomized trial of electronic clinical reminders to improve quality of care for diabetes and coronary artery disease. (LOE 1 1) 5. JAMA. are particularly prone to delayed diagnosis and delayed treatment (28. Leape LL. Health Aff (Millwood ). Patients With Type 2 Diabetes Mellitus The most common error that leads to preventable complications is delayed diagnostic screening (25). Cook EF. Kuperman GJ. (LOE 4 4) 14. Endocr Pract. Weekers F. Effect of intensive treatment of diabetes on the risk of death or renal failure in NIDDM and IDDM. Chassin MR. (LOE 4 4) 13.20:6881. Clapp MD.6:512-522. Harrison's Principles of Internal Medicine. Hellman R. Diabetes Care. Cullen DJ. Patients may not realize how important medications are for promoting their health and safety. et al.
(LOE 2 2) 19. Ronnemaa T. Clarke W. J Gen Intern Med.. Hypoglycemia as a predictor of mortality in hospitalized elderly patients. Newman JH. Polonsky W. Novo Nordisk Inc. Novartis. Committee on Quality of Health Care in America. (LOE 4 4) 22. et al. Dr. Pfizer Inc. Kessels RP. Cox DJ. 2005. Eli Lilly and Company. Baxter JK III. Novartis.. Dr. Teich JM. Biessels GJ. Institute of Medicine. (LOE 4 4) 18. MannKind Corporation. and consultant honoraria from Abbott Laboratories. The impact of computerized physician order entry on medication error prevention. 2001. 2004. Inc. Mahwah. Merck & Co. AstraZeneca LP. Inc.S. Ann Intern Med. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. 2003. Lehto S.. et al.95:1472-1474. Inc. de Haan EH. (LOE 2 2) 32. in an account that is not part of their community property.24:637642. Haffner SM. Amalberti R. and Novartis and consultant honoraria from Abbott Laboratories. 1986. Medical liability and patient safety. Diabetes Care. Brett reports that her spouse is an employee of Novo Nordisk Inc. and sanofi-aventis U. 2004.26:2329-2334. Pyorala K. Buie MM. N Engl J Med. Wilson IB.... Merck & Co. Inc. Barach P. Pfizer Inc. Diabetes Care. Zrebiec J. Lawrence Blonde reports that he has received grant/ research support from Amylin Pharmaceuticals. 2003. Arch Intern Med. (LOE 3 3) 29. Chang H. Braithwaite reports that she does not have any financial relationships with any commercial interests.159:281-284. Lee J. Ben-Ami H..163:1825-1829.. (LOE 2 2) 34. Washington. Washington. Committee on Data Standards for Patient Safety. Brands AM. Bristol-Myers Squibb Company. Gonder-Frederick LA.142:756-764. 1999. Gonder-Frederick L. Elise M. Adverse drug events in ambulatory care. 2003. Patient Safety: Achieving a New Standard for Care.6:313-321. Costrelated skipping of medications and other treatments among Medicare beneficiaries between 1998 and 2000.20:715-720. et al. Bristol-Myers Squibb Company. Pomposelli JJ. (LOE 4 4) 21. Rogers WH. Inc. (LOE 2 2) 20. Inc. Amylin Pharmaceuticals. Cobin reports that she has received speaker honoraria from GlaxoSmithKline. Berwick D. Susan S. and Pfizer Inc. 1998.. sanofiaventis U.315:1245-1250.S. Hospital hypoglycemia: not only treatment but also prevention. Weiss MB. He has received speaker and consultant honoraria from Abbott Laboratories. Merck & Co. Arch Intern Med. GlaxoSmithKline. Inc. To Err is Human: Building a Safer Health System. Borus J. Endocr Pract. Yehuda Handelsman reports that he has received speaker honoraria from Abbott Laboratories.S.S. Aronow WS. 2004. Five system barriers to achieving ultrasafe health care. (LOE 1 1) 24. et al. 1998. DeLuca AJ. Safran DG. Kagansky N.10(suppl 2):89-99. Board on Health Care Services. N Engl J Med. Cox DJ. Sage WM. Weingart SN. Lees JA. Pfizer Inc. Kovatchev BP.. Penberthy JK. et al.22:77-81. 2005. . (LOE 4 4) 16. Eli Lilly and Company. Bates DW. DC: National Academies Press. 2003. Braithwaite SS. LifeScan.. Tamsma JT. et al. Misadventures in Health Care: Inside Stories.348:15561564. and sanofiaventis U. (LOE 3 3) 28. Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes.. Diabetes Care. et al. Auroy Y. 2005. Fischer KF. Saulle LN. Novo Nordisk Inc.. Diabetes and driving mishaps: frequency and correlations from a multinational survey. et al.28:1675-1679.13(Suppl 1) 2007 7 15. Babineau TJ. (LOE 3 3) 27. Dr.. Blonde has also disclosed that his spouse is a stock shareholder of Amylin Pharmaceuticals. Blood glucose awareness training (BGAT-2): long-term benefits. (level 3) 31. Daiichi Sankyo. JPEN J Parenter Enteral Nutr. 2005. (LOE 4 4) 23. Endocr Pract. Beishuizen ED. The effects of type 1 diabetes on cognitive performance: a meta-analysis. Drug-induced hypoglycemic coma in 102 diabetic patients... Amylin Pharmaceuticals. No effect of statin therapy on silent myocardial ischemia in patients with type 2 diabetes without manifest cardiovascular disease. 1999. (LOE 4 4) 17. Thompson CL. Levy S. NJ: Lawrence Erlbaum Associates. (LOE 1 1) 33.28:71-77. 1999. Jukema JW. Kovatchev B. 2007. J Am Med Inform Assoc.22:26-36. Novartis Corporation. Inc. Rhoda H. Inc. Inc. Health Aff (Millwood ). Inc. AstraZeneca LP. Diabetes Care. (LOE 3 3) 30. Hypoglycemia in hospitalized patients. Nagachandran P. Institute of Medicine.339:229234. Results of a national study.. Causes and outcomes. Gandhi TK. (LOE 2 2) 26. Rimon E. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. 2005. Surgical. DC: National Academies Press. Prevalence of silent myocardial ischemia in persons with diabetes mellitus or impaired glucose tolerance and association of hemoglobin A1c with prevalence of silent myocardial ischemia. Kappelle LJ.S. Diabetes Care.AACE Diabetes Mellitus Guidelines. GlaxoSmithKline. Ravipati G. Bogner MS. N Engl J Med. (LOE 2 2) 25. Am J Cardiol.. Laakso M.28:726735. (LOE 3) DISCLOSURE Dr. and U.S. Edoute Y. Dr. Cox DJ. He has received consultant honoraria from Kos Pharmaceuticals. and sanofi-aventis U. 2005. Novartis. Schlundt D. Dr. Mendelson A. and sanofi-aventis U.
S.. Pfizer Inc. Novo Nordisk Inc. Richard Hellman reports that he has received speaker honoraria from Daiichi Sankyo. Inc.13(Suppl 1) 2007 Dr. Roche Pharmaceuticals.. Pfizer Inc.. Novo Nordisk Inc. GlaxoSmithKline. and sanofi-aventis U. Novo Nordisk Inc. Jellinger reports that he has received speaker honoraria from Eli Lilly and Company. and sanofi-aventis U. Inc. and Takeda Pharmaceuticals North America.. Rodbard reports that she has received consultant honoraria from Ortho-McNeil. . Inc. Merck & Co.S. Mechanick reports that he does not have any financial relationships with any commercial interests. AACE Diabetes Mellitus Guidelines. and Pfizer Inc. Inc.. Novo Nordisk Inc.. Merck & Co.S.. DexCom Inc.. Inc. LifeScan. Dr. Novartis.. Novo Nordisk. Inc. and Medtronic. Helena W.. speaker honoraria from Abbott.... sanofi-aventis U.S. Eli Lilly and Company... Inc. and sanofi-aventis U. Pfizer Inc. Inc. and sanofi-aventis U. Inc. and research grants from Amylin Pharmaceuticals. Novartis. Pfizer Inc. Philip Levy reports that he has received speaker honoraria from Abbott Laboratories. Dr. and Sensys Medical.. Dr. and Takeda Pharmaceuticals North America.. Inc. Pfizer Inc. Roche Pharmaceuticals. Inc..S. Inc. and Takeda Pharmaceuticals North America. Jeffrey I. Pfizer Inc... Amylin Pharmaceuticals.S. Novartis. sanofi-aventis U. Paul S. sanofi-aventis U. Merck & Co.S. Pfizer Inc.. Dr.. Inc. Inc. Lois G.. and research support from Biodel. Dr. 2007... MannKind Corporation.. GlaxoSmithKline. Jovanovic reports that she has received research grants for her role as investigator from Eli Lilly and Company. and research grants for his role as an independent contractor from Abbott Laboratories. Endocr Pract. Novo Nordisk Inc. GlaxoSmithKline. Dr. Farhad Zangeneh reports that he has received speaker honoraria from Eli Lilly and Company..
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How to Take Charge of Your Health After Forty
In this fast-paced life, time is scarce. Many people hardly prioritize a healthy lifestyle when they are young and energetic. Unfortunately, youth is fleeting, and shortly after, you are in your forties and beyond!
While long life is a blessing, the golden years come with their fair share of problems like health challenges. Several studies prove that age-related diseases are on the rise, compromising the quality of life among many people in their forties and above.
Whether you were a fitness enthusiast or lived a carefree life, you will need to evaluate your lifestyle and prioritize a healthy living as you age. Read on to learn how to take charge of health as you prepare for your golden years.
Get Active
Physical exercise has immense benefits for people of all age brackets. According to scientists, people that consistently exercise live better and longer lives. Research indicates that adults over 40 years have a lower risk of death by taking 8,000 steps every day.
Keep your body moving by taking the stairs instead of the elevator, walking the dog, gardening, or intentionally having the evening walk.
If you are new to fitness, start slowly as you gradually increase the intensity. Vigorous exercises at the beginning can discourage newbies and cause you to ditch this helpful lifestyle.
Eat Smart and Healthy
A healthy diet is essential for general well-being. Like with exercise, the right food benefits your body beyond perfect weight. Generally, a diet rich in whole grains, fresh produce, healthy fats, more fish, and less dairy is advisable. Ensure you drink enough water.
The Dietary Approaches to Stop Hypertension (DASH), also known as a low-salt diet, has significant health benefits. Besides lowering blood pressure, the DASH diet helps in weight loss and reduces the risk of heart disease and type 2 diabetes, common in old age.
Choosing the right diet for your age can be confusing as numerous diet advice is available. Dietary Guidelines for Americans recommend proven healthy diets for each stage of life.
Have a Good Night’s Sleep
Adults need 7-9 hours of sleep to keep healthy, alert, and happy. People in their 50s and 60s who sleep for less than six hours are at a higher risk of developing dementia. Inadequate sleep also increases your risk of developing Alzheimer’s disease due to the buildup of a beta-amyloid protein associated with the condition.
Getting adequate sleep as you age becomes a challenge as some medicines, pain, and feeling sick make it harder to enjoy a good night’s rest. You may need close medical attention and health checks to address any prevailing medical conditions.
As you age, a good night’s sleep is an important aspect that you can never compromise on.
Did you know that your bedroom plays a huge role in determining the quality of sleep you enjoy? Improving your sleeping space is another way to enhance sleep. Invest in a good mattress and beddings. Ensure your bedroom has free air circulation at the right temperature always. Also, make sure that you wear the right attire to bed.
There is so much information today on how to get quality sleep. Reach out to experts in the field if you have sleep disorders.
Avoid Substance and Alcohol Abuse
Aging comes with physical, social, geographical, or even financial changes. This shift from the norm may make adults in their forties and beyond more vulnerable and susceptible to substance abuse. Addicts may indulge more in substance and alcohol abuse at this stage.
Opioids for pain relief, sleeping pills, or medication to relieve anxiety are commonly prescribed for older adults. Because of the comfort and relaxation effect, patients may misuse the drugs.
To enjoy good health in your old age, you will need to stop substance abuse and limit alcohol intake. Avoid self-medication or over-the-counter medicine. It takes a lot of effort, strong will, dedication, and help, for this very reason it’s best to seek help from professionals such as Find Recovery who can provide you with the best resources.
Overcoming drug or alcohol addiction is one of the best things to gift yourself, family, and friends as you age.
Take Care of Your Mental and Cognitive Health
Depression, which adversely affects mental and physical health, is common in older adults. Some people may exhibit spells of sadness, lose interest in most activities, be unwilling to express their feelings, or feel numb, as symptoms of depression. Depressive tendencies may increase the risk of metabolic disorders and heart diseases.
Mental health is a crucial part of your overall well being. If you notice any signs of depression, see a health practitioner for proper evaluation.
There are many stressors at every stage of life, like positive or negative changes, which may threaten your mental and general health. Meditation techniques and engaging in activities you love are proven ways to keep stress at bay.
Consider keeping a journal to help identify and arrest unhelpful and negative thoughts early enough. Journaling is also crucial in improving your mood, identifying stress triggers, and learning how to control them. Some studies suggest that using a journal assists in unpacking trauma. Unresolved trauma is a significant setback in mental health.
Stay positive and join social groups. Physical interactions with friends and family are a great way to help you feel young and mentally fit. Engage in more social fun activities that you love. If there is a skill you want to learn on your bucket list, go for it! Learning a new skill will help improve your memory function.
Conclusion
As you advance in years, quality of life becomes more crucial. Life slows down, and you pay closer attention to things you may have missed. Forty is a good age to pay close attention to your lifestyle and take charge of your health.
Taking charge of your health after forty will require intentional efforts in many aspects. If you are looking for things to fill the gaps in your time, revisit your hobbies and leisure activities.
You may need to increase doctor’s visits and have frequent health checks to ensure any condition is promptly addressed.
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There are a variety of definitions of what moderate-intensity exercise is, but it typically falls between about 70 to 80 percent of your maximum heart rate, which would be a level 4 to 6 on a 10-point perceived exertion scale. That means you are breathing harder than normal but can carry on a conversation without much difficulty and you feel pretty comfortable with what you're doing. The American College of Sports Medicine (ACSM) often recommends this level of intensity in its exercise guidelines. The lower end of this range usually incorporates the fat burning zone.
The pre-training meal may just be the most important meal of the day. This is the meal that will fuel your workout. For this meal it is important to get protein and carbs which will make their way into the blood stream around the time your training session is getting underway. The glucose in the bloodstream from the carbs will be used for energy, while the amino acids from the protein will spare stored amino acids from being catabolized during training.
Carbohydrates are essential to keeping a fast metabolism. Leptin and other fat burning hormones are directly related to carbohydrate intake and body fat levels. Leptin is a fat burning hormone that serves many functions. One of the most important functions is the control of energy expenditure. When food intake, and most notably carb intake is high, leptin levels will be high. This sends signals to you body that it is in a fed state and this can cause your metabolism to remain high.
Give crosstraining a go. Whatever your workout is — whether it's a 15 minute walk with the dog or a 10K through the park — your body gets used to it. You can actually burn fewer calories when your body is familiar with the level and type of exertion it’s experiencing. So to keep your body a bit off guard, try crosstraining. Consider it a good excuse to pick up that hobby you've been eying.
Chloe Madeley is a Level 2 Gym Instructor and Level 3 Personal Trainer with an Active IQ nutrition qualification. She has been an active personal trainer since 2013, helping both men and women achieve their body transformation goals in London gyms, parks and even online. She is the author of the popular health and fitness blog FitnessFondue.com and has two best-selling apps (15 Minute Fat Loss and Weights 4 Women) and is the best-selling author of The 4-Week Body Blitz and The Fat-Loss Blitz.
3. Stand up more: By now, we all know sitting for too long increases your risk for most diseases, including obesity. But it also shuts down your body’s ability to metabolize fat. According to a study from Missouri University, certain enzymes in the blood vessels of muscles that are responsible for burning fat are “shut off” if you sit still for too long. The good news? The researchers say standing and moving just lightly will re-engage the enzymes.
"Your body needs a healthy balance of exercise and rest. Doing too much prevents the body from shifting excess fat. Exercising without rest can impact our levels of the steroid hormone cortisol and cause an increase of stubborn fat stored in the belly. Not allowing your body to recover can increase the risk of injury too, so make sure you factor in rest days to your plan."
Since only two HIIT sessions should be performed per week another type of cardio will be needed for the rest of the cardio sessions throughout the week. MISS (Moderate Intensity Steady State) cardio is the perfect type of cardio to fill in any remaining cardio that needs to be performed during the week. This will burn a great amount of calories while sacrificing very little muscle tissue and burning fat through different pathways from the HIIT.
These fatty acids rocketed to fame for their ability to decrease the harmful inflammation that is associated with many chronic diseases—including obesity. Crandall is quick to point out that researchers have yet to find a cause-and-effect link—so don’t expect to pop a fish oil supplement, for example, and drop 10 pounds. But, she says, getting omega-3s from whole foods such as nuts, seeds, and fatty fish like salmon is a good way to hedge your bets. And bonus: If you’re suffering from other kinds of inflammation, that can lessen your willingness to be active, omega-3s might help there, too. Find out the fat-burning foods you should add to your diet.
I started my first round in March, just a few weeks into recovery, and the results I have seen are incredible. My doctor could not believe how well I healed and how fast I was able to bounce back. Amanda's program truly made that possible. I feel so much better about myself. I have so much more confidence. I'm not nearly as stressed, and I have more energy. Before I started doing Amanda's program, I was obsessive about the scale. I would get on the scale several times a day. I would work out because I thought I was gaining weight. That first day when I took my measurements and then got rid of my scale 14 weeks ago, I had a burden lifted off of me. It has been absolutely liberating. Realizing that there is more to me than a number on the scale and seeing my results in a different light has been one of the biggest successes of this program. I have had so many non-scale victories.
“Poor sleep quality or quantity can make it difficult to lose or even maintain your weight,” says Darria Long Gillespie, MD, a clinical assistant professor of emergency medicine at The University of Tennessee. When you are sleep deprived, your body becomes less sensitive to the effects of leptin, the hormone that usually signals that you’ve had enough to eat. At the same time, the amount of the hunger hormone, ghrelin, increases, so you want to eat more. Together, it’s a recipe for overeating.
You may be confused about exactly how hard to work during cardio. You may even think that high-intensity exercise is the only way to go. After all, you can burn more calories and, even better, you don't have to spend as much time doing it. But having some variety can help you stimulate all of your different energy systems, protect you from overuse injuries, and help you enjoy your workouts more. You can use a sample cardio workout schedule to set up a cardio program that includes a variety of different workouts at different intensities.
Protein is an absolute must have after training since it is the only thing that can immediately shift your body from a catabolic state to an anabolic state. The period right after training is commonly referred to as the anabolic window because the body is ultra sensitive to nutrients for 2 hours after training. This is prime time for muscle growth.
As chronic obstructive pulmonary disease (COPD) advances, about 35% of patients experience severe weight loss called pulmonary cachexia, including diminished muscle mass.[32] Around 25% experience moderate to severe weight loss, and most others have some weight loss.[32] Greater weight loss is associated with poorer prognosis.[32] Theories about contributing factors include appetite loss related to reduced activity, additional energy required for breathing, and the difficulty of eating with dyspnea (labored breathing).[32]
When I signed up for this program, I was in a pretty dark place. I was using all kinds of unhealthy coping mechanisms to deal with (hide from) hurts and insecurities that had piled up over the last few years. I was approaching my highest pregnancy weight- and I wasn't even pregnant. Every day was a struggle, and my poor habits were spiraling out of control. I didn't like or recognize the shell of a woman who looked back at me in the mirror. Something had to change, for myself, and also for my husband and 3 kids. They deserve better.
A 2012 study also showed that people on a low-carb diet burned 300 more calories a day – while resting! According to one of the Harvard professors behind the study this advantage “would equal the number of calories typically burned in an hour of moderate-intensity physical activity”. Imagine that: an entire bonus hour of exercise every day, without actually exercising. A later, even larger and more carefully conducted study confirmed the effect, with different groups of people on low-carb diets burning an average of between 200 and almost 500 extra calories per day.
High-intensity interval training—HIIT—has gained a reputation as an efficient way to get fast results. This workout involves short (30 seconds to five minutes), vigorous bursts of activity interspersed with periods of rest for maximum results. Incorporating HIIT into your strength training may offer even more results, according to a recent study by the American Council on Exercise—the results suggest the combo may be even more effective in burning fat fast.
If you’ve got weight to lose and you want it gone fast, try swapping out your usual proteins in favor of fish. Not only is fish lower in calories than an equivalent amount of beef or chicken, a study published in Obesity reveals study subjects who added omega-3 fatty acids, like those found in fish, to their diets shed more weight and had an easier time keeping it off than those who skipped them.
Another misconception about HIIT is that it will cause muscle loss. This is just not true either. This myth got started because a higher amount of calories burned during HIIT will come from stored amino acids (muscle tissue) when compared to lower intensity cardio. As long as HIIT sessions are kept to a short duration muscle loss not be a problem. In fact, muscle growth and muscle retention are increased due to the effects HIIT has on anabolic hormones. Just one 10-15 minute session of HIIT can increase testosterone and growth hormone levels for hours after the workout has ended.
EFAs stand for Essential Fatty Acids. Just as the name implies EFAs are essential to the human body because play a role in many different biological processes. Essential fatty acids differ from others fats in that they cannot be synthesized within the human body. This means that EFAs must be consumed through the diet. If not enough EFAs are consumed the body will sense that it does not have the nutrients that it needs to function properly. As a result it will essentially “hold on to” body fat. This is just one of the reasons EFAs are so important though.
In other words? "Drinking makes you more likely to eat sh*t," Dr. Seltzer says, referring to drunk foods. At the same time, he stops short of asking patients to quit alcohol cold-turkey to lose weight. Plus, research suggests you don’t have to, as long as your intake is moderate—i.e., less than about a drink a day. "If you drink a glass of wine every night and notice you eat more afterward, eat less early to account for this," he says. "Or, if you’re drinking four glasses of wine a week, drink three instead so you’ll won’t feel such a big difference."
Eat more fat: The idea that eating fat makes you fat has been dethroned hard in recent years. And in fact, dietary fat can help you burn more off your body—as long as you’re eating the right kinds. Healthy polyunsaturated or monounsaturated fats—like salmon, trout, avocado, sunflower oils, olive oil, and nuts—can decrease appetite, improve heart health, and stabilize glucose levels which can help trim body fat, Montenegro explains.
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Clinical
DIESER MENUPUNKT BEFINDET SICH NOCH IN DER ÜBERSETZUNG
SOLLTEN SIE DEUTSCHSPRACHIGE INFORMATIONEN DRINGEND BENÖTIGEN, WENDEN SIE SICH BITTE AN PHYSIOASSIST IN DEUTSCHLAND
Fabien
Cystic fibrosis
Fabien is a 28 year old patient living in Brittany. He has a job and is married. He is a spirited, determined, and very demanding patient. He presents with cystic fibrosis, with an FEV1 of 40%. He has attended many rehabilitation sessions in various specialist centers. During a conference, he heard about CKRF of Marcq-en-Baroeul and made a request to come do a two week program with a friend who also suffers from cystic fibrosis.
The program took place in June 2016. He was the first patient to use the Simeox, and to discover how it was used, along with the caregiving staff.
Objective
The patient must learn about autogenic drainage. He would like to be able to perform it autonomously and be able to guide his physical therapists in the everyday drainage techniques.
He also needs to improve his physical performance, strengthen his musculature, and make his chest and spine more flexible.
Initial assessment
The patient is a disease carrier. He presents with severe lung hyperinflation and his distal flow rates have plummeted.
Testimonial
The Simeox is an excellent device. I first discovered it last July. I was expecting to come back to learn it.
The best part about this device is that everything is done in relaxation, without forcing. That way, you manage to mobilize mucus that could not be mobilized in a normal drainage.
I hope this device will be able to be used at home in the future. I think that it will become the new device for assisting and carrying out an autogenic drainage.
Care provided
• A regular antibiotic
• Pulmozyme & hypertonic saline solution
Bronchial congestion clearance
Fabien was used to performing physical therapy by forced expiration. His bronchial tubes are reactive and he gets tired during the fits of an unproductive cough that exacerbate his shortness of breath.
The first autogenic drainage sessions will enable him to:
• Control his cough,
• Delay it,
• Master expiration with the glottis open,
• Produce a quality inspiratory flow that will make it possible to homogenize the distribution of air in his lungs.
He very quickly understood the usefulness of a properly conducted aerosol therapy, and the importance of the air brought behind the mucus. Autogenic drainage enables him to gradually improve the speed of air flowing in the targeted areas, while fully relaxed, without ever needing to compress the bronchial tubes. Giving him the pleasure of breathing, and making his drainage sessions comfortable are the objectives of his therapeutic education. The goal of the program is to make him an expert in his disease.
Fabien quickly understood that the mucus must be able to be mobilized before it can be expectorated. Therefore he agreed, with a great deal of interest, to participate in the Simeox usage protocol, the purpose of which is to act on the thixotropy of the mucus. He performs an inspiration at the functional tidal volume, which enables him to generate a quality sigh, optimized by the Simeox.
Results
Starting with the first session, he was particularly surprised by the effects of the Simeox vibrational signal on the transport of his secretions.
The initial secretions, expectorated without effort, in line with autogenic drainage, have an extremely positive impact on the evaluation the patient will have of the new congestion clearance technique.
Fabien requested the use of the Simeox every day during his program. As the lung function tests show, the results are signfiicant and demonstrate a real improvement. His chest expansion went from 5.5 cm to 9.5 cm.
He did another program in December 2016. Today, Fabien is asking to be able to use the Simeox at home.
Conclusion
Fabien will have contributed, with the caregiving staff, to the understanding of a protocol that is personalized and adapted to each patient based on their perception of the machine.
There cannot be a question of one size fits all. The Simeox requires a learning period. Each patent must be able to use it based on their state of congestion, but also based on their bronchial reactivity.
The Simeox is an advantage, an instrumental aid of choice, for physical therapy that is gentle, without fatigue, and in total relaxation.
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0
Notifications
• You're all caught up!
Muscles of the Human Body
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|
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Surviving with Diabetes after SHTF
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BIG-diabetCoping with diabetes is hard under normal circumstances. Diabetics need to take regular medication; they must stick to a strict diet and are prone to illness and infection. All of these problems get exacerbated when SHTF. If a disaster happens, a diabetic is left much more vulnerable than the average person. He must take special precautions in order to ensure that he is fit to handle the situation.
After an SHTF event, people with diabetes need to attend to their special medical needs. If they are lucky, they still have access to medical help soon after the disaster strikes. This is not always the case, however, but, if it is, they need to be prepared. They might not be able to communicate with the healthcare professionals due to injury or shock.
Furthermore, the people treating them might not have access to their medical history. That is why they must identify themselves as diabetics so they can receive the proper care. Therefore, the first important guideline for someone with diabetes is to always wear a medical bracelet which provides valuable information regarding their situation.
Preparation Is Key
Oftentimes when SHTF, help is not immediately available. In fact, on many occasions, it can be days or even weeks until you would be able to reach a hospital or any other kind of medical facility. A diabetic simply cannot wait this long without proper medication.
That is why it is highly recommended to create a diabetes disaster kit. It should be easy to carry around, waterproof and insulated so that it does not get damaged. It should also be placed in an area which you can easily access, even after an earthquake, tornado or flood.
There are several items which should be part of this kit:diabet1
• Medication and medical supplies. This is the most important resource for a diabetic in an SHTF situation. You should pack as many medical supplies as you have access to since you can never know when you will have access to outside help. A 30-day pack would be ideal. If this is not possible, make sure that the medicine will last you at least 2 or 3 days. The supplies should include insulin, insulin pumps, syringes, glucagon, testing strips, glucose tablets, glucose meters, extra batteries and anything else that you use on a regular basis to treat your diabetes.
• Extra supply of drinking water. Again, it is a good idea to store a lot of water around the home since it becomes a valuable commodity when SHTF. However, keep the water in the disaster kit to about 2 or 3 days worth. Any more and the kit would become cumbersome and difficult to handle.
• A few days worth of food. Besides medication and water, food is extremely important to a diabetic as they need to stick to a specific diet. That is why the food kept in the disaster kit should have two qualities: be nonperishable and be safe for a diabetic.
• Copies of your health records and medical history. In addition to these, you should also keep a list detailing all the medications you are currently taking plus the diet you are on.
• Contact information for family, friends and physician.
When talking about something as dangerous as diabetes, there is no such thing as being overprepared. That is why it is a good idea to keep vital extra supplies such as medication and snacks around other places you regularly visit such as your workplace, homes of friends and family, your neighbors etc.
Insulin is the most important medication for any diabetic so you need to look after it properly. It does not matter how many vials of insulin you have in an emergency if they have not been preserved in an adequate manner.
The good news with insulin is that it does not need to be refrigerated. It can safely be stored at room temperature for as long as a month, as long as that temperature does not exceed 84 degrees Fahrenheit. However, in many areas, the temperature will routinely pass that limit. That is why it is also a good idea to have a cooler to keep your emergency supply of insulin in.
Adding to the disaster kit would be several packets of re-freezing gel in order to maintain proper storage for the insulin even if the electricity goes out.
How to Spot Hypoglycemia
The biggest emergency that a diabetic has to deal with is when blood sugar levels are too high or too low. For a diabetic on insulin, it is important to monitor blood sugar levels at all time in order to make sure that they do not dip below recommended levels.
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When this happens, there is a huge risk of suffering from hypoglycemia, a problem which can occur in both Type 1 and Type 2 diabetics. It is most often brought on by missing meals or medications at regular intervals, two scenarios which are very possible when SHTF.
The standard threshold for hypoglycemia is 70 mg/dl, although the actual limit differs from person to person. Even so, knowing and detecting the symptoms of hypoglycemia early on can give you enough time to take the necessary precautions.
The symptoms include dizziness, sweating, shakiness, hunger, fatigue, confusion, an erratic heartbeat and even loss of consciousness. The best course of action if you feel any of these symptoms is to take something that raises blood sugar levels and acts fast. Recommendation would include glucose tablets or natural juice.
Dealing without Medication
By their very nature, SHTF scenarios are unexpected. It is quite possible that you get caught in one such emergency without the medication you require or with lower levels than needed. It is important to know what to do when your insulin is in short supply.
Basically, you will need to stretch out your supply as long as possible in order to wait it out before help arrives. Your diet will play a big factor. Try to avoid eating food rich in carbohydrates and instead go for food full of proteins.
Moreover, you should know who you can contact if the communications lines are up. The Red Cross, the International Diabetes Federation and even the American Embassy can all provide you with an emergency supply of insulin if access is cut off to your regular supplier.
As you can see, having the proper knowledge and the proper guidance can help anyone overcome a SHTF scenario, even someone with diabetes.
Do you fear about living with chronic disease after disaster? Share your thoughts with us using the comment form below.
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This article has been written by Bella Scotton for Survivopedia.
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Comments
1. I've been a Type-2 Diabetic for over 15 years. So I comment from experience... The graphic included in this article is lacking 'real' information. I have never seen any blood glucose meter ever display any of this kind of 'numbers'. Typically these test meters are the [no pun intended] life-blood information we as diabetics use to regulate any +/- of insulin, and their displays are in mg/dl [milligrams per deciliter] like the graphic. However, the actual 'numbers' in the graphic would mean you are dead from those who have educated me. For example I struggle to keep my 'reading' below the 140 mg/dl, and I'm advised that average people [non-diabetics] operate in the 85-120 mg/dl. If perchance these 'numbers' represent some other value, they should reflect the real world to a wider audience.
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• John Gramer says:
The best I can tell, the numbers shown should be labeled as mmol/l not mg/dl,
by using a conversion factor of 18 (mmol/l *18 = mg/dl) you should see more familiar numbers. This conversion factor is not exact but is close enough to work with. The actual conversion as best as I can find is 18.018018018018018018018018018018~ or 18.01802
Note that this conversion rule refers only to glucose.
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• Karen r. says:
The numbers are what show up in the Canadian glucometers. Most glucometers have a choice of mmol/dl or mg/dl and are usually set either by the healthcare practitioner or the patient when first obtained.
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• MIchael says:
Had the same reaction to the diagram. While I'm not a diabetic, my wife is a Type II, and I'm quite familiar with her blood meter. I think anyone associated with a diabetic needs to learn how to take their blood. Low blood sugar can be misleading and mistaken for something else. Just because the person is getting quiet, perhaps slurring words or not using complete sentences, don't assume they're tired or consumed too much alcohol or "something" - ask them to check their blood sugar OR be prepared to assist. Missing this window of opportunity can mean they'll soon be passed out on the floor.
Solid article. Chart needs to reflect what's actually seen on a common blood meter, and I would ensure that everyone involved with a diabetic knows how to use the meter (and associated "poker" and test strips).
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• Since it appears there are 2 different scales, perhaps it's best to know both since in grid down events, no one will be up to figuring out conversions when other things take priority. If we can't know both, the perhaps have a copy of both in your carry kits for others to know if you or your loved one can't speak up for self.
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2. My mum cured her type two diabetes with the Atkins diet. She monitored her blood sugar and had to cut back on her tablets over a two week period according to her blood sugar levels. It's all over the net that eating grains could be the cause of diabetes and I've seen comments on the net that a strict caveman diet (just like Atkins diet) will get diabetes in check.
Food for thought.....
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• With due respect to your mum. Like so many other chronic health issues, each person responds differently. Having several family members and friends with diabetes, your mum's method may work for some but not for some others. Other health considerations, along with which foods actually work for one's own body is so important when managing diabetes. The important thing is to find what works for each person, then also be prepared for changes, because like anything else, our bodies change as well. What worked 3 years ago, may not work in the future. Just like other stuff we prepare for, if you have a medical challenge, stay on top of any advance which may give you an edge, because as some of us know, life gives us the unexpected just to see if we're ready for it. 😉
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3. Mr Charles J Bowen says:
I am glad that someone actually has an article on what is needed in a disaster. I am a diabetic, type 2 on pills till I had my liver transplant. After the transplant I had to go on insulin, pills were bad for the liver. Everything I read about prepping, that had medical advice, nothing for diabetics until now. now all I have to find is what to have on hand and how to get extra medications for treating my transplant when a disaster happens.
Again thanks for this great article.
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4. I've been a diabetic for years. When I was working I took medication, but for the past year since I lost my health care, I have taken no doctors prescribed medications. I'm still here. My problem is that I love to eat, so my gluecose numbers can get much higher than the normal range. I want to share my solution to control my glucose spikes and bring them back down under 180. I buy a large supply of a glucose control drink, called "Boost", which is most reasonable delivered monthly, from CVS. I drink a bottle after a meal and I'm fine. If I test later and my level is too high, I have another. Each bottle of Boost brings my glucose level down about 50 points, making my levels closer to normal. It is also part of my SHTF preparation, having no other medication.
Also, save some money by asking for "free diabetic related samples from your doctor" to put in your Diabetic SHTF Kit. That's how I started mine.
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5. My insurance company will only release a new med if I only have only a few pills(Medicare)
How do I build up a stock of medecine
Thanks
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• Walk in and ask your pharmacy if you can buy some extra stock because you are leaving for some reason. When I tried this, I was able to pay for an extra months worth of meds for my wife. It is more expensive to do this, but it works. Find out how much they will charge, before you decide if it is worth the expense. Consider how it would be without it.
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• Most insurance companies will let you refil a prescription a few days before your supply runs out. By getting your refills early you can build up a supply pretty quick.
I am a type 1 diabetic and have built up about a years supply of insulin this way.
For those of you looking to keep insulin cool in warm weather look up a "Zeer pot" it is a kind of evaporative cooler made from 2 clay pots and some sand. After it is built simply wet the sand and as it evaporates it will cool whatever is inside.
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• Just a note on the zeer pot. It works better in a drier climate than a more humid climate.
Ryan, I do has you have done and working up to a 1 year supply. I also know of a few creeks locally where I can store my cache to keep in cool and hidden.
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6. DARLENE says:
Thank you for this well-written article concerning emergency preparations for those with diabetes.
As a person with Type-II diabetes, a retired registered nurse, and a retired certified diabetes educator, I would caution your readers about some of the comments that have been written.
Diabetes cannot be "cured" by eating the Atkins diet. Blood sugars can sometimes be controlled by a diet low in carbohydrates, but the root metabolic disorder of Type II diabetes - insulin resistance - is still there. For obese people who have type II diabetes, weight loss will often produce an improvement in insulin resistance and the results will be better blood sugars. For thin diabetics, such as myself, weight loss makes no difference. Diet does make a difference, but depending on the individuals metabolic system, medication may still be required regardless of the person's diet.
Also, Boost Glucose Control drinks do not contain anything to treat diabetes. These drinks are very low in carbohydrates and high in protein, so when used as a substitution for a high carb snack or meal, they can help keep blood sugar lower. And the protein helps to prevent hypoglycemia.
And yes, the chart with blood sugar levels is listed in mmol/l, a system that is used in other countries. It would be helpful to your readers to post a graphic showing blood glucose in mg/dl, the system most often seen in the U.S.
Each diabetic's metabolic system is different and what works for one may not work for another. It is essential that people with diabetes consult with their medical professional to formulate a regimen that works for them.
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• Darlene,
You are correct, and have clairified our comments very well. Thank you for your perspective. My comments about Boost are what I have seen for myself. It is true that other people may have different results. You give good advice.
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• I've read several publications explaining that TYPE 2 diabetes is caused by lifestyle and therefore is absolutely reversible. To say there is no cure is incorrect, but the "cure" is not a magic pill or surgery. Certainly it is not easy to change ones lifestyle in this processed food culture and I suspect that many who have tried have not succeeded. I agree with you though Darlene, that what works for one will not work for another. Each persons biochemistry is a little different, but in every diabetic that chemistry is unbalanced and needs to be reset.
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• I agree to Todd's summation of this article and the comments. I just found out through journaling that some of my blood pressure meds and heart meds run my sugars high. Sometimes 100-200 pts. If your numbers are high start a journal and what is new or changed. even with meds.
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• Thanks for your "educated" comments! We need more of this type of info when planning for emergencies! Not sure my Dr. will cooperate with me on this, but we'll see! Again, thanks!
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7. Hi Darlene,
We watched a video put out by DOCTOR Atkins who stated it would cure diabetes. After being on the Atkins diet for a few months my mother was able to give up all medication and even eat chocolate Tim tams without her blood sugar levels going up. Other friends, taking my mothers advice did the same and no longer need meds. Doctors are always stating that something doesn't work when what they really mean is that it's outside of their knowledge base or outside of their own interests. I've spoken with doctors who've stated, "no, don't say that; we aren't allowed to talk about that". Do you really believe they'll find a cure for diabetes (or cancer) when the money being raked in is massive?
There are books written on how to prep, paleo style. Wouldn't that be easier than trying to store meds? You don't even have to think that you might be cured.... Just stash proper food supplies to "control" the diabetes.
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• Mr Charles J Bowen says:
Thank You Fay for the reply. I have heard of the Atkins diet, but never looked into it. I have been doing some reading on the, paleo style, on some of the prepper sites. Since we are growing our own vegetables, this might be a better choice.
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8. Bitter melon contains a chemical that acts like insulin to help reduce blood sugar levels.
(This information from webmd)
Also, I've read where mulberry leaf tea or crepe myrtle tea will reduce blood sugar.
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9. Hi
Solid article and for those who are seriously interested in participating or attending the first ever Reversing Diabetes World Summit on May 5, 2014 with a panel of over 40 experts who are guaranteed to knock your socks off ... registration is free today at http://www.thediabetessummit.com
Namaste,
(And no - this is not an affiliate link)
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10. I come from several generations of diabetics. Just know there are more than just type 1 and 2. There are several sub types of which LADA (1.5) is one. It's also not about people who 'overeat' or have a sweet tooth. There are some fat people who are really malnourished, their bodies are just showing it in a different way than the stereotype. This is just to say, this article can't cover all of such a complex illness. I have seen and know many who are managing diabetes just with diet. Cured? No, I do not believe this. When I hear this said, I want to ask, how long have you been 'cured'? I believe from personal experience AND from family history that diabetes, like cancer and other illnesses, can go into 'remission' but once triggered, is there for the rest of one's life.
This is a great article even though short, therefore some information is missing just by the comments. One example of missing info is there is a form of low blood sugar event which people also need to know---low sugar unaware----this is when there are no signs of blood sugar levels dropping or the signs happen just before the person become unconscious.
So here's what my preps: 1) I now have a letter (sent via snail mail to make it more 'official') in my medical carry bag which says I am diabetic, what type of insulin I use and dosages, what type of meter and other equipment I use.
2) In my medical carry bag, contains 2 of each type of insulin + meter and other needed supplies to last 2 perhaps up to 4 days depending on the food supply, plus the letter and ICE information. For those lows, I now carry a couple of containers of raw honey with instructions on the outside of container--clearly stating what to do with it and how much to give. On the outside of the bag (less than the size of a small pencil box) is a large "+" sign with Medical Alert written out.
3) I have spent the past couple of years, learning what medicinals I can find by foraging around my area. Learning the symptoms of my body's needs not just to hunger, but differing from thirst, low blood sugars (wasn't ready for those low bl sugars unaware, but now know they exist and am figuring out those). And learning how to stretch my insulin and still maintain a relatively stable level of sugar levels.
4) I've trained my dog to alert for highs and he's now learning how to alert for lows cuz I so dislike getting so low I can't speak loud enough to get help.
Thanks so much for posting this article. It can help not just diabetics but those around them. Just being diabetic doesn't mean a grid down event makes one useless or a death sentence. 🙂
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11. I fear that this will happen but are they really positive about when. If it doesn't come about on Sept 23, does that mean where safe for awhile.
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• joyce yoder says:
I too am in the same boat as the rest of you, and think about positive ways to help myself in the event of. We shouldn't become overly obsessed and dwell on it, stress, as I found out produces what is call cortisol which raises your blood sugar, even though I was following my low carb diet, getting my sleep etc. Talking and getting together with other individuals like myself have helped me to be more responsible and less worrisome over things I can't control and more secure about the things I can control. Like having an emergency pack in your car with medi alert sign on it in plain view, in case of accident.
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12. I'm old, so I get to make some mistakes. Thought you were an Aussie, my bad. No false aimardtion intended. You are one of the better posters and that is a real compliment, without any fawning. Yes, I do remember the CSA gardens and the light shines now. As far as well adjusted kids ooohaa! You done good, girl! ALL children should be raised that way. My favorite author is Robert A. Heinlein. He has a book, Tunnel in the Sky , where high school graduates are teleported to another planet with meager supplies and to finish graduation they have to be at the designated pick up point in six weeks to graduate . Oh, God, would that they do that today. There would be a lot less pollution in the gene pool, deep or shallow end. LOL. Hope things are good. Survive well. Enjoy.VA:F [1.9.22_1171]0 0
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1. […] This article first appeared at Survivopedia: Surviving with Diabetes after SHTF […]
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2. […] Surviving with Diabetes after SHTF | Survival skills … – Coping with diabetes is hard under normal circumstances. Diabetics need to take regular medication; they must stick to a strict diet and are prone to illness and …… […]
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3. […] being said, if disaster strikes and you ARE diabetic, stockpiling foods can be a challenge especially if you’re insulin-dependent. If your body […]
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4. […] being said, if disaster strikes and you ARE diabetic, stockpiling foods can be a challenge especially if you’re insulin-dependent. If your body […]
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The Secret Life Of Trees
Rays of sunlight pouring through branches and vines in the forest
You’ve probably heard or been told, “You can’t see the forest for the trees.” Usually people are telling us that we are caught up in the details and not seeing the big picture, but there may be more to it. The trees may be hiding their secret of survival in the forest. If humans seek and embrace their survival secret, it will transform life as we know it.
The trees in a forest depend on cooperation to ensure long-term survival. Research has shown that trees are a connected community and actually care for each other. Why?
The health of the forest depends on the health of the individual trees, but a tree is not a forest. When they stand together they are stronger than we they stand alone. Standing together, trees and plants create an ecosystem that moderates extremes.
For example:
Wind – groups of trees provide protection from strong winds, making it more difficult for the wind to break or uproot trees.
Moisture – groups of trees actually create humidity providing the vital moisture needed to survive.
Erosion – trees are entangled by their roots and make it difficult for the soil to erode away.
Protecting the whole is so important that trees will actually assist a sick member of the forest. Scientists have discovered that trees share nutrients either through the fungal networks around the root tips, or the roots themselves may be interconnected.
Not only do trees help each other in times of stress, they communicate when danger is present.
On the African Savanna, scientists made a shocking discovery on how trees communicate. A herd of giraffes were feeding on umbrella thorn acacias. Well, the trees didn’t like the fact they were being eaten and within a few minutes of being munched upon, the trees began pumping toxic substances into their leaves to get rid of the giraffes. It wasn’t enough to harm the giraffes, just enough to make them move on to better tasting food.
It worked, the giraffes moved on, but what surprised the scientists was that they didn’t just move a few feet away and continue eating. They moved 100 feet away.
After several tests, the scientists discovered that the trees that were being eaten gave off a warning gas for the other trees. The scent messages were carried to nearby trees on the breeze. The trees that received the warning began pumping toxins to their leaves even before being eaten. To continue to eat, the giraffes needed to move far enough away to the trees that hadn’t received the warning.
People can benefit from the trees communication through scent. In Japan it’s know as forest bathing. Research on the health benefits of walking through a forest were found when a group of Korean scientists tracked older women on their daily walks. These women were monitored as they walked thru the forest and through urban areas.
What scientists found was that when the women walked through the forests, their blood pressure, lung capacity and the elasticity of their arteries improved. The excursions to town showed none of this.
Another important reason to protect our planet’s forests – they are good for our health.
Humans can learn a great deal from the forest. Their cooperation provides a protected environment that allows the trees to live a long life. That is why even sick trees are nourished and looked after. To get to this point the community must remain in tact and everyone must look out for each other. If they did not do this, the trees would not survive.
Is this the secret the trees are hiding in the forest?
If you are interested in learning how to connect with nature and animals through the practice of Reiki, contact Jamie on FaceBook @Jamie Lee Animal Bonds or at her website, www.Animal-Bonds.com
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Burn
injury
Burn, damage caused to the body by contact with flames, hot substances, certain chemicals, radiation (sunlight, X rays, or ionizing radiation from radioactive materials), or electricity. The chief effects of contact with flame, hot water, steam, caustic chemicals, or electricity are apparent promptly. There is a delay of several hours before the full effects of sun or ultraviolet burns are apparent and a delay of 10 to 30 days before the full effects of ionizing radiation burns are apparent.
The severity of a burn depends largely on the depth of tissue destruction and the amount of body surface affected. Other factors—including the patient’s age and prior state of health, the location of the burn wound, and the seriousness of any associated injuries—can also influence recovery from a burn.
For an appreciation of how depth and size of a burn affect the severity of the injury, some understanding of the anatomy and physiology of the skin is necessary. Human skin is composed of two layers: an upper layer called the epidermis, and a lower layer known as the dermis (or corium). The largest of the body’s organs, skin performs a number of vital functions. Its foremost job is to separate the external environment from the body’s interior. The epidermis, the outer surface of which consists of dead, cornified cells, prevents infectious microorganisms and other harmful environmental agents from gaining entrance to the body. The dermis, by contrast, is made up of fibrous connective tissues that prevent the evaporation of body fluids. Embedded within the dermis and opening to the skin surface are the sweat glands. These secrete perspiration, the evaporation of which helps regulate body temperature. Perspiration also contains small amounts of sodium chloride, cholesterol, aluminum, and urea; it thus plays a role in regulating the composition of body fluids. The dermis also contains all of the skin’s blood vessels and nerves, including sensory nerve endings that respond to touch, pressure, heat, cold, and pain. The skin therefore also serves as a sense organ that enables a person to adjust to changing environmental conditions. One final function of the skin is the synthesis of vitamin D, a compound essential to growth and maintenance, particularly of bone. Vitamin D is formed by the action of sunlight on certain cholesterol compounds in the dermis. Destruction of the skin by deep or extensive burns can disrupt all of these functions, subjecting the victim to serious complications.
Physicians have traditionally categorized burns as first-, second-, or third-degree injuries, according to the depth of skin damage (see illustration). In a first-degree burn, only the epidermis is affected. These injuries are characterized by redness and pain; there are no blisters, and edema (swelling due to the accumulation of fluids) in the wounded tissue is minimal. A classic example of a first-degree burn is moderate sunburn.
The damage in a second-degree burn extends through the entire epidermis and part of the dermis. These injuries are characterized by redness and blisters. The deeper the burn the more prevalent the blisters, which increase in size during the hours immediately following the injury. Like first-degree burns, second-degree injuries may be extremely painful. The development of complications and the course of healing in a second-degree burn depend on the extent of damage to the dermis. Unless they become infected, most superficial second-degree burns heal without complications and with little scarring in 10 to 14 days.
Third-degree, or full-thickness, burns destroy the entire thickness of the skin. The surface of the wound is leathery and may be brown, tan, black, white, or red. There is no pain, because the pain receptors have been obliterated along with the rest of the dermis. Blood vessels, sweat glands, sebaceous glands, and hair follicles are all destroyed in skin that suffers a full-thickness burn. Fluid losses and metabolic disturbances associated with these injuries are grave.
Occasionally burns deeper than a full thickness of the skin are incurred, as when part of the body is entrapped in a flame and not immediately extricated. Electrical burns are usually deep burns. These deep burns frequently go into the subcutaneous tissue and, at times, beyond and into the muscle, fascia, and bone. Such burns are of the fourth degree, also called black (because of the typical colour of the burn), or char, burns. Fourth-degree burns are of grave prognosis, particularly if they involve more than a small portion of the body. In these deep burns toxic materials may be released into the bloodstream. If the char burn involves only a small part of the body, it should be excised down to healthy tissue. If an extremity is involved, amputation may be necessary.
Test Your Knowledge
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Surgeons measure the area of a burn as a percentage of the body’s total skin area. The skin area on each arm is roughly 9 percent of the body total, as is the skin covering the head and neck. The percentage on each leg is 18, and the percentage on the trunk is 18 on the front and 18 on the back. The percentage of damaged skin affects the chances of survival. Most people can survive a second-degree burn affecting 70 percent of their body area, but few can survive a third-degree burn affecting 50 percent. If the area is down to 20 percent, most people can be saved, though elderly people and infants may fail to survive a 15 percent skin loss.
Severe burns cause immediate nervous shock. The victim grows pale and is confused, anxious, and frightened by the pain and may faint. Much more dangerous is the secondary shock that comes a few hours later. Its chief features are a dramatic fall in blood pressure that leads to pallor, cold extremities, and eventual collapse. This secondary shock is precipitated by loss of fluid from the circulation, not just the fluid lost in the destroyed tissue but fluid that leaks from the damaged area that has lost its protective covering of skin.
Burns kill not just by damaging tissue but by allowing this leakage of fluid and salts. If more than a fifth of the blood volume is lost to the circulation, insufficient blood returns to the heart for it to maintain blood pressure. And the loss of salts, particularly sodium and potassium salts, not only disturbs their balance in the body but changes the osmotic balance of the blood and body fluids. The significance of these physiological changes was understood in 1905, but not until the 1930s were doctors able to correct them with transfusions of blood or plasma.
The treatment of a burn is, of course, dependent upon the severity of the injury. In general, first-degree burns can be adequately treated with proper first-aid measures. Second-degree burns that cover more than 15 percent of an adult’s body or 10 percent of a child’s, or that affect the face, hands, or feet, should receive prompt medical attention, as should all third-degree burns, regardless of size.
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You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameDesmopressin
Accession NumberDB00035 (BTD00112, BTD00061, BIOD00112, BIOD00061)
TypeSmall Molecule
GroupsApproved
Description
Desmopressin is a chemical that is similar to Antidiuretic Hormone (ADH) which is found naturally in the body. It increases urine concentration and decreases urine production. Desmopressin is used to prevent and control excessive thirst, urination, and dehydration caused by injury, surgery, and certain medical conditions, allowing you to sleep through the night without awakening to urinate. It is also used to treat specific types of diabetes insipidus and conditions after head injury or pituitary surgery.
Structure
Thumb
Synonyms
1-(3-mercaptopropionic acid)-8-D-arginine-vasopressin
1-deamino-8-D-arginine vasopressin
1-Desamino-8-D-arginine vasopressin
DDAVP
Desmopresina
Desmopressin
Desmopressine
Desmopressinum
Minirin
Stimate
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Ddavpinjection4 ug/mLintravenousFerring Pharmaceuticals Inc.1984-03-30Not applicableUs
Ddavpsolution.1 mg/mLnasalSanofi Aventis U.S. Llc1978-02-21Not applicableUs
Ddavptablet.2 mg/1oralFerring Pharmaceuticals Inc.1995-09-06Not applicableUs
Ddavpsolution4 ug/mLintravenousSanofi Aventis U.S. Llc1984-03-30Not applicableUs
Ddavptablet.1 mg/1oralFerring Pharmaceuticals Inc.1995-09-06Not applicableUs
Ddavpspray.1 ug/mLnasalFerring Pharmaceuticals Inc.1978-02-21Not applicableUs
Ddavptablet.2 mg/1oralSanofi Aventis U.S. Llc1995-09-06Not applicableUs
Ddavpspray.1 ug/mLnasalFerring Pharmaceuticals Inc.1978-02-21Not applicableUs
Ddavptablet.1 mg/1oralSanofi Aventis U.S. Llc1995-09-06Not applicableUs
Ddavpinjection4 ug/mLintravenousFerring Pharmaceuticals Inc.1984-03-30Not applicableUs
Ddavp Inj 4mcg/mlliquid4 mcgintramuscular; intravenous; subcutaneousFerring Inc1993-12-31Not applicableCanada
Ddavp Melttablet (orally disintegrating)120 mcgsublingualFerring Inc2006-11-02Not applicableCanada
Ddavp Melttablet (orally disintegrating)60 mcgsublingualFerring Inc2006-11-02Not applicableCanada
Ddavp Melttablet (orally disintegrating)240 mcgsublingualFerring Inc2009-05-05Not applicableCanada
Ddavp Rhinal Tubesolution.1 mg/mLnasalSanofi Aventis U.S. Llc1978-02-21Not applicableUs
Ddavp Rhinylesolution0.1 mgnasalFerring Inc1992-12-31Not applicableCanada
Ddavp Spraymetered-dose aerosol10 mcgnasalFerring Inc1989-12-31Not applicableCanada
Ddavp Tablets 0.1mgtablet0.1 mgoralFerring Inc1995-12-31Not applicableCanada
Ddavp Tablets 0.2mgtablet0.2 mgoralFerring Inc1995-12-31Not applicableCanada
Desmopressintablet0.2 mgoralMeliapharm Inc2011-07-272014-06-25Canada
Desmopressintablet0.1 mgoralMeliapharm Inc2011-07-272014-06-25Canada
Desmopressin Acetatesolution4 ug/mLintravenousFerring Pharmaceuticals Inc.1999-10-26Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralFerring Pharmaceuticals Inc.2008-05-05Not applicableUs
Desmopressin Acetatesolution4 ug/mLintravenousAmring Pharmaceuticals Inc.1999-10-26Not applicableUs
Desmopressin Acetatesolution.1 mg/mLnasalFerring Pharmaceuticals Inc.1999-08-10Not applicableUs
Desmopressin Acetatesolution4 ug/mLintravenousAmring Pharmaceuticals Inc.1999-10-26Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralAmring Pharmaceuticals Inc.2008-05-05Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralAmring Pharmaceuticals Inc.2008-05-05Not applicableUs
Desmopressin Acetatespray10 ug/.1mLnasalPrasco Laboratories2014-01-01Not applicableUs
Desmopressin Acetatespray10 ug/.1mLnasalAmring Pharmaceuticals, Inc.2016-03-01Not applicableUs
Desmopressin Acetatesolution4 ug/mLintravenousFerring Pharmaceuticals Inc.1999-10-26Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralFerring Pharmaceuticals Inc.2008-05-05Not applicableUs
Desmopressin Sprayspray, metered dose10 mcgnasalAa Pharma Inc2000-08-18Not applicableCanada
Desmopressin Tabletstablet0.2 mgoralRainbow Pharmaceuticals Inc2005-02-182012-08-03Canada
Desmopressin Tabletstablet0.1 mgoralRainbow Pharmaceuticals Inc2005-02-182012-08-03Canada
Minirintablet0.1 mgoralFerring Inc2003-01-152015-07-22Canada
Minirinmetered-dose aerosol10 mcgnasalFerring Inc2000-08-212005-08-02Canada
Nocdurnatablet (orally disintegrating)50 mcgsublingualFerring Inc2014-11-17Not applicableCanada
Nocdurnatablet (orally disintegrating)25 mcgsublingualFerring Inc2013-07-31Not applicableCanada
Nu-desmopressin Spraymetered-dose pump0.1 gnasalNu Pharm IncNot applicableNot applicableCanada
Octostim Liq Inj. 15mcg/mlliquid15 mcgintravenous; subcutaneousFerring Inc1995-12-31Not applicableCanada
Octostim Sprayspray150 mcgnasalFerring Inc1998-12-01Not applicableCanada
PMS-desmopressintablet0.1 mgoralPharmascience Inc2008-01-23Not applicableCanada
PMS-desmopressintablet0.2 mgoralPharmascience Inc2008-01-23Not applicableCanada
Stimatespray, metered1.5 mg/mLnasalCSL Behring LLC2011-09-16Not applicableUs
Teva-desmopressintablet0.2 mgoralTeva Canada Limited2007-07-16Not applicableCanada
Teva-desmopressintablet0.1 mgoralTeva Canada Limited2007-07-16Not applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-desmopressintablet0.2 mgoralApotex Inc2007-01-31Not applicableCanada
Apo-desmopressintablet0.1 mgoralApotex Inc2007-01-31Not applicableCanada
Desmopressin Acetatetablet.1 mg/1oralGlenmark Pharmaceuticals Inc.,Usa2015-05-28Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralPhysicians Total Care, Inc.2007-07-19Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralAmerican Health Packaging2010-01-122015-12-29Us
Desmopressin Acetatetablet.1 mg/1oralApotex Corp.2006-03-07Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralTeva Pharmaceuticals USA Inc2006-01-27Not applicableUs
Desmopressin Acetateinjection, solution4 ug/mLintravenous; subcutaneousSun Pharmaceutical Industries Limited2013-01-30Not applicableUs
Desmopressin Acetateinjection4 ug/mLintravenousTeva Parenteral Medicines, Inc.1997-11-01Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralMylan Institutional Inc.2007-12-26Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralCarilion Materials Management2006-01-27Not applicableUs
Desmopressin Acetatesolution.1 mg/mLnasalSun Pharmaceutical Industries Limited2012-04-14Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralNcs Health Care Of Ky, Inc Dba Vangard Labs2011-01-17Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralAv Pak2013-07-24Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralAmerican Health Packaging2012-10-08Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralActavis Pharma, Inc.2011-08-15Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralAmerican Health Packaging2015-09-15Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralAmerican Health Packaging2012-10-08Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralAv Pak2013-07-24Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralAmerican Health Packaging2015-09-15Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralActavis Pharma, Inc.2011-08-15Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralBlue Point Laboratories2014-02-27Not applicableUs
Desmopressin Acetatesolution.1 mg/mLnasalSun Pharma Global FZE2013-12-24Not applicableUs
Desmopressin Acetatespray10 ug/1nasalApotex Corp.2005-01-27Not applicableUs
Desmopressin Acetateinjection, solution4 ug/mLintravenous; subcutaneousHospira, Inc.2000-08-28Not applicableUs
Desmopressin Acetatetablet.1 mg/1oralBlue Point Laboratories2014-02-27Not applicableUs
Desmopressin Acetatesolution.1 mg/mLnasalBauch & Lomb Incorporated1999-01-25Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralGlenmark Pharmaceuticals Inc.,Usa2015-05-28Not applicableUs
Desmopressin Acetatesolution.1 mg/mLnasalPhysicians Total Care, Inc.2006-05-22Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralAmerican Health Packaging2010-01-122015-12-29Us
Desmopressin Acetatetablet.2 mg/1oralApotex Corp.2006-03-07Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralTeva Pharmaceuticals USA Inc2006-01-27Not applicableUs
Desmopressin Acetatetablet.2 mg/1oralbryant ranch prepack2011-08-15Not applicableUs
Desmopressin Acetateinjection4 ug/mLintravenousTeva Parenteral Medicines, Inc.1997-11-01Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AdiuretinFerring
DesmoMeltFerring
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Desmopressin acetate
Thumb
• InChI Key: MLSVJHOYXJGGTR-IFHOVBQLSA-N
• Monoisotopic Mass: 1128.448084334
• Average Mass: 1129.269
DBSALT000044
Desmopressin acetate trihydrate
ThumbNot applicableDBSALT001154
Categories
UNIIENR1LLB0FP
CAS number16679-58-6
WeightAverage: 1069.217
Monoisotopic: 1068.426954962
Chemical FormulaC46H64N14O12S2
InChI KeyInChIKey=NFLWUMRGJYTJIN-NXBWRCJVSA-N
InChI
InChI=1S/C46H64N14O12S2/c47-35(62)15-14-29-40(67)58-32(22-36(48)63)43(70)59-33(45(72)60-18-5-9-34(60)44(71)56-28(8-4-17-52-46(50)51)39(66)53-23-37(49)64)24-74-73-19-16-38(65)54-30(21-26-10-12-27(61)13-11-26)41(68)57-31(42(69)55-29)20-25-6-2-1-3-7-25/h1-3,6-7,10-13,28-34,61H,4-5,8-9,14-24H2,(H2,47,62)(H2,48,63)(H2,49,64)(H,53,66)(H,54,65)(H,55,69)(H,56,71)(H,57,68)(H,58,67)(H,59,70)(H4,50,51,52)/t28-,29-,30-,31-,32-,33-,34-/m0/s1
IUPAC Name
(2S)-2-{[(2S)-1-[(4R,7S,10S,13S,16S)-13-benzyl-10-(2-carbamoylethyl)-7-(carbamoylmethyl)-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosane-4-carbonyl]pyrrolidin-2-yl]formamido}-5-carbamimidamido-N-(carbamoylmethyl)pentanamide
SMILES
NC(=O)CC[C@@H]1NC(=O)[[email protected]](CC2=CC=CC=C2)NC(=O)[[email protected]](CC2=CC=C(O)C=C2)NC(=O)CCSSC[[email protected]](NC(=O)[[email protected]](CC(N)=O)NC1=O)C(=O)N1CCC[[email protected]]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as cyclic peptides. These are compounds containing a cyclic moiety bearing a peptide backbone.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentCyclic peptides
Alternative Parents
Substituents
• Cyclic alpha peptide
• N-acyl-alpha amino acid or derivatives
• Macrolactam
• Alpha-amino acid amide
• N-substituted-alpha-amino acid
• Pyrrolidine-2-carboxamide
• Pyrrolidine carboxylic acid or derivatives
• N-acylpyrrolidine
• Phenol
• Fatty acyl
• Benzenoid
• N-acyl-amine
• Fatty amide
• Monocyclic benzene moiety
• Tertiary carboxylic acid amide
• Pyrrolidine
• Cyclic alcohol
• Tertiary amine
• Secondary carboxylic acid amide
• Primary carboxylic acid amide
• Organic disulfide
• Lactam
• Guanidine
• Carboxamide group
• Azacycle
• Organoheterocyclic compound
• Carboximidamide
• Carboxylic acid amide
• Hydrocarbon derivative
• Organooxygen compound
• Organonitrogen compound
• Imine
• Carbonyl group
• Amine
• Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationOral formulations may be used to manage primary nocturnal enuresis in adults and vasopressin sensitive diabetes insipidus, and for control of temporary polyuria and polydipsia following head trauma or surgery in the pituitary region. Intranasal and parenteral formulations may be used to manage spontaneous or trauma-induced bleeds (e.g. hemarthrosis, intramuscular hematoma, mucosal bleeding) in patients with hemophilia A or von Willebrand's disease Type I. May also be used parenterally to prevent or treat bleeding in patients with uremia.
PharmacodynamicsDesmopressin is a synthetic analogue of the natural antidiuretic hormone (ADH or vasopressin) that is produced by the hypothalamus and stored in the posterior pituitary gland. The main function of ADH is to regulate extracellular fluid volume in the body. ADH secretion is stimulated by angiotensin II, linking it to the renin-angiotensin-aldosterone system (RAAS). ADH stimulates water reabsorption in the kidneys by causing the insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. It also causes vasoconstriction through its action on vascular smooth muscle cells of the collecting tubules. The efficacy of desmopressin for managing bleeds in patients with hemophilia A or von Willebrand’s disease Type I arises from its ability to elicit dose-dependent increases in plasma factor VIII (antihemophilic factor), plasminogen activator, and to a lesser extent, factor VIII-related antigen and ristocetin cofactor activities; these changes improve blood clotting.
Mechanism of actionDesmopressin emulates the actions of endogenous human ADH (refer to Pharmacology section above). Desmpressin is a structural analogue of ADH modified by deamination of 1-cysteine and substitution of 8-L-arginine by 8-D-arginine. Compared to natural ADH, desmopressin elicits a great antidiuretic response on weight basis.
Related Articles
AbsorptionMinimally absorbed from the GI tract (average absolute bioavailability = 0.08-0.16%). 10-20% absorbed from nasal mucosa.
Volume of distributionNot Available
Protein binding50%
Metabolism
Metabolic fate unknown. Is not affected by liver microsomal cytochrome P450 enzymes.
Route of eliminationNot Available
Half lifeOral t1/2=1.5-2.5 hours. Intranasal t1/2=3.3-3.5 hours. IV t1/2 is biphasic: initial t1/2=7.8 minutes, terminal t1/2=0.4-4 hours.
ClearanceNot Available
ToxicityOverdose may lead to increased duration of action and lead to symptoms such as fluid retention, headaches, abdominal cramps, nausea, and facial flushing. Adverse effects include headache, nausea, abdominal pain, facial flushing, dizziness, dry mouth, and hyponatremia. Nasal congestion and rhinitis have been reported with nasal spray formulations.
Affected organisms
• Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.7979
Blood Brain Barrier-0.8866
Caco-2 permeable-0.7612
P-glycoprotein substrateSubstrate0.8242
P-glycoprotein inhibitor INon-inhibitor0.7864
P-glycoprotein inhibitor IINon-inhibitor0.9237
Renal organic cation transporterNon-inhibitor0.5915
CYP450 2C9 substrateNon-substrate0.7833
CYP450 2D6 substrateNon-substrate0.7901
CYP450 3A4 substrateNon-substrate0.5497
CYP450 1A2 substrateNon-inhibitor0.8383
CYP450 2C9 inhibitorNon-inhibitor0.7906
CYP450 2D6 inhibitorNon-inhibitor0.8735
CYP450 2C19 inhibitorNon-inhibitor0.765
CYP450 3A4 inhibitorNon-inhibitor0.7663
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9331
Ames testNon AMES toxic0.6679
CarcinogenicityNon-carcinogens0.8428
BiodegradationNot ready biodegradable0.9445
Rat acute toxicity2.7183 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.83
hERG inhibition (predictor II)Inhibitor0.6036
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
• Sanofi aventis us llc
• Bedford laboratories div ben venue laboratories inc
• Hospira inc
• Teva parenteral medicines inc
• Ferring pharmaceuticals inc
• Bausch and lomb pharmaceuticals inc
• Apotex inc richmond hill
• Csl behring llc
• Apotex inc etobicoke site
• Teva pharmaceuticals usa
• Watson laboratories inc
Packagers
Dosage forms
FormRouteStrength
Solutionintravenous4 ug/mL
Spraynasal.1 ug/mL
Tabletoral.1 mg/1
Tabletoral.2 mg/1
Liquidintramuscular; intravenous; subcutaneous4 mcg
Tablet (orally disintegrating)sublingual120 mcg
Tablet (orally disintegrating)sublingual240 mcg
Tablet (orally disintegrating)sublingual60 mcg
Solutionnasal.1 mg/mL
Solutionnasal0.1 mg
Metered-dose aerosolnasal10 mcg
Tabletoral0.1 mg
Tabletoral0.2 mg
Injectionintravenous4 ug/mL
Injection, solutionintravenous; subcutaneous4 ug/mL
Spraynasal10 ug/.1mL
Spraynasal10 ug/1
Spray, metered dosenasal10 mcg
Tablet (orally disintegrating)sublingual25 mcg
Tablet (orally disintegrating)sublingual50 mcg
Metered-dose pumpnasal0.1 g
Liquidintravenous; subcutaneous15 mcg
Spraynasal150 mcg
Spray, meterednasal1.5 mg/mL
Prices
Unit descriptionCostUnit
Stimate 1.5 mg/ml nasal spray334.2USD ml
Ddavp 0.01% nasal spray50.76USD ml
Ddavp 4 mcg/ml ampul43.27USD ml
Desmopressin 0.1 mg/ml spray39.6USD ml
Ddavp 0.1 mg/ml Solution21.26USD ml
Octostim 150 mcg/dose Metered Dose Spray17.39USD dose
Ddavp 4 mcg/ml11.33USD ml
Desmopressin ac 4 mcg/ml amp7.28USD ml
Desmopressin ac 4 mcg/ml vial7.08USD ml
Ddavp 0.2 mg tablet6.43USD tablet
Ddavp 0.1 mg tablet4.47USD tablet
Desmopressin acetate 0.2 mg tablet4.44USD tablet
Desmopressin acetate 0.1 mg tablet3.08USD tablet
Ddavp 0.2 mg Tablet2.98USD tablet
Ddavp 10 mcg/dose Metered Dose Spray2.13USD dose
Apo-Desmopressin 0.2 mg Tablet1.67USD tablet
Novo-Desmopressin 0.2 mg Tablet1.67USD tablet
Pms-Desmopressin 0.2 mg Tablet1.67USD tablet
Ddavp 0.1 mg Tablet1.49USD tablet
Apo-Desmopressin 10 mcg/dose Metered Dose Spray1.48USD dose
Apo-Desmopressin 0.1 mg Tablet0.83USD tablet
Novo-Desmopressin 0.1 mg Tablet0.83USD tablet
Pms-Desmopressin 0.1 mg Tablet0.83USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2484724 No2007-01-162023-05-07Canada
CA2486833 No2005-08-022024-04-30Canada
US5500413 No1993-06-292013-06-29Us
US7022340 No2003-04-302023-04-30Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP-4.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.11 mg/mLALOGPS
logP-1ALOGPS
logP-6.1ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)9.5ChemAxon
pKa (Strongest Basic)11.77ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count15ChemAxon
Hydrogen Donor Count14ChemAxon
Polar Surface Area435.41 Å2ChemAxon
Rotatable Bond Count19ChemAxon
Refractivity279.78 m3·mol-1ChemAxon
Polarizability106.19 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference
Krister Larsson, Thomas Mellbrand, Birgitta Mornstam, Jan Roschester, Jan-Ake Skoldback, “High purity desmopressin produced in large single batches.” U.S. Patent US5674850, issued November, 1991.
US5674850
General References
1. Leissinger C, Becton D, Cornell C Jr, Cox Gill J: High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A. Haemophilia. 2001 May;7(3):258-66. [PubMed:11380629 ]
External Links
ATC CodesH01BA02
AHFS Codes
• 68:28.00
PDB EntriesNot Available
FDA labelDownload (90.1 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AcenocoumarolDesmopressin may increase the anticoagulant activities of Acenocoumarol.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Desmopressin is combined with Acetylsalicylic acid.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Desmopressin.
Aminosalicylic AcidThe risk or severity of adverse effects can be increased when Desmopressin is combined with Aminosalicylic Acid.
AmitriptylineThe risk or severity of adverse effects can be increased when Amitriptyline is combined with Desmopressin.
AmoxapineThe risk or severity of adverse effects can be increased when Amoxapine is combined with Desmopressin.
BetamethasoneThe risk or severity of adverse effects can be increased when Betamethasone is combined with Desmopressin.
Bismuth SubsalicylateThe risk or severity of adverse effects can be increased when Desmopressin is combined with Bismuth Subsalicylate.
BuprenorphineThe risk or severity of adverse effects can be increased when Buprenorphine is combined with Desmopressin.
ButorphanolThe risk or severity of adverse effects can be increased when Butorphanol is combined with Desmopressin.
CaffeineThe risk or severity of adverse effects can be increased when Desmopressin is combined with Caffeine.
CarbamazepineThe risk or severity of adverse effects can be increased when Carbamazepine is combined with Desmopressin.
CelecoxibThe risk or severity of adverse effects can be increased when Celecoxib is combined with Desmopressin.
ChlorpromazineThe risk or severity of adverse effects can be increased when Chlorpromazine is combined with Desmopressin.
CitalopramThe risk or severity of adverse effects can be increased when Citalopram is combined with Desmopressin.
ClomipramineThe risk or severity of adverse effects can be increased when Clomipramine is combined with Desmopressin.
CorticotropinThe risk or severity of adverse effects can be increased when Corticotropin is combined with Desmopressin.
Cortisone acetateThe risk or severity of adverse effects can be increased when Cortisone acetate is combined with Desmopressin.
DemeclocyclineThe therapeutic efficacy of Desmopressin can be decreased when used in combination with Demeclocycline.
DesipramineThe risk or severity of adverse effects can be increased when Desipramine is combined with Desmopressin.
DesvenlafaxineDesvenlafaxine may increase the antiplatelet activities of Desmopressin.
DexamethasoneThe risk or severity of adverse effects can be increased when Dexamethasone is combined with Desmopressin.
DiclofenacThe risk or severity of adverse effects can be increased when Diclofenac is combined with Desmopressin.
DiflunisalThe risk or severity of adverse effects can be increased when Diflunisal is combined with Desmopressin.
DihydrocodeineThe risk or severity of adverse effects can be increased when Desmopressin is combined with Dihydrocodeine.
DoxepinThe risk or severity of adverse effects can be increased when Doxepin is combined with Desmopressin.
DuloxetineDuloxetine may increase the antiplatelet activities of Desmopressin.
EscitalopramThe risk or severity of adverse effects can be increased when Escitalopram is combined with Desmopressin.
EtodolacThe risk or severity of adverse effects can be increased when Etodolac is combined with Desmopressin.
FenoprofenThe risk or severity of adverse effects can be increased when Fenoprofen is combined with Desmopressin.
FentanylThe risk or severity of adverse effects can be increased when Fentanyl is combined with Desmopressin.
FloctafenineThe risk or severity of adverse effects can be increased when Floctafenine is combined with Desmopressin.
FludrocortisoneThe risk or severity of adverse effects can be increased when Fludrocortisone is combined with Desmopressin.
FluoxetineThe risk or severity of adverse effects can be increased when Fluoxetine is combined with Desmopressin.
FlurbiprofenThe risk or severity of adverse effects can be increased when Flurbiprofen is combined with Desmopressin.
FluvoxamineThe risk or severity of adverse effects can be increased when Fluvoxamine is combined with Desmopressin.
HydrocodoneThe risk or severity of adverse effects can be increased when Hydrocodone is combined with Desmopressin.
HydrocortisoneThe risk or severity of adverse effects can be increased when Hydrocortisone is combined with Desmopressin.
HydromorphoneThe risk or severity of adverse effects can be increased when Hydromorphone is combined with Desmopressin.
IbuprofenThe risk or severity of adverse effects can be increased when Ibuprofen is combined with Desmopressin.
ImipramineThe risk or severity of adverse effects can be increased when Imipramine is combined with Desmopressin.
IndomethacinThe risk or severity of adverse effects can be increased when Indomethacin is combined with Desmopressin.
InfliximabThe risk or severity of adverse effects can be increased when Infliximab is combined with Desmopressin.
KetoprofenThe risk or severity of adverse effects can be increased when Ketoprofen is combined with Desmopressin.
KetorolacThe risk or severity of adverse effects can be increased when Ketorolac is combined with Desmopressin.
LamotrigineThe risk or severity of adverse effects can be increased when Lamotrigine is combined with Desmopressin.
LevomilnacipranLevomilnacipran may increase the antiplatelet activities of Desmopressin.
LevorphanolThe risk or severity of adverse effects can be increased when Levorphanol is combined with Desmopressin.
LithiumThe therapeutic efficacy of Desmopressin can be decreased when used in combination with Lithium.
Magnesium salicylateThe risk or severity of adverse effects can be increased when Desmopressin is combined with Magnesium salicylate.
Mefenamic acidThe risk or severity of adverse effects can be increased when Mefenamic acid is combined with Desmopressin.
MeloxicamThe risk or severity of adverse effects can be increased when Meloxicam is combined with Desmopressin.
MethadoneThe risk or severity of adverse effects can be increased when Methadone is combined with Desmopressin.
MethylprednisoloneThe risk or severity of adverse effects can be increased when Methylprednisolone is combined with Desmopressin.
MilnacipranMilnacipran may increase the antiplatelet activities of Desmopressin.
MorphineThe risk or severity of adverse effects can be increased when Morphine is combined with Desmopressin.
NabumetoneThe risk or severity of adverse effects can be increased when Nabumetone is combined with Desmopressin.
NalbuphineThe risk or severity of adverse effects can be increased when Nalbuphine is combined with Desmopressin.
NaproxenThe risk or severity of adverse effects can be increased when Naproxen is combined with Desmopressin.
NortriptylineThe risk or severity of adverse effects can be increased when Nortriptyline is combined with Desmopressin.
OxaprozinThe risk or severity of adverse effects can be increased when Oxaprozin is combined with Desmopressin.
OxycodoneThe risk or severity of adverse effects can be increased when Oxycodone is combined with Desmopressin.
OxymorphoneThe risk or severity of adverse effects can be increased when Oxymorphone is combined with Desmopressin.
ParoxetineThe risk or severity of adverse effects can be increased when Paroxetine is combined with Desmopressin.
PemetrexedThe serum concentration of Pemetrexed can be increased when it is combined with Desmopressin.
PentazocineThe risk or severity of adverse effects can be increased when Pentazocine is combined with Desmopressin.
PethidineThe risk or severity of adverse effects can be increased when Pethidine is combined with Desmopressin.
PiroxicamThe risk or severity of adverse effects can be increased when Piroxicam is combined with Desmopressin.
PrednisoloneThe risk or severity of adverse effects can be increased when Prednisolone is combined with Desmopressin.
PrednisoneThe risk or severity of adverse effects can be increased when Prednisone is combined with Desmopressin.
PromazineThe risk or severity of adverse effects can be increased when Promazine is combined with Desmopressin.
ProtriptylineThe risk or severity of adverse effects can be increased when Protriptyline is combined with Desmopressin.
RemifentanilThe risk or severity of adverse effects can be increased when Remifentanil is combined with Desmopressin.
Repository corticotropinThe risk or severity of adverse effects can be increased when Repository corticotropin is combined with Desmopressin.
SalsalateThe risk or severity of adverse effects can be increased when Desmopressin is combined with Salsalate.
SertralineThe risk or severity of adverse effects can be increased when Sertraline is combined with Desmopressin.
SufentanilThe risk or severity of adverse effects can be increased when Sufentanil is combined with Desmopressin.
SulindacThe risk or severity of adverse effects can be increased when Sulindac is combined with Desmopressin.
TapentadolThe risk or severity of adverse effects can be increased when Tapentadol is combined with Desmopressin.
Tiaprofenic acidThe risk or severity of adverse effects can be increased when Tiaprofenic acid is combined with Desmopressin.
TolmetinThe risk or severity of adverse effects can be increased when Tolmetin is combined with Desmopressin.
TolvaptanThe therapeutic efficacy of Desmopressin can be decreased when used in combination with Tolvaptan.
TramadolThe risk or severity of adverse effects can be increased when Tramadol is combined with Desmopressin.
TriamcinoloneThe risk or severity of adverse effects can be increased when Triamcinolone is combined with Desmopressin.
TrimipramineThe risk or severity of adverse effects can be increased when Trimipramine is combined with Desmopressin.
VenlafaxineVenlafaxine may increase the antiplatelet activities of Desmopressin.
VilazodoneThe risk or severity of adverse effects can be increased when Vilazodone is combined with Desmopressin.
VortioxetineThe risk or severity of adverse effects can be increased when Vortioxetine is combined with Desmopressin.
WarfarinDesmopressin may increase the anticoagulant activities of Warfarin.
Food InteractionsNot Available
Targets
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Vasopressin receptor activity
Specific Function:
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption.
Gene Name:
AVPR2
Uniprot ID:
P30518
Molecular Weight:
40278.57 Da
References
1. Del Tredici AL, Vanover KE, Knapp AE, Bertozzi SM, Nash NR, Burstein ES, Lameh J, Currier EA, Davis RE, Brann MR, Mohell N, Olsson R, Piu F: Identification of novel selective V2 receptor non-peptide agonists. Biochem Pharmacol. 2008 Oct 30;76(9):1134-41. doi: 10.1016/j.bcp.2008.08.004. Epub 2008 Aug 12. [PubMed:18761325 ]
2. Slusarz MJ, Slusarz R, Ciarkowski J: Investigation of mechanism of desmopressin binding in vasopressin V2 receptor versus vasopressin V1a and oxytocin receptors: molecular dynamics simulation of the agonist-bound state in the membrane-aqueous system. Biopolymers. 2006 Apr 5;81(5):321-38. [PubMed:16333859 ]
3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
General Function:
Vasopressin receptor activity
Specific Function:
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system. Has been involved in social behaviors, including affiliation and attachment.
Gene Name:
AVPR1A
Uniprot ID:
P37288
Molecular Weight:
46799.105 Da
References
1. Loichot C, Cazaubon C, De Jong W, Helwig JJ, Nisato D, Imbs JL, Barthelmebs M: Nitric oxide, but not vasopressin V2 receptor-mediated vasodilation, modulates vasopressin-induced renal vasoconstriction in rats. Naunyn Schmiedebergs Arch Pharmacol. 2000 Mar;361(3):319-26. [PubMed:10731046 ]
2. Mechaly I, Laurent F, Portet K, Serrano J, Cros G: Vasopressin V2 (SR121463A) and V1a (SR49059) receptor antagonists both inhibit desmopressin vasorelaxing activity. Eur J Pharmacol. 1999 Nov 3;383(3):287-90. [PubMed:10594321 ]
3. Barthelmebs M, Krieger JP, Grima M, Nisato D, Imbs JL: Vascular effects of [Arg8]vasopressin in the isolated perfused rat kidney. Eur J Pharmacol. 1996 Oct 31;314(3):325-32. [PubMed:8957254 ]
4. Pequeux C, Keegan BP, Hagelstein MT, Geenen V, Legros JJ, North WG: Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathway. Endocr Relat Cancer. 2004 Dec;11(4):871-85. [PubMed:15613460 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
General Function:
Vasopressin receptor activity
Specific Function:
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system.
Gene Name:
AVPR1B
Uniprot ID:
P47901
Molecular Weight:
46970.345 Da
References
1. Pequeux C, Keegan BP, Hagelstein MT, Geenen V, Legros JJ, North WG: Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathway. Endocr Relat Cancer. 2004 Dec;11(4):871-85. [PubMed:15613460 ]
2. Dinan TG, O'Brien S, Lavelle E, Scott LV: Further neuroendocrine evidence of enhanced vasopressin V3 receptor responses in melancholic depression. Psychol Med. 2004 Jan;34(1):169-72. [PubMed:14971638 ]
3. Craighead M, Milne R, Campbell-Wan L, Watson L, Presland J, Thomson FJ, Marston HM, Macsweeney CP: Characterization of a novel and selective V1B receptor antagonist. Prog Brain Res. 2008;170:527-35. doi: 10.1016/S0079-6123(08)00440-8. [PubMed:18655906 ]
Enzymes
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Prostaglandin-endoperoxide synthase activity
Specific Function:
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the gener...
Gene Name:
PTGS1
Uniprot ID:
P23219
Molecular Weight:
68685.82 Da
References
1. Kotnik P, Nielsen J, Kwon TH, Krzisnik C, Frokiaer J, Nielsen S: Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus. Am J Physiol Renal Physiol. 2005 May;288(5):F1053-68. Epub 2005 Jan 11. [PubMed:15644490 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Prostaglandin-endoperoxide synthase activity
Specific Function:
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, p...
Gene Name:
PTGS2
Uniprot ID:
P35354
Molecular Weight:
68995.625 Da
References
1. Kotnik P, Nielsen J, Kwon TH, Krzisnik C, Frokiaer J, Nielsen S: Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus. Am J Physiol Renal Physiol. 2005 May;288(5):F1053-68. Epub 2005 Jan 11. [PubMed:15644490 ]
Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23
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• Scientists predict that COVID-19 will become endemic over time.
• An endemic virus is constant in a population with largely predictable patterns.
• Endemic comes from the Greek word endēmos, which means 'in population'.
• Another buzzword, 'epidemic', describes a disease concentrated in certain areas, experts explain.
• The Ebola virus that spread within three West African countries from 2014–2016 was an epidemic.
• Countries will enter an endemic phase of COVID-19 at different times, due to incompatible vaccination rates and other variables.
Most people are wondering when and how the COVID pandemic will end and there are still no easy answers.
The word “endemic” is regularly mentioned, especially among public health leaders and experts as they discuss potential future scenarios. So, it’s important to define exactly it would mean for COVID to be endemic.
Scientists predict COVID will become endemic over time but there will still be sporadic outbreaks where it gets out of control. The transition from pandemic to endemic will likely play out differently in different locations around the world.
‘Outbreak’, ‘Epidemic’, ‘Pandemic’ and ‘Endemic’
First let’s recap the public health terms Australians have been increasingly using in conversation over the last 18 months. These words cover the lifecycle of disease and include “outbreak”, “epidemic”, “pandemic” and “endemic”.
An outbreak is a rise in disease cases over what is normally expected in a small and specific location generally over a short period of time. Foodborne diseases caused by Salmonella contamination provide frequent examples of this.
a diagram showing the difference between an endemic, epidemic and pandemic
“Epidemic”, “pandemic” and “endemic” all mean different things.
Image: Wellcome Trust
Epidemics are essentially outbreaks without the tight geographical restrictions. The Ebola virus that spread within three West African countries from 2014–2016 was an epidemic.
A pandemic is an epidemic that spreads across many countries and many continents around the world. Examples include those caused by influenza A(H1N1) or “Spanish Flu” in 1918, HIV/AIDS, SARS-CoV-1 and Zika virus.
Finally, the normal circulation of a virus in a specified location over time describes an endemic virus. The word “endemic” comes from the Greek endēmos, which means “in population”. An endemic virus is relatively constant in a population with largely predictable patterns.
Viruses can circulate endemically in specific geographical regions, or globally. Ross River virus circulates endemically in Australia and the Pacific island countries, but is not found in other regions of the world. Meanwhile, rhinoviruses which cause the common cold circulate endemically around the world. And influenza is an endemic virus we monitor for its epidemic and pandemic potential.
What’s the usual path from pandemic to endemic look like?
Over time and thanks to public health efforts from mask wearing to vaccination, the pandemic could disappear like small pox and polio did — or it might gradually become endemic.
Host, environment and virus factors combine to explain why some viruses are endemic while others are epidemic.
When we look at the SARS-CoV-2 virus that causes COVID, we see it is infecting human hosts with no prior immunity.
In terms of environment, the virus transmits better in cold, dry, crowded, close-contact, confined settings with poor ventilation.
Each virus has its own characteristics, from speed of virus replication to drug resistance. The new COVID strains are transmitted faster and cause different symptoms.
Viruses are more likely to become endemic if they become adapted to a local environment and/or have a continuous supply of susceptible hosts. For COVID these would be hosts with low or zero immunity.
How long will it take for COVID-19 to become an endemic disease?
Scientific mathematical modelling provide some idea of likely COVID epidemic outcomes.
Most public health experts currently agree COVID is here to stay rather than likely to disappear like small pox, at least for a while. They expect the number of infections to become fairly constant across years with possible seasonal trends and occasional smaller outbreaks.
Globally, the road from pandemic to endemic will be a rocky one. In Australia our national and state leaders are announcing future plans to reopen businesses and eventually borders. The process of doing this will result in the second nation-wide epidemic of COVID. People will die and our health systems will be challenged. Vaccination rates will protect many, but there are still those who won’t, or can’t get vaccinated. Herd immunity (from vaccination or infection) will play a key role in ensuring we move towards an endemic COVID.
With time, scientists predict COVID will become more prevalent among unvaccinated youths or those without prior exposure to the virus. This is what happens with common cold coronaviruses. Despite periodical spikes in caseloads each season or immediately after relaxation of economic, social, and travel restrictions, COVID will eventually become more manageable.
health and healthcare, COVID
How has the Forum navigated the global response to COVID-19?
One year on: we look back at how the Forum’s networks have navigated the global response to COVID-19.
Using a multistakeholder approach, the Forum and its partners through its COVID Action Platform have provided countless solutions to navigate the COVID-19 pandemic worldwide, protecting lives and livelihoods.
Throughout 2020, along with launching its COVID Action Platform, the Forum and its Partners launched more than 40 initiatives in response to the pandemic.
The work continues. As one example, the COVID Response Alliance for Social Entrepreneurs is supporting 90,000 social entrepreneurs, with an impact on 1.4 billion people, working to serve the needs of excluded, marginalized and vulnerable groups in more than 190 countries.
Read more about the COVID-19 Tools Accelerator, our support of GAVI, the Vaccine Alliance, the Coalition for Epidemics Preparedness and Innovations (CEPI), and the COVAX initiative and innovative approaches to solve the pandemic, like our Common Trust Network – aiming to help roll out a “digital passport” in our Impact Story.
It won’t be the same everywhere
Countries will not enter an endemic phase at the same time because of variable host, environmental, virus factors including vaccination rates. The availability and rollout of booster vaccine shots each year or season will also shape this path. Poor vaccine coverage could allow the virus to continue at an epidemic level for longer. In a location where immunity wanes quickly and there are no booster shots available, COVID could go from endemic back to epidemic.
Once we see a stable level of SARS-CoV-2 transmission indicating a new “baseline” of COVID, we will know the pandemic has ended and the virus is endemic. This will likely include minor seasonal trends as we see now with flu.
The most important thing we can do to help reach a safe level of endemic COVID is to get vaccinated and continue to adhere to COVID-safe practices. By doing this we protect ourselves, those around us, and move together towards an endemic phase of the virus. If we don’t work together, things could turn for the worse very quickly and prolong the end of the pandemic.
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"Feeling stressed can wreak havoc on our bodies. It can cause our body to produce the steroid hormone cortisol, which can make you crave sugary foods that provide instant energy and pleasure. Short-term bursts of cortisol are necessary to help us cope with immediate danger, but our body will also release this hormone if we’re feeling stressed or anxious. When our cortisol levels are high for a long amount of time, it can increase the amount of fat you hold in your belly."
Fermented foods: These enhance the function of good bacteria while inhibiting the growth of bad bacteria. Sauerkraut, kimchi, kefir, yogurt, tempeh, and miso all contain good amounts of probiotics, which help to increase good bacteria. Researchers have studied kimchi widely, and study results suggest that it has anti-obesity effects. Similarly, studies have shown that kefir may help to promote weight loss in overweight women.
The main advantage of the low-carb diet is that it causes you to want to eat less. Even without counting calories most overweight people eat far fewer calories on low carb. Sugar and starch may increase your hunger, while avoiding them may decrease your appetite to an adequate level. If your body wants to have an appropriate number of calories you don’t need to bother counting them. Thus: Calories count, but you don’t need to count them.
A calorie isn’t always a calorie. Eating 100 calories of high fructose corn syrup, for example, can have a different effect on your body than eating 100 calories of broccoli. The trick for sustained weight loss is to ditch the foods that are packed with calories but don’t make you feel full (like candy) and replace them with foods that fill you up without being loaded with calories (like vegetables).
Be choosy about carbs. You can decide which ones you eat, and how much. Look for those that are low on the glycemic index (for instance, asparagus is lower on the glycemic index than a potato) or lower in carbs per serving than others. Whole grains are better choices than processed items, because processing removes key nutrients such as fiber, iron, and B vitamins. They may be added back, such as in “enriched” bread.
Frequent and sustained cardio training is one of the best ways to burn fat and boost metabolism. One of the best cardio exercises to perform is running, according to the American College of Sports Medicine, as it burns a high number of calories per hour and improves cardiovascular health. ACSM recommends training five days a week, with a minimum of 60 minutes per session.
This drug is an injected variant of a satiety hormone called GLP-1. It slows down how quickly the stomach empties and tells the brain that you don’t need to eat yet – a great idea for losing weight. As a bonus this drug works fine while one is on the keto diet and it works even better with intermittent fasting – for a rapid weight loss with no hunger.
The scale is not necessarily your friend. You may want to lose fat – but the scale measures muscles, bone and internal organs as well. Gaining muscle is a good thing. Thus weight or BMI are imperfect ways to measure your progress. This is especially true if you’re just coming off a long period of semi-starvation (calorie counting), as your body may want to restore lost muscles etc. Starting weight training and gaining muscle can also hide your fat loss.
Drop Off Paper Shredding — The national average for drop off shredding is $1 per pound. One copy paper box full of papers usually weighs about 30 pounds. Since drop off shredding is charged by the pound, it is convenient to drop off your boxes of papers to be shredded at a retail location. You don’t get to witness your papers being shredded if you use the drop off service.
We all get by with a little help from our friends, and this is especially true of people who have lost weight and kept it off. In one study among women who went through a 12-week weight loss program, 74 percent of them maintained their loss or lost more in the three years after the program ended. Those who reported having a support system around eating well were more likely to keep the weight off. (Support around exercise didn’t seem to matter.) Another study found that the type of support you receive matters, too. Your friend who’s cheering you on isn’t likely to be as helpful as your friend who will pass on the fries when you’re trying to eat well. When you’re going out to eat, join friends who will support your healthy eating goals and go to a museum or movie with those who are less likely to be in it with you. Your pals who are in the trenches with you are more likely to hold you accountable, and that’s going to help you in the long run.
In fact, a study published in 2016 in the International Journal of Obesity looked at the metabolic health markers of more than 40,0000 adults and found that nearly half of people who are overweight, and 29 percent of people classified as having obesity, were cardiometabolically healthy. It also found that more than 30 percent of people at so-called “healthy weights” had poor cardiometabolic health—which can include hypertension, high cholesterol, inflammation, and insulin resistance.
It’s very rare for a manufacturer to mention side effects on their website. K Shred weight loss is no different. They don’t say anything about them. We know that there is always a slight risk of side effects when adding this or any other supplement to your daily routine, so if you notice any severe problems, stop taking the supplement and consult a doctor right away.
Certain carbohydrates have a tendency to be poorly absorbed in your intestines and then rapidly fermented, leading to gas and bloating. Common culprits include refined carbohydrates and simple sugars—like those found in processed foods with added sugars. Excess sodium can also cause bloating due to increased water retention. Opt for freshly prepared foods and reduce processed, packaged foods to cut back on belly bloaters. In the morning, swap your sugar-laden bowl of cereal for this Green Smoothie, made with fresh fruits and vegetables to get your day started the right way.
During the first week of a reduced calorie and carbohydrate diet, you will flush a lot of excess water and lose weight rapidly. This is neither unhealthy, nor an indication of what your rate of weight loss will be like during weeks 2 and 3. With that said, men should expect to see an 8 to 12 pound loss during these 3 weeks, and women will likely lose 5 to 10 pounds.
You may have heard the widely quoted statistic that 95% of people who lose wait on a diet will regain it within a few years—or even months. While there isn’t much hard evidence to support that claim, it is true that many weight-loss plans fail in the long term. Often that’s simply because diets that are too restrictive are very hard to maintain over time. However, that doesn’t mean your weight loss attempts are doomed to failure. Far from it.
There’s more: According to a 2017 review that looked at and analyzed more than 70 studies of over one million people, 42 percent of adults reported having tried to lose weight some time in the previous 12 months. So, lots of people are trying to lose weight, and lots of people are gaining it back. But we also all know someone (or several someones) who have lost weight and kept it off. So, what gives?
While many people turn to artificial sweeteners in a misguided attempt to whittle their waistlines, those fake sugars are likely to have the opposite effect. According to Yale researchers, artificial sweeteners are actually linked with an increased risk of abdominal obesity and weight gain, possibly because they can trigger cravings for the real stuff and spike insulin levels in a similar fashion to real sugar.
If you’ve got weight to lose and you want it gone fast, try swapping out your usual proteins in favor of fish. Not only is fish lower in calories than an equivalent amount of beef or chicken, a study published in Obesity reveals study subjects who added omega-3 fatty acids, like those found in fish, to their diets shed more weight and had an easier time keeping it off than those who skipped them.
1. The side plank exercise is the best way to reduce belly fat. There are only two points of contact with the floor which helps the core muscles to contract even harder. Lie on your side with your legs top of each other, rest on your lower forearm that is bent on the elbow. Force your upper body off the floor by using your forearm and place other hand on your hips. You should resemble a diagonal line from head to toe. After you lift your bodies just hold it for 30-60 seconds.
The sad truth is that conventional ideas – eat less, run more – do not work long term. Counting calories, exercising for hours every day and trying to ignore your hunger? That’s needless suffering and it wastes your time and precious willpower. It’s weight loss for masochists. Eventually almost everyone gives up. That’s why we have an obesity epidemic. Fortunately there’s a better way.
Tempting as that post-workout shower may be, making time to hold a static stretch at the end of your workout can increase your muscle mass by as much as 13 per cent, according to US research. How? It has much the same effect on your muscles as resistance training, a study published in the Journal of Applied Physiology found. Both cause micro tears that prompt the manufacture of muscle fibres. Stretch yourself swole.
Being in optimal ketosis for a prolonged period of time (say, a month) will ensure that you experience the maximal hormonal effect from eating a low-carb diet. If this doesn’t result in noticeable weight loss, you can be certain that too many carbs are NOT part of your weight issue and not the obstacle to your weight loss. There are, in fact, other causes of obesity and being overweight. The next three tips in this series might help you.
Track your progress. Weigh yourself and measure your body fat and record your results prior to beginning 30-Day Shred. Always weigh yourself first thing in the morning on an empty stomach for better accuracy. You should expect to lose an average of one to two pounds a week, maybe more, depending on your behavior, according to the Mayo Clinic. Weigh and measure your body fat once a week and not every day. Record your weekly results in a journal.
If you’re routinely skimping on the recommended seven to nine hours, or you have difficulty falling or staying asleep, it’s time to get serious about your bedtime rituals. Your better-sleep strategy includes: limiting caffeine past the early afternoon; sticking to alcohol caps of one drink for women, two for men (since alcohol can interfere with the quality of your sleep); and staying off the phone and iPad within an hour of bedtime.
Being in optimal ketosis for a prolonged period of time (say, a month) will ensure that you experience the maximal hormonal effect from eating a low-carb diet. If this doesn’t result in noticeable weight loss, you can be certain that too many carbs are NOT part of your weight issue and not the obstacle to your weight loss. There are, in fact, other causes of obesity and being overweight. The next three tips in this series might help you.
You may have an apple-shaped or a pear-shaped body structure. Accumulation of fat occurs differently for different people, it actually depends on the body structure. For those whose bodies are pear-shaped, the fat tends to accumulate in the lower part of the body, like the buttocks. But for those whose bodies are apple-shaped, your body tends to store fat around the middle section, thus resulting in fat accumulation around the belly. You must know that there are two types of belly fat – visceral, which accumulates around the abdominal organs, and subcutaneous, which occurs between the skin and abdominal wall.
Instead of satisfying your sweet tooth with some refined sugar, turn to berries and enjoy a slimmer waistline in no time. Berries are loaded with antioxidants, which can help reduce inflammation throughout the body, and research from the University of Michigan reveals that rats given a cherry-rich diet shaved off a significant proportion of their belly fat when compared to a control group. Berries like strawberries, raspberries, blueberries, and blackberries are also loaded with resveratrol, an antioxidant pigment that has been linked to reductions in belly fat and a reduced risk of dementia, to boot.
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What Definitely Is CBD and How Does It Function?
CBD is definitely the short type for cannabidiol. It is an important phytocannabinoid that may be present in the hemp and is thought to help the mind and the human body in lots of alternative ways. CBD solutions in the shape of Cachets also have cannabinoids, which have CBD extracts.
What will make CBD get the job done?
How does CBD get to operate? Your body of humans incorporates a significant network of constituent receptors, the procedure of endocannabinoids, that's critical to preserving the overall wellness, in addition to aiding the support units for most of the Bodily processes Pet CBD inside our system. Cannabinoids and CBD in shape inside of these receptors that help the human human body with its endeavours in sustaining good wellbeing.
Working experience much better well being with using the CBD
You receive to love a sense of calmness plus more concentration. CBD affects Understanding positively and In addition it motivates Discovering. It is also beneficial in reversing the indications of the Alzheimer illness. You can obtain a coronary heart that is definitely much healthier by using the CBD. CBD has many Gains that it provides to the center, these involve the potential of reducing superior amounts of blood pressure. Additionally you get aid with the stresses which are element of your lifestyle. CBD has actually been known to offer therapeutic cures for signs and symptoms like worry and anxiety, thus aiding while in the reduction of psychological levels of nervous habits. Furthermore, it aids in lessening the sensation of depression and nervousness.
The wonder of CBD
CBD is just a molecule, not any miracle. A great deal of individuals can reap the significant Added benefits Should they be furnished accessibility lawfully to those wide array of remedies of cannabis, not merely to no THC or small THC solutions. CBD by by itself may well not normally be more than enough to find the trick to work. There's a great deal of compelling evidence to prove that CBD features greatest when it can be coupled with the likes of THC and all the spectrum consisting of other parts of cannabis.
To have the ability to figure out the way to go about optimizing your therapeutic software of cannabis is the driving variable that's behind among the greatest experiments in the days of democracy. The result of this getting is named healthcare cannabis and it has been noticed from a single condition to a different and one particular nation to a different in the very the latest several years.
The coming up from the really strong oil concentrates of cannabis, CBD loaded non intoxicating products and very revolutionary and smokeless techniques of shipping and delivery have improved the therapeutic place. This has also brought about a large modify in the general public conversation all-around cannabis.
This is not anymore a subject matter of debate if cannabis has adequate merit as a potent herbal medication - as of currently, the main problem is in comprehension the utilization of cannabis to acquire optimum therapeutic Gains.
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Does Neurontin cause weight gain or weight loss?
Does Neurontin cause weight gain or weight loss?
Gabapentin (Neurontin) is a medication that’s FDA-approved to treat seizures and postherpetic neuralgia, which is a specific type of nerve pain. Although they’re not common side effects, gabapentin has been reported to potentially cause weight gain and fluid buildup in the legs (edema).
How can I avoid weight gain on gabapentin?
Tips on How to Avoid Weight Gain on Gabapentin
1. Talk to Your Doctor About Switching Medications.
2. Talk to Your Doctor About Lowering Your Dose.
3. Limit Food Portion Sizes.
4. Drink Water Before Meals.
5. Avoid Refined Sugars.
6. Exercise Regularly.
7. Avoid Alcohol.
8. Eat More Protein.
Does gabapentin affect metabolism?
However, in contrast to valproate, metabolic side effects accompanying use of carbamazepine, pregabalin and gabapentin are thought to be secondary to the induced weight gain rather than weight-independent mechanisms (80).
Does gabapentin affect appetite?
Gabapentin can cause weight gain, but this side effect is usually rare. People may gain weight while taking gabapentin because the drug increases their appetite and causes water retention, mainly in the arms, hands, legs, and feet.
How common is weight gain with gabapentin?
Does gabapentin make you retain water?
Another symptom is water retention, which causes swelling of the hands, arms, legs, and feet. This may lead to weight gain. Children who take Gabapentin may have different side effects, including anxiety and behavioral problems.
What is the number one side effect of gabapentin?
a high temperature, swollen glands that do not go away, your eyes or skin turn yellow (this may be less obvious on brown or black skin), unusual bruises or bleeding, severe tiredness or weakness, unexpected muscle pain or weakness, with or without a rash – these may be symptoms of a serious reaction.
Does gabapentin 300 mg make you gain weight?
Does gabapentin make your face puffy?
Call your doctor right away if you have a rash, itching, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine. Gabapentin may cause vision changes, clumsiness, unsteadiness, dizziness, drowsiness, sleepiness, or trouble with thinking.
Is gabapentin hard on kidneys?
Gabapentin does not directly influence or damage the kidney.
What drugs should not be taken with gabapentin?
Gabapentin can interact with losartan, ethacrynic acid, caffeine, phenytoin, mefloquine, magnesium oxide, cimetidine, naproxen, sevelamer and morphine. Gabapentin use is contraindicated in patients with myasthenia gravis or myoclonus.
What percentage of people gain weight on gabapentin?
Duration of use also affects whether you gain weight on gabapentin. One study measuring the correlation of gabapentin and weight gain in 44 patients found that 10 patients gained more than 10% of their baseline weight, and 15 patients gained 5% to 10% of their baseline weight.
Does gabapentin cause water retention?
People may gain weight while taking gabapentin because the drug increases their appetite and causes water retention, mainly in the arms, hands, legs, and feet. Patients taking medications like Neurontin and Gralise may gain a few pounds after about six weeks into treatment.
What are the dangers of using gabapentin?
Common side effects of gabapentinoids include drowsiness, dizziness, blurry or double vision, difficulty with coordination and concentration, and swelling of the hands, legs, and feet.
Does gabapentin affect urination?
Gabapentin-Induced Urinary Incontinence: A Rare Side Effect in Patients with Neuropathic Pain.
What are the disadvantages of taking gabapentin?
How many years can you take gabapentin?
According to the World Health Organization (WHO), “the efficacy and safety of gabapentin have not been examined in clinical studies for treatment periods longer than five months.” However, gabapentin can be taken longer than five months, should a treating physician deem it necessary, provided the patient does not …
Can gabapentin affect your eyes?
Gabapentin and impairment
Double vision was reported in 8% of people taking gabapentin for nerve pain. Other vision impairments such as lazy eye, nystagmus (uncontrolled eye movements), and blurred vision were reported by at least one in 50 participants.
Is gabapentin hard to get off of?
Withdrawal symptoms can begin within 12 hours to 7 days after quitting the medication and last up to 10 days. Symptoms of gabapentin withdrawal may include nausea, dizziness, headaches, insomnia, and anxiety. The safest way to stop using gabapentin is to taper off the medication under the supervision of a doctor.
What are the uncommon side effects of gabapentin?
Rare side effects
• suicidal thoughts or behavior.
• violent behavior, aggressiveness, or anger.
• anxiety that is worse or new.
• depression that is worse or new.
• irritability that is worse or new.
• hallucinations.
• mania.
• panic attacks.
What are the long term effects of using gabapentin?
According to researchers, long-term use of gabapentin — a nonopioid pain medication — among older adults may cause altered mental status, dizziness, drowsiness and renal dysfunction, and it could also lead to polypharmacy, which in itself can lead to adverse events and hospital stays.
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Lockwood ligament
sus·pen·so·ry lig·a·ment of eye·ball
[TA]
a thickening of the inferior part of the bulbar sheath that supports the eye within the orbit; it extends between the lateral and medial orbital margins and includes the medial and lateral check ligaments.
Lockwood ligament
(lok′wud″)
[Charles B. Lockwood, Brit. surgeon, 1856–1914]
The suspensory ligament of the lens of the eye.
Lockwood,
Charles B., English anatomist and surgeon, 1858-1914.
ligament of Lockwood - Synonym(s): suspensory ligament of eyeball
Lockwood clamp
Lockwood forceps
Lockwood ligament - Synonym(s): suspensory ligament of eyeball
Lockwood tendon
References in periodicals archive ?
Besides, surgery, trauma, or disease may cause a rent in the surrounding connective tissue including Tenon's capsule, the orbital septum, and Lockwood ligament allowing the extraconal fat to herniate into the eyelids or the intraconal fat to herniate into the subconjunctival space, medial to the lacrimal gland.
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Showing posts with label disease. Show all posts
Showing posts with label disease. Show all posts
Tuesday, July 25, 2023
Meat is nutritious, but it also increases disease
Meat is nutritious, but it also increases disease
Now the community of those who stop eating meat is growing all over the world. According to a report published in the BBC, the number of people giving up meat for the sake of the environment and animal welfare is increasing.
It is written in the BBC, "If we talk about Britain, one third of citizens are claiming that they have stopped eating meat." Even in America, two-thirds of citizens say that they are eating much less meat than in the past.
But even though the number of vegetarians is increasing in the world, the consumption of meat has not decreased. In the last 50 years, meat consumption has been increasing rapidly in the world. In addition, meat production has also increased. There are basically two reasons for the increase in meat consumption, one is population growth. Another thing is people's purchasing power.
The method of meat production is also different in developed countries. Animals are raised there for any purpose. Young and healthy animals are slaughtered with as little pain as possible. The meat produced in this way is stored and sold according to healthy standards.
But we do not have a procedure to check how much meat produced is edible. Nor is the animal's health checked before slaughter. For this reason, doctors here suggest to control the amount of meat as much as possible. A summary of some studies says, "Especially red meat can cause heart disease, heart attack and some types of cancer."
Nutritionist Bhupal Baniyan says that consumers in Nepal are forced to eat low-quality meat because the Meat Inspection Act cannot be implemented effectively. He says, "When businessmen sell and distribute meat without testing, the people here are forced to eat low-quality and unhealthy meat."
The Slaughterhouse Acts have been framed under the Animal Slaughterhouse and Meat Inspection Act-2055. There are many laws such as checking before slaughtering animals, checking the meat of slaughtered animals, marking or marking the meat. If the law is not implemented, there is a provision of a fine ranging from 5 to 20 thousand rupees and imprisonment for up to one month. But all these laws have not been implemented, nor have the relevant agencies monitored whether they have been implemented.
We eat chicken meat because chicken meat is healthier than red meat. But in order to make the chicken marketable quickly, the businessmen use a large amount of different types of antibiotics in the feed,'' he says.
It is not that all businessmen have given antibiotics to chickens beyond the standard. Some have even produced and sold chicken meat according to the standards. An example of that is the Valley Cold Store, said Baniyan.
Baniyan says, "Earlier, Khasiboka was reared in the village. But now, grain is fed to make the chicken grow faster. As a result, it takes a lot of fat. He says, 'The amount of saturated fat in beef is high. As a result, consuming too much beef can cause heart problems.
The raw meat of Ranga contains various types of germs including worms and 'microbacterial contamination'. Baniyan says, 'If this meat is not cooked properly and eaten, it can cause kidney and liver problems in the long run.'
"How to cut meat, how to sell, etc. standards are not only in foreign countries but also in Nepal. But since there is no body to monitor whether that standard is met, Baniyan says that diseased and low-quality meat can cause various diseases.
In this way, eating meat with a lot of antibiotics may not cause any problems, but over time, chronic diseases may increase. Therefore, if any animal's meat is fit to be eaten, the vet doctor advises that it should be sold and distributed only after examining it and saying that it is fit to be eaten.
How edible is the fish?
From the point of view of health, Baniyan says that it is better to eat fish because it contains protein and omega three. "But since the fish produced in Nepal cannot meet the market demand, fish are imported from India and other countries," he says.
Even after bringing it to Nepal, formalin is used to keep it on sale for a long time. Baniyan says that eating fish that has been kept in formalin for a long time can affect the kidneys and liver in the long term. Therefore, he suggests that when buying fish from the market, it is better to bring live fish than dead fish.
What does the food research officer say?
According to Food Research Officer Ujjwal Rayamazhi, protein obtained from meat has more biological value than that obtained from legumes. This means that the protein in the meat can be absorbed and used more by the body. That's why eating meat is good for health, Rayamazhi says, so it is consumed all over the world.
How healthy is the meat found in Nepal? How healthy are the animals used for meat? The relevant agency is responsible for monitoring the matter. But there has not been as much monitoring as there should be," says Rayamazhi.
He says that it is not true that the market is filled with meat that has been used in large amounts of antibiotics. Rayamazhi says. "According to some of our monitoring, many businessmen have worked according to the standards. But in Nepal, cattle rearing for meat and selling meat is done at home. this Some businessmen may have given too many hormones for profit.
Sunday, August 28, 2022
Cholesterol itself is not a disease
Cholesterol itself is not a disease
A fat-like substance produced by the liver in the body is called cholesterol. Cholesterol is a very important part of human blood cells.
Thursday, June 30, 2022
'Playing on soil enhances disease resistance'
'Playing on soil enhances disease resistance'
The month of Asar-Saun is the paddy sowing season. Farmers are exposed to muddy soil for planting paddy. Our emotional connection with the soil is also connected.
Thursday, February 17, 2022
What is the OSA disease of Bappi Lahiri?
What is the OSA disease of Bappi Lahiri?
Famous Indian singer and musician Bappi Lahiri passed away at the age of 69 on Wednesday. Doctors say Bappi's death was due to sleep-related obstructive sleep apnea (OSA).
Bappi Lahiri breathed his last at the Criticare Hospital in Mumbai at 11:45 pm on Tuesday. The director of the hospital, Dr. Deepak Namjoshi has issued a statement after Bappi's death.
Monday, November 1, 2021
There is a reason why different companies recommend drugs for the same disease
There is a reason why different companies recommend drugs for the same disease
When we are sick, the doctor prescribes medicine. If the medicine does not cure the problem, we blame the doctor or the pharmacist. But have we used and safely used the medicine we bought? The side effects of any medicine can be just as frightening if it is not used properly instead of being stored properly. About the quality and use of the medicine given by the doctor, Dr. Manipal College of Medical Sciences, Pokhara. Sudesh Gyawali was asked some questions by online news.
Sunday, March 14, 2021
Some misconduct can be the cause of diabetes
Some misconduct can be the cause of diabetes
Diabetes is a disease that, if left unchecked, can lead to other diseases. For example, high blood pressure, heart disease, kidney disease, etc. But, there is nothing to be afraid of. Because with some precautions, all these dangers can be avoided. When someone first finds out they have diabetes, they are very worried. They keep asking themselves, 'Can diabetes be eradicated from the roots?'
Causes of diabetes:
Diabetes is one of the fastest-growing diseases in Nepal. Not only adults but also children suffer from this disease. Often people think that it is their faulty diet that causes them problems. The biggest cause of diabetes is some bad habits that are adopted in daily life. If these habits are improved, diabetes can be controlled to a great extent.
Staying in the office all-day
Most people stay in the office all day because they do not have time to get up. But this habit of yours can cause you heart problems along with diabetes.
Never sit in the sun
According to research, the biggest cause of diabetes is the lack of vitamin-D, which is found in the sun's rays. People with vitamin D deficiency have a higher risk of diabetes, so everyone should stay in the sun for at least half an hour without sunscreen.
Food wrapped in a plastic container
Researchers have also found that chemicals in plastic-wrapped foods increase insulin resistance. This is an early sign of diabetes.
Breakfast
Ignoring breakfast is also one of the biggest causes of diabetes. In fact, not eating breakfast in the morning disturbs the insulin balance in the body, which increases the chances of diabetes.
Intake of refined carbohydrates
White bread, white rice, flour, or other refined carbohydrates make the body produce more insulin. Because of this you soon start to feel hungry. This increases the risk of developing diabetes.
Intake of probiotics in the diet
Probiotics improve the digestive system but they also help regulate blood sugar levels. It causes you insomnia and stress. It raises blood sugar levels and puts you at risk for diabetes.
Drink at least 2/3 cup of coffee
Experts recommend drinking at least 2-3 cups of coffee a day. It can reduce the risk of type 2 diabetes. If you don't even drink coffee, you may have an increased risk of diabetes in some way.
Unhealthy habitual behavior
Wrong habits such as waking up late at night, sleeping less, not eating on time, smoking, and drinking alcohol also promote diabetes. In fact, it raises triglycerides in the body, which puts you at risk for type 2 diabetes.
Hanging on a lot of TVs
Even if you watch TV for at least 7 hours a day, you may have a higher risk of diabetes. A study has shown that every hour spent in front of the TV increases the risk of diabetes.
Drink less water
Drink at least 10 glasses of water a day. Because lack of water does not hydrate the body and increases the amount of sugar in the blood. This is also a must for diabetics.
Monday, February 15, 2021
What is Parkinson's disease?
What is Parkinson's disease?
Parkinson's disease is the spread or development of nerves or microscopic parts of the body. Which gradually affects your every move. Parkinson's is a problem that develops slowly in the human body. Sometimes only one hand vibrates to indicate this and sometimes the body itself begins to tremble. When Parkinson's becomes the main symptom of the disease, then the person may become unconscious due to abnormal tremors. In the early stages of Parkinson's disease, the gestures on your face tend to weaken.
Symptoms of Parkinson's disease
The symptoms and signs of this disease may vary from person to person. There may not be a complete signal at the beginning. The initial signs may be low and may not be easily detected. Symptoms often begin to appear on one side of your body and the condition worsens. After this, the whole body becomes affected by its symptoms.
The signs and symptoms of Parkinson's disease are as follows.
Vibration: Your hands and fingers begin to tremble while walking or sitting still. This will cause your fingers and index finger to start rubbing against each other. This is called a pill-rolling trimmer. Cutting off the body or hands is a symptom of Parkinson's disease. We can take the vibration of your hand when you are at rest as its main symptom.
Laziness at work: This disease reduces your ability to walk and work. Due to which even a simple task can be difficult and time-consuming. It can take a long time for you to walk.
Tight Muscles: There may be pain in any part of your body or muscles. Stiff muscles can be restricted to limit movement.
Loss of automatic activity: Parkinson's patients may have a reduced ability to function unconsciously. These include blinking, smiling, or moving your hands. You can't gesture for a long time while talking.
Voice changes: Parkinson's disease can result in speech problems. This can be a problem even if your voice is less intense or blurred.
Causes and risk factors for Parkinson's disease
In Parkinson's disease, some of the nerves or cells present in the brain gradually become damaged or destroyed. Neurons produce a chemical in our brain called dopamine. Decreased levels of dopamine are caused by abnormal brain activity. As a result, there are signs of Parkinson's disease. The cause of Parkinson's disease is unknown.
Your genes: Researchers have identified specific genetic mutations. Which can cause Parkinson's disease. But it is uncommon in rare cases involving family members with Parkinson's disease.
Environmental Reasons: Some toxins or environmental influences may increase the risk to end-stage Parkinson's patients. But overall, it reduces the risk of Parkinson's disease.
In short, more research is needed to identify the factors responsible for Parkinson's disease.
What are the risk factors for Parkinson's?
The risk factors for Parkinson's disease are as follows
Aging - Parkinson's disease is very rare in young people. It usually starts in the middle or late stages of life and the risk increases with age. Patients are more likely to be over 60 years of age or older.
Heredity - If a close relative has Parkinson's, you are more likely to have it. As long as no one in your family has this problem, you are less likely to have this problem.
Men are at higher risk - Men are more likely than women to develop Parkinson's disease.
Exposure to toxins - Frequent exposure to herbicides and pesticides can increase your risk of developing Parkinson's disease.
Ways to prevent Parkinson's disease
The cause of Parkinson's disease is unknown. Therefore, the method of its prevention is also a mystery. Some research has now shown that the caffeine found in coffee, tea, and Coca-Cola is a drug that reduces the risk of Parkinson's disease. Green tea also reduces the risk. Regular aerobic exercise also helps reduce the risk of this disease.
Tuesday, January 26, 2021
What is leukemia?
What is leukemia?
Leukemia is an early stage of a type of blood cancer. It can be easily treated. But, for that, the disease must have been known at an early stage. If not treated in time, it can be dangerous and even fatal.
How to know
How do you know if your child has leukemia? Because its symptoms are normal, which we do not take seriously. However, from the following things, it can be known that the child is afraid of this disease.
- Repeatedly having the same type of infection
- Very high fever
- Weakening of the child's immune system
-Feeling tired and weak all the time
- Having anemia
- There is a problem of bleeding from nails and gums
- Experiencing pain in the joints
-Swelling different parts of the body
-There are knots in different parts of the body
- Having problems with the liver
- Frequent headaches. Or migraine
- Paralysis means having a stroke
- To be confused about something again and again. That is to be mentally stressed
-Vomiting
-Increased skin itching problem
- Having a problem of not feeling hungry
- It takes a long time for any wound to heal
Leukemia spreads rapidly
Early symptoms of leukemia include the flu and other serious illnesses. However, when leukemia spreads rapidly, all the above-mentioned problems start appearing at once. If these problems are ignored, leukemia can spread to other parts of the body. This is why the body begins to swell abnormally. But if the symptoms of leukemia are identified and treated at the right time, there is no risk of blood cancer.
Leukemia is a dangerous disease
Leukemia cells directly affect the blood. Of course, the symptoms of leukemia can be easily detected now. If one ignores it, and leukemia is not treated in time, his life will be only four years at most. This age also depends on the immune system and the type of leukemia.
Risk of disease while benefiting
Risk of disease while benefiting
Now we are the beneficiaries. You have become more interested. You have become fashionable. This has led to many health problems.
Car and motorcycle riders are now suffering from back pain. Because the position they take in bike riding, car driving, is very wrong. Prolonged exposure to such a position is the root of the problem.
In the car, sitting on the bike is the right position. In particular, it is better to sit comfortably in the seat with the spine straight. That doesn't mean you shouldn't bow down. All bending and kneeling should be done in the correct position.
We also sit in the same chair, in the same position for a long time in the office. Sitting like this is affecting our spinal cord as well as the internal organs of the body. We do not change our position as there is no immediate reaction. But, in time, that position starts to cause us problems.
The practice of wearing high heels is widespread now. High heels have become a must in formal wear. This has also led to the problem of back pain. Many now work on laptops. Watching movies, photos, videos, using Facebook is done on the laptop. Sitting in the same position for an hour with a laptop in your lap hurts your back and neck.
This problem is also seen in young children. According to doctors, children are now being brought to the hospital with neck pain. This problem has been seen in children who play games and watch videos on mobile phones and tablets.
Sitting, we feel very normal. But, there is a right position to sit. Often when we sit down, we sit down, bend over, bend over.
However, the backbone should be kept very straight. Due to this, the functioning inside our body can be done better. The heart, kidneys, digestive system, lungs can all work easily. Muscles are not affected. Blood flow is good. Because of this, we don't have any problem.
However, most of us Nepalis, i.e. 90 percent, do not come to life. Whether in an office chair, whether in a car, whether on a bike. Can't sit properly.
People in the army and the army stand in a straight position. The reason for this was not known before. Especially standing and sitting in that kind of position is a health-friendly style.
Our sleeping position is also not good. There is a correct position on how to sleep while sleeping. Sleeping in such a position does not affect blood flow, respiration, digestive process. But, we don't know that way of sleeping.
When we work in the office, we sit in the same position for hours, which brings physical complications. It doesn't matter what position you are in. This mistake can lead to problems later. When a problem arises, it takes a long time to improve. The treatment takes time, money.
No matter where you sit and work, do not sit in the same position for hours. Change position at most one hour. Take a walk around. Feel relaxed. Work comfortably. Keep rehearsing it until you can say it with conviction and confidence. Drink enough water. After drinking water, he also gets up to urinate.
Do you exercise When asked, many respond, I work all day, why exercise? . The illusion is that exercise is not necessary after work or physical activity. That is exercise. This is a misconception.
While working, not all parts of our body exercise in a balanced way. On the one hand, there is more pressure. There is stress. So while working, the body does not get the exercise it needs.
Exercise is a systematic action that moves the limbs of the body properly.
The root of the problem of nerve entrapment, bone loss, neck ache, back pain is our bad lifestyle. Our bad habit is sleeping, working. So the natural solution is a lifestyle change. You go to the hospital with the disease, but if you do not change your lifestyle, the process of going to the hospital will continue. That never ends.
So you have to pay attention to how to sleep, how to live, how to work. Don't bend over, don't bend, don't bend. But, you have to know how to bend down, how to bend.
1. Always sit with your back straight.
2. When sitting in a chair, car seat, or anywhere, the back of the hip and knee should fit in the chair.
3. Don't stay in one place for long. Take a break from time to time. Moving the body
4. When riding a car, do not lean too much, but sit straight in the seat. Do not allow the spine to contract even when riding a bike.
5. The position of kneeling, lying on the left side, sleeping on the crotch is not correct.
6. Sitting on your feet can also be fatal to your health.
Not only the lifestyle of today's people but also the nature of the disease has changed. These diseases did not exist in the past. Or the disease that our forefathers did not get is plaguing us.
Friday, January 15, 2021
Does being happy increase the body's resistance to disease?
Does being happy increase the body's resistance to disease?
We get more satisfaction from anything only when our body is in good condition. When the body is not well, no matter how sweet the food is, no matter how good the place is. This means that the body must be healthy for us to enjoy life to the fullest.
How is the body healthy?
For this, we must have strong immunity. There are many rules to strengthen the immune system. One of them is a simple rule, happiness.
Being happy both externally and internally can keep you healthy for a long time. It is very important to be happy to live a good life. When our body's ability to fight disease is reduced, various diseases occur.
So it is very important to be happy to boost the immune system. Many things around us control our happiness and stress. According to which our body reacts. To stay healthy and happy, it is very important to stay emotionally healthy. Even if mental health is not good, it harms the body. So it is important to take care of what is happening in our lives.
1. Health effects of positive thinking
Positive thinking is very important in life. When negative things are around, you also start to be negative. So try to keep the surrounding environment positive. Which helps to keep the body healthy and happy.
2. Happiness boosts the immune system
When you are happy, your body gets energy. So it is very important to be happy to improve the immune system.
3. Laugh a lot
Laughing out loud reduces stress and boosts the body's immune system. Laughter improves blood circulation in the body. As a result, the production of stress hormones in the body is reduced.
4. Exercise
Most people do not like to exercise. But when we exercise, our body produces a hormone called endorphins. Which improves our mood. And stress and anxiety are reduced. Swimming, cycling, and skipping are good for boosting immunity.
5. Sleep
Sleep calms the mind. A good night's sleep relaxes the body and relieves stress by forgetting the fatigue of the day. So you need enough sleep to improve your immune system.
6. Dance
Regular dancing makes you physically healthy. Besides, our body's immune system is strong. Dancing makes our body feel happy and reduces calories in the body.
Thursday, October 1, 2020
Excessive food risk of serious disease, study says.
Excessive food risk of serious disease, study says.
Most people get sick because of their unhealthy eating habits. Not only can this cause stomach problems, but it can also be the cause of many other serious illnesses.
Recent research has shown that this is contrary to popular belief. Not only people who eat badly but also people who eat a lot of food are more likely to have problems including heart attack.
Various researches have described how unhealthy food increases heart insecurity. Eating too many increases the risk of heart attack for up to two hours after eating. So let's go into detail about what this research says.
What does the research say?
According to the US Centers for Disease Control and Prevention (CDC), 610,000 people die of heart attacks in the United States each year. When investigators wanted to know the reason, they discovered some strange habits. One of the main habits of these is to eat too much food. This research shows that heavy food is the trigger for heart attack. This is especially harmful to people who are overweight or obese.
Eating too much increases the risk of heart attack
Eating too much food also causes problems related to cholesterol and high blood pressure. Which is most related to heart health. In fact, high levels of cholesterol can clog your arteries and cause circulatory problems. This circulatory problem is linked to high blood pressure and increases the risk of a heart attack. There are many other causes as well, due to which heavy eating can increase the chances of a heart attack. In fact, it takes energy to eat and digest food, which raises blood pressure along with the need for oxygen. It pumps more blood to the heart.
Similarly, high blood pressure obstructs the blood vessels in the arterial wall. Which causes a heart attack or stroke. Similarly, a high-fat diet impairs the function of the endothelium, the lining of the arteries. Researchers have found that the risk of heart attack increases almost fourfold within two hours of eating a lot of heavy foods. This problem is especially common in people with pre-existing heart disease. For example, a person with coronary artery disease or a previous heart attack is more likely to have this problem.
Nepalis have a balanced ratio of carbohydrates, proteins, and other essential nutrients in their regular diet. But even eating such food can be a problem. Excessive consumption of fried foods with cream or butter can also easily lead to heart disease. So food should be eaten in a balanced way.
Saturday, September 26, 2020
Alzheimer's disease: a complication
Alzheimer's disease: a complication
The statistics are alarming, with an average of one person losing memory every three seconds in the world. Especially because of Alzheimer's. In the past, only the elderly had Alzheimer's disease. Today, even young people and adults are victims.
Stating that the growth rate of Alzheimer's disease has accelerated, it is estimated that the number of people suffering from this disease will increase by 70 million by 2030.
In Asia alone, 2.29 million people suffer from dementia, while in South Asia alone, 9.8 million people suffer from the disease, according to the World Alzheimer's Report.
What is Alzheimer's disease?
With Alzheimer's, a person's memory is impaired by drying out and gradually eroding brain cells. It is also called neurodegenerative disease as it is a brain-related problem. This disease causes constant damage to brain cells.
Why Alzheimer's?
Age also increases a person's risk of developing Alzheimer's disease. Similarly, 70 percent of Alzheimer's diseases are caused by heredity. Besides, high blood pressure, head injuries, obesity, etc. can also cause Alzheimer's disease, so in recent times, Alzheimer's disease has become a 'thread' for the world. Therefore, it is necessary to spread public awareness to raise public awareness about it.
These are the symptoms of Alzheimer's disease.
Symptoms
- Forgetting (forgetting recent and immediate work done within 48 hours)
- Decreased ability to think
- Changes in behavior
- Difficulty speaking and swallowing
- Increased depression
- And, as the problem progresses, people will stop recognizing the people around them.
Stages of Alzheimer's disease
Generally, Alzheimer's disease has three stages.
Early-stage- In the early stage, the patient's friends, family, and other people may feel this problem. However, people with this disease can easily drive and do other things. Even so, owning one is still beyond the reach of the average person. And, forgetting where you put the word you know or the object you use, having a problem with the name, forgetting what you read, being unable to make any plans.
Moderate-stage Alzheimer's disease can last for years if it is in the middle stage. As the disease progresses, the person may need more care. Because people with Alzheimer's often get confused about the word and start behaving strangely.
Besides, the person with the problem may forget their past, be moody, forget their home and office address, have difficulty choosing clothes for the weather and special occasions, have difficulty urinating and stopping, sleep during the day instead of at night, and be restless at night and change behavior. Begins to show.
Final Stage - In this stage the person becomes unable to react to the environment around them, communicate with the people around them, and control their activities. As a result, as their memory diminishes, so does the person.
And, they need to be taken care of all the time, constantly reminded of the environment around them, taught to eat, swallow, and talk.
How to avoid
There is no definitive way to prevent Alzheimer's disease. Scientists are still researching it. However, the risk of Alzheimer's can be reduced by controlling the risk of heart disease, cholesterol, obesity, and diabetes. Besides, regular exercise from a young age can reduce the risk of Alzheimer's.
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Tokophobia
Tokophobia: The Extreme Fear Of Pregnancy
If you resent the thought of ever having a baby so much that even being near a pregnant woman is unbearable for you, you could very well be suffering from Tokophobia. Let us explore this strange fear that is almost a taboo in our society, so that we understand it a little better.
Tokophobia is defined as a debilitating phobia of both pregnancy as well as childbirth. What makes it worse is that many women cannot talk openly about it because we live in a world where pregnancy is naturally expected to be the happiest phase of a woman’s life.
However, do not confuse Tokophobia with pregnancy related anxiety; every pregnant woman faces bouts of anxiety and some even experience mild depression, but Tokophobia is something a lot more serious.
Could You Have Tokophobia?
The most important thing to understand is that Tokophobia could be a serious disorder and can result in long term damages if not understood. What makes it even more dangerous is that it is not easy to diagnose; many women mistake Tokophobia for a ‘lack of interest in ever having a baby’ and make life-changing decisions without realizing they are dealing with a phobia.
While many women living with Tokophobia choose elective termination not because they ‘do not want the baby at this point of time’ but because ‘they are afraid to have a baby’, they are not open about the same with their doctors and sometimes even their partners.
Some Symptoms of Tokophobia:
• Feelings of dread when someone mentions childbirth
• Not wanting to have a baby until the doctor agrees to a C-section
• Intense anxiety and depression while pregnant because thoughts of childbirth give cause to panic
• Wanting to become a mother but not wanting to go through childbirth
• Termination of previous healthy pregnancies because the thought of going through the agony of normal childbirth was frightening
• Extreme fear that relies on the assumption that childbirth will cause death or serious damage
A Closer Look At Tokophobia
Tokophobia is a specific and harrowing condition that needs acknowledging Like all other phobias, Tokophobia also has many degrees and each case might be unique. However, for most patients, the common factor will be their fear of a natural childbirth. Some will be brave enough to not abort the fetus but then elect for a C-section and have it no other way, while others will refuse to get pregnant even though they are not opposed to being a parent and the responsibilities attached to it, and will even show an interest in adoption.
For most women with Tokophobia, postnatal depression is also common, especially if they have been forced by the family and doctors to go through a normal pregnancy.
In fact, those who fear childbirth so much that the thought of ever becoming pregnant is repulsive to them will use multiple methods of contraception at a time to ensure that they do not conceive.
This is often called as Secondary Tokophobia, wherein the fear is not just of childbirth, but of pregnancy itself. Such women find the very idea of pregnancy ‘disgusting and undignified’, and actually dislike being in the company of other pregnant women because even listening to their ‘pregnancy talk’ is unbearable.
Is Tokophobia Serious?
The answer depends on you and your choices. If you do want to become a mother and have a family someday, it could be a serious problem, considering you will need to find a gynecologist and obstetrician who can understand what you are going through and work with you to make your pregnancy and childbirth more bearable.
But if it has become a case for concern then seek therapy or counselling from an expert. Just all all phobias, Tokophobia can take over your life if not dealt effectively and swiftly.
14 Comments
1. rubygloommel
Hi, thanks for writing about tokophobia – it’s a horrible thing to have! However I think you’ve got a couple of terms mixed up. Primary tokophobia is when you’re afraid of childbirth before having a child, and secondary tokophobia is when you’re afraid as the result of a traumatic birth. Fear of pregnancy is a related but different phobia.
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1. ouidepuis1
Wow. I couldn’t imagine feeling like that. I am probably the opposite… You know, when kids stuff pillows under their shirt pretending to be pregnant kinda thing :p Does it effect you a lot in the day-to-day?
Like
2. putthatcheeseburgerdown
Hey,
Yes, it’s pretty difficult for me since I find it difficult to be around pregnant women and they seem to lot around, everywhere. The sight of the huge belly freaks me out and since I can’t really explain to the happy mom-to-be how I am feeling, I am usually termed as a ‘snob’. But trust me, the fear of pregnancy and pregnant woman is pretty nerve-wracking. But thankfully this is a legit condition and I am not the only one suffering from it.
Like
2. kc
Thank you for the information. I doubt I will ever get over my fear but it’s nice to know I’m not the only one this afraid of just the idea of being pregnant. However that last picture really bothered me. That is the image I get when I think of being pregnant, and I feel instantly sick.
Like
3. childlessandlovingit
Why is this termed as a condition? Just because a woman is capable to reproduce doesn’t mean she is meant to reproduce. There are so many women who make lousy mothers. Yet they go through the experience because society expects them to. There is absolutely nothing wrong with a woman who dislikes or is disgusted by pregnancy and childbirth – it is really not a pretty sight! Maybe there is nothing to overcome. A society that labels women as having a “clinical condition” because they lack the inclination to reproduce, that is something out of the dark ages. I hope we will someday evolve into a society, where women are not seen as baby machines.
Liked by 1 person
4. Childfree
I think it’s a very good thing that I don’t want to have kids ever because they freak me out like the pregnancy and birth stuff itself. I don’t think it’s serious enough to be a phobia in my case (for example, I don’t have panic attacks when I see a preggo) but I still feel a strong disgust over the entire topic. Thank god I have a choice! Oh, and that belly picture… It’s going to haunt me!
Like
5. Mona
Thanks for publishing this! I suffer from Tokophobia. In fact, it’s so bad that even seeing pictures of pregnancy or being around pregnant women can drive me to anxiety. In fact, today, I was at a cook out and a friend’s friend is heavily pregnant. It puts me in a awkward position, because they tried for a long time to have a child, so their joy is happiness times ten. But then there’s me who insists on not looking at her, and had to pretend to go to the bathroom, because she wanted to sit in the comfy chair next to me.
Last year, she even scolded me when I spoke openly about not wanting children. She said the same old things I heard before. “Not all of us can have children easily.” Maybe I shouldn’t have been annoyed. She was going through a tough time getting pregnant. But I kept wondering why just because I can have children, I should. I dislike the thought of pregnancy, never wanted to be a mother, and it’s best if I don’t.
I’ve been working with myself to not get so anxious being around someone who is pregnant. And it’s getting better and better each day. It’s mostly so it’s not debilitating to my social life and mental sanity. But I will probably remain child free for the rest of my life. That’s why I have the sweetest dog in the world. My personal preference over children.
Sorry for my rambling. It’s early in the morning and I’m going on two hours of sleep. 🙂
Like
6. anony
Hi,
thanks for sharing such a thing which I can relate to myself….I have all kinds of phobia related to pregnancy you have mentioned here or can exist anywhere else. I can relate some of the comments also to myself, even the sight of a pregnant woman haunts me…. I am afraid of the damages and pains which a woman’s body undergoes during and after pregnancy… I don’t understand how can somebody call a picture of a big tummy beautiful… I never find these pictures beautiful or divine…When somebody is pregnant, I never feel to say congrats, but I say that just to make the lady feel good. But seriously I never feel good when I see somebody pregnant. I immediately start to imagine the pain she will be going through and she will go through in the future… I feel really surprised when I see my friends pregnant, I feel “she also”. I don’t know why I feel that the child birth is such an unusual thing and believe many people would not go for it and they will feel the same way I do..
Like
7. Rahul Kumar
Hi, I like your blog. Very informative. I visited Mallige Hospital. This was one of the best hospitals in Bangalore, with very caring and courteous staff and doctors. That was my first time as a patient at Mallige Hospital which was in Crescent road. I felt very safe and comfortable and in capable hands. Nurses were very caring and helpful.
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Collagen
Vitamin A
By Ben Fuchs | Pharmacist Ben
While all nutrients play important and unique roles, in the world of nutrition one vitamin stands out like a diamond among ordinary gemstones. In a nutritional world of betas this stuff is truly vitamin version of an alpha male. In fact, it’s actually called Vitamin Alpha or more simply, as most people refer to it, as Vitamin A.
Actually there’s really no such thing as Vitamin A. Instead, the term is an umbrella designation for a family of compounds called retinoids that are found through the plant and animal kingdoms. These ubiquitous chemical structures exist in a variety of forms and perform multiple functions in a healthy biological system.The three most common forms of retinoids are called retinyl palmitate, retinol and retinoic acid.
Vitamin A Alpha
Perhaps the most important retinoid role involves the division of parent cells and the development of resultant offspring, so-called “daughter cells”. These processes, known as mitosis and differentiation are the most important of cellular events.Mitosis involves a cell splitting in two and forming a parent and an offspring. Via this process one cell, made up of the combined female egg cell and male sperm cell (it’s called a zygote from the Greek word for combined) turns into the 100 trillion cells or so of the human body. Obviously, the division is critical to formation of an animal body and this most fundamental of all biological phenomena is initiated and regulated by Vitamin A.
Differentiation is even more critical. Once a cell it divides it may need to shape up, so to speak. Daughter cells have to develop to become mature liver, muscle, bone, heart or “whatever”cells. They have to shape up and take on a certain form. Offspring lung cells have to mature to do the things that a parent lung cells can do and the same is true for heart cells or muscle or bone cells any other cells that divide. This maturation processes is what is called differentiation and it is a sophisticated affair that requires a tightly choreographed chemistry, and biological precision.And, much like the maturation of human being from baby to teenager to adult, the process is fraught with danger. Anytime a system is growing and maturing and developing it reaches critical points where its survival is threatened. These tumultuous juncture points can be a matter of life or death for any system including a cell. Fortunately nature has provided support to sustain the cell in its stressful differentiation periods…it’s called nutrition! In fact one of the most important roles for nutrients is to assure healthy differentiation and of the entire support nutrient the most important bar none, the most powerful maturation nutrient is none other than the biochemical family known as Vitamin A.
Under conditions of vitamin A deficiency cell division is accelerated and cell differentiation is suppressed. The net result is the production of lots of un-differentiated.,immature cells. This can show up as various health issues ranging from to asthma to cancer to birth defects to skin conditions like psoriasis and acne all of which involve the appearance of large numbers of rapidly dividing immature cells that can muck up ordinarily organized chemistry. In all these conditions relatively high doses of Vitamin A (we’ll get to those in a moment) can provide effective therapeutic treatment.
Vitamin A plays another important role in the biochemical play of life. It turns on the production of meat. Not the kind of meat you get at McDonalds, but rather the kind of meat of that makes up the mass of the body. Technically the meat is called collagen and connective tissue and muscle protein and it gets pumped out cells called fibroblasts when commanded to do so by the alpha vitamin, Vitamin A. Breakdowns in connective tissue are behind degenerative disease and that means Vitamin A can be used to help prevent diverse and distinct disorders including osteoporosis, heart disease, aneurysms and circulatory issues. It can accelerate the healing of tissue after surgery or burns or wounds or other physical trauma. It can reduce the development of fine lines and wrinkle saggy skin and plain old regular aging. And, it’s not just sick or old folks that benefit from the body building benefits Vitamin A. Kids need it too. The most important sign of Vitamin A deficiency in children which 100 million kids worldwide is suboptimal growth and development. Without enough Vitamin A children will stop growing and eventually die. [Vitamin A Part 2]
Posted by Ben Fuchs in Nutrition
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Time-Restricted Eating and Menopause
Time-Restricted Eating and Menopause
Time-restricted eating (TRE) is a form of intermittent fasting that is gaining popularity, but is this just another fad? Research on the benefits of intermittent fasting has been inconclusive, but a recently published randomized controlled trial in JAMA Internal Medicine (August 2022) offers new information to consider when it comes to eating habits during menopause.
Intermittent fasting focuses on when to eat, unlike diets that focus on what to eat. Most TRE programs focus on eating within a 10-hour window or less followed by fasting for 14 or more hours but don’t indicate an optimal time for this window. This recent study showed when adults with obesity started their eating window earlier in the day, for example, 7 AM to 3 PM, they were able to lose more weight than if they started eating later in the day. The earlier time frame correlates with the body’s natural circadian rhythm for optimal food metabolism. The body’s best glycemic (blood sugar) control occurs during mid to late morning, so we may be better able to burn calories during this time.
“Eat like a queen at breakfast, a princess at lunch, and a pauper at dinner” might be an easy way to think about this. Front-loading the day’s food intake at breakfast and lunch reduces caloric intake by around 200 calories daily and improves blood sugar control and levels of sex steroids which influence mood.
Most people in the U.S. consume food in a window of time greater than 12 hours. This new JAMA study demonstrated that shortening the eating window to less than 12 hours resulted in greater weight loss without negative effects on muscle mass.
Mealtime is often an enjoyable, social time, and still can be with TRE! It just requires planning ahead. In addition to considering when to eat your meals, focus on eating fresh over processed foods as much as possible to cut unhealthy calories and further boost the benefits of TRE. Manage portion sizes and slow down when chewing your food. Chew 20-25 times per mouthful to allow more time for digestion and you’ll feel full sooner. If you want to lose weight, set realistic goals. TRE is a safe, low-risk option for most women who don’t have medical conditions that require special diets or timing of food to correspond with their medications. If you are wondering if TRE is right for you, check with your healthcare provider.
Narrowing your eating window to less than 10-12 hours daily for six days followed by one day off and consuming most of your calories earlier in the day, maximizes the benefits of TRE for weight loss. Combined with eating less processed foods and choosing more healthy options, TRE can be a simple method to jumpstart changes toward a healthier lifestyle during and after menopause to lose and/or maintain your weight.
Tags
health education, healthy lifestyle, lifestyle, weight, weight management
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A supplement I see many women choosing to take is CoQ10 (otherwise known as Ubiquinol), but does it help improve fertility and is it safe to take?
As a fertility nurse consultant, I see a lot of patients who want to try everything possible to boost their fertility. Taking the right supplements is one of the aspects I discuss with my patients. It is recommended that women who are trying to conceive take folic acid and vitamin D, however depending on previous medical history there may be other supplements that would be beneficial.
CoQ10 has been promoted as a treatment for heart disease, migraines, cancer and muscle soreness as well as infertility. CoQ10 is naturally present in the membrane of almost every cell in the body and is required for mitochondrial ATP synthesis, which is responsible for creating cellular energy, therefore CoQ10 has been called the ‘power supply’ of cells.
Research has suggested that the eggs of older women or young women with diminished ovarian reserve may not produce enough CoQ10, resulting in poor egg quality. Inadequate mitochondria have been associated with premature menopause, infertility and miscarriage.
CoQ10 supplementation became popular following animal studies in mice that identified better performance and longevity with supplementation. A more recent human study conducted in 2018 identified improvements in ovarian response to stimulation in young women with poor ovarian reserve undergoing IVF-ICSI cycles. The pregnancy rate was higher in women who used CoQ10 than in the control group, but the difference was not statistically significant. This study was conducted with a small sample size and have been criticised as poor quality, therefore further research is required to fully determine any benefits.
Another concern with regards to CoQ10, is that it is unclear what is a safe dose to take and we are unsure of what possible side effects of taking too much CoQ10.
So by way of a summary, CoQ10 supplementation does look encouraging in improving egg quality but more research is needed before I would recommend it as a supplement for women with poor ovarian reserve or for women with unexplained infertility.
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Ulnocapitate ligament
Last revised by Joachim Feger on 10 Dec 2021
The ulnocapitate ligament is the most superficial of the three extrinsic palmar ulnocarpal ligaments and a volar stabilizer of the ulnocarpal complex 1-3.
The ulnocapitate ligament is the only ulnocarpal ligament directly attaching to the ulnar head. It runs superficial to the ulnolunate and ulnotriquetral ligament reinforcing the palmar component of the lunotriquetral interosseous ligament. It connects the ulnar fovea to the capitate and interdigitates distally with fibers of the radioscaphocapitate ligament and fibers of the scaphotriquetral ligament, forming the palmar greater arc or arcuate ligament 1-3.
The ulnocapitate ligament originates directly at the fovea of the ulnar head near the attachments of the volar and dorsal radioulnar ligaments 1-3.
Distally ulnocapitate ligament inserts onto the body of the capitate 1-5.
The ulnocapitate ligament can be visualized on ultrasound with the transducer placed at the volar ulnar aspect of the wrist in the longitudinal plane slightly rotated radially towards the capitate bone. The long axis of the ligament is displayed as an echogenic, fibrillary structure coursing over the lunotriquetral joint and connecting the distal ulna to the capitate 2,3.
The ulnocapitate ligament is difficult to appreciate on MRI even with proper anatomic knowledge ref.
The ligament is most likely injured or involved in the following pathologic conditions 6:
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Cases and figures
• Figure 1: volar wrist ligaments (Gray's illustrations)
Drag here to reorder.
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Vertigo En Espanol
Vertigo Treatment
Your doctor will ask questions about your symptoms, as well as the times they occur. This helps identify the cause of the symptoms. They’ll also do a physical examination, including tests to assess your hearing and balance.
Problems with the inner ear can cause peripheral vertigo. It can be caused by head movements and typically lasts only a few minutes.
Particles that move in a repositioning motion
The Epley maneuver is a series of head movements that relieve BPPV symptoms. The movements assist in moving the calcium carbonate out of the utricle into your semicircular canals where they belong. The crystals that have escaped may disintegrate or be absorbed by your body.
You can practice the Epley maneuver at home, although it is recommended that a doctor or audiologist show you how. Incorrect technique can increase your dizziness.
CRP is another treatment for BPPV. It involves the removal of the particles that cause your vertigo out of the semicircular canals filled with fluid of your inner ear to a region of your ear that doesn’t cause dizziness. After a few treatments the procedure is typically successful. It’s also possible to have a surgical procedure that requires the placement of a bone plug inside your ear’s ear canal. This procedure is only available when other treatments fail.
Home balance exercises
A variety of exercises at home for balance can help to improve vertigo symptoms, including instability or dizziness. These could include walking in the same place or focusing on eye movements, among other movements. Your healthcare professional will customize the exercises to meet your needs. You may also be given medication to treat motion sickness or nausea.
You can perform the Epley maneuver to assist in repositioning calcium crystals within the semicircular canals in case your vertigo is caused by BPPV. This can help reduce or eliminate vertigo attacks. The technique involves reclining on the bed and turning your head 90 degrees to one side (for instance to the left). After 30 seconds you should stand up on the other side of the table.
Vertigo can be caused by a variety of ailments, including heart disease and diabetes. In these instances treatment of the underlying issue usually cures vertigo. Other causes could be treated with a treatment that targets the symptom, such as medication for anxiety or nausea.
Physical Therapy
Most often, you can eliminate dizziness caused by benign vertigo by making a few simple movements. These involve rapid repositioning of your head. This technique is known as canalith repositioning, also known as Epley maneuvers. You are able to learn how to do it yourself, or have your doctor demonstrate it to you. The maneuvers are designed to move otoconial agglomerates out of the semicircular space and into the utricular area which is where they will no longer cause vertigo due to positioning.
Other treatments may be necessary dependent on the underlying issue that is causing your symptoms. For instance, if suffer from an ear condition that causes BPPV, your doctor might prescribe a medication to relieve your symptoms. They might also recommend physical therapy or counseling.
If you are suffering from vertigo, it is important to take the necessary precautions. For instance, you should remove any hazards that could cause tripping around your home. You should lay or sit down when you feel symptoms appear and avoid reading or work until they disappear.
Surgery
The most common cause of vertigo is benign paroxysmal vertigo (BPPV). This occurs when tiny calcium particles (canaliths) get dislodged from the utricle of the ear’s inner part and move into one of the semicircular canals which is where they shouldn’t be. Dizziness can be caused by the movement of your head, or the change in your body position. Canalith repositioning maneuvers, like the Epley maneuver, aid in shifting crystals back into utricle. These are specific head moves that your healthcare professional can perform in their office or teach you how to do at home.
Your doctor might also suggest tests to determine the root cause of your vertigo. These may include electronystagmography (ENG) or videonystagmography (VNG), which measure involuntary eye movements while you move your head and try to maintain a steady gaze. The head’s structure and ears can be assessed by using magnetic resonance imaging (MRI). The prescription of medication can be used to reduce nausea and vomiting.
Vertigo En Español
Vertigo Treatment
Your doctor will ask questions regarding your symptoms, as well as when they occur. This helps identify the cause of the symptoms. Your doctor will also perform a physical exam, including tests for your hearing and balance.
Problems with the inner ear can lead to vertigo that is peripheral. It can be caused by head movements, and generally lasts just several minutes.
Particles repositioning movements
The Epley maneuver is a series head movements that can relieve BPPV symptoms. The movements help move calcium carbonate out of the Utricle into your semicircular channels and into the semicircular channels, where they belong. The crystals that have escaped may disintegrate or be absorbed by your body.
You can practice the Epley maneuver at home, however, it is recommended that a doctor or audiologist show you how to do it. A wrong technique could make your dizziness worse.
Another treatment option for BPPV is a procedure called canalith repositioning processes (CRP). The particles that cause vertigo are shifted from the semicircular canals that are filled with fluid inside your the ear to a location that doesn’t trigger dizziness. After a few sessions it is generally effective. It is also possible to have surgery where a bone plug is put in your inner ear. This procedure is only utilized when other treatments are unsuccessful.
Home balance exercises
Balance exercises that are varied at home can aid in improving vertigo symptoms, such as dizziness and instability. These exercises could include eye movement control, marching in place and other maneuvers. Your doctor will tailor the exercises to suit your particular requirements. Medicines can also be prescribed to treat motion sickness.
You can use the Epley maneuver to help reposition calcium crystals within the semicircular canals if your vertigo is caused by BPPV. This can help reduce or eliminate vertigo attacks. The method involves lying on your back and bending your head 90° to one side, such as to the left. After 30 seconds, stand up on the other side of the table.
Vertigo can be caused by a variety of ailments, including heart disease and diabetes. In these cases the treatment of the underlying condition typically cures vertigo. For other reasons, treatment to treat the symptoms may be helpful by using medication to calm nausea or anxiety.
Physical therapy
If your dizziness is caused by benign paroxysmal vertigo caused by position (BPPV) it is possible to generally eliminate it with just a few maneuvers. They involve rapid head shifting. This technique is referred as Epley maneuvers or canalith repositioning. You can either learn how to perform it yourself or have a medical professional show you. The procedure moves the otoconial aggregate from the semicircular canal into the utricular space, from where it no longer can cause vertigo due to positioning.
Other treatments may be needed in the case of an underlying issue that’s causing your symptoms. If you have a problem in your ear which causes BPPV your doctor might prescribe medication to help relieve the symptoms. They might also suggest counseling or physical therapy.
If you suffer from vertigo it is important to take the appropriate precautions. For instance, you should remove any hazards that could cause tripping around your home. When symptoms start to appear, you should lie down or sit down and not read or work until the symptoms are gone.
Surgery
BPPV is the most frequent cause of vertigo. It is caused by small calcium particles (canaliths) which are normally found in the utricle of the inner ear, get dislodged and end up in the semicircular cannulae. The movement of your head or changes in your body’s position could trigger the dizziness. Canalith techniques for repositioning, like the Epley maneuver, can help you shift crystals back into your Utricle. These are specific head movements which your healthcare provider may perform in their office, or show you how to do them at home.
Your doctor may recommend other tests to identify the cause of vertigo. These may include electronystagmography (ENG) or videonystagmography (VNG), which measure involuntary eye movements while you move your head and try to maintain a steady gaze. Magnetic resonance imaging (MRI) is a method to determine the structure of your ears and head. You could be prescribed medication to help reduce nausea and vomit.
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Kamus Online
suggested words
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Online Dictionary: translate word or phrase from Indonesian to English or vice versa, and also from english to english on-line.
Hasil cari dari kata atau frase: Glandes (0.01161 detik)
Found 2 items, similar to Glandes.
English → English (WordNet) Definition: glandes glans n : a small rounded gland-like structure; especially that at the end of the penis or clitoris [also: glandes (pl)] glandes See glans
English → English (gcide) Definition: Glandes Glans \Glans\n.; pl. Glandes. [L. See Gland.] [1913 Webster] 1. (Anat.) The vascular body which forms the apex of the penis, and the extremity of the clitoris. [1913 Webster] 2. (Bot.) The acorn or mast of the oak and similar fruits. --Gray. [1913 Webster] 3. (Med.) (a) Goiter. (b) A pessary. [Obs.] [1913 Webster]
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Repairing effects of interleukin 11 (IL-11) towards high dose methotrexate-induced rat small intestinal mucositis and its impacts on T-lymphoblastic leukemia cell line
Document Type : Original Article
Authors
1 Department of Pediatrics, Liaocheng People's Hospital, Liaocheng 252000, Shandong, China
2 Departments of Pharmacy, the Fourth People's Hospital of Liaocheng, Liaocheng 252000, Shandong, China
3 Department of Pediatrics, Shandong Province-owned Hospital, Jinan 250021, Shandong, China
Abstract
Objective(s): To investigate the efficacy of interleukin 11 (IL-11) towards the high dose methotrexate (HDMTX)-concurrent rat small intestinal mucositis and its impacts on the proliferation of the human T-lymphoblastic leukemia (CEM) cell line.
Materials and Methods:95 Wistar rats were randomly divided into five groups, the normal control group (A), the methotrexate (MTX) control group (B), the IL-11-pre-treated high-dose group (C), the post-IL-11-treatment high-dose group (D) and the post-IL-11-treatment low-dose group (E). After the intraperitoneal injection of MTX in the groups B-E, the rats were sacrificed at 1, 3, 5 and 7 days. The mortality, morphological and ultrastructural changes of small intestine of each group were observed. The cells were then cultured in vitro, and the MTT method was used to investigate the effects of different concentration of IL-11 on CEM proliferation and also on HDMTX-induced mucositis.
Results: IL-11 could reduce the intestinal histopathological score, increase the height of small intestinal villi, promote the proliferation of intestinal lacunar cells and reduce the mortality rate of rats. The IL-11 pre-treatment group exhibited the best efficacies, demonstrating significant difference with the control group (P<0.01). In addition, the proliferation of CEM was not promoted, indicating that IL-11 could not inhibit HDMTX.
Conclusion: IL-11 could reduce the severity of HDMTX-induced intestinal mucositis, and improve the survival rate of experimental rats, and could be safely used as the adjuvant treatment of HDMTX in childhood leukemia.
Keywords
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1a01aa77535b9ecfb87b9fc36adbcd2f
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Abstract
Ankylosing Spondylitis and Systemic Lupus Erythematosus: A Rare Coexistence
Author(s): Xaria Cobin
Ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) are distinct autoimmune diseases, each with its own set of clinical and immunological characteristics. The coexistence of these two conditions within the same individual is exceedingly rare and presents unique challenges in diagnosis, management, and understanding the underlying pathogenic mechanisms. This case report explores the clinical presentation, diagnostic considerations, and treatment strategies for a patient with concurrent AS and SLE. We discuss the potential immunological and genetic factors contributing to this uncommon comorbidity and emphasize the importance of multidisciplinary care in optimizing the patient's quality of life. This case sheds light on the complex interplay between different autoimmune disorders and underscores the need for further research to elucidate the mechanisms underlying their coexistence.
PDF
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-6,991,124,863,452,863,000
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Dental Implants Q&A with our Oakland Dentist
Oakland dentist dental implantsWe spend a great deal of time talking about how incredible dental implants are on this blog. But nothing can impress you until you understand exactly what dental implants are. This week’s blog post from our Oakland dentist introduces new patients to dental implants and their role in restorative dentistry. If you’re missing a tooth and considering ways you can replace it, read on to gain an understanding of these stabilizing root replacements.
Oakland Dentist Answers Common Questions about Dental Implants
1. What do dental implants do? Dental implants replace missing tooth roots by creating new tooth structure below the gum line. This tooth root then supports accompanying dental restorations to create an entire new tooth (both root and crown).
2. What are dental implants made of? Dental implants are made of titanium, a material that fuses with the jaw bone over time. This allows the dental implant to become fully stable and feel like a natural part of your mouth.
3. What is the dental implant procedure like? Your implant surgery will be performed in our office; you needn’t visit an oral surgeon. During your dental implant surgery, you will be sedated and receive local anesthesia to numb the site. Our Oakland dentist will make a small incision in your gums and place the implant so that it touches your jaw bone. We will then suture the area. You will need a period of time to heal before we bond an accompanying restoration.
4. How long do dental implants last? With proper care and bone density to support them, dental implants can last a lifetime. Once they successfully fuse with your jaw bone, they are a part of your mouth.
5. What restorations can be paired with dental implants? Most restorations work with dental implants! Crowns, bridges, and dentures can all be bonded to an abutment over a dental implant. The restorations will look and feel natural, thanks to their stability.
If you have any other questions about dental implants, please get in touch with us! They can make a remarkable difference in your life.
Author Bio
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-385,971,000,065,427,700
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1921
Volume 47, Issue 3
• ISSN: 0002-9637
• E-ISSN: 1476-1645
USD
Abstract
Abstract
Breath hydrogen tests were performed after a rice meal (3 g of cooked rice/kg of body weight, equivalent to 1 g of carbohydrate/kg of body weight) on 256 village children (age range 1–59 months) who were known hydrogen (H) producers. Anthropometric measurements were made every three months and growth rates were calculated. A breath H excretion pattern that suggested small bowel bacterial overgrowth (SBBO), which was recognized as a transient maximum level of 10 ppm or more at 20-, 40-, or 60-min breath samples following the rice meal, was present in 53 (20.7%) children, and was more frequent in children 36–47 and 48–59 months old. This breath H excretion pattern was detected in 48 (33.3%) of 144 children who were rice malabsorbers (> 10 ppm H above baseline values in one of the breath samples taken between 90 and 240 min), and in only five (4.5%) of 112 rice absorbers. Children who had SBBO had a high relative risk (10.7) of being rice malabsorbers. Rice malabsorbers have a high relative risk (59.7) of having faltered growth, accompanied by a large etiologic fraction (94%). This same risk (6.68) and an etiologic fraction of 62% exist in children with untreated SBBO. These findings emphasize the need for interventions aimed at reducing the prevalence of SBBO or similar conditions as detected by the breath H excretion pattern to prevent rice malabsorption and growth faltering.
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2018-11-13
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TY - JOUR A1 - Sebat, Christian A1 - Albertson, Timothy A1 - Morrissey, Brian T1 - Cerebral gas embolism in a case of Influenza A-associated acute respiratory distress syndrome treated with high-frequency oscillatory ventilation Y1 - 2013/4/1 JF - Annals of Thoracic Medicine JO - Ann Thorac Med SP - 124 EP - 126 VL - 8 IS - 2 UR - https://www.thoracicmedicine.org/article.asp?issn=1817-1737;year=2013;volume=8;issue=2;spage=124;epage=126;aulast=Sebat DO - 10.4103/1817-1737.109839 N2 - A 22-year-old obese asthmatic woman with Influenza A (H1N1)-associated acute respiratory distress syndrome died from cerebral artery gas emboli with massive cerebral infarction while being treated with High-Frequency Oscillatory Ventilation in the absence of a right to left intracardiac shunt. We review and briefly discuss other causes of systemic gas emboli (SGE). We review proposed mechanisms of SGE, their relation to our case, and how improved understanding of the risk factors may help prevent SGE in positive pressure ventilated patients. ER -
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They are primarily all of the particular behavioral characteristics demonstrated by particular people while I discover the numerous problems within to become extremely subjective. It is my proposal that centered on era of times of emotional support, the character of ecological elements, and the emotional support may have a job in what response happens, and that behind disturbing encounter lies and what actions are shown. Upheaval seems to be the primary causation of nearly all what are called ‘problems’ in teenagers and children present in his research, youth stress and hallucinations in bipolar affective disorder that there is a very important organization of these experiencing hallucinations and also the actions which are described bipolar disorder and people experiencing natural emotional support, especially youth sexual abuse.
Natural emotional support
Mckenzie 1998 mentioned that the symptom determining stress just before 1 5 years can lead to the improvement of psychotic characteristics once a-precipitating stress happened later in existence. Mckenzie 1998 additionally suggested that upheaval between 18 and two years might result in what could be phrase as ‘schizoaffective’ faculties, which upheaval between 24 and 34 weeks might reveal later as ‘major depression.’ I suggest that upheaval within during later youth roughly age 6-10 can result in the improvement of actions in kids that might be called conduct disorder. Wayne 1989 says that upheaval disturbs one’s capability to have sympathy and violates fundamental confidence. Throughout the era between 6-10 can also be the time in which a kid starts to build up a feeling of justice, there is between what a delineation ‘right’ and ‘incorrect’. Then your result will be the symptom later of severe conduct if your stress must happen during this time period of development. Chemtob, novaco, hamada, gross, & smith 1997 record that upheaval canlead toan person acting-out by violent means.
If your kid encounters neglect and substantial misuse inside life’s first-year can form what is referred to as’ attachment disorder’. The kid has trouble forging relational ties that are suitable. They are naturally distrustful. Highes 2003 is promoting dyadic developing psychotherapy which centers on building the caregiveris relationship in addition to pushing the usage of speed playfulness, approval, curiousity, sympathy in addition to the development of some intellectual methods. The kid who would fall under the categorization of attachment’ should be classified from individuals with developmental disorder that is persistent whereas trouble may be manifested by individuals with developing problems in relational ties, a varying causation is there.
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What is the significance of professional Therapeutic Communication in Mental Health Nursing and how this tool significantly affects mental health consumers?
style=”text-align: justify;”>What is the significance of professional Therapeutic Communication in Mental Health Nursing and how this tool significantly affects mental health consumers?
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What is the significance of professional Therapeutic Communication in Mental Health Nursing and how this tool significantly affects mental health consumers?
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Assessment Is Required to:
Extensively discusses the background of the question providing insightful analyses of the rationale and identifying alternative questions.
Provides extensive and detailed synopsis of the literature. Thoroughly critiques articles considering strengths and weakness of evidence provided. Clarifies evidence in support of alternative views. All literature is peer reviewed or primary resources from credible contemporary sources.
Thoroughly analyses clinical practice in relation to the question. Discriminates rationally using reasonable judgment when evaluating and critiquing clinical practice against contemporary literature. Provides extensive consideration for changes to practice based on findings.
This is an introduction I wrote for the writer to gain a sense of the direction of the essay.
“The effective development of therapeutic relationships with clients in a Mental Health setting at extremely significant for the provision of care as they allow for the exploration of feelings and allows for patients to explore fundamental information about themselves and their illnesses (Morrissey & Callaghan, 2011).
Banar (2011) and Daniels (2004) discuss the significant idea that the value of a therapeutic relationship between a nurse and client is dependent on the nurse’s capacity to develop report effectively through communicating not only verbally through words but also nonverbally through actions. Daniells (2004) goes on to discuss that most people are born with the ability and urge to express themselves and therefore, in instances concerning the relationship between a mental health consumer and the registered nurse, a nurse ought to establish qualitative therapeutic relationship with their client which will be influenced by worth full communication skills (Desmond & Copeland 2000., & Daniels 2004).
As a student nurse studying to become Registered Mental Health Nurse, I found during my clinical placements for mental health; therapeutic communication and the development of interpersonal relationships have been fundamental to my learning and pave the way for the development of my skills in mental health. However, during my placement I have found that some mental health nurses obtain this skill more so than others and this matter ultimately has the potential to significantly impose a nurses potential to better care for their patients. Ultimately I have found that therapeutic communication in mental health nursing is a crucial intervention tool as it paves the path for my patients to gain confidence to play an active role in their own care and recovery. Thus the basis of my question for this assessment.”
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-7,385,318,730,506,659,000
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Consult Best Eye Doctor Near You!
Vision is one of the most neglected areas in maintaining good health. Eye care specialists recommend that every person has an eye exam annually to assess their eyes' health and determine their vision quality.
Most people ignore this important piece of advice. They put off their annual exams until they need to see an eye doctor. The reason behind a visit to an eye doctor can vary depending on which type of licensed ocular healthcare professional the patient is seeking.
Optometrists (OD) are the most popular type of eye doctors. You can avail various optometric services from Optometrists (OD) . They will examine your vision and determine if you need glasses or contacts that can be worn all day, or if you need glasses for special situations like reading at night or driving at night.
SOURCE:GOOGLE
Optometrists are qualified and trained to evaluate the eye's overall health and make recommendations on how to improve it. They may be able to spot common diseases like glaucoma and offer specific treatment recommendations.
Depending on the severity of the problem, they may refer the patient to an optometrist for further examination and/or treatment. They are able to both perform surgeries and prescribe medicine. Four years of medical school are required for ophthalmologists. They also need to complete an internship and at least three years in a residency program.
Lasik Eye Surgery is one of the most popular and well-known surgeries many Ophthalmologists do today. The eye doctor uses a laser with a sharp blade to shape the eye and correct vision. This allows the patient to no longer wear glasses or contacts.
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What do I do about blood blister on 4 month old breast lift scar? (Photos)
I had a breast lift with 200 cc saline implants 4 months ago. Everything has been healing nicely, except I now have a blood blister that popped open to reveal a small hole on incision line. I was told by the Dr's nurse to wash with soap and water and not bandage it. I already had another spot open up and I followed the same procedure, but now I have an ugly scar there. What are some other possible ways to deal with it? I do not want it to open up further.
Doctor Answers 3
Blood Blister on Left Scar
Depending on your procedure, those with incisions around the nipples, there is the potential to affect your areolae during the healing process. Most commonly, we prefer the lollipop or donut lift because of the shape, small scars and easier healing. The nipple-areola complex is repositioned higher, the excess skin is removed, and the breast is reshaped in a pleasing contour and in a more normal position.
Over time, gravity will continue to have an effect and the breast skin will tend to stretch. The degree of #stretching and #sagging varies between women: generally, women with smaller breasts experience less recurring sagging. If sagging does occur, further excision of the skin on an outpatient basis can be used to correct the problem. Heavy and large breasts may lead to recurrent sagging and may require the removal of a small amount of breast tissue to achieve an optimal shape and size. One key to a satisfying result is realistic expectations.
All surgical procedures carry some degree of risk. Any breast operation can result in changes in sensation. This happens less with lifts than reductions but is still possible. Occasionally, minor complications occur and do not affect the surgical outcome. Major complications associated with this procedure are rare. The suitability of the breast lift procedure and specific risks may be determined during your consultation.
#Hypertrophic or #keloid scars can be a problem. The worst are usually under the breast with an #AnchorLift or inverted “T”. These can be treated like all thickened scars with re-excision, laser, kenalog/5-FU injections, creams, silicone strips and other methods to reduce and improve healing.
If you are worried that your incisions or scars are not healing well, then it is a good idea to visit your surgeon for an examination of the area to determine how well the healing process is going.
Orange County Plastic Surgeon
5.0 out of 5 stars 94 reviews
Wound Healing Issues
Great question and thank you for providing photos. From your photos it appears to be a spitting suture (suture coming through the skin). You should see your plastic surgeon for them to remove it and then follow their care instructions. If for some reason an area does not heal well you can have area(s) revised, if needed.
What do I do about blood blister on 4 month old breast lift scar?
This problem arises due to the dissolving sutures in the incision line. Frequently, this is seen around 3 to 4 months after the surgery. The good news is that the area will heal and likely no additional treatment will be needed. It is best to follow up with your surgeon and get advice there.
You might also like...
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.
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Acupressure Points
These are acupressure points for emotional well-being. Their location, photograph, use and warnings are listed.
GB-44
Name: Yin Portals of the Foot (Gall Bladder 44)
Location: On the fourth toe, in the outer corner of the nail (so near the smallest toe).
Use: Press.
Effects: Enhances decisiveness and focus, while resolving anger. For timidity.
location of GB-44 location of GB-44
KI-3
Name: Supreme Stream (Kidney 3)
Location: On the inside of the foot, halfway between the Achilles-tendon and the side of the ankle-bone.
Use: Press.
Effects: Heals effects on the body of too much fear. (Also for lower backpain.)
location of KI-3
KI-4
Name: Great Bell (Kidney 4)
Location: On the inside of the foot, near the Achilles-tendon, level with the lower part of the ankle-bone.
Use: Press.
Warning: Using this point to go against your heart or beyond your limits will damage your health even further. This will be the case when there are dark circles around your eyes.
Effects: Strengthens the will and dispels fear. For timidity.
location of KI-4
KI-6
Name: Shining Sea (Kidney 6)
Location: On the inside of the foot, directly below the middle of the ankle bone.
Use: Press.
Effects: Heals effects on the body of too much fear. Enhances vision.
location of KI-6
LI-11
Name: Crooked Pond (Large Intestine 11)
Location: On the side of the elbow, on the outer side of the arm. Bend your forearm with your hand towards your neck, the point is located at the end of the crease at the elbow. This is halfway up the side of the arm.
Use: Reduce, so move your finger in counterclockwise direction over this point.
Warning: Use this point only when there is Heat, as when you're red in the face or your skin feels hot to the touch and you're feeling warm from prolonged anger (not from exertion). Don't use when weak or low on energy.
Effects: Heals effects on the body of too much anger.
location of LI-11, click for animation
move counterclockwise
(click for animation)
LI-4
Name: Joining of the Valleys (Large Intestine 4)
Location: On the top side of the hand, on the web between thumb and index finger. To locate, squeeze the thumb against the base of the index finger. The point is located on the highest point of the bulge of the muscle, level with the end of the crease.
Use: Press.
Warning: Don't use this point during pregnancy.
Effects: Letting go of grief. Calms.
location of LI-4 location of LI-4
LIV-1
Name: Great Esteem (Liver 1)
Location: On the big toe, at the bottom corner of the nail at the side of the other toes.
Use: Press.
Effects: Assertiveness, discerning when to go along with others and when to assert oneself. Self-esteem.
location of LIV-1
LIV-2
Name: Moving Between (Liver 2)
Location: On the foot, between the big toe and the second toe, a half thumb width from the margin of the web.
Use: Reduce, so move your finger in counterclockwise direction over this point.
Warning: Use this point only when there is Heat, as when you're red in the face or your skin feels hot to the touch and you're feeling warm from prolonged anger (not from exertion). Don't use when weak or low on energy.
Effects: Heals effects on the body of too much anger.
location of LIV-2, click for animation
move counterclockwise
(click for animation)
LIV-3
Name: Great Rushing (Liver 3)
Location: On the foot, on the line between the big toe and the second toe. It is about 3 finger widths from the edge, in the pronounced depression the size of a finger tip you can feel there.
Use: Reduce, so move your finger in counterclockwise direction over this point.
Warning: Don't use when weak or low on energy (in that case use SP-6 instead).
Effects: Relaxes and unblocks emotions (especially repressed anger). Depression.
location of LIV-3, click for animation
move counterclockwise
(click for animation)
LU-1
Name: Middle Palace (Lung 1)
Location: On the top of the chest, under the shoulder. First locate the depression under the end of the clavicle, next to the muscle. LU-1 is one thumbwidth under this point, slightly to the side.
Use: Press.
Effects: For internal emptiness and making contact to one's inner worth. (Also for cough and asthma.)
location of LU-1
LU-3
Name: Heavenly Palace (Lung 3)
Location: On the upper arm, one handwidth under the armpit (axillary fold). It's in the depression between the muscles from the shoulder and the biceps (under the shoulder muscle).
Use: Press.
Effects: For grief, feelings of loss and longing, internal emptiness and making contact to one's inner worth. (Also for cough and asthma.)
location of LU-3
LU-7
Name: Broken Sequence (Lung 7)
Location: Keep your hand with the nail of the thumb up. Move your thumb up and back (away from the palm of your hand), this reveals a depression at the bottom of the thumb, called the "anatomic snuffbox" (between two tendons). Move your finger from the anatomic snuffbox down, until you feel a bone sticking out (about a thumb's width from it). LU-7 is on that bone, in between the two tendons you feel there. You can press it with the nail of your thumb or index finger.
Use: Press.
Effects: Heals effects on the body of too much grief.
location of LU-7
LU-9
Name: Very Great Abyss (Lung 9)
Location: On the palm-side of the wrist, in the depression beneath the thumb, between the point where you can feel your pulse and the tendon that goes to your thumb.
Use: Press. To increase the effectiveness of this point, combine it with SP-6 or ST-36.
Effects: For grief, feelings of loss and longing, spiritual emptiness, many regrets. (Also moistens skin, and for cough and asthma.)
location of LU-9
P-7
Name: Great Mount (Pericardium 7)
Location: On the middle of the palm-side of the wrist, in the depression between the two tendons, on or just below the crease of the wrist.
Use: Reduce, so move your finger in counterclockwise direction over this point.
Warning: Don't use when weak or low on energy.
Effects: Heals effects on the body of too much joy or emotion.
location of P-7, click for animation
move counterclockwise
(click for animation)
SI-19
Name: Palace of Hearing (Small Intestine 19)
Location: Near the ear, just before the small projection in front of the ear canal. It's in the depression that forms when the mouth is opened.
Use: Press.
Warning: Don't use on a regular basis; this point is meant for gaining insight only.
Effects: To focus and listen to one's heart and the hearts of others.
location of SI-19
SI-5
Name: Yang Valley (Small Intestine 5)
Location: Near the wrist, on the pinky-side of the hand. It is a finger's width under the crease of the wrist, in the depression just above the bone that is sticking out. It's not straight above the bone, but straight under the pinky finger.
Use: Press.
Effects: Improves concentration, reduces distractability. Clarity of mind to distinguish the right path to take among several.
location of SI-5
SP-6
Name: Three Yin Intersection (Spleen 6)
Location: On the inside of the lower leg, one hand width (four fingers) above the tip of the ankle bone, on the back of the shin bone.
Use: Press.
Warning: Don't use this point during pregnancy.
Effects: Calms, relaxes and reduces irritability. Heals effects on the body of too much fear, worrying and thinking. (Also used for gynaecological conditions.)
location of SP-6 location of SP-6
ST-36
Name: Leg Three Miles (Stomach 36)
Location: On the front of the leg, one hand width (four fingers) below the kneecap, on the outside, in the depression between the shinbone and the leg muscle. What can go wrong is that you may be locating it somewhat too low on the leg. The point is immediately one hand breadth below the kneecap, so if you'd use something thick, like a finger, you might get half a finger breadth to low. It's at the outside of the bone that's on the front of the lower leg, one finger breadth from the crest of that bone.
Use: Press. A fingernail or thumbnail is particularly suited for this point, as you will be able to press more closely to the bone and on a broad range.
Warning: Using this point to go beyond your limits (e.g. overwork) will damage your health even further.
Effects: Increases stamina and energy. Provides stability and grounding. Heals effects on the body of too much worrying and thinking.
location of ST-36 location of ST-36
TB-17
Name: Wind Screen (Triple Burner 17)
Location: At the bottom part of the ear, behind the earlobe, in the depression the size of a fingertip.
Use: Press.
Effects: Makes one less sensitive to what people think of you.
location of TB-17
TB-5
Name: Outer Frontier Gate (Triple Burner 5)
Location: On the lower arm, on the top side, two thumb widths below the crease of the wrist. In the middle, in the depression between the bones and tendons.
Use: Press.
Effects: Increases expressiveness and sensitivity to feelings.
location of TB-5
You might also be interested in these books about acupressure at Amazon
Acupressure's Potent Points, by Michael Reed Gach
A Guide to Self-Care for Common Ailments
Instructions on how to do acupressure, and how to treat specific disorders.
Emotional Healing in Minutes, by Valerie & Paul Lynch
Simple Acupressure Techniques for Your Emotions
About Emotional Freedom Technique (EFT), which is tapping a sequence of energy points on your body, to clear emotional charge.
See longer book descriptions
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The necessity for medicines with fewer unwanted effects can’t be overemphasized.
The necessity for medicines with fewer unwanted effects can’t be overemphasized. of medicines that may selectively modulate the activation of only one 1 (M1 muscarinic) from the 12 various kinds of acetylcholine receptors. These medicines are being examined for schizophrenia treatment. It really is anticipated the fact that drug breakthrough exploiting allosteric sites will result in more effective healing agencies with fewer unwanted effects. Pushes Maintenance of low cytosolic Ca2+ focus during the relaxing condition is pivotal towards the success of mammalian cells. Although various other pathways are likely involved during sign transduction cycles, you can find two types of Ca2+ pushes, which use the power of ATP hydrolysis to move Ca2+ ions against an electrochemical gradient [16,17,18]. One kind of Ca2+ pump is situated in the internal mobile organelle sarco/endoplasmic reticulum (SERCA) and transports cytosolic Ca2+ into its lumen. The various other type is situated in the plasma membrane (PMCA) and expels Ca2+ through the cells in to the exoplasm. SERCA pushes are loaded in the skeletal and cardiac muscle groups and their framework has been analyzed by X-ray crystallography [19]. They play a significant function in reducing cytosolic Ca2+ instantly by the end from the cell excitation condition. On the other hand, PMCA possess higher affinity for Ca2+ and will maintain low cytosolic Ca2+ amounts also in the relaxing condition. PMCA are low-abundance protein, and unlike SERCA, their overexpression at high amounts has been difficult. Because of this, the crystal framework from the PMCA protein is not established. Just a hypothetical framework of PMCA computed through the homology using the framework of SERCA is certainly available. Predicated on this framework, the proteins provides 10 transmembrane domains, the N- and C-terminals from the proteins are cytoplasmic and you can find 5 extracellular domains. PMCA function is certainly important in preserving mobile Ca2+ homeostasis. Flaws in PMCA are connected with center failing, hypertension and various other disorders, and therefore PMCA could be potential healing goals in the administration of these illnesses [16]. PMCA are encoded by 4 genes (PMCA1-4), that are in different ways expressed in a variety of tissue with PMCA1 and PMCA4 getting many ubiquitous [20]. The initial expression pattern from the 4 PMCA genes may reveal their functions in tissue-specific physiology. In pig coronary arteries, a rise in cytosolic RB Ca2+ focus in smooth muscle mass cells prospects to vasoconstriction, whereas an identical upsurge in endothelial cells prospects to vasodilation. Therefore, an inhibition of PMCA4 in easy muscle cells is usually anticipated to trigger coronary vasoconstriction, while an identical inhibition in endothelial cells will probably result in vasodilation. Both cells also differ in the PMCA gene manifestation: smooth muscle mass cells express even more PMCA4 than PMCA1 while endothelial cells have significantly more PMCA1 than PMCA4 [21,22]. The above mentioned example illustrates the uniqueness in the features from the PMCA isoforms in the physiology of different cells. To be able to understand the part of the isoforms in the coronary artery physiology, we’ve developed allosteric inhibitors that are selective for the isoforms PMCA1 and PMCA4. Extracellular Domains as Potential Allosteric Sites At that time we started the task to build up selective inhibitors of PMCA, vanadate and eosin had been the two popular inhibitors to review PMCA physiology [10,21,23,24,25,26,27,28,29]. Both substances are orthosteric inhibitors from the ATP binding site within PMCA protein. These websites are similar for all those ATPases and therefore both vanadate and eosin inhibit all ATPases that were tested. Therefore, these inhibitors weren’t selective for PMCA. PMCA and SERCA, like additional ion Refametinib pushes, shuttle between two different conformational says during their response routine – E1 and E2 (fig. ?(fig.2a).2a). Many allosteric inhibitors of SERCA which hinder the E1-E2 changeover have been found out. For instance, thapsigargin, that includes a high affinity for SERCA, can be an allosteric inhibitor. It binds firmly towards the E2 type of the pump in the cavity encircled from the transmembrane domains 3, 5 and 7 and prevents it from reverting towards the E1 type. Thus, the response routine of SERCA can’t Refametinib be completed. To be able to invent selective allosteric inhibitors of PMCA, we made a decision to utilize the extracellular domains from the proteins as targets. Predicated on the proteins sequence, PMCA possess 5 brief extracellular domains, as the almost all the proteins is Refametinib around the cytosolic part from the membrane [16,20,30]. The cytosolic part provides the sites.
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progressive lenses article
Progressive Lenses
One of the main problems with bifocal and trifocal lenses is the issue of eye fatigue. It can be difficult to switch from one focusing power to another. Your eyes can tire, which can even lead to a headache, sore neck and sore back.
A variation of bifocals and trifocals is the no-line lens or progressive lens. No-lines provide a smooth transition from focusing on nearby to distant objects because they do not have a distinct line separating the focusing powers. Instead, a gradual change in power allows the wearer to focus on objects at all distances. Distant objects are viewed through the upper portion of the lens, while near objects are viewed through the middle or lower portion of the lens. These are also great for computer users.
Mission Statement
Our doctors and staff are committed to providing thorough care with personal attention. At Eye Doctors of Madison, you will find the compassionate care of a small-town doctors' office with the knowledge of a big-city institution. It is our mission to not only treat each patient uniquely but also like family.
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Hypersensitivity reactions to echinacea
Hypersensitivity reactions to echinacea
Echinacea is a popular herbal supplement known for its immune-boosting properties. Many people use it to prevent and treat colds, flu, and other respiratory infections. However, like any other substance, echinacea can cause adverse reactions in some individuals, including hypersensitivity reactions. In this article, we will explore hypersensitivity reactions to echinacea, their types, symptoms, and possible treatments.
Understanding hypersensitivity reactions
Hypersensitivity reactions are abnormal immune responses to normally harmless substances, such as echinacea, that can cause various symptoms and health issues. There are four main types of hypersensitivity reactions, classified based on the immune mechanisms involved. These types are:
1. Type I: Immediate hypersensitivity reactions
2. Type II: Cytotoxic hypersensitivity reactions
3. Type III: Immune complex-mediated hypersensitivity reactions
4. Type IV: Delayed-type hypersensitivity reactions
Each of these types has distinct characteristics, and the severity of the reaction can vary depending on the individual's sensitivity to echinacea.
Echinacea and hypersensitivity reactions
Echinacea is known to cause skin reactions and, in rare cases, hypersensitivity reactions. These reactions can manifest in various ways, depending on the type of hypersensitivity reaction and the individual's immune response.
Type I hypersensitivity reactions
Type I hypersensitivity reactions, also known as immediate hypersensitivity reactions, are the most common type of allergic reaction to echinacea. They are mediated by immunoglobulin E (IgE) antibodies and mast cells. Symptoms can include itching, hives, and, in severe cases, anaphylaxis. Anaphylaxis is a life-threatening allergic reaction that requires immediate medical attention.
Type II hypersensitivity reactions
Type II hypersensitivity reactions involve cytotoxic reactions in which the immune system attacks and destroys the body's own cells. These reactions are rare in response to echinacea, but they can lead to conditions such as hemolytic anemia, in which red blood cells are destroyed faster than the body can replace them.
Type III hypersensitivity reactions
Type III hypersensitivity reactions are immune complex-mediated reactions, in which immune complexes (combinations of antigens and antibodies) accumulate in blood vessels and tissues, causing inflammation and damage. These reactions can result in conditions like glomerulonephritis (inflammation of the kidney's filtering units) and are uncommon in response to echinacea.
Type IV hypersensitivity reactions
Type IV hypersensitivity reactions, also known as delayed-type hypersensitivity reactions, involve T cells and can cause symptoms like skin rashes, eczema, and contact dermatitis. These reactions typically occur hours or even days after exposure to echinacea and can be triggered by echinacea supplements or topical products containing echinacea.
Identifying and managing hypersensitivity reactions to echinaceaIdentificar y manejar las reacciones de hipersensibilidad a la equinácea
If you suspect you may be experiencing a hypersensitivity reaction to echinacea, it is essential to consult your healthcare provider for a proper assessment and diagnosis. Your doctor may perform tests, such as skin prick tests or blood tests, to confirm the presence of an allergic reaction and identify the type of hypersensitivity involved.
In cases where a hypersensitivity reaction to echinacea is confirmed, the primary treatment is to discontinue the use of echinacea-containing products. Your healthcare provider may also recommend medications to manage symptoms, such as antihistamines for type I reactions or corticosteroids for type IV reactions.
For individuals with a history of hypersensitivity reactions to echinacea, it is crucial to avoid echinacea products and inform healthcare providers about the allergy. Additionally, it is essential to read product labels carefully to ensure they do not contain echinacea or any of its derivatives.
In some cases, alternative treatments or supplements may be recommended for individuals who cannot use echinacea due to hypersensitivity reactions. For instance, vitamin C, zinc, or other herbal supplements like elderberry might be suggested for immune support.
Precautions and considerations for echinacea use
While echinacea is generally considered safe for most people, there are certain populations who should exercise caution when using this herbal supplement. These include:
• Individuals with a history of allergies or hypersensitivity reactions to echinacea or other members of the Asteraceae family, such as ragweed, chrysanthemums, marigolds, and daisies.
• People with autoimmune conditions like lupus, rheumatoid arthritis, or multiple sclerosis, as echinacea may stimulate the immune system and potentially worsen these conditions.
• Pregnant or breastfeeding women, as there is limited research on the safety of echinacea during pregnancy and lactation.
• Individuals taking certain medications, such as antibiotics or antifungal drugs, as echinacea may interact with these medications and affect their efficacy.
It is always a good idea to consult with a healthcare provider before starting any new supplement, including echinacea, to discuss potential risks, benefits, and appropriate dosages.
Deerforia: A reliable source for high-quality supplements
At Deerforia, we are committed to providing high-quality, safe, and effective supplements, including echinacea gummies, to support your health and well-being. Our products are made with care, ensuring that they meet the highest standards of safety and efficacy.
If you are considering adding echinacea to your health regimen but are concerned about potential hypersensitivity reactions or other echinacea side effects, our team of experts is here to help. We can provide guidance on the appropriate use of echinacea and suggest alternative options for immune support if needed.
Frequently Asked Questions (FAQ)
What are the common signs of a hypersensitivity reaction to echinacea?
Common signs of a hypersensitivity reaction to echinacea include itching, rash, hives, swelling of the face or throat, difficulty breathing, and chest tightness. If you experience any of these symptoms after taking echinacea, stop using it and consult your healthcare provider immediately.
Can I develop a hypersensitivity reaction to echinacea even if I have used it before without any issues?
Yes, it is possible to develop a hypersensitivity reaction to echinacea even if you have used it before without any problems. Hypersensitivity reactions can occur at any time and may be triggered by changes in your immune system, increased exposure to echinacea, or other factors.
How can I avoid hypersensitivity reactions when using echinacea products?
To reduce the risk of hypersensitivity reactions when using echinacea products, start with a low dose and gradually increase it as tolerated. Also, choose high-quality echinacea supplements from trusted sources like Deerforia. If you have a history of allergies or hypersensitivity reactions, consult your healthcare provider before using echinacea.
Are there any alternative supplements I can take for immune support if I am hypersensitive to echinacea?
Yes, there are alternative supplements you can take for immune support if you are hypersensitive to echinacea. Some options include vitamin C, zinc, elderberry, and astragalus. Always consult your healthcare provider before starting any new supplement, especially if you have a history of allergies or hypersensitivity reactions.
Are there any potential interactions between echinacea and medications?
Echinacea may interact with certain medications, such as antibiotics and antifungal drugs. If you are taking any medications, consult your healthcare provider before using echinacea to ensure it is safe and appropriate for your specific circumstances.
Conclusion
Hypersensitivity reactions to echinacea are relatively rare but can be severe in some cases. Understanding the different types of hypersensitivity reactions, their symptoms, and treatments is essential for individuals who may be at risk. If you suspect you have a hypersensitivity reaction to echinacea, consult with your healthcare provider for proper evaluation and management.
By being cautious with echinacea use and seeking guidance from healthcare professionals, you can enjoy the immune-boosting benefits of this popular herbal supplement while minimizing the risk of adverse reactions. And remember, if you are looking for high-quality echinacea supplements or other immune-supporting products, Deerforia is a trusted source for all your needs.
Back to blog
Get A Boost To Your Immune System Today!
Deerforia offers a fun and tasty way to consume Echinacea, so you can be excited to having a boosting immune system in a non boring pills kinda way!
SEE Deerforia's Echinacea Gummies
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Spiral Yoga
Spiral yoga is an energy-stimulating dynamic yoga sequence that combines yoga, gyrokinesis and dance. Circular movements’ cycles from heart to kidneys symbolise strength and harmony between these two key organs.
The Dynamic Spiral Yoga System allows us to practice the balance of the autonomic nervous system.
Stretching and breathing are used to activate the sympathetic nervous system and soothe the parasympathetic system – two parts of the autonomic nervous system. By stimulating the nervous system and soothing it, we achieve the balance of yin and yang forces.
TThe creator of the Dynamic Spiral Yoga system is Beta Lisboa. She shares it with the world along with her partner, Simon Calder. If you want to listen to what Beta says about spiral yoga and see how she practices it, watch the video that is posted below.
Spiral yoga is characterised by a large variety of movement forms. It offers stretching, bending, movements of lifting and lowering the limbs, rotations and circular movements. Each form of movement creates a different fascial pattern.
What are the fascial patterns? Fascial patterns are built by amplifying specific movements performed by the body. The limitation occurs when, by strengthening a given pattern more and more, we expose our body to an injury. It comes to it exactly when we leave this movement, which is too intense, and which was supposed to amplify the pattern after all. Spiral movements activate all forms of movements at the same time, those which we have mentioned above. This allows the body to have a wide range of different movements within the joints. The fascial patterns that are created then affect all tissues, muscles, organs and deep fasciae.
Practising the dynamic spiral yoga system with the conscious use of breath restores our innate grace, thaws out the individual parts of the body, arms, shoulders, chest, opens our hearts to ourselves and others and increases stability.
When we achieve inner freedom and balance with the world, life becomes a dance - beautiful and full of gratitude to ourselves.
- Colors of Yoga
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footer-logo
About Us
SL Raheja Hospital is located in the suburb of Mahim in Mumbai It is associated with Fortis Hospitals and has established a high standard of healthcare services and medical facilities since its inception. We are one of the best multispecialty hospitals in Mumbai
Contact Info
S.L. Raheja Hospital (A Fortis Associate) Raheja Rugnalaya Marg, Mahim (W), Mumbai, Maharashtra - 400016, India.
Emergency No- 022-66529888
info@rahejahospital.com
CGSQ1588272845.jpg
Arthritis: What You Must Know And Can Do About It
Joints are the connections between the bones which help in movement. They also provide support to the body by bearing the weight of the different parts of the body. Joint pain is an extremely common condition. It can affect any part of the body, be it the hands, shoulders, hips, ankles, thighs etc. Joint pain is usually known as Arthritis, characterized by joint inflammation because of the decrease in cartilage, a rubbery tissue covering our bones. The bones then rub against each other, which triggers the pain. Although there is no cure, there are several treatments for arthritis pain, mostly pertaining to diet and lifestyle management.
What are the Symptoms of Arthritis?
The common signs and symptoms of arthritis are:
1.Pain in the joints, which may be constant or intermittent in nature.
2.Inflammation of the joints due to stiffness, swelling, which causes the joints to become warm.
3.Difficulty in motion and loss of motion
4.Tenderness of the inflamed joint
5.Fever, weight loss, fatigue and abnormalities of organs such as kidneys, heart etc. in the case of
rheumatoid arthritis.
Which are the Treatment Options for Arthritis?
The medical treatment for arthritis mainly involves medications and surgery. Of course, there are other
measures such as physical therapy, weight loss etc.
• Medications: Over-the-counter medicines such as aspirin, ibuprofen, acetaminophen, Tylenol help provide relief from the joint pain by reducing inflammation, albeit with the probability of certain side-effects like ulcers and bleeding. Tropical jells inhibit the pain signals in the nervous system, thus providing relief. Corticosteroids reduce the inflammation and suppress the immune system, which especially addresses the cause of rheumatoid arthritis.
• Physical Therapy: Exercise can help a great deal in reducing the damage to joints and aiding in arthritis pain management. Some of the recommended exercises include low-impact ones like cycling, swimming and aerobics.
Weight Management: Excess weight adds to the pressure and stress on the joints. Therefore,
weight loss is an effective strategy to minimize the disability and pain due to arthritis.
What are the Dietary tips for Arthritis Care?
Certain foods have been found to be helpful in reducing the inflammation associated with arthritis, especially the rheumatoid type.
These are rich in omega-3 fats and include:
1.Salmon and sardines
2.Walnuts
3.Eggs and margarines
4.Linseeds and flaxseed oil
5.Fish oil supplements
Keep in mind that you should avoid the saturated fats found in processed foods, savoury snacks and similar foods. Make sure you remove the excess fat from meat before cooking, and as far as possible opt for poultry and fish.
The Myths and Facts about Arthritis
SL.No Myths Facts
1 Arthritis affects only old people This is not completely true. Older and elderly people are certainly at a greater risk of developing arthritis, but it can affect people of all age groups, including children and young adults.
2 Physical activity will exacerbate joint pain. The opposite is true. Not indulging in any exercise or outdoor activity weakens the joints and increases the weight. Swimming, aerobics and running all help in fortifying the joints and muscles.
3 You cannot prevent the onset of arthritis. On the other hand, maintaining a healthy weight range, staying physically active and avoiding straining oneself can drastically reduce the risk of getting this disease.
4 Cracking knuckles causes arthritis. The sound we hear when we crack our knuckles is just due to the release of gas that has accumulated in the area of the joints.
The bottom line is that arthritis is very much avoidable. However, there is no guarantee that one cannot be develop arthritis at some point in his/her life. For any complications arising out of this disease, it is advisable to seek prompt medical care. S.L Raheja (A Fortis Associate) is reputed to administer one of the best treatments for arthritis in Mumbai, thanks to its expert and dedicated staff as well as its state-of-the-art infrastructure.
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1a01aa77535b9ecfb87b9fc36adbcd2f
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562,253,134,661,868,700
|
Eur Rev Med Pharmacol Sci 2019; 23 (10): 4118-4125
DOI: 10.26355/eurrev_201905_17913
LncRNA NKILA inhibits invasion and migration of osteosarcoma cells via NF-κB/Snail signaling pathway
G.-D. Zhang, Y. Li, G.-J. Liao, H.-W. Qiu
Department of Sport Medicine, Yantaishan Hospital, Yantai, China. qiuhongwei86@outlook.com
OBJECTIVE: Our research explored the possible biological function of long non-coding RNA (lncRNA) NKILA in the pathogenesis of osteosarcoma and its underlying mechanism.
PATIENTS AND METHODS: NKILA expression in 60 cases of osteosarcoma and adjacent tissues was detected. The correlation between NKILA expression and clinical information was analyzed by Chi-square test. The overexpression plasmid or siRNA of NKILA were transfected into osteosarcoma cells by liposome. Cell proliferation was detected by cell counting kit-8 (CCK-8) assay. Transwell assay was used to check the migratory and invasive abilities. Western Blot was used to detect the expressions of nuclear factor-κB (NF-κB)-related proteins. In addition, we analyzed the cell invasion and migration after treatment of NF-κB inhibitor (JSH) to further verify whether NKILA can participate in the occurrence of osteosarcoma through the NF-κB / Snail signaling pathway.
RESULTS: The expression level of NKILA in osteosarcoma tissues was significantly lower than that in adjacent tissues, and was related to tumor size, Enneking stage, and metastasis. After KNKS/NP cells were transfected with NKILA-siRNA, cell proliferation, invasion and migration were enhanced. Transfection of the NKILA overexpression plasmid in Saos2 cells reduced cell proliferation, invasion and migration. NKILA knockdown downregulated the expressions of p65 and E-cadherin, but strikingly increased Snail expression. The RNA binding protein co-immunoprecipitation experiments illustrated that p65 could bind to NKILA. Additionally, JSH was found to reverse the inhibitory effect of NKILA on cell migration and proliferation.
CONCLUSIONS: NKILA was lowly expressed in osteosarcoma tissues. In addition, high expression of NKILA could suppress the migration and invasion of osteosarcoma cells by inhibiting the NF-κB/Snail signaling pathway.
Free PDF Download
To cite this article
G.-D. Zhang, Y. Li, G.-J. Liao, H.-W. Qiu
LncRNA NKILA inhibits invasion and migration of osteosarcoma cells via NF-κB/Snail signaling pathway
Eur Rev Med Pharmacol Sci
Year: 2019
Vol. 23 - N. 10
Pages: 4118-4125
DOI: 10.26355/eurrev_201905_17913
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-5,434,282,735,769,020,000
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CORDIS
EU research results
CORDIS
English EN
Comprehensive anatomical, genetic and functional identification of cerebellar nuclei neurons and their roles in sensorimotor tasks
Objective
How does the brain integrate diverse sensory inputs and generate appropriate motor commands? Our cerebellum is a key region for such a sensorimotor processing, empowered by its sophisticated neural computation and constant communication with other brain regions. The well-timed cerebellar information is integrated and funneled to other brain regions through the cerebellar nuclei (CN). Yet, how CN circuitry contributes to the cerebellar control of sensorimotor processing is unclear. My recent work indicates that the CN activity serves various functions ranging from the online motor control, the amplitude amplification of cerebellar outputs to the control of motor planning. Given these advances, I am now in a unique position to decipher the properties of CN neurons and identify their specific roles in different forms of sensorimotor processing. It is my central hypothesis that depending on the specific demands of the task, CN neurons can either facilitate or suppress the activity of downstream regions with millisecond precision; and the anatomical, genetic and functional properties of CN neurons are tailored to the particular task involved. To test this hypothesis, I will 1) identify the activity patterns of different CN modules during the acquisition and execution of two sensorimotor tasks and characterize the relevant extra-cerebellar inputs to these modules; 2) identify the connectivity-transcription logic of different CN modules and link them to their task-specific outputs; and 3) examine the impacts of manipulating anatomically and/or genetically defined CN neurons on the downstream regions during different sensorimotor tasks. I will accomplish these key objectives by developing various novel electrophysiological, optogenetic, molecular and imaging techniques. My research is likely to break new ground, demonstrating that the identity of CN neurons is determined by their differential temporal demands of sensorimotor tasks controlled by different brain structures.
Leaflet | Map data © OpenStreetMap contributors, Credit: EC-GISCO, © EuroGeographics for the administrative boundaries
Host institution
ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Address
Dr Molewaterplein 40
3015 Gd Rotterdam
Netherlands
Activity type
Higher or Secondary Education Establishments
EU Contribution
€ 1 400 000
Beneficiaries (1)
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Expand all
ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Netherlands
EU Contribution
€ 1 400 000
Project information
Grant agreement ID: 852869
Status
Ongoing project
• Start date
1 November 2019
• End date
31 October 2024
Funded under:
H2020-EU.1.1.
• Overall budget:
€ 1 400 000
• EU contribution
€ 1 400 000
Hosted by:
ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Netherlands
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-6,230,239,375,296,435,000
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What Type of Procedure Would I Need? My Cheekbones Are Very Low, How Can They Be Raised? (photo)
My cheeks are very low and I would like them to look somewhat like they do in the second picture where I am pulling one upwards. The lines around my mouth have always bothered my because they look so dark and I want something that will correct this. Also, the general prices of the procedure(s) recommended.
Doctor Answers 6
Volumizing Fillers Work Well for Cheek Augmentation
There is no substitute for a face to face consultation. In general,, volumizing agents are a simple, quick and wonderful "Wow" way for augmenting cheeks and softening smile lines around the nose and marionette lines extending down from the angles of the mouth. However, there are some general points that need to be kept in mind when dealing with individuals with naturally fuller, rounder faces or in those who have a few pounds to lose. In such cases, the injector has to be cautious in performing cheek augmentation so as not to create a "chipmunk"-like overall look. or to contribute to the appearance of too full a face. To Avoid this only relatively small amounts should be artistically added to accent the cheeks.
When there are accompanying prononounced smile lines and marionette lines in such individuals, they can be treated with volumizing fillers, but here, too, extra care needs to be taken to soften the lines without pushing the adjacent cheeks too much up upward and outward to avoid accentuating the impression of a more full or rounded face.
New York Dermatologic Surgeon
5.0 out of 5 stars 13 reviews
Have a question? Ask a doctor
Defining Cheek Bones
Defining cheek bones can mean different things for different patients. Essentially, there are a few main categories of issues:
• A support problem, where the cheek bones themselves are too flat. The solution here is a cheek implant or cheek fillers
• A volume issue, which is more typical of older patients. The loss of skin volume leads to sagging, which creates deepending of folds and flattening of the cheek area. Volume addition whether with fillers, implants, or fat can solve the issue. Alternatively, midface lifting procedures can be a strategy, depending on a patient's exact anatomy.
• A cheek issue, where the cheek fat is too prominent. This creates a roundness in the area which makes the cheeks look poorly defined. The solution here is buccal fat removal.
From your photos, you seem to have full cheeks, which overpower the cheek bones you have. Buccal fat excision and, potentially, filler into the nasolabial folds would give you the closest result to the photo submitted.
Best of luck
Richard W. Westreich, MD
Manhattan Facial Plastic Surgeon
5.0 out of 5 stars 27 reviews
What Type of Procedure Would I Need? My Cheekbones Are Very Low, How Can They Be Raised?
The anterior cheeks are flat and there is evidence of Nasolabial folds. The cheeks can be shaped aesthetically using Perlane, Radiesse or a similar filler or using Cheek Implants. Be sure that the MD or plastic and cosmetic surgeon understands and follows the proper aesthetics of facial beauty.
Francis R. Palmer, III, MD
Beverly Hills Facial Plastic Surgeon
4.5 out of 5 stars 12 reviews
Cheek Elevation
There are two options to make the cheek fuller. One is to fill it with fat or a filler such as Radiesse. The second is to surgically elevate it. This would achieve what you are doing in the second picture. Whether this would require a cheek lift, mid-face lift or facelift would require an examination. The cost would vary on what you choose.
Cheek bone correction
Of course, you need an in office opinion to determine the exact procedure that should be done. However, with the photos given, you would benefit from a midface lift, cheek implants, and/or fillers (fat injections would be a good option). All the best.
David Alessi, MD
Beverly Hills Facial Plastic Surgeon
4.5 out of 5 stars 7 reviews
Cheek lift and nasolabial folds prominence
There are several procedures that can address your concerns. You can have fillers in order to give more fullness under your eyes and correct the nasolabial folds prominence. Surgically, midface lift or infraorbital implants and fat transfer could achieve a more long lasting results.
Mohsen Tavoussi, MD, DO
Huntington Beach Facial Plastic Surgeon
4.0 out of 5 stars 6 reviews
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.
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Not to be outdone, oolong tea—a Chinese beverage—can help those who drink it shed up to a pound per week. According to a study in the Chinese Journal of Integrative Medicine, participants who regularly sipped oolong tea lost six pounds over the course of six weeks. What’s more? The tea’s antioxidants are thought to remove harmful free radicals and improve bone health.
Participants were recruited from the Durham Veterans Affairs Medical Center (VAMC) outpatient clinics. Inclusion criteria were age 35–75 years; body mass index (BMI) >25 kg/m2; and fasting serum glucose >125 mg/dL or hemoglobin A1c >6.5% without medications, or treatment with oral hypoglycemic agents (OHA) and/or insulin. Exclusion criteria were evidence of renal insufficiency, liver disease, or unstable cardiovascular disease by history, physical examination, and laboratory tests. All participants provided written informed consent approved by the institutional review board. No monetary incentives were provided.
Cyclical keto diet: The Bulletproof Diet falls into this category. You eat high fat, low carb (less than 50 grams of net carbs a day) five to six days of the week. On day seven, you up your carb intake to roughly 150 grams, during what’s called a carb refeed day. Carb cycling this way helps you avoid the negative effects some people experience when they restrict carbs long term, like thyroid issues, fatigue and dry eyes.[9][10] Learn more here about how carb cycling works.
I’m not Edward, but I’ve been on a keto diet for 3 weeks. I don’t find it difficult at all. I’ve attended 2 birthday parties, and it’s easy to say “No thank you” when I’m offered cake because my health is my top priority. Drinking a lot of water to support the kidneys is an absolute must. Also, supplementing sodium, potassium and magnesium keeps electrolytes in balance. A Naturopathic doctor is a great source of information on true lifestyle modifications.
If you are pregnant or are nursing, you should not follow a Ketogenic diet. You will not receive enough of the recommended carbohydrates, vitamins and nutrients necessary for yourself and your growing baby on this diet. Your obstetrician will recommend how many carbohydrates you should consume per meal and for snacks during each phase of your pregnancy. They will likely refer you to a Certified Diabetes Educator for nutritional counseling as well. Please check out The Diabetes Council’s FAQ’ About Gestational Diabetes for all your gestational diabetes related questions.
I know it is hard when you have been taught something, and believed it, and taught it to others…only to be shown that what you have been taught is not the end all be all that you were led to believe. It sucks. But, you can choose to ignore the truth, and continue to follow the incorrect path. Or, you can look at the facts, and realize that what you have been taught is not the truth…and you can take a new path, which will lead many to wonderful new lives.
A survey in 2005 of 88 paediatric neurologists in the US found that 36% regularly prescribed the diet after three or more drugs had failed; 24% occasionally prescribed the diet as a last resort; 24% had only prescribed the diet in a few rare cases; and 16% had never prescribed the diet. There are several possible explanations for this gap between evidence and clinical practice.[33] One major factor may be the lack of adequately trained dietitians, who are needed to administer a ketogenic diet programme.[30]
My principal hope in this article is to provide journalists with a resource to do what basic journalism demands, namely to ensure that stories are scientifically balanced and accurate. At the end of this post I provide contacts for some of the credentialed experts who helped me compile this research. Reporters, please seek out these or other low-carb diet experts so you can provide accurate, up-to-date information for your readers.
“So many of us sacrifice this for work, family, or social experiences, but sleep is a basic tenet of health; you will not function properly, cognitively or physically, without adequate sleep,” Moreno explains. "Adequate usually means at least 8 hours. Set strict sleep time rules and practice good sleep hygiene. When you prioritize sleep, other aspects of good health may line up more easily.”
You can eat what you love. It’s evident that with such a variety of whole, fresh foods available to you as options, it’s easy to build meals based on the diet. And, you don’t have to eliminate your favorites, either. They may just require some tweaks. For instance, rather than a sausage and pepperoni pizza, you’d choose one piled high with veggies and topped with some cheese. You can also fit in a lot of food into one meal. Filling up on fresh foods like fruits and vegetables will allow you to build volume into meals for fewer calories.
You’re very welcome, Judy! I’m glad it’s helpful. If you are keto (as opposed to low carb), unfortunately peaches would not allow you to stay in ketosis. You can check my keto food list to help determine what is keto friendly. Of course, there are worse things than fresh fruit 🙂 but in the end our bodies still see the sugar. That being said, it doesn’t mean you sabotaged the whole day. Just pick up again – you got this!! (And for next time, try some fresh berries in moderation when you’re craving fruit.)
Since avocados are packed with nutrients and healthy fats that can stimulate weight loss, it’s no surprise that avocado oil acts in a similar fashion. When Penn State University researchers compared those who consumed avocado oil with those who consumed a flax-safflower oil blend, they found that those who used just three tablespoons of avocado oil daily lost nearly two percent of their belly fat in just one month.
Con: Results can vary depending on how much fluid you drink. By drinking more water, you dilute the concentration of ketones in the urine and thus a lower level of ketones will be detected on the strips. The strips don’t show a precise ketone level. Finally, and most importantly, as you become increasingly keto-adapted and your body reabsorbs ketones from the urine, urine strips may become unreliable, even if you’re in ketosis.
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We work with all insurance companies. Call for a complimentary benefits check at 469.685.1700
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Simple Sleep Services, LLC, Sleep Disorders Sleep Apnea, Dallas, TX
Sleep And Memory
Sleep is essential for boosting your brain power, especially when it comes to memory retention. Not only are you able to store away any important facts and new pieces of information you picked up during the day while your eyes are closed, but you’re also able to hold on to essential memories, like your child’s birthday or your anniversary date, for years to come.
But sleep and memory can be a double-edged sword. Just as plenty of sleep can help your memory perform at its best, poor-quality sleep can actually hurt your recollections, and can result in an increased likelihood of developing cognitive conditions, including and especially dementia.
So if you want to ensure your brain functions at peak performance for the long haul, especially when it comes to memory retention and combatting your risk for dementia, look out for these habits or conditions that can hurt your cognitive health.
Three Bad Sleep Habits That Can Increase Your Risk for Dementia
1. Sleeping In
7-9 hours of sleep is healthy, but if you go too much over this amount, it could inevitably backfire.
A recent study has found that people who sleep for more than nine hours every night have an increased risk of both Alzheimer’s and dementia. This is compared to those individuals who sleep the recommended 8 hours per night.
So feel free to sleep in only rarely, but don’t overindulge on a long-term basis.
2. Distracted Snoozing
Sleep interruptions can range from a snoring partner to neighborhood noise. But if you are subject to regular distractions and interruptions in your sleep, it could lead to trouble.
Research has found alarming evidence for people who have restless and poor quality sleep, and who wake up throughout the night due to interruptions. They have a higher risk of cognitive decline than those who sleep soundly.
So if you keep waking up due to outside factors, try noise cancelling headphones to drone out the outside activity. Most of all, encourage a snoring partner to seek testing for obstructive sleep apnea – a common culprit and cause of loud snoring.
3. Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) can lead to a decline in your cognitive abilities in both the short term, and the long term.
Because OSA interferes with your brain’s normal activity at night, you’ll likely feel forgetful, anxious, and all-around foggy during the day.
Worse yet, without treatment, OSA has been shown to promote a much higher risk of cognitive conditions, including dementia and Alzheimer’s.
So if you think you may have sleep apnea, get an at-home diagnosis test, see a sleep specialist, and get treatment as soon as possible. Sleep apnea does not go away on its own! And the risk for health issues – including dementia – tends to increase the longer that it is ignored.
A good night’s sleep can do a world of good for your mind, as well as your body. So pay attention to possible issues with the quality of your rest. And seek help if you think there may be an issue, like obstructive sleep apnea. Get a solid routine of 7-9 hours of sleep every night. This way your brain – and your memory – will stay clear and well-functioning for days, weeks, years, and even decades.
Contact us if you or a loved wake up and remain groggy each day. It could be sleep apnea. We can help you get back to great sleep and good health fast!
Image Attribution
Summary
Article Name
Sleep And Memory
Description
Sleep and cognitive abilities are related, especially when it comes to memory. Avoid these habits that cause long-term memory issues, especially dementia.
Author
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Category:
What is Caspase 8?
Article Details
• Written By: James Carew
• Edited By: A. Joseph
• Last Modified Date: 01 May 2018
• Copyright Protected:
2003-2018
Conjecture Corporation
• Print this Article
Caspase 8 is a protein found in humans, numerous other mammals and some birds. It is part of the caspase family of inactive proenzymes that play a crucial role in cell apoptosis. Caspases are composed of a prodomain, a large protease subunit and a small protease subunit.
When related to apoptosis, caspase 8 is specifically known as a death receptor. Cell apoptosis is the process by which programmed cellular death occurs at a controlled and expected rate, as opposed to necrosis, which is when cellular death occurs traumatically because of an injury. The programmed cell death of apoptosis is responsible for the development of individual digits in embryos as the cellular matter between them is broken down, and caspase 8 is a crucial aspect of this process. As the death receptor, it is responsible for receiving the signal to begin the cellular breakdown, essentially beginning the caspase cascade that leads to the cleaving of the cellular proteins.
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Upon receiving the signal, caspase 8 activates, causing a cascade of caspase protein activations, eventually leading to the activation of caspase 3 and caspase 6. These proteins are directly responsible for the cellular breakdown that marks apoptosis. There are, however, instances of caspase 8 activation without receiving the precursor signal. Even without the precursor signal, this still causes the caspase cascade to occur, resulting in an unprogrammed apoptosis. These instances and the unprogrammed cellular death that necessarily follows have connected the protein with certain degenerative brain disorders and other ailments.
Research into degenerative brain disorders has uncovered a link between caspase 8 and several mental illnesses. There have been studies that link the activation of the protein to illnesses such as Alzheimer’s disease and Huntington's disease. Caspase 8 was found in the brain matter of sufferers of Huntington's disease, but not in people without the disease, implicating the protein as a possible cause of mental illness. There has been speculation that a greater understanding of the chemical process behind apoptosis and, specifically, caspase 8 could lead to the development of treatments for these disorders.
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Catalogo Articoli (Spogli Riviste)
OPAC HELP
Titolo:
A prospective study of human papillomavirus (HPV) type 16 DNA detection bypolymerase chain reaction and its association with acquisition and persistence of other HPV types
Autore:
Liaw, KL; Hildesheim, A; Burk, RD; Gravitt, P; Wacholder, S; Manos, MM; Scott, DR; Sherman, ME; Kurman, RJ; Glass, AG; Anderson, SM; Schiffman, M;
Indirizzi:
Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA Univ PittsburghPittsburgh PA USA 15213 idemiol, Pittsburgh, PA 15213 USA NCI, Dept Canc Epidemiol & Genet, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 Canc Epidemiol & Genet, Bethesda, MD 20892 USA Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA Johns HopkinsMed Inst Baltimore MD USA 21205 ol, Baltimore, MD 21205 USA Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA Albert EinsteinColl Med Bronx NY USA 10467 t Pediat, Bronx, NY 10467 USA Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA Albert Einstein Coll Med Bronx NY USA 10467 Immunol, Bronx, NY 10467 USA Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10467 USAAlbert Einstein Coll Med Bronx NY USA 10467 cial Med, Bronx, NY 10467 USA Kaiser Fdn Res Inst, Oakland, CA USA Kaiser Fdn Res Inst Oakland CA USAKaiser Fdn Res Inst, Oakland, CA USA Kaiser Permanente Ctr Hlth Res, Portland, OR USA Kaiser Permanente Ctr Hlth Res Portland OR USA lth Res, Portland, OR USA Lab Corp Amer, Res Triangle Pk, NC USA Lab Corp Amer Res Triangle Pk NC USA Corp Amer, Res Triangle Pk, NC USA
Titolo Testata:
JOURNAL OF INFECTIOUS DISEASES
fascicolo: 1, volume: 183, anno: 2001,
pagine: 8 - 15
SICI:
0022-1899(20010101)183:1<8:APSOHP>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
CYTOLOGICALLY NORMAL WOMEN; CERVICAL-CANCER; INFECTION; PARTICLES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
18
Recensione:
Indirizzi per estratti:
Indirizzo: Liaw, KL Univ Pittsburgh, Dept Epidemiol, 513 Parran Hall,130 De Soto St, Pittsburgh, PA 15213 USA Univ Pittsburgh 513 Parran Hall,130 De Soto St Pittsburgh PA USA 15213
Citazione:
K.L. Liaw et al., "A prospective study of human papillomavirus (HPV) type 16 DNA detection bypolymerase chain reaction and its association with acquisition and persistence of other HPV types", J INFEC DIS, 183(1), 2001, pp. 8-15
Abstract
Human papillomavirus (HPV)-16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the risk of infection with other types, a theoretical concern with current vaccination efforts.
ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/01/21 alle ore 06:06:57
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Synthetic biology - recombineering proteins to generate cellular powerhouses
Recoding the genetic code to design unnatural amino acids and rewiring gene networks for biomolecular applications.
Synthetic biology - recombineering proteins to generate cellular powerhouses
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Synthetic biology is an avant-garde field of nascent multidisciplinary research that primarily aims to re-engineer cells as industrial machines. I have always found the concept and the process of rewiring gene networks of a natural biological cell for customized behavior to be promising (and simultaneously fascinating) in the fields of biomedicine and biotechnology. Previously, I made notes looking into some of the advances of gene circuit engineering, and of gene editing and recombineering methods that are built on the futuristic goals of rebuilding a cell to carryout human designed functions (Figure 1) [Healy 2019]. These efforts provide a window to interrogate the pathophysiology of cells, to then design and develop therapeutic interventions, to highlight the epitome of ambition in biology. Since I recently emphasized the significance of proteomics relative to detecting culprit proteins that underly the origin of disease, this post initially looks into recombineering proteins through synthetic biology, to briefly highlight mechanistic details of the biomolecular engine.
Figure 1: Hypothetical applications of gene circuit engineering: a) chemical production of non-toxic alternatives to diesel, b) gene therapy for early detection and to edit genetic anomalies in diseases, c) engineering therapeutic gut bacteria, d) smart plants that sense environmental cues to implement responses. Credit: [Brophy 2014].
Synthetic biology is a very young field relative to the advent of gene circuit engineering that debuted in the year 2000, with bottom-up engineering approaches that can assemble genetic parts into more complex gene circuits to facilitate new functionalities into cells (Figure 2) [Healy 2019]. Such advances include ‘smart plants’ and therapeutic agents that can correct genetic diseases, most of these ideas must expand beyond their hypothetical stage to meet the test of time [Brophy 2014]. Very briefly, gene circuit development depends on modularity, where the composing units do not change upon interconnection, allowing scientists to predict gene circuit behaviors. The process of upgrading protein synthesis for synthetic biology on the other hand, depends on the expansion of the genetic code [Donoghue 2013], and this therefore forms the primary focus here.
This post ventures to describe the development of non-standard and non-canonical amino acids that are either chemically modified after their incorporation into a protein via posttranslational modifications or are present as organic molecules containing an amino and a carboxylic acid, to form ‘peptidomimetic’ building blocks [Castro 2023]. Unnatural amino acids or non-canonical amino acids are not located naturally in the genetic code of organisms and are either found in nature as intermediates of biosynthesis pathways or are developed synthetically in the lab [Chen 2010]. Such designs can be used to form new bioactive molecules and new biomaterials. The post examines a few methods of gene editing and recombineering to rewire cells, to understand and intervene pathological cascades for diagnostics and therapeutic applications.
Figure 2: Milestones in the history of synthetic biology and landmark research achievements span from 1961 to 2020. The advent of synthetic biology relative to synthetic circuits is attributed to the year 2000. Each timeframe presents brief summaries of some key research milestones. Credit: [Del Vecchio 2009, Meng 2020].
The origin of the genetic code and its ‘non-frozen’ nature.
The origin of the genetic code takes us to the early years, when Francis Crick, James Watson and Rosalind Franklin were famously investigating the blueprint of life and the architecture of the DNA. In a Letter to Nature, Crick postulated the genetic code to have originated from a ‘frozen accident’ [Crick 1967, Ambrogelly 2007]. This concept thawed with time, to reveal the non-immutable or non-frozen nature of the genetic code that came to light with several findings, for instance in the 1970s, the stop codon was reassigned to encode tryptophan in yeast and in mitochondria [Macino 1979]. In nature, all 64 codons in the genetic code can be assigned to 20 different kinds of proteinogenic amino acids and three stop codon signals (ochre UAA, umber UGA, and amber UAG) during protein translation (Figure 3) [Chavatte 2003]. Similarly, it is possible to incorporate non-standard amino acids (NSAAs) in the lab, for enhanced properties of new proteomics for diverse applications [Lajoie 2013].
Figure 3: The wheel of codons used to translate a genetic code into a sequence of amino acids. The 64 codons encode 20 amino acids. Credit: [Ambrogelly 2007].
The next big surprise in proteomics came to be in the 1980s, when selenocysteine was discovered as the 21st genetically encoded amino acid by recoding the UGA stop codon for its incorporation in many species, including humans [Böck 1988]. The synthesis of selenocysteine is specifically targeted for human health and development [Bell, 2024]. The 22nd amino acid encoding pyrrolysine was discovered in 2002 [Hao 2002, Gaston 2011] thus overcoming the assumption of the immutability of the genetic code. While the genetic code can evolve, its translation can be rewired to genetically encode more than the 20 standard amino acids by recoding the stop codon.
Protein synthesis with synthetic biology – adding new chemistries to the genetic code
Expanding the genetic code is a definitive goal in synthetic biology with an established amount approximating 100 distinct noncanonical amino acids (ncAAs) generated via orthogonal translational systems. The process can allow the facile in vitro production of proteins with hardwired post-translational modifications to include unnatural amino acids containing a photo-cage or photolabile protecting group, or site-specific fluorescent labels for further expansion [Liu 2010]. There are limits to the natural protein synthesis machinery that must be understood at a mechanobiology level to further rewire the genetic code for expansion in this way. Protein synthesis for synthetic biology can expand the genetic code beyond the 20 canonical amino acids via specific-orthogonal translational systems that must optimize the following factors (Figure 4):
• An ‘open’ codon to encode
• Noncanonical amino acids that can permeate the cell.
• An aminoacyl-tRNA synthetase to efficiently ligate a desired non-canonical amino acid,
• A tRNA that can decode the ‘open’ codon, and
• Compatible elongation factors and ribosomes
Tailor-made genetic codes can be synthetically produced by using a reconstituted in vitro translation system to facilitate the synthesis of unnatural amino peptides with unmatched flexibility [Jewett 2016]. Geneticists can accomplish this by preparing the genetic code by engineering an efficient orthogonal translational system with the illustrated components (Figure 4).
Figure 4: The mechanism-of-action of protein synthesis requires amino acid-tRNAs as building blocks for ribosomal protein synthesis. Each stage of synthesis, is labelled from A-F, (A) Amino acid-tRNAs are in use to form building blocks for ribosomal protein synthesis, (B) The amino-acid can be ligated to the tRNA by using a dedicated enzyme to develop a protein, subsequently this leads to (C) The assembly of a protein complex, which leads to (D) The development of a product of amino acid-tRNAs delivered by an elongation factor such as EF-TU to the ribosome. (E) Once inside the ribosome, the anticodon of the tRNA matches the triplet codon of the mRNA, this then leads to (F) Protein synthesis to create an expanded genetic code that incorporates the unnatural peptides. Credit: [Donoghue 2013].
When compared to the use of natural peptide drugs, the strategies described here have successfully established site-directed insertion of noncanonical amino acids into proteins to generate ‘peptidomimetics’ and overcome the problems of pharmacokinetics and enzymatic stability [Donoghue 2013, Castro 2023] (Table 1). To develop more optimal orthogonal pairs, novel genomic recombineering methods such as multiplex automated genome engineering (MAGE) and clustered regularly interspaced short palindromic repeats (CRISPR) offer better options [Wang 2009, Doudna, Charpentier 2014]. The high-throughput capacity for structure-guided design and rational mutagenesis plays a significant role to engineer enzymatic activity and successfully redesign active sites for broad-ranging biomedical applications.
Table 1: Backbone modifications – biological applications and preferable secondary structure of peptidomimetics for precision medicine [Castro 2023].
Accelerated evolution - versatile methods of genomic diversity
One of the challenges of bioengineering is to disentangle specific factors that encode observed biological behaviors. Scientists often accomplish this by perturbing the cell to measure the effects of agitations on cellular physiology. Thus far, the development of new orthogonal aminoacyl-tRNA synthetase/tRNA pairs has led to the addition of approximately 70 unnatural amino acids to the genetic codes, in model organisms such as Escherichia coli, yeast, and mammalian cells (Figure 5). Escherichia coli is the workhorse organism of most synthetic biology experiments and is a widely used expression host [Liu 2010].
In fact, I briefly detailed bacterial expression systems within a practical setting with Escherichia coli to recombineer the human protein tropoelastin, when describing the ‘then nascent era’ of synthetic biology, on a previous post published here on Nature Portfolio. The increasingly multidisciplinary nature of modern science can promote the innovation of new theories and techniques with synthetic biology spearheading the niche [Meng 2020, Zhao 2023]. MAGE or multiplex automated genome engineering, for instance, represents a set of highly multiplexed single-stranded DNA-mediated methods of recombineering that were also first described in E. coli, and rapidly transferred into diverse prokaryotes and eukaryotic cell lines [Wang 2009, Wannier 2021].
Figure 5: Chemical diversity of amino acids in the standard and expanded genetic codes. Amino acid similarity reflects the substitution frequency of one amino acid for another in standardized sets of multiple sequence alignments. Credit: [Donoghue 2013].
Alongside synthetic biology, the sequential advent of systems biology can detail the high throughput -omics methods from genomics to transcriptomics, proteomics, and metabolomics for bottom-up engineering (another recently covered topic), to provide massive datasets that garner a more comprehensive understanding of complex biological networks, to facilitate the identification of pathological irregularities [Del Vecchio 2009, Donoghue 2013].
The advent of multiplex automated genome engineering (MAGE)
Most interdisciplinary concepts of genome engineering tease apart the workings of cellular processes to shed light on key biomolecular events governing the behavior of pathological cascades. For instance, MAGE in its mechanism-of-action can rapidly and continuously generate a diverse set of rapid genetic changes in a cyclic and scalable manner within cells (Figure 6) [Wang 2009]. By using the high-throughput technology, bioengineers have optimized the 1-deoxy-D-xylulose-5-phosphate biosynthesis pathway in E. coli, to overproduce an industrially significant isoprenoid lycopene as proof-of-concept [Lichtenthaler 1999].
Figure 6: Multiplex automated genome engineering or MAGE enables the rapid and continuous generation of sequence diversity at many targeted chromosomal locations across a large population of cells through the repeated introduction of synthetic DNA. Each cell contains a different set of mutations, producing a heterogeneous population of rich diversity. Credit: [Wang 2009, Wannier 2021]
The isoprenoid superfamily of compounds are precursors of metabolic pathways; integral in commercial biotechnology to deliver therapeutics, nutraceuticals, and fine chemicals [Klein-Marcuschamer 2007]. The premise of engineering ‘microbial cell factories’ has a stronghold in metabolic engineering, with broad-ranging impact across basic research and industry applications. A classic example of this complexity details the synthesis of isoprenoids beyond lycopenes by combining synthetic biology and systems biology for metabolic engineering in microbial cells [Klein-Marcuschamer 2007]. These early efforts have collectively seen through to bioengineer new compounds via protein engineering or genetic engineering methods [Tobias 2006].
Mechanisms-of-action: genome editing without inducing double-strand breaks
The MAGE method relies on oligonucleotide-mediated allelic replacement at multiple sites, and the introduction of synthetic DNA to facilitate genetic modifications at high efficiency within favorable evolutionary paths [Carr 2012]. Several years after the MAGE proof-of-concept study was conducted in E. coli, a research team incorporated the same method with eukaryotes to precisely edit multiple sites in Saccharomyces cerevisiae, without generating DNA double-strand breaks [Wrighton 2017, Barbieri 2017]. This is a significant feature, since the process of multisite editing is typically limited by double-strand break mechanisms due to three reasons (Figure 7):
• First, cleaving the genome is cytotoxic, and cell lethality increases when double-strand breaks are introduced across multiple target sites.
• Second, in eukaryotes double strand break repair is subject to additional, unwanted insertions or deletions for cleavage even after editing,
• Third, it is difficult to simultaneously modify many loci in a single cell due to the inefficiency of generating targeted single base pair edits with double-strand breaks.
Creating precise edits at single base pair resolution in eukaryotes is thus challenging via DNA double-strand breaks for applications of gene correction and genetic disease treatment [Barbieri 2017]. Most genetic diseases arise from point mutations. Methods that are in use to correct such defects nevertheless continue to rely on inefficient double strand DNA breaks. Generally, CRISPR-Cas9 induced double-strand breaks and non-homologous end joining repair offer a knock-in strategy for the site-specific introduction of nonnatural chemical groups into proteins in living cells [Meineke 2023]. While Cas9-guided deamination can edit DNA base-pairs efficiently without inducing a double strand break, the method is limited to specific mutations alone [Komor 2016].
Figure 7: Replication forks can be co-opted to introduce multisite mutations in eukaryotes, without the need for double-strand breaks [Barbieri 2017].
The multisite genetic editing technique of MAGE for eukaryotic genome engineering thus varies from most other eukaryotic genome editing methods such as Zinc finger nucleases and CRISPR-Cas9 [Doudna, Charpentier 2014], to introduce genomic modifications without creating double-strand breaks. While earlier methods of zinc finger nucleases (ZFNs) and transcription activator-like efficient nucleases (TALENs) recognize DNA sequences of interest and identify protein-DNA interactions to induce the usual double-strand breaks at genomic loci, their construction too remains laborious and costly [Barbieri 2017].
Comparatively, MAGE can be automated to generate large numbers of precise edits into a single cell during many cycles, for molecular evolution of single genes within cells for a lofty goal of re-engineering cells as powerhouses for synthetic biology. While this technique can recode the whole genome in eukaryotes, it can target viral genomes, bacteria, plasmids, and artificial chromosomes too [Gallagher 2014]. The goal is to tinker MAGE to overcome its inherent limitations and arrive at an optimal version for multisite genome editing of stem cells to treat cancer and other rare diseases, while expanding its industrial portfolio [Bohannon 2011, Singh 2015].
Bioengineering complex biological systems – from the lab to the clinic
Synthetic biology is accurately defined as a field of risk-takers, where researchers from multidisciplinary areas come together to design and develop ‘wild experiments,’ to hack complex biological systems and arrive at solutions to advance the fields of medicine and industrial biotechnology [Bohannon 2011]. This view is exemplified on this post, by highlighting multiple site editing techniques to change the function of a cell or of a protein, by simply manipulating its genetic code.
Decades of synthetic biology have seen to the development of the most hyped topics of the century, with landmark achievements that highlight the pinnacle of human invention [Meng 2020]. The preceding decade has seen standout technologies including Cello; an end-to-end computer-aided design platform for logic circuit construction in E. coli designed by Christopher Voigt and team [Neilsen 2016], as well as in vivo event recorders using DNA as a memory device to track biological events across time [Sheth 2018], and the capacity to use DNA for data storage, beyond genomics for archival potential [Church 2012].
Figure 8: A) synthetic biology platforms for diagnostics: platforms a-c indicate applications of engineered bacteria, mammalian synthetic biology, and phage-based diagnostics in sensing disease and producing a diagnostic readout. B) A modified design-build-test-learn-based framework can direct researchers to choose or engineer synthetic receptors for their applications in cell therapy or gene therapy. The ‘goal’ defines the design objectives for engineered cell or gene therapy, for clinical applications. Credit: [Zhao 2023, Teng 2024].
Among the variety of existing possibilities, I have focused on the integration of biotic signals such as ions, metabolites, nucleic acids, or proteins involved in signaling cascades, for genetic and epigenetic regulation at transcriptional, translational, and post-translational stages, to develop robust cell behaviors. The most promising practical aspects of the existing hype apply to cell and gene therapies, to treat and correct a range of rare diseases [Teng 2024]. The niche is rampant with targeted and personalized treatments such as CAR T (chimeric antigen receptor T) cell therapies to treat blood cancers [Kimbrel 2020], hematopoietic stem cells engineered to correct hematological disorders [Ferrari 2021], and gene therapies to treat spinal muscular atrophy and restore vision - that are already approved for clinical use [Cehajic-Kapetanovic 2023].
More recent efforts in the field of biomedicine have seen delicately designed and engineered synthetic receptors to regulate the function of therapeutic cells to fine-tune therapeutic intervention, alongside user-defined signals or biomarkers for clinical translation (Figure 8) [Teng 2024]. Synthetic receptors notably include CARs (chimeric antigen receptors) with a long-standing history of landmark achievements generated with natural or artificial components to endow designer cells with custom functions, to rewire the cellular input-output relationships [Teng 2024]. Such designer cells can be of mammalian origin to sense and respond to a variety of disease biomarkers to trigger downstream signaling and fine-tune custom therapeutic effects. By humanizing synthetic receptors, it is possible to expand their therapeutic applications through stem-cell engineering for cancer immunotherapy, to develop next-generation medicine [Li 2021].
The work here describes a very small fragment of the vast potential and promise of a growing multidisciplinary field with ample scope to understand the impact of synthetic biology in medicine and biotechnology. The research field is a fertile ground to devise and develop unprecedented experimental ideas for rapid progress in gene therapy and commercial biotechnology that have hitherto remained unreachable by established approaches.
Header Image: Gene editing and ethics, via the Harvard Magazine.
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1a01aa77535b9ecfb87b9fc36adbcd2f
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319,561,933,553,783,550
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Unknown
Dataset Information
0
Concordance of PD-L1 expression and CD8+ TIL intensity between NSCLC and synchronous brain metastases.
ABSTRACT: Programmed death-ligand 1 (PD-L1) is suggested to be a predictive biomarker in non-small-cell lung carcinoma (NSCLC). However, the differential expression of PD-L1 in primary lung tumor vs. synchronous metastases, especially brain metastasis (BM), remains unclear. This study assessed the concordance of PD-L1 expression on tumor cells and tumor-infiltrating lymphocytes (TILs) and CD8+ TIL intensity between primary lung tumors and synchronous BMs from 24 NSCLC patients. PD-L1, CD3, and CD8 positivity was determined by immunohistochemistry (IHC). PD-L1 scoring was based on the proportion of tumor cells with membranous expression of PD-L1 and the cutoff values <1%, 1-49%, and ?50%. CD3 and CD8 positivity in TILs was evaluated semi-quantitatively and the proportion of CD3+/CD8+ TILs was determined. PD-L1 expression on tumor cells and TILs was evaluated in relation to CD3+/CD8+ TIL proportions and the intensity of CD8+ TILs between the paired primary lung and BM tissues. In the primary lung tumors, PD-L1 positivity was observed in 25%, 37.5%, and 37.5% cases for the cutoff values <1%, 1-49%, and ?50%, respectively. PD-L1 expression on tumor cells was strongly correlated between the paired primary lung and BM tissues, in all cutoff groups. However, PD-L1 expression on TILs and the proportion of CD3+/CD8+ TILs were not strongly correlated in all three groups between the paired primary lung tumors and BMs. The intensity of CD8+ TILs was concordant in only 54.16% of the paired primary lung tumors and BMs. This study showed a high concordance of PD-L1 expression in neoplastic cells between primary NSCLC and synchronous BMs.
SUBMITTER: Batur S
PROVIDER: S-EPMC7416171 | BioStudies | 2020-01-01
REPOSITORIES: biostudies
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1a01aa77535b9ecfb87b9fc36adbcd2f
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-8,817,970,037,843,914,000
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+357 70070035
Holistic Approach
Holistic Approach
What is Holistic Medicine?
Holistic medicine is an integrated approach to healthcare that treats the whole person body, mind, spirit and emotions.
The holistic approach in medicine, emphasizes the need to analyze the patient physical, emotional, nutritional, social, environmental, spiritual and lifestyle values. The primary goal of the holistic approach is to achieve optimal health by gaining proper balance in life.
Holistic or else Integrative medicine, which is also called integrated, combines alternative medicine with evidence-based medicine. Practitioners claim that it treats the "whole person", focuses on wellness and health rather than on treating disease, and emphasizes the patient-physician relationship.
Holistic practitioners use a variety of treatment techniques. Depending on the practitioner's training, these may include:
• Western Medicine which includes all types of conventional medical treatment, encompassing surgery, chemotherapy, radiation, and physical therapy.
• Alternative medicine such as acupuncture, chiropractic care, homeopathy, naturopathy, and massage therapy.
• Psychological support. This may include psychotherapy, relaxation methods such als hypnosis, imagination, awareness, full mind exercises, relationship and spiritual counseling.
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How Much Weight Can You Lose on Phentermine in a Month?
The weight-loss drug phentermine (which is chemically similar to amphetamine) was originally approved for use in the 1950s and 1960s, but it was never really taken off the market due to issues with abuse. That is, people would often go above and beyond the recommended dose, which in turn led to more health problems. Although, in some instances, phentermine had serious side effects, such as high blood pressure, cardiac arrest, or death, the drug has proven to be incredibly effective at helping people shed off extra pounds and prevent obesity-related health problems.
Phentermine Has One Of The Highest Approved Doses
Based on the available clinical trial data, it seems that phentermine’s highest approved dose is 16 mg. This means that the recommended starting dose for the drug is 12.5 mg. After you start taking this dose, you should expect to lose around 2.2 pounds in the first week and then 0.7 to 1.1 pounds per week in the following weeks. At this point, you would need to continue taking the medication for at least 4 weeks to start seeing weight loss benefits. Some patients have even reported losing up to 5 pounds in the first week of treatment and 1 to 2 pounds per week thereafter.
No Longer Approved For Use
Although originally approved for use in the United States in the 1950s and 1960s, phentermine did not achieve widespread popularity until later in the decade. In 1966, a U.S. National Institute of Health report found that it was one of the most effective drugs in the treatment of obesity, noting that it worked in around 75% of patients who tried it. In the 1970s, physicians would often prescribe the medication to help patients control appetite and prevent obesity-related health problems, such as heart disease and type 2 diabetes. In fact, around this time, it was even approved for use in the treatment of sleep apnea, a serious sleep disorder where breathing is disrupted during sleep. In the 1980s, the FDA began to hear more reports of cardiovascular complications, such as abnormal heart rhythms and high blood pressure. This led to the drug’s removal from the market in the United States in 1987. Although, the medication was approved for use in the United States until 2004, it is no longer recommended for use due to its potential side effects. Instead, physicians are now opting to prescribe diet pills and exercise to their patients.
Phentermine Is Still Available For International Use
While the medication was once popularly available in the United States for use in the treatment of obesity, it never really took off in other countries. This is likely because it was too readily available in the States and people there began to abuse it. That is, patients would sometimes go above and beyond the recommended dose, which resulted in more severe side effects. It is still available for use in Canada, Mexico, and parts of Europe, where it is prescribed for the treatment of obesity. However, it is important to note that since phentermine was taken off the market in the United States, countries where it is still available have changed the labeling to indicate that the drug should no longer be used there.
In summary, the drug phentermine has one of the highest approved doses of any medication available, which makes it an attractive option for weight loss. However, since it was taken off the market in the United States due to safety concerns, people in other countries where it is still available should consult their doctors before using this medication.
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Question: What Infections Can Apple Cider Vinegar Cure?
Can Apple cider vinegar help with viruses?
Research has shown that apple cider vinegar has antimicrobial properties and can kill bacteria, yeasts, and fungal infections.
However, one study found that apple cider vinegar was not effective against influenza and may not have any effect against viruses, which are the cause of the common cold..
What is a natural antibiotic?
Hold the prescription: Try these 7 natural antibiotics insteadGoldenseal. Commonly consumed as a tea or taken as a supplement, the herb goldenseal (Hydrastis canadensis) is often combined with echinacea for the prevention or treatment of the common cold. … Pau d’arco. … Myrrh. … Oregano. … Thyme essential oil. … Neem oil. … Anise.
What Bacteria Does vinegar kill?
Vinegar only works against some germs, like E. coli and Salmonella. The best way to disinfect your home or workspace is to use an EPA-registered disinfectant.
Who should not take apple cider vinegar?
02/7When on diabetes drugs and Insulin Indeed, apple cider vinegar is known to prevent diabetes, but when you are already on diabetes drugs or on insulin, avoid having apple cider vinegar. These medications decrease your blood sugar level and when combined with ACV, your blood sugar might get too low.
Is turmeric an antibiotic?
The role of natural bioactive substances in treating infections has been rediscovered as bacterial resistance become common to most of the antibiotics. Curcumin is a bioactive substance from turmeric. Owing to antimicrobial properties, its prospect as an antibacterial agent is currently under focus.
Can you get rid of a bacterial infection without antibiotics?
Even without antibiotics, most people can fight off a bacterial infection, especially if symptoms are mild. About 70 percent of the time, symptoms of acute bacterial sinus infections go away within two weeks without antibiotics.
Does apple cider vinegar kill bacterial infections?
A 2018 research study found that ACV can be used to effectively treat infections caused by several common strains of bacteria.
Does apple cider vinegar kill fungus in the body?
ACV apparently breaks this protective coating down so your body can then kill the fungus. A: Thanks for sharing your approach. Researchers have noted that acetic acid (vinegar) has antifungal properties (Mycoses, May 2016).
Can a bacterial infection go away without antibiotics?
When Antibiotics Aren’t Needed Antibiotics are only needed for treating infections caused by bacteria, but even some bacterial infections get better without antibiotics. Antibiotics aren’t needed for many sinus infections and some ear infections.
What are the side effects of drinking apple cider vinegar everyday?
7 Side Effects of Apple Cider VinegarDelayed Stomach Emptying. … Digestive Side Effects. … Low Potassium Levels and Bone Loss. … Erosion of Tooth Enamel. … Throat Burns. … Skin Burns. … Drug Interactions.
Is apple cider vinegar an antifungal?
Apple cider vinegar (ACV) is a scientifically proven antifungal. Laboratory research shows that it can inhibit the growth of candida cultivating in a petri dish.
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Publication numberUS20020128563 A1
Publication typeApplication
Application numberUS 09/802,316
Publication dateSep 12, 2002
Filing dateMar 8, 2001
Priority dateMar 8, 2001
Also published asEP1365836A2, US6678547, US7248919, US20040193066, WO2002072196A2, WO2002072196A3
Publication number09802316, 802316, US 2002/0128563 A1, US 2002/128563 A1, US 20020128563 A1, US 20020128563A1, US 2002128563 A1, US 2002128563A1, US-A1-20020128563, US-A1-2002128563, US2002/0128563A1, US2002/128563A1, US20020128563 A1, US20020128563A1, US2002128563 A1, US2002128563A1
InventorsGerrard Carlson, Julio Spinelli
Original AssigneeCarlson Gerrard M., Spinelli Julio C.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Cardiac rhythm management system using time-domain heart rate variablility indicia
US 20020128563 A1
Abstract
A cardiac rhythm management system that provides an indication of patient well-being based on the autonomic balance between the sympathetic and parasympathetic/vagal components of the autonomic nervous system, using time-domain processing of frequency components of a heart rate interval signal.
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Claims(32)
What is claimed is:
1. A method including:
detecting heart contractions over a time period;
obtaining a time-domain first signal representing time intervals between the detected heart contractions;
filtering the first signal to obtain a time-domain second signal including frequency components substantially in a first frequency band, wherein the second signal is influenced by both sympathetic and parasympathetic components of an autonomic nervous system;
filtering the first signal to obtain a time-domain third signal including frequency components substantially in a second frequency band, wherein the third signal is influenced by the parasympathetic component of the autonomic nervous system and not substantially influenced by the sympathetic component of the autonomic nervous system; and
providing an indication associated with a balance between the sympathetic and parasympathetic components of the autonomic nervous system based on the time-domain second and third signals.
2. The method of claim 1, further including obtaining a variance of at least one of the second and third signals.
3. The method of claim 1, further including squaring at least one of the second and third signals.
4. The method of claim 3, further including lowpass filtering the squared one of the second and third signals.
5. The method of claim 1, further including:
obtaining a variance of each of the second and third signals; and ratioing the variance of the second and third signals.
6. The method of claim 5, in which obtaining the variance of each of the second and third signals includes:
squaring each of the second and third signals; and
lowpass filtering the squared second and third signals.
7. The method of claim 5, further including lowpass filtering the ratioed variance of the second and third signals.
8. The method of claim 5, in which providing an indication associated with an autonomic nervous system includes extracting a signal feature of the ratioed variance of the second and third signals.
9. The method of claim 1, in which filtering the first signal to obtain a time-domain second signal includes bandpass filtering using a lowpass cutoff frequency that is approximately equal to 0.15 Hz and a highpass cutoff frequency that is approximately equal to 0.04 Hz.
10. The method of claim 1, in which filtering the first signal to obtain a time-domain third signal includes bandpass filtering using a lowpass cutoff frequency that is approximately equal to 0.40 Hz and a highpass cutoff frequency that is approximately equal to 0.15 Hz.
11. The method of claim 1, in which detecting heart contractions includes detecting ventricular heart contractions.
12. The method of claim 1, in which providing an indication associated with a balance between the sympathetic and parasympathetic components of the autonomic nervous system includes selecting a time period on which the indication is based by comparing intervals between heart contractions, during the time period, to a predetermined criterion.
13. The method of claim 12, in which selecting the time period on which the indication is based includes comparing intervals between heart contractions, during the time period, to a maximum value and an average value.
14. The method of claim 12, in which selecting the time period on which the indication is based is performed by determining when a patient is asleep or resting and using the selected time period for providing the indication associated with the autonomic nervous system.
15. The method of claim 1, further including providing therapy to the heart based on the indication associated with the balance between the sympathetic and parasympathetic components of the autonomic nervous system.
16. The method of claim 15, in which providing therapy includes providing antitachyarrhythmia therapy.
17. The method of claim 16, in which providing antitachyarrhythmia therapy includes providing antitachyarrhythmia pacing.
18. The method of claim 16, in which providing antitachyarrhythmia therapy includes providing an antiarrhythmic drug.
19. The method of claim 1, in which obtaining a time-domain first signal representing time intervals between the detected heart contractions includes:
detecting R-wave peaks;
measuring time intervals between R-wave peaks;
providing a continuous-time R-R interval signal based on the measured time intervals between R-wave peaks; and
sampling the continuous-time R-R interval signal using a plurality of sample points, that, when the sample points span a pair of R-R intervals, are weighted according to a time associated with each R-R interval in the pair of R-R intervals.
20. A method including:
detecting heart contractions over a time period;
obtaining a time-domain first signal representing time intervals between the detected heart contractions;
bandpass filtering the first signal, using a lowpass cutoff frequency that is approximately equal to 0.15 Hz and a highpass cutoff frequency that is approximately equal to 0.04 Hz, to obtain a time-domain low frequency (LF) signal;
bandpass filtering the first signal, using a lowpass cutoff frequency that is approximately equal to 0.40 Hz and a highpass cutoff frequency that is approximately equal to 0.15 Hz, to obtain a time-domain high frequency (HF) signal; and
obtaining variances of the LF and HF signals; and
ratioing the variances of the LF and HF signals to obtain an LF/HF ratio signal.
21. The method of claim 20, in which obtaining the variances includes squaring the IF and HF signals to obtain squared LF and HF signals, and lowpass filtering the squared LF and HF signals.
22. The method of claim 20, in which ratioing the variances of the LF and HF signals further includes lowpass filtering the LF/HF ratio signal to provide the indication of the balance between the sympathetic and parasympathetic components of the autonomic nervous system.
23. A system including:
a heart contraction detection module, providing a heart rate interval signal carrying information regarding intervals between heart contractions;
a low frequency (LF) bandpass filter, coupled to the detection module for receiving the heart rate interval signal, the LF bandpass filter providing a time-domain LF signal output that is influenced by both sympathetic and parasympathetic components of an autonomic nervous system;
a high frequency (HF) bandpass filter, coupled to the detection module for receiving the heart rate interval signal, the HF bandpass filter providing a time-domain HF signal output having higher frequency components than the LF signal output, the HF signal output being influenced by the parasympathetic component of the autonomic nervous system and not substantially influenced by the sympathetic component of the autonomic nervous system;
an LF variance module coupled to the LF bandpass filter for receiving the LF signal, the LF variance module providing a resulting LF variance signal;
a HF variance module, coupled to the HF bandpass filter for receiving the HF signal, the HF variance module providing a resulting HF variance signal; and
an autonomic balance indicator module, coupled to the LF and HF variance modules, and providing an indication of a balance between sympathetic and parasympathetic components of the autonomic nervous system based on the LF and HF variance signals.
24. The system of claim 23, further including a ratioing module, coupled to each of the LF and HF variance modules for receiving the LF and HF variance signals, and providing an output ratio of the LF and HF variance signals, and in which the autonomic balance indicator is coupled to the LF and HF variance modules through the ratioing module, and in which the autonomic balance indicator provides an indication of the balance between sympathetic and parasympathetic components of the autonomic nervous system based on the ratio of the LF and HF variance signals provided by the ratioing circuit.
25. The system of claim 24, further including a lowpass filter, coupled to the ratioing circuit for receiving and filtering the ratio of the LF and HF variance signals for output to the autonomic balance indicator module.
26. The system of claim 23, in which the LF bandpass filter includes a lowpass cutoff frequency that is approximately equal to 0.15 Hz and a highpass cutoff frequency that is approximately equal to 0.04 Hz.
27. The system of claim 23, in which the HP bandpass filter includes a lowpass cutoff frequency that is approximately equal to 0.40 Hz and a highpass cutoff frequency that is approximately equal to 0.15 Hz.
28. The system of claim 23, further including a therapy module, adapted to be coupled to a heart, the therapy module providing therapy to the heart based at least in part on the indication of the balance between the sympathetic and parasympathetic components of the autononic nervous system.
29. The system of claim 23, further including a sleep detector module, coupled to the heart contraction detection module and the autonomic balance indicator module, the sleep detector module selecting a period of time for evaluating autonomic balance based on detected time intervals between heart contractions.
30. The system of claim 23, in which the heart rate contraction detection module includes a R-R interval sampling and filter module providing a sampled data heart rate interval signal including R-R interval information.
31. The system of claim 23, in which the heart rate contraction detection module includes a means for performing the function of sampling a continuous-time R-R interval signal and providing a filtered sampled data heart rate interval signal output including R-R interval information.
32. A system including:
a heart contraction detection module, providing a heart rate interval signal carrying information regarding intervals between heart contractions;
a bandpass filter, coupled to the detection module for receiving the heart rate interval signal, the bandpass filter providing a time-domain bandpass filtered signal output;
an variance module coupled to the bandpass filter for receiving the bandpass filtered signal, the variance module providing a resulting variance signal;
an autonomic balance indicator module, coupled to the variance module, and providing an indication of a balance between sympathetic and parasympathetic components of an autonomic nervous system, based on the variance signal; and
an antitachyarrhythmia therapy module, adapted to be coupled to a heart, the therapy module providing antitachyarrhythmia therapy to the heart based at least in part on the indication of the balance between the sympathetic and parasympathetic components of the autonomic nervous system.
Description
TECHNICAL FIELD
• [0001]
The present system relates generally to cardiac rhythm management systems and particularly, but not by way of limitation, to such a system using time-domain heart rate variability indicia.
• BACKGROUND
• [0002]
When functioning properly, the human heart maintains its own intrinsic rhythm, and is capable of pumping adequate blood throughout the body's circulatory system. However, some people have irregular cardiac rhythms, referred to as cardiac arrhythmias. Such arrhythmias result in diminished blood circulation. One mode of treating cardiac arrhythmias uses drug therapy. Drugs are often effective at restoring normal heart rhythms. However, drug therapy is not always effective for treating arrhythmias of certain patients. For such patients, an alternative mode of treatment is needed. One such alternative mode of treatment includes the use of a cardiac rhythm management system. Such systems are often implanted in the patient and deliver therapy to the heart.
• [0003]
Cardiac rhythm management systems include, among other things, pacemakers, also referred to as pacers. Pacers deliver timed sequences of low energy electrical stimuli, called pace pulses, to the heart, such as via an intravascular leadwire or catheter (referred to as a “lead”) having one or more electrodes disposed in or about the heart. Heart contractions are initiated in response to such pace pulses (this is referred to as “capturing” the heart). By properly timing the delivery of pace pulses, the heart can be induced to contract in proper rhythm, greatly improving its efficiency as a pump. Pacers are often used to treat patients with bradyarrhythmias, that is, hearts that beat too slowly, or irregularly. Such pacers coordinate atrial and ventricular contractions to improve pumping efficiency. Cardiac rhythm management systems also include coordination devices for coordinating the contractions of both the right and left sides of the heart for improved pumping efficiency.
• [0004]
Cardiac rhythm management systems also include defibrillators that are capable of delivering higher energy electrical stimuli to the heart. Such defibrillators also include cardioverters, which synchronize the delivery of such stimuli to portions of sensed intrinsic heart activity signals. Defibrillators are often used to treat patients with tachyarrhythmias, that is, hearts that beat too quickly. Such too-fast heart rhythms also cause diminished blood circulation because the heart isn't allowed sufficient time to fill with blood before contracting to expel the blood. Such pumping by the heart is inefficient. A defibrillator is capable of delivering an high energy electrical stimulus that is sometimes referred to as a defibrillation countershock, also referred to simply as a “shock.” The countershock interrupts the tachyarrhythmia, allowing the heart to reestablish a normal rhythm for the efficient pumping of blood. In addition to pacers, cardiac rhythm management systems also include, among other things, pacer/defibrillators that combine the functions of pacers and defibrillators, drug delivery devices, and any other implantable or external systems or devices for diagnosing or treating cardiac arrhythmias.
• [0005]
One problem faced by physicians treating cardiovascular patients is assessing patient well-being for providing a prognosis or for adjusting therapy to improve the patient's prognosis. Heart rate variability (“HRV”) is thought to provide one such assessment of cardiovascular health. The time interval between intrinsic ventricular heart contractions changes in response to the body's metabolic need for a change in heart rate and the amount of blood pumped through the circulatory system. For example, during a period of exercise or other activity, a person's intrinsic heart rate will generally increase over a time period of several or many heartbeats. However, even on a beat-to-beat basis, that is, from one heart beat to the next, and without exercise, the time interval between intrinsic heart contractions varies in a normal person. These beat-to-beat variations in intrinsic heart rate are the result of proper regulation by the autonomic nervous system of blood pressure and cardiac output; the absence of such variations indicates a possible deficiency in the regulation being provided by the autonomic nervous system.
• [0006]
The autonomic nervous system itself has two components: sympathetic and parasympathetic (or vagal). The sympathetic component of the autonomic nervous system is relatively slow acting, and is associated with a tendency to raise heart rate, blood pressure, and/or cardiac output. The parasympathetic/vagal component of the autonomic nervous system, which provides a relatively faster response than the sympathetic component, is associated with a tendency to reduce heart rate, blood pressure, and/or cardiac output. A proper balance between the sympathetic and parasympathetic components of the autonomic nervous system is important. Therefore, an indication of this balance of the components of the autonomic nervous system, which is sometimes referred to as “autonomic balance,” “sympathetic tone,” or “sympathovagal balance,” provides a useful indication of the patient's well-being.
• [0007]
One technique for providing an indication of the balance of the components of the autonomic nervous system is provided by the beat-to-beat heart rate variability, as discussed above. More particularly, intrinsic ventricular contractions are detected. The time intervals between these contractions, referred to as the R-R intervals, are recorded after filtering out any ectopic contractions, that is, ventricular contractions that are not the result of a normal sinus rhythm. This signal of R-R intervals is typically transformed into the frequency-domain, such as by using fast Fourier transform (“FFT”) techniques, so that its spectral frequency components can be analyzed. Two frequency bands are of particular interest: a low frequency (LF) band in the frequency (“f”) range 0.04 Hz≦f<0.15 Hz, and a high frequency (HF) band in the frequency range 0.15 Hz≦f≦0.40 Hz. The HF band of the R-R interval signal is influenced only by the parasympathetic/vagal component of the autonomic nervous system. The LF band of the R-R interval signal is influenced by both the sympathetic and parasympathetic components of the autonomic nervous system. Consequently, the ratio LF/HF is regarded as a good indication of the autonomic balance between sympathetic and parasympathetic/vagal components of the autonomic nervous system. An increase in the LF/HF ratio indicates an increased predominance of the sympathetic component, and a decrease in the LF/HF ratio indicates an increased predominance of the parasympathetic component. For a particular heart rate, the LF/HF ratio is regarded as an indication of patient wellness, with a lower LF/HF ratio indicating a more positive state of cardiovascular health.
• [0008]
Such spectral analysis of the frequency components of the R-R interval signal has required an FFT (or other parametric transformation, such as autoregression) transformation from the time domain into the frequency domain. Implantable cardiac rhythm management devices, however, typically do not presently have the dedicated hardware to perform such FFT transformations. Even if an implantable cardiac rhythm management device did have such dedicated FFT hardware, performing the transformation would be computationally expensive, requiring increased power consumption, and shortening time during which the implanted battery-powered device can be used before its replacement is required. Therefore, there is a need to provide such an indication of patient well-being without requiring a computationally expensive transformation of the R-R interval signal into the frequency domain.
• SUMMARY
• [0009]
This document describes a cardiac rhythm management system that provides an indication of patient well-being based on the autonomic balance between the sympathetic and vagal components of the autonomic nervous system, using time-domain processing of frequency components of a heart rate variability signal.
• [0010]
In one embodiment, the cardiac rhythm management system provides a method that detects heart contractions over a time period. A time-domain first signal represents time intervals between the detected heart contractions. The first signal is filtered to obtain a time-domain second signal including frequency components substantially in a first frequency band. The first signal is also filtered to obtain a time-domain third signal including frequency components substantially in a second frequency band that is different from the first frequency band. Based on the second and third signals, the system provides an indication associated with an autonomic nervous system.
• [0011]
In another embodiment, the cardiac rhythm management system provides a method that detects contractions of a heart over a time period. A time-domain first signal represents time intervals between the detected heart contractions. The first signal is filtered to obtain a time-domain second signal having frequency components substantially in a first frequency band. The system provides a substantially real-time time-domain indication, based on the second signal, of a balance between a sympathetic and a parasympathetic/vagal components of an autonomic nervous system. In a further embodiment, the system delivers therapy to a heart based on this indication of autonomic balance.
• [0012]
In another embodiment, the cardiac rhythm management system includes a heart contraction detection module, providing a heart rate interval signal carrying information regarding intervals between heart contractions. A bandpass filter is coupled to the detection module for receiving the heart rate interval signal. The bandpass filter provides a time-domain bandpass filtered signal output. A variance module is coupled to the bandpass filter for receiving the bandpass filtered signal. The variance modules provides a resulting variance signal. An autonomic balance indicator module is coupled to the variance module, and provides an indication of a balance between sympathetic and parasympathetic components of an autonomic nervous system, based on the variance signal. In a further embodiment, a therapy module, which is adapted to be coupled to a heart, provides therapy to the heart based at least in part on the autonomic balance indication. Other aspects of the invention will be apparent on reading the following detailed description of the invention and viewing the drawings that form a part thereof.
• BRIEF DESCRIPTION OF THE DRAWINGS
• [0013]
In the drawings, which are not necessarily drawn to scale, like numerals describe substantially similar components throughout the several views. Like numerals having different letter suffixes represent different instances of substantially similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.
• [0014]
[0014]FIG. 1 is a schematic/block diagram illustrating generally one embodiment of portions of a cardiac rhythm management system.
• [0015]
[0015]FIG. 2 is a schematic/block diagram illustrating generally one embodiment of portions of a heart rate interval extraction module.
• [0016]
[0016]FIG. 3 is a graph illustrating generally one embodiment of a technique for processing a signal that includes R-wave information including providing a substitute R-wave to replace a premature ventricular contraction (PVC) or ectopic beat.
• [0017]
[0017]FIG. 4 is a graph illustrating generally one embodiment of a technique for processing a signal that includes R-wave information, including forming a continuous-time R-R interval signal and a sampled data heart rate interval signal that includes R-R interval information.
• [0018]
[0018]FIG. 5 is a graph illustrating generally one embodiment of a technique for sampling and filtering a continuous-time R-R interval signal to obtain a resulting sampled data heart rate interval signal that includes R-R interval information.
• [0019]
[0019]FIG. 6 is a graph illustrating generally one embodiment of a LF/HF signal representing autonomic balance based on an illustrated corresponding heart (e.g., R-R) interval signal, and illustrating generally one embodiment of a technique for extracting one or more features of the LF/HF signal to further quantify a state of the patient's well-being.
• [0020]
[0020]FIG. 7 is a schematic/block diagram illustrating generally one embodiment of portions of a cardiac rhythm management device including a therapy module providing therapy based at least in part on the indication of autonomic balance.
• [0021]
[0021]FIG. 8 is a schematic/block diagram illustrating generally one embodiment of portions of a cardiac rhythm management system including a means (such as a “sleep” detector) for identifying one or more particular time periods of interest for obtaining the indication of autonomic balance.
• [0022]
[0022]FIG. 9 is a graph illustrating generally one technique for identifying a time period of interest for determining autonomic balance, in which the time period of interest is based on data regarding the intervals between heart contractions.
• DETAILED DESCRIPTION
• [0023]
In the following detailed description, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration specific embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that the embodiments may be combined, or that other embodiments may be utilized and that structural, logical and electrical changes may be made without departing from the spirit and scope of the present invention. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present invention is defined by the appended claims and their equivalents. In the drawings, like numerals describe substantially similar components throughout the several views. Like numerals having different letter suffixes represent different instances of substantially similar components. The term “and/or” refers to a nonexclusive “or” (i.e., “A and/or B” includes both “A and B” as well as “A or B”).
• [0024]
The present methods and apparatus will be described in applications involving implantable medical devices including, but not limited to, implantable cardiac rhythm management systems such as pacemakers, cardioverter/defibrillators, pacer/defibrillators, biventricular or other multi-site coordination devices, and drug delivery systems. However, it is understood that the present methods and apparatus may be employed in unimplanted devices, including, but not limited to, external pacemakers, cardioverter/defibrillators, pacer/defibrillators, biventricular or other multi-site coordination devices, monitors, programmers and recorders, whether such devices are used for providing a diagnostic, a therapy, or both a diagnostic and a therapy.
• [0025]
This document describes a cardiac rhythm management system that provides an indication of patient well-being, based on an autonomic balance between the sympathetic and vagal components of the autonomic nervous system, using time-domain processing of frequency components of a heart rate interval signal.
• [0026]
[0026]FIG. 1 is a schematic/block diagram illustrating generally one embodiment of portions of a cardiac rhythm management system 100. In this embodiment, system 100 includes, among other things, a cardiac rhythm management device 105 and a leadwire (“lead”) 110 for communicating signals between device 105 and a portion of a living organism, such as a heart 115. Embodiments of device 105 include, among other things, bradycardia and antitachycardia pacemakers, cardioverters, defibrillators, combination pacemaker/defibrillators, drug delivery devices, and any other implantable or external cardiac rhythm management apparatus capable of providing therapy and/or diagnostics to heart 115. System 100 may also include additional components such as, for example, a remote programmer 190 capable of communicating with device 105 via a transmitter or receiver, such as telemetry transceiver 187.
• [0027]
In one embodiment, portions of system 100 (e.g., device 105) are implantable in the living organism, such as in a pectoral or abdominal region of a human patient, or elsewhere. In another embodiment, portions of system 100 (e.g., device 105) are alternatively disposed externally to the human patient. In the illustrated embodiment, portions of lead 110 are disposed in the right ventricle, however, any other positioning of lead 110 is included within the present invention. For example, in various alternative embodiments, lead 110 may alternatively be positioned in a location that is associated with the right atrium and/or superior vena cava, the coronary sinus or great cardiac vein, the left atrium or ventricle, epicardially, or elsewhere. In one embodiment, lead 110 is a commercially available bipolar pacing lead having a tip electrode 120 and a ring electrode 125 configured to be disposed in a right ventricle of heart 115. System 100 can also include other leads and/or electrodes in addition to lead 110, appropriately disposed, such as in or around heart 115, or elsewhere. For example, in one external embodiment, device 105 is not implanted and lead 110 provides external surface ECG electrode connections for sensing heart signals. In a unipolar example, implanted device 105 itself includes one or more electrodes for sensing heart signals or providing therapy, such as housing electrode 130 or header electrode 135.
• [0028]
[0028]FIG. 1 also illustrates generally portions of device 105, together with schematic illustrations of example connections to the various electrodes. Device 105 includes a heart contraction detection module 137 that receives intrinsic heart signals from electrodes that are communicatively associated with heart 115. Module 137 provides an output heart rate interval signal carrying information about the time intervals between heart contractions. Because, as discussed above, the interval between heart contractions manifests intrinsic variations, the output heart rate interval signal provided by module 137 includes heart rate variability information.
• [0029]
In one embodiment, module 137 includes a sense amplifier 140, which, in this illustration, is coupled to tip electrode 120 and ring electrode 125 for receiving intrinsic heart signals that include electrical depolarizations corresponding to heart contractions (right ventricular heart contractions, in this example). Sense amplifier 140 detects such input heart depolarizations and provides an output electrical signal carrying such information to subsequent portions of device 105. In a further embodiment, sense amplifier 140 also includes filtering or other signal processing circuits for detecting the desired electrical depolarizations associated with heart contractions, as is known in the art. Device 105 also includes an analog-to-digital (A/D) converter 145, which receives the sensed electrical depolarization signal and provides an output digital representation thereof. In a further embodiment, A/D converter 145 includes associated sample and hold circuits for sampling the electrical signal output by sense amplifier 140. Peak detector 150 receives the digitized signal from A/D converter 145 and detects signal peaks associated with heart contractions. In this embodiment, these signal peaks are the R-waves in the QRS complexes associated with ventricular heart contractions. However, it is understood that the disclosed structure and techniques could also be used to detect atrial heart contractions using P-waves associated with atrial depolarizations.
• [0030]
In the illustrated embodiment, peak detector 150 outputs information about the timing of each R-wave to heart interval extraction module 155. Based on this information, heart rate interval extraction module 155 provides a discrete-time signal that is periodically sampled, i.e., the time difference between such samples is uniform. Each such sample includes an associated time interval (“heart rate interval”) corresponding to the detected heart rate.
• [0031]
[0031]FIG. 2 is a schematic/block diagram, illustrating generally one embodiment of portions of heart rate interval extraction module 155, which includes an ectopic detection/processor module 200, an R-R interval calculation and storage module 205, and an R-R interval sampling and filter module 210. Heart rate interval extraction module 155 outputs a sampled data heart rate interval signal 215 that includes R-R interval information. In FIG. 2, ectopic detection/processor module 200 receives the detected R-wave peaks from peak detector 150. Module 200 deletes, replaces, and/or suppresses from further processing ectopic R-waves (sometimes referred to as premature ventricular contractions, or “PVCs”). Ectopic R-waves do not result from a normal sinus rhythm, that is, from a conducted atrial depolarization.
• [0032]
In one embodiment, ectopic detection/processor module 200 also receives detected P-wave peaks, corresponding to atrial depolarizations, from electrodes associated with an atrium and sensed by an atrial sense amplifier (not shown). This embodiment of operating ectopic detection/processor module 200 is illustrated generally by the signal graph of FIG. 3. The input signal 300 of FIG. 3 illustrates instances of detected R-wave peaks, depicted by upward arrows. In FIG. 3, any detected R-wave for which no P-wave was detected since the preceding R-wave is deemed a PVC. PVCs are suppressed in output signal 305 from further signal processing. Such PVCs are replaced in output signal 305 by a substitute R-wave at the estimated time at which such R-wave would have occurred had there not been an ectopic event. In FIG. 3, beat number 10 represents a PVC that is replaced by a substitute R-wave.
• [0033]
Many techniques exist for generating a substitute R-wave. In one example, the PVC is replaced by a substitute R-wave placed at time that is interpolated from that of following and preceding nonectopic R-waves. Because PVCs sometimes occur in groups, however, other techniques may also be used. Such techniques include using a moving average-like technique, spline-like technique, or median-like technique. A predetermined number of R-R intervals before and/or after the PVC may be used to calculate a time of occurrence of the substitute R-wave when a PVC occurs.
• [0034]
[0034]FIG. 4 is a signal graph illustrating generally one embodiment of the operation of R-R interval calculation and storage module 205 and R-R interval sampling and filter module 210. R-R interval calculation and storage module 205 receives, from ectopic detection/processor module 200, a signal 220 including R-wave peaks with any substituted R-waves. Module 205 includes a timer that determines the R-R time interval between detected R-wave peaks, and stores the R-R intervals in memory to provide a resulting continuous time R-R interval signal 225. Signal 225 is sampled by module 210 to produce the resulting sampled data heart rate interval signal 215, which includes R-R interval information.
• [0035]
In one embodiment, module 210 includes a sampling module that samples signal 225 at a sampling frequency, fs exceeding the Nyquist criterion. For example, if the maximum expected heart rate (after PVC removal) is 180 beats per minute, then a sampling rate that is greater than or equal to 6 Hz is sufficient. In one embodiment, this sampling module portion of module 210 also includes a finite impulse response (FIR) lowpass filter (or similar lowpass filter, averager, decimator, or downsampler) that provides a smoothed sampled data heart rate interval signal 210.
• [0036]
In one embodiment, a three sample point FIR filter is used to sample and filter continuous time R-R interval signal 225. These sample points are separated from each by a time interval, ΔTs, where ΔTs is the inverse of the sampling frequency, fs. In operation, if the three sample points (at times t=ti−1, t1, and ti+1) fall within the same R-R interval of continuous time R-R interval signal 225, then that R-R interval value is used as the corresponding output sample, RRi. Otherwise, if the three sample points span a pair of R-R intervals (i.e., first and second R-R intervals, RR1 and RR2) on continuous time R-R interval signal 225, a weighted average of the first and second R-R interval values is used as the corresponding output sample, RRi. Each of the first and second R-R interval values is weighted according to the fraction of the time, (ti+1−ti−1) associated with that one of the first and second R-R intervals, RR1 and RR2. Operation of such a filter is illustrated generally by FIG. 5.
• [0037]
[0037]FIG. 1 also illustrates a time-domain heart rate variability (HRV) signal processing module 160 that receives the heart rate interval signal 215 from heart rate interval extraction module 155, and provides a resulting indicator of patient well-being. In one embodiment of HRV signal processing module 160, the input heart rate interval signal 215 is received by a low frequency (LF) bandpass filter 165 and by a high frequency (HF) bandpass filter 170. In one embodiment, LF bandpass filter 165 is a finite impulse response (FIR) type filter having a lowpass cutoff frequency that is approximately equal to 0.15 Hz, and a highpass cutoff frequency that is approximately equal to 0.04 Hz. As a result, LF bandpass filter 165 outputs a filtered heart rate interval signal having frequency components that are primarily approximately between 0.04 Hz and 0.15 Hz inclusive. In this embodiment, HF bandpass filter 170 is an FIR type filter having a lowpass cutoff frequency that is approximately equal to 0.40 Hz, and a highpass cutoff frequency that is approximately equal to 0.15 Hz. As a result, HEF bandpass filter 170 outputs a filtered heart rate interval signal having frequency components approximately between 0.15 Hz and 0.40 Hz inclusive. Appropriate infinite impulse response (IIR) filter structures could also be used. Since the ultimate measurement of patient well-being is based on variance, waveform distortion is not of great concern and, therefore, the filter need not provide linear phase.
• [0038]
LF variance module 175 and HF variance module 180 receive the output signals from LF bandpass filter 165 and HF bandpass filter 170, respectively. These variance modules 175 and 180 each perform a variance-type or similar computation, respectively outputting LF variance and HF variance signals to ratio module 185. In one embodiment, variance modules 175 and 180 each include a squaring circuit (i.e., a circuit that multiplies the input by itself to provide an output signal that is equivalent to the input signal raised to the second power) followed by a lowpass filter (or integrator or averager) to provide the resulting output signal. This squaring and lowpass filtering operation is equivalent to a variance computation that provides an indication of heart rate variability within the associated frequency range. In one embodiment, the lowpass filter used by variance modules 175 and 180 is an IIR type filter having a single lowpass pole with exponential weighting of past samples occurring during a moving time window that is approximately between 2 and 5 minutes, inclusive, in length.
• [0039]
Ratio module 185 receives the LF and HF variance output signals from LF variance module 175 and HF variance module 180, respectively, and divides the value of the LF variance by the HF variance. The resulting LF/HF ratio output by ratio module 185 provides an indication of the sympathovagal balance between the sympathetic and parasympathetic/vagal components of the autonomic nervous system. As discussed above, an increase in the LF/HF ratio indicates an increased predominance of the sympathetic component, and a decrease in the LF/HF ratio indicates an increased predominance of the parasympathetic component. For a particular heart rate, the LF/HF ratio is regarded as an indication of patient wellness, with a lower LF/HF ratio indicating a more positive state of cardiovascular health. In one embodiment, this LF/HF ratio output by ratio module 185 is itself used as a patient wellness indicator. In further embodiments, however, this LF/HF ratio signal undergoes further processing, as discussed below.
• [0040]
For example, in one such further embodiment, the LF/HF ratio signal output by ratio module 185 is received by a lowpass filter (or integrator or averager) 190 to provide additional smoothing of the indication of patient well-being. In one such example, lowpass filter 190 is implemented as an exponential-weighted averager (i.e., more recent samples are weighted more than older samples) over a sliding time window that is approximately between 2 minutes and 5 minutes inclusive, such as about 5 minutes. The resulting smoothed LF/HF ratio signal output by lowpass filter 190 provides a more stable indication of the patient's sympathovagal balance; one such smoothed LF/HF ratio signal is illustrated generally, by way of example, but not by way of limitation, in the graph of FIG. 3, together with a corresponding sample heart rate interval signal on which the smoothed LF/HF ratio is based.
• [0041]
In a still further embodiment, the smoothed LF/HF ratio signal is received by autonomic balance indicator module 195 for further processing. In one example, module 195 includes a peak detector for obtaining the local minima and/or maxima of the smoothed LF/HF ratio signal, as illustrated in FIG. 6. Thus, in one embodiment, the indication of autonomic balance is based on one or more features of the smoothed LF/HF ratio signal, such as the local minima (e.g., using the lowest local minima during a given time period, an average of the local minima during a given time period, etc.), the local maxima, slope of the smoothed LF/HF ratio signal, and/or slope of portions of the LF/HF envelope (e.g., lines drawn between successive local minima and lines drawn between successive local maxima). In a further embodiment, the desired indication of autonomic balance is communicated by telemetry transceiver 187 to external programmer 190, such as for processing and/or for visual, audible, or other diagnostic display to the physician or other user.
• [0042]
[0042]FIG. 7 is a schematic/block diagram illustrating generally, by way of example, and not by way of limitation, one embodiment of portions of device 105 including a controller 700 and a therapy module 705. Therapy module 705 provides cardiac rhythm management therapy to heart 115 via electrodes that are communicatively associated therewith. Examples of such therapy include, without limitation, atrial or ventricular pacing therapy, antitachyarrhythmia therapy, multi-site coordination therapy such as biventricular pacing, drug delivery. In one such embodiment, the parameters of such therapy are adjusted and/or optimized by controller 700 based at least in part on one or more indications of sympathetic/parasympathetic balance obtained from time-domain HRV signal processing module 160. For example, such parameters for providing dual chamber pacing therapy are well known in the art (e.g., rate, amplitude, pulsewidth, AV-delay, etc.); such parameters are adjusted, either individually or in combination, to increase or decrease a particular indication of autonomic balance (e.g., to decrease the lowest local minima of the smoothed LF/HF signal). Such parameter optimization is performed either in device 105 or, alternatively, in external programmer 190.
• [0043]
In another example, the real-time (i.e., not substantially delayed) indicator of sympathetic/vagal balance provided by module 160 alerts the device to time periods during which heart 115 is particularly susceptible to tachyarrhythmias, such as when the smoothed or unsmoothed LF/HF signal increases (e.g., beyond a threshold value or at a rate that exceeds a threshold rate). In this embodiment, the increase in the LF/HF indication predicts the likely present or future onset of a tachyarrhythmia and, as a result, controller 700 triggers the delivery of preventative antitachyarrhythmia therapy to prevent the occurrence of the tachyarrhythmias. Such antitachyarrhythmia therapy includes antitachyarrhythmia pacing (ATP) sequences and/or antiarrhythmic drug therapy using drugs that increase parasympathetic and/or decrease sympathetic activity. Thus, this embodiment provides real-time control of therapy delivery based on the then-existing (or slightly delayed) indication of sympathetic/vagal balance.
• [0044]
[0044]FIG. 8 is a schematic/block diagram illustrating generally, by way of example, but not by way of limitation one embodiment of portions of device 105 in which controller 700 (or, alternatively, external programmer 190) includes a “sleep detector” module 800 or other similar module for identifying one or more particular time periods of interest for obtaining the indication of sympathetic/vagal balance. In one embodiment, sleep detector 800 includes a long term (e.g., 24 hour) averager 805 for storing the long term average interval between heart contractions (e.g., R-R interval), and a long term (e.g., 24 hour) peak detector 810 for storing a corresponding long term maximum interval between heart contractions (e.g., maximum R-R interval). In this embodiment, autonomic balance indicator module 195 of FIG. 1 provides an indication of patient well-being based on sympathetic/vagal balance as obtained only when the interval between heart contractions exceeds the long term average value over a time period that: (1) extends forward in time from the time corresponding to the maximum interval between heart contractions to the first time, Tf, at which the interval between heart contractions drops back to the long term average value; and (2) extends backward in time from the time corresponding to the maximum interval between heart contractions to a time that is not more than 8 hours (by way of example) earlier than the time Tf. Intervals during this time period in which the interval between heart contractions is less than the long term average value are, in one embodiment, ignored for the purposes of providing an indication of sympathetic/parasympathetic balance. This described technique is illustrated generally, by way of example, but not by way of limitation, in FIG. 9. This technique is particularly useful for ascertaining longer term (e.g., over a period of days or months) variations in the patient's well-being as determined from sympathetic/parasympathetic balance. Because exercise, posture, and even being awake affect the sympathetic/parasympathetic balance, these factors are de-emphasized for ascertaining such longer term variations in the patient's well-being. While the time periods used in such techniques may be deemed “sleep,” as referred to in this document by the use of the term “sleep detector module,” it is understood that such times may not correspond exactly to periods during which the patient is sleeping. Other suitable time periods may also be used to de-emphasize components of the patient's sympathetic/vagal balance that tend to confound an assessment of long-term well-being.
• Conclusion
• [0045]
This document describes, among other things, a cardiac rhythm management system that provides an indication of patient well-being based on the autonomic balance between the sympathetic and vagal components of the autonomic nervous system, using time-domain processing of frequency components of a heart rate interval signal. It is to be understood that the above description is intended to be illustrative, and not restrictive. For example, the above-described embodiments may be used in combination with each other. Many other embodiments will be apparent to those of skill in the art upon reviewing the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. In the appended claims, the terms “including” and “in which” are used as plain-English equivalents of the respective terms “comprising” and “wherein.”
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Classifications
U.S. Classification600/509
International ClassificationA61N1/372, A61N1/362
Cooperative ClassificationA61B5/4035, A61N1/362, A61N1/3622, A61N1/37252
European ClassificationA61N1/362A2
Legal Events
DateCodeEventDescription
Jul 9, 2001ASAssignment
Owner name: CARDIAC PACEMAKERS, INC., MINNESOTA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CARLSON, GERRARD M.;SPINELLI, JULIO C.;REEL/FRAME:011965/0006;SIGNING DATES FROM 20010531 TO 20010601
Jul 13, 2007FPAYFee payment
Year of fee payment: 4
Jun 15, 2011FPAYFee payment
Year of fee payment: 8
Jul 1, 2015FPAYFee payment
Year of fee payment: 12
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Peptide immunotherapy for childhood allergy - addressing translational challenges
Abstract
Allergic sensitisation usually begins early in life. The number of allergens a patient is sensitised to can increase over time and the development of additional allergic conditions is increasingly recognised. Targeting allergic disease in childhood is thus likely to be the most efficacious means of reducing the overall burden of allergic disease. Specific immunotherapy involves administering protein allergen to tolerise allergen reactive CD4+ T cells, thought key in driving allergic responses. Yet specific immunotherapy risks allergic reactions including anaphylaxis as a consequence of preformed allergen-specific IgE antibodies binding to the protein, subsequent cross-linking and mast cell degranulation. CD4+ T cells direct their responses to short "immunodominant" peptides within the allergen. Such peptides can be given therapeutically to induce T cell tolerance without facilitating IgE cross-linking. Peptide immunotherapy (PIT) offers attractive treatment potential for allergic disease. However, PIT has not yet been shown to be effective in children. This review discusses the immunological mechanisms implicated in PIT and briefly covers outcomes from adult PIT trials. This provides a context for discussion of the challenges for the application of PIT, both generally and more specifically in relation to children.
Introduction
Allergic disease including atopic eczema, allergic rhinitis, allergic asthma and food allergy causes significant patient morbidity and economic costs to healthcare systems [1, 2]. Current clinical management primarily relies on allergen avoidance, treating symptoms as they arise (often using medications such as β2 agonist inhalers, antihistamines and adrenaline) and generalised suppression of immune responses (e.g. using corticosteroids). Therapeutic blockade of cytokines such as interleukin-5 (IL-5) and of IgE have had varied clinical results and such approaches are reserved for highly selected patient groups at present [35]. Many allergic patients will first experience symptoms during childhood [6] and allergic sensitisation may begin very early in infancy, even prenatally [7, 8]. Children with atopy are at risk of developing new sensitisations and additional allergic conditions as they get older [1, 9]. Identifying atopic children early and modifying disease progression is therefore a hugely attractive therapeutic goal [10].
Evidence suggests a key role for CD4+ T cells, particularly the T helper (Th) 2 subset, in allergy. These cells express the transcription factor GATA-binding protein 3 (GATA-3) and can produce allergy-associated cytokines such as IL-4, IL-5 and IL-13 which are implicated in a host of allergic responses such as eosinophil recruitment and airway hyperreactivity [reviewed in [11]]. Th2 cells also provide B cells with help, driving immunoglobulin class-switching towards allergen-specific IgE [11]. Less commonly, and often in concert with Th2 cells, other helper subsets such as Th1, Th17 and Th9 cells have also been implicated in the pathogenesis of allergic asthma in some patients [reviewed in [12]]. Therapeutic targeting of allergen-reactive CD4+ T cells therefore has the capacity to abrogate downstream allergic responses [11]. One way of doing this is through specific immunotherapy (SIT) which targets CD4+ T cells via the administration of protein allergen. First used over a century ago [13], much of SIT's therapeutic effects have been shown to result from the induction of tolerance of allergen-reactive CD4+ T cells so they no longer mount an allergic response to the allergen. This can occur either through direct effects on allergen-reactive T cells and/or through the actions of T regulatory cells [14]. SIT can significantly improve symptoms in allergic patients [15], therapeutic effects can be long-lasting [16] and SIT for allergic rhinitis may reduce the likelihood of future asthma development [reviewed in [17]]. Yet SIT can also be risky. Pre-existing allergen-specific IgE can bind to multiple sites on protein allergen, leading to IgE cross-linking on mast cells, inducing mast cell degranulation and subsequent allergic reactions, even anaphylaxis [1820].
Such SIT-associated risks can be overcome by identifying short peptides from within the protein allergen to which the CD4+ T cell response is directed [10]. Such "immunodominant" peptides can bind efficiently to major histocompatibility complex II (MHC II) to induce T cell responses and can therefore be used to generate T cell tolerance, while their short length and lack of tertiary conformational structure do not facilitate IgE cross-linking [21]. Such therapeutic application of peptides [hereafter referred to as peptide immunotherapy (PIT)] was first developed in rodent autoimmune disease models [22]. However, clinical translation of PIT has been faster for allergy than for autoimmune disease [10]. The early manifestation and often progressive nature of allergic disease means that maximising PIT's disease-modifying potential would require targeting allergic children (Figure 1). However, clinical trials of PIT have so far not included children and the need for scrupulous safety concerning novel paediatric treatments necessitates further understanding of the mechanisms involved in successful PIT.
Figure 1
figure1
Proposed model of the effects of PIT on disease progression in children with severe atopy. Evidence suggests that in susceptible individuals, allergic sensitisation begins early in life, even prenatally, preceding development of allergic conditions such as eczema. The number of allergens an individual is sensitised to and the number of diagnosed allergic conditions can increase with age. Inducing tolerance to an allergen using PIT early, rather than later, in life has the potential to reduce sensitisation to additional allergens and reduce the risk of progression to multiple allergic conditions particularly for children with severe atopy.
Immunological mechanisms of PIT
PIT harnesses the body's capacity to induce peripheral T cell tolerance. This capacity is paramount to prevent inflammatory responses both to harmless exogenous antigens and to self antigens [23]. Lack of pathogen-associated or inflammation-associated "danger signals" in such circumstances promote a tolerogenic rather than an inflammatory response. Hence, administering a soluble peptide in the absence of danger signals (e.g. in the absence of lipolysaccharide (LPS) and/or an adjuvant) can induce tolerance, whereas administration of the same peptide with an adjuvant promotes an inflammatory/immunogenic response [21]. Soluble peptides administered by intranasal, oral, intravenous, subcutaneous and intradermal routes all have the potential to induce tolerance [2427].
Dendritic cells
In order to elicit a T cell response, peptide must be presented to T cells by antigen presenting cells in the context of MHC II, facilitating engagement of the T cell receptor (TCR). Dendritic cells (DCs), antigen presenting cells optimally able to stimulate T cells, are strongly implicated in driving tolerance. CD11c-deficient mice (lacking conventional DCs, plasmacytoid DCs and Langerhans cells) develop spontaneous autoimmunity, implicating DCs in the maintenance of peripheral tolerance [28]. Peptide is rapidly presented on DCs after therapeutic administration [29]. It appears that the activation status of the DC is the prime orchestrator of whether or not a T cell becomes tolerant since "immature" DCs expressing low levels of costimulatory molecules have been found to induce T cell tolerance, in contrast to activated DCs [25, 30]. Considering that different DC subtypes may be tissue-specific with particular anti-inflammatory or pro-inflammatory characteristics [31], the nature of DC-T cell interactions, and hence the mechanism of tolerance induction, could vary with different PIT delivery routes.
T cells and the 3 Pillars of Tolerance
The strength of the TCR signal induced by a peptide can affect the outcome of PIT. Peptides with strong MHC II avidity form a stable peptide-MHC II interaction, hence generate a strong TCR signal and have an improved ability to induce tolerance [32]. This may be due to a resultant rapid, and synchronous T cell response [33]. Studies, predominantly in mice, have shown that the induction of T cell tolerance is likely to be effected by three fundamental mechanisms - deletion, adaptation and regulation [34]. All have variably been thought to contribute to the effects of PIT [2527, 35, 36], however, certain mechanisms may be more therapeutically desirable than others.
Deletion
PIT can lead to targeted deletion of CD4+ T cells [25]. This mechanism is advantageous in that deletion removes the possibility of such cells reverting to pathogenicity in the future. High dose PIT and/or induction of a strong but transient TCR signal appear to favour deletion [25, 37].
Adaptation
T cells can also be rendered tolerant through anergy - a state of unresponsiveness. A particular form of T cell anergy, known as adaptive tolerance, may be most relevant in vivo[38]. Adaptive tolerance is associated with inhibition of proliferation and cytokine production and has been demonstrated, to varying degrees, to occur after PIT in several murine and human studies [35, 36, 3941]. One drawback is that adaptive tolerance is not necessarily permanent, and persistence of the peptide may be required to maintain tolerance [39]. Hence, adaptive tolerance alone may be insufficient to maintain long-term therapeutic effects after a short course of treatment.
Regulation
Several subsets of T regulatory cells capable of constraining immune responses have been described [reviewed in [42]]. Generating regulatory T cells using PIT is therapeutically desirable because of the potential for long-lived suppression of unwanted allergic responses. Using PIT to induce allergen-reactive T regulatory cells also has the potential to down-regulate responses to other allergens. This "bystander suppression" [10] could be particularly beneficial in the allergic lung where multiple potential allergens are continually encountered, and because allergic lung inflammation has been found to increase the likelihood of developing allergic sensitisation to additional aeroallergens [43].
Different T regulatory cell subsets vary in their mechanism(s) of action and whether or not they express the transcription factor Foxp3. In fact, there are limited data concerning the ability of PIT to induce Foxp3+ T regulatory cells. That said, peptide-reactive Foxp3+ T regulatory cells were generated in a model using a peptide complex designed to specifically target peptide to DCs, ensuring peptide uptake and presentation [44]. Interestingly, generation of Foxp3+ T regulatory cells was reduced using high dose peptide or when peptide was presented by activated DCs [44].
One means whereby T regulatory cells often effect regulation is via production of immunosuppressive cytokines such as IL-10. In beekeepers, the frequency of IL-10 producing allergen-reactive T cells has been found to increase following tolerance induction to bee venom, which develops naturally in response to multiple bee stings [45]. Some murine studies of PIT have clearly demonstrated peptide-reactive T regulatory cells as the source of IL-10 following PIT [26]. IL-10 was also implicated in the therapeutic effects of PIT in a mouse model of allergic airways disease [35]. In one clinical study, IL-10 production increased from allergen-reactive T cells after PIT [36] and, in another, CD4+ T cells obtained from patients after PIT had suppressive activity in vitro[40]. It appears that the development of regulatory mechanisms following PIT may be favoured by regimens using repeated peptide dosing [26], however the optimal dosage and delivery regimes favouring regulation remain unclear.
Overall, therapeutic targeting of allergen-reactive (principally Th2) CD4+ T cells using PIT could, therefore, occur via deletion, adaptation, or regulation, or most probably a combination of these, echoing the varied mechanisms attributed previously to clinical effectiveness following SIT [[46, 47] and reviewed in [14]]. By targeting allergen-specific CD4+ T cells, and consequently modulating the provision of B cell help, PIT has also been found to be capable of beneficially altering allergen-specific antibody levels in some studies [[35] and discussed in [48]]. While deletion or adaptation of allergen-reactive Th2 cells should reduce allergic responses to that particular allergen (in part because reductions in Th2 cytokine production should inhibit the recruitment of innate immune cells such as eosinophils), the induction of regulatory mechanisms also confers the potential to suppress allergic responses to a variety of other allergens and is thus particularly advantageous. Existing data from limited human studies of PIT and from experimental murine PIT models (discussed above) indicate that the mechanism of tolerance induction that predominates following PIT is likely to be influenced by factors such as the nature of disease, the dose of peptide and the delivery route (Figure 2).
Figure 2
figure2
Possible impact of the mode of peptide delivery on the mechanisms of T cell tolerance. The nature of peptide delivery may influence the mechanism(s) of tolerance that are evoked. High dose peptide or peptides that lead to strong, transient TCR stimulation may favour deletion of allergen-reactive T cells. Persistence of peptide may favour adaptive tolerance and thus anergy/unresponsiveness of allergen-reactive T cells. Adaptive tolerance may, however, be reversed when peptide no longer persists. Regulatory mechanisms may be favoured by multi-dose regimens and/or low dose applications.
PIT in adult allergy trials
Since the first clinical PIT trial in adult allergic patients in the 1990s [49] significant advances have been made, but as yet there are no PIT studies involving children. The majority of clinical PIT studies have utilised peptides from the major cat allergen Fel d 1. The outcomes from these trials have been comprehensively reviewed previously [24] and will therefore not be covered in detail here. Briefly, however, initial trials used two 27 amino acid immunodominant Fel d 1 peptides. In those studies, short term improvements in lung function tests and improvements in clinical symptoms were described to a variable extent [4952]. More recently, there has been a move towards using shorter peptides, typically 15-17 amino acids in length. For Fel d 1, these were administered in the form of multiple, overlapping peptides encompassing the majority of the Fel d 1 protein. This has the advantage of maximising the number of allergen-reactive T cells that may be tolerised since patients may respond to multiple immunodominant peptides and immunodominant peptides may vary between individuals with different HLA types. Using shorter peptides also abrogated the risk of allergen-specific IgE binding which had occasionally been reported in studies using longer peptides [50]. This approach using multiple short, overlapping peptides reduced late-phase skin reactions to cat allergen, reduced proliferation of peripheral blood mononuclear cells (PBMC) to cat allergen and improved symptoms in some patients [53, 54]. In one study, PBMC responses to Fel d 1 peptides not included in the treatment vaccine were also reduced, implying linked-suppression, whereby tolerance induced to one peptide inhibits responses to other peptides within the same protein [35].
PIT also offers a potentially safer approach to allergen-specific immunotherapy for bee venom allergy, where SIT has a high frequency of severe allergic reactions [55]. PIT using peptides from the phospholipase A2 bee venom allergen has led to reduced T cell proliferation to those peptides and altered cytokine profiles e.g. by increasing IL-10, in some studies [36, 56, 57]. PIT has also been found to reduce the severity of allergic responses to deliberate bee stings [56].
PIT can therefore improve clinical outcomes in allergic patients in some instances. Furthermore, although PIT studies have so far focused on aeroallergens or venom allergies, future application of PIT for the treatment of food allergies is also a possibility, particularly given the continued identification of food allergen derived T cell epitopes [58]. It is, however, apparent from clinical studies so far that the effects of PIT can be variable and therapeutic effects are not necessarily seen across all clinical readouts. These inconsistencies are likely due in part to inter-trial variability of factors such as clinical readouts, PIT regimens, nature of disease and whether patients have received immunotherapy previously, which can complicate the assessment of clinical effectiveness.
Difficulties with PIT
Does PIT remove the risk of anaphylaxis associated with SIT?
The need to avoid severe IgE-driven hypersensitivity reactions, including anaphylaxis, is the primary reason why PIT rather than SIT may be more applicable to treating allergic children. Crucially, anaphylaxis and other severe hypersensitivity reactions are extremely rare after PIT. However, a PIT trial involving multiple sclerosis (MS) patients was halted due to a number of hypersensitivity reactions [59]. The peptide used contained sequence alterations designed to improve its therapeutic effects [an altered peptide ligand (APL), further discussed below]. Interestingly, it was levels of IgG1 and not IgE which were elevated in patients displaying hypersensitivity reactions [59]. This potential for generation of anaphylaxis-promoting peptide-specific IgG1 should be noted, although importantly this has not been reported in PIT allergy studies.
Long-term disease exacerbation
To our knowledge, there are no reports of PIT inducing long-term exacerbation of allergic disease. However, a phase II PIT trial using an APL in MS patients was discontinued due to disease exacerbations [60]. The APL displayed low immunogenicity and good tolerogenic potential in vitro yet seemed to promote an inflammatory T cell response in some patients. Exacerbation of disease has also been noted to occur using an unaltered peptide in a murine allergy model [61]. These rare examples highlight that there is a small risk that peptide administration may induce an inflammatory instead of a tolerogenic response in some circumstances, illustrating the need for incisive understanding of the mechanisms involved in PIT.
Late Asthmatic Reactions
PIT has induced late asthmatic reactions (LARs) in some patients during Fel d 1 allergy trials. LARs resulted in reduced lung function occurring at 2-3 hours following treatment and peaking at around 6 hours [62]. LARs were not associated with immediate hypersensitivity reactions/anaphylaxis. It appears that patients with certain HLA types are more likely to experience a LAR, although HLA type alone is not predictive of LAR development [63]. These MHC associations and the timing of LARs point to a T cell mediated mechanism implying that in some patients, cytokines produced by T cells responding to peptide can mediate airway hyperresponsiveness. Crucially, induction of LARs is not required in order to induce T cell tolerance [53] and LARs can be managed by careful regimen planning. In patients who have developed a LAR with PIT, repeating treatment within 2 to 8 weeks using the same dose of peptide induces T cell tolerance without promoting further LARs [53].
Challenges of applying PIT to a diverse population, with particular regard to children
HLA variation
CD4+ T cells recognise peptide in the context of MHC II and TCR specificity for a peptide is a function of the peptide itself and the MHC II it is presented on. The polygenicity and polymorphic nature of the human leucocyte antigen (HLA) region means that there is extensive variation in the MHC II molecules expressed by different individuals. Most allergens will contain multiple peptide epitopes which can vary in their ability to bind to different MHC II molecules [64], meaning that there will be differences in the allergen-derived peptides which are recognised by different patients' T cells. This poses difficulties for identifying immunodominant peptides capable of inducing tolerance in a HLA-diverse patient population [10]. HLA class II allele associations have been described for allergic diseases [65], yet the complex nature of allergy means that, with the exception of coeliac disease [66], these associations are weaker than for many autoimmune diseases [67]. Although technically possible to characterise immunodominant peptides on an individual patient basis, this approach is unlikely to be feasible both in terms of cost and practicality [68]. But HLA diversity does not preclude the application of PIT to a diverse population [68]. Peptides exhibit considerable promiscuity in their ability to bind to MHC II molecules. A single peptide may bind to MHC II molecules derived from multiple HLA loci [e.g. HLA-DP, -DQ and -DR [69]], and/or to multiple alleles of an HLA molecule [(e.g. HLA-DR1 and HLA-DR53) [70]]. Additionally, use of multiple, overlapping allergen-derived peptides increases the likelihood that a PIT vaccine will contain peptides recognised by a range of HLA-disparate individuals. These characteristics, together with the fact that some HLA types are more common than others, means that a strategic selection of a small number of allergenic peptides could be used to treat a wide range of patients.
Nature of the peptide
There are advantages to altering the sequence of a therapeutic peptide. APLs have defined amino acid substitutions which can change MHC and/or TCR binding properties of the peptide [21]. Different alterations can modulate the T cell response elicited by the peptide e.g. APLs that instead of inducing an allergy-associated Th2 T cell response, generate a Th1 response. The latter induces cytokines such as interferon-γ (IFN-γ) which can sometimes antagonise allergic responses [71] and has been found to be expressed by an increased frequency of CD4+ cells in some PIT studies [72]. The stimulatory capacity of a peptide can also be modulated. A "superagonist" APL has an increased ability to stimulate a T cell response whereas an "antagonist" APL can inhibit T cell activation, even in the presence of an agonist. Antagonists have obvious therapeutic applications and have been shown capable of preventing disease in animal models [73, 74]. There is concern, however, that an APL defined as an antagonist from its effect in vitro on T cells with a limited TCR repertoire may behave differently in vivo on encountering a more diverse T cell repertoire [75]. Using APL antagonists therefore risks unpredictable effects, borne out by the aforementioned MS trial [60].
Other applications of APLs could be more amenable to clinical translation. For example, APLs can be generated to reduce the allergenicity of a peptide. Leech et al altered a myelin-based peptide reducing its IgG1 binding affinity while maintaining its tolerising capacity [76]. Hence, whilst antagonist APLs may not have widespread application, the potential to alter peptides to improve tolerogenicity or reduce allergenicity should not be dismissed.
Route
The most desirable route of delivery of PIT for children would be oral or intranasal as they are minimally distressing. PIT delivered in these ways can be effective in inducing tolerance [32, 77], raising hope that these routes may be applicable to the treatment of allergic children in future. It is also possible that a sublingual approach, which has been used to deliver SIT [78], may also prove applicable to PIT. At present however, most allergy-based clinical studies focus on subcutaneous or intradermal PIT administration.
Dose and Regimen
There remains no clear consensus as to the optimal peptide dose or regimen which have varied considerably in different trials [4951, 79]. Dose-escalation is advantageous because it is less likely to cause adverse effects and, if side effects such as a LAR develop following a particular dosage, withholding dosage increase until LAR is no longer provoked can be effective [79]. Different regimens may induce different tolerogenic mechanisms. For example, high dose regimens may be more likely to promote a deletional mechanism of tolerance [25] whereas lower dose or multi-dose regimens may provoke induction of IL-10 producing cells capable of regulation [26, 35]. Hence, low dose, incremental regimens may be more attractive therapeutically because of the potential for production of regulatory T cells which could exert their effects on pathogenic T cells reactive to other allergens.
A key question is how long PIT needs to be given to induce long-term tolerance? Limited data on this exist from PIT allergy studies which to date have focused on short-term clinical outcomes. However, tolerance following SIT has been demonstrated up to 7 years after completion of treatment [80]. Although these studies involve initial up-dosing followed by maintenance dosing for around 3 years, the frequency and duration of maintenance dosing necessary for long-term tolerance remains undefined. For PIT it is probable that a maintenance regimen will be required to generate long-term tolerance. Ideally such a regimen would be infrequent to encourage compliance, particularly for children. Additionally, maintenance dosage will need to be determined. A high maintenance dose may risk adverse events, particularly if a child has missed a previous dose. Indeed, a review of near fatal reactions to SIT found the majority occurred during maintenance and not during up-dosing [81]. It would be ideal if a low, infrequent maintenance dose was capable of preserving long-term tolerance.
Concurrent illness
Concurrent illness may hold particular relevance for application of PIT to children. Data concerning this do not exist for PIT. However, giving SIT during concurrent systemic illness has been associated with fatalities [20] and current guidelines advise against giving SIT during an acute systemic illness [82]. It may be that giving SIT during a period of systemic inflammation can precipitate an inflammatory response and exacerbate disease. It would therefore be advisable to apply these conditions to the use of PIT. There is, however, a lack of data concerning immunotherapy and concurrent viral infection. Children experience a higher frequency of viral infections than adults. Such infections may not cause systemic illness or fever but may still locally activate immune cells such as DCs [83]. Peptide presented to T cells by DCs which have been activated by a viral infection theoretically risks incurring an inflammatory response rather than a tolerant one. Interestingly, in a murine allergic airways model, concurrent influenza infection prevented tolerance induced by intranasal SIT and enhanced allergic inflammation of the airways [84]. In a different study, allergen exposure via the airways at the time of viral infection induced allergen-specific IgG1 and subsequently led to anaphylaxis upon allergen re-exposure [85]. Clearly, these examples may only represent the effects of exposure to whole protein allergen, not peptide, during severe, systemic viral infection. It is thus important to address whether a variety of viral infections, particularly mild non-systemic ones, have any detrimental impact on the outcome of PIT.
Conclusions
PIT holds promise for the treatment and modification of allergic disease. There have been significant advances in the application of PIT to adult allergic patients, and there is substantial scope for future opportunities for the application of PIT. Yet to maximise therapeutic efficacy necessitates translation to allergic children. For this, further understanding of the underlying mechanisms involved in PIT, potential confounding factors such as viral infection and the interplay between dose, regimen and route need to be further elucidated. Mechanistic studies utilising experimental models together with carefully structured, appropriately powered clinical trials looking at a host of outcome measures should aid future translation to the paediatric clinic.
Abbreviations
APL:
altered peptide ligand
GATA-3:
GATA-binding protein 3
HLA:
human leukocyte antigen
LARs:
late asthmatic reactions
LPS:
lipopolysaccharide
MHC:
major histocompatibility complex
PBMC:
peripheral blood mononuclear cells
PIT:
peptide immunotherapy
SIT:
specific immunotherapy
TCR:
T cell receptor.
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Correspondence to Jürgen Schwarze.
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All 3 authors framed the scope of the article, KJM wrote the article and SMA and JS contributed to refine the substance. All authors read and approved the final manuscript.
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Mackenzie, K.J., Anderton, S.M. & Schwarze, J. Peptide immunotherapy for childhood allergy - addressing translational challenges. Clin Transl Allergy 1, 13 (2011). https://doi.org/10.1186/2045-7022-1-13
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Keywords
• Allergy
• Children
• Peptide Immunotherapy
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E-Cancer Smoking and its own Related MEDICAL ISSUES
An electric cigarette is Vape Pen Battery really a device which simulates traditional tobacco smoking without actually taking tobacco products in to the body. It basically includes an Atomizer, a rechargeable power source like batteries, and a tank or cartridge. Rather than actual smoking tobacco, the user just inhales vapor instead.
So, precisely what are the ramifications of vaping? As with smoking, there are various negative effects associated with vaping. One particular effect is second hand smoking. Used smoking is harmful to your lungs just as much as smoking in most cases. Also, because e-cigs usually do not supply the actual flavor of a cigarette, users could be at risk of developing an oral fixation – a craving to suck on the electronic cigarettes rather than real cigarettes.
Nicotine is really a highly addictive substance. For long-term use, it has shown to be extremely toxic to both the body and the brain. It has additionally been shown that long-term cigarette smoking is extremely damaging to the heart. But, will there be really any correlation between vaping and long-term smoking? Will be the benefits of vaping simply a marketing ploy to help make the product more popular?
Studies on the subject haven’t found any significant correlation between long-term vaping and lung injury. That is particularly noteworthy since you can find so many different types of e Cigarettes available to buy right now. You can find electronic cigars, inhalators, gum, patches, lollipops, you name it! E-Cigarette companies are literally flying by the seat of their pants in terms of determining which product is most beneficial to advertise.
In addition to the increased threat of lung injury, gleam causal relationship between smoking and reduced brain development in children. In the same way that nicotine is incredibly toxic to the body, it really is equally toxic to the mind. Ingesting it during the developmental stages of a child’s life reduces her or his ability to learn and experience things. And, if they do manage to obtain lungs damaged through the use of tobacco products, it is likely that they will have problems with long-term neurological damage.
Probably the most compelling evidence that suggests a causal relationship between smoking and impaired brain development comes from young adults. Young adults, especially teens, are in the prime of their lives when they begin thinking about quitting tobacco products. Even though some research indicates that quitting cigarettes might help adults delay their aging and add years to their lives, many young adults simply do not want to quit. The fact that many of these young adults have not yet fully developed cognitive abilities when they begin smoking at an early age supports the belief that there could be a causal relationship between smoking and diminished brain development.
One method to test because of this causal link between smoking and diminished brain function would be to perform brain scans on people who quit and on those that do not quit. Those who are still smoking show abnormal brain activity while those who do not smoke show normal brain activity. There is absolutely no clear explanation for this finding. It might simply be that the increased amounts of certain chemicals such as dopamine in their bodies that are connected with smoking are enough to cause them to perceive things differently than those who don’t smoke. It could also be that the chemicals cause the activation of certain proteins of their brains. However, all these different chemical compounds may actually are likely involved in the development of brain dysfunction, and vaporizing nicotine has been found to be remarkably similar to the actions of many of these different chemicals.
The above studies are preliminary and more studies should be conducted in order to establish a conclusive link between smoking and the development of various types of respiratory and other health problems. In the meantime, it really is clear that e-cokers are putting themselves at risk of developing some very serious lung disease if they do not stop utilizing their cigarettes. Because of this, every e-smoker should consider whether or not she or he wants to continue smoking, especially if he or she is a person who frequently smokes. Lung disease isn’t something that will go away by itself. The easiest method to protect oneself is to stop smoking, especially if the smoker is a person who regularly uses an electric cigarette.
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You certainly can still build muscle without all those weight plates and barbells, like build muscle with only bodyweight exercises. But, of course, there’s a little more to the story about using bodyweight training to add muscle. Here’s what you need to know.You already know that lifting weights will help you build muscle. (And that heavy lifting won’t make you bulky!) But if you’re working out at home with no equipment except your own body, you might wonder whether you’ll still see gains—or, frankly, lose some you worked hard to get previously. The simple answer:
Can Bodyweight Exercises Build Muscle?
If you’re used to lifting super heavy at the gym, grabbing barbells, or moving weight on machines, replicating that at home can prove somewhat difficult, says Alexis Colvin, M.D., an orthopedic sports medicine surgeon at the Mount Sinai Health System. But that doesn’t mean you can’t build muscle with only bodyweight exercises; it just means you’ll have to switch up the way you typically train. Maybe for you, that means moving through exercises much more slowly or upping the reps, sets, or timing of each move. “In order to build muscle, you need to challenge the muscle,” says Colvin. So, whatever change it takes to challenge your muscles, that’s the goal. And figuring out what works best for you or what tests your body that most? Well, that’ll take some trial and error.
The advantages of bodyweight exercises are that you’re doing functional, compound movements that let you focus on form without the added resistance. You’ll get stronger in movement patterns you use in everyday life, plus you’ll work multiple joints and muscles at one time with exercises like squats, push-ups, and lunges, says Colvin. You also work many smaller muscles, particularly when doing stabilizing exercises, like bird dogs, planks, and single-sided moves, she adds. These types of moves target your upper and lower body, along with your core, challenging muscles you don’t always work with weights.
Some research has compared loaded exercises with bodyweight moves, showing similar results in how much muscle the participants gained. For example, one small study comparing a loaded bench press to a bodyweight push-up demonstrated similar muscle gains in the pecs and triceps after an eight-week period. Another small study on post-menopausal women at high risk for type 2 diabetes found that 12 weeks of high-intensity bodyweight interval training increased muscle mass to a similar extent as a combination of aerobic and resistance training. And, in another study, one group did a series of elbow flexion exercises (think: bicep curls) with a heavy load, and the other did the exercises with bodyweight, making sure to maintain tension throughout the full range of motion. The bodyweight group had a comparable increase in muscle size to the group with a heavy load.
To help you understand exactly how build muscle with only bodyweight exercises, though, it’s important to know how your muscles get bigger in the first place.
How Does the Body Build Muscle?
Building muscle mass—known in science as hypertrophy—involves challenging muscle tissue and increasing protein synthesis, which is the process of cells building new proteins, explains Molly Galbraith, C.S.C.S., co-founder of Girls Gone Strong. You can do this via exercise in three ways: creating mechanical tension, metabolic stress, or microtrauma. While most types of training will incorporate all three ways to induce hypertrophy, which results in the biggest benefit (plus, these systems tend to work together), different workout techniques may target one method more than the other, says Galbraith. You don’t need to design your workouts to focus on one or another, but it can be helpful to understand precisely how each method build muscle with only bodyweight exercises:
Mechanical tension: Mechanical tension typically comes into play during weightlifting. You load the muscle with enough resistance to create tension, causing cellular and molecular responses that then lead to gains, says Galbraith. Upping the number of reps and sets (aka the total volume) you do of each exercise can increase mechanical tension, too, which provides muscle-building benefits. (This is also part of the science behind progressive overload.) Slowing down the eccentric action or downward phase of a move, like lowering into a squat, might also provide some extra tension. For some people, certain bodyweight exercises offer enough resistance on their own, as well, like in a push-up or a pull-up.
Metabolic stress: That burning sensation you feel when you’re pulsing through squats, holding the bottom of a push-up, or on that final rep of sit-ups? That’s a result of metabolic stress, which occurs when metabolites (aka waste products that form as a result of exercise, such as lactate) build up in the muscle tissue, explains Galbraith. This causes hormonal, cellular, and growth factor reactions, offering another way to pump up your muscles. It can increase anabolic hormone release, (hormones like testosterone or growth hormone that stimulate protein synthesis), lead to cell swelling, and lead to an increase in growth factors, proteins that can stimulate tissue growth by promoting cell reproduction. (Related: How to Improve Your Lactate Threshold)
Microtrauma: This is when you get small tears in muscle tissue thanks to exercising—but, namely, resistance training. Your body then works to repair that damage and that jumpstarts muscle growth, says Galbraith. While any exercise can do this to your muscles (squats, planks, deadlifts, you name it), new moves you haven’t done before or haven’t performed can also cause this microtrauma. Dance, running, bodyweight moves, etc. can cause microtrauma—it’s not always a result of mechanical tension.
How to Increase the Muscle-Building Benefits of Bodyweight Exercise
So many options! There are numerous methods for switching up your typical bodyweight workout—even small changes can lead to bigger muscle gains. But Galbraith offers a few concrete tips for challenging your body and encouraging muscle building. These are in no particular order and the best way to incorporate these strategies is individualized. (Relayed: The Best Bodyweight Exercises for Getting Fit Anywhere)
Try one or all five of these tactics in your next workout and see what tests your muscles the most:
1. Increase reps and sets; decrease rest time. The more you do an exercise, the more you’ll increase the metabolic stress you put on your muscles. Do more reps and sets of bodyweight exercises than you’d typically do at the gym with weights for similar results. You also want to limit breaks between those reps and sets, too, without sacrificing proper form. This puts more stress on the muscle, promoting growth. In fact, research shows that low-load resistance training (with a light weight or bodyweight) combined with little rest may enhance metabolic stress and increase muscle size even more than lifting heavy weights and taking longer breaks. If you typically lift weights for about eight reps in the gym, try doing that same move for 20 reps at home with just your body.
2. Change the angle or tempo of the exercise. To increase microtrauma, try taking your lunges for a walk or stepping out on a diagonal. Or add an incline or decline to your push-ups, suggests Galbraith. Changing the angle can both incorporate other muscles into the move, but also work different parts of the same muscle group. It’s also a good idea to slow down the eccentric or downward phase of an exercise (like when you lower to the bottom of a deadlift) and then explode up (quickly moving up from a deadlift or hinged position). Another option: Slow down the entire exercise. For example, lower into a squat on a count of three, holding at the bottom for three, then stand up on another count of three. This increases the time your muscle is under tension, meaning you’re more likely to create microtraumas within your slow-twitch muscle fibers, which have more endurance capacity than fast-twitch fibers. (Try it: This 20-Minute HIIT Tempo Workout Plays with Speed In an Insane New Way)
3. Add some holds and half-reps. This can add more metabolic stress to the muscles, thus resulting in more gains. For example, if lunges feel easy, hold the bottom of the movement (both knees bent 90 degrees) for a few seconds before standing up. Or, step back into your lunge, lift halfway up, then drop back down before you come back up to standing. Also, try stopping short of standing all the way up from a squat or lunge, or stop short of lowering all the way down in a glute bridge. This works because you’re putting the muscle under tension for a longer period of time, or eliminating any points in the movement where the working muscle gets a break. (Related: Why You Should Add Partial Reps to Your Training and How to Do It)
4. Do more plyometrics. To increase the tension on your muscles, add some explosiveness to your moves. Squat jumps, lunge jumps, hinge jumps, burpees—they all count toward more muscle building. When a muscle is stretched, it leads to nerve firing that signals a concentric contraction (shortening of the muscle). A quicker stretch (like what happens during the explosive portion of a plyometric exercise) leads to a stronger nerve firing and greater resulting contraction of the muscle. That stronger contraction means your muscle is working harder, and will likely result in more microtrauma and thus more gains. One study on young soccer players found that those who performed plyometric moves had similar muscle gains to those who did resistance training.
5. Perform single-sided exercises. Switch your typical bilateral (or two-sided) exercises to unilateral (or one-sided) movements. That means turning a squat to a pistol squat, making your glute bridge a single-leg bridge, or turning your plank into a single arm (and/or leg) plank. These simple switches can increase the microtrauma to a muscle, as well as add more tension or load to that muscle, says Galbraith. Think about it: One side is handling all the weight rather than splitting it. (Related: What Is Unilateral Training and Why Is It Important?)
Never Stop Progressing
As with any type of exercise, there’s always a risk of hitting a plateau if you keep doing it over and over again without playing around with any variables or continuing to test your muscles in new ways. That’s why it’s important to progress your program, adding variations to the exercises and increasing the challenge on moves with the methods Galbraith mentions above—that’s how muscle building continues to happen.
“If everything starts to feel really easy, you’re probably not gaining much [muscle],” Colvin says. Keep that in mind as a sign to switch up your routine. If you’re working out at home and looking for a way to add external load, you can always try these moves with household items that trainers love.
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1a01aa77535b9ecfb87b9fc36adbcd2f
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862,806,235,946,271,200
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cosmetic stem cells
Article by: Perry Romanowski
Right now there are a bunch of cosmetic brand that claim to use stem cells to provide benefits. For example, there is the Swiss Botany brand with their apple stem cells or the Peter Thomas Roth rose stem cell product. cosmetic stem cells
The stem cells in these products have virtually no effect. You can bet that if you left the stem cells out of those formulas no one would be able to tell the difference. It is pure marketing hype and nothing more.
But stem cell technology does have some promise. Here is an excellent piece of research that shows scientists have grown human hair from stem cells. It’s pretty cool. They took human pluripotent stem cells and were able to coax them into converting into human hair follicles. This was all done in a lab and on human cell cultures but it represent the first time it was ever achieved. Apparently growing dermal stem cells outside of the body makes them quickly lose their hair producing properties.
There are two important things to note here which separates this research from the stem cell nonsense that is put into cosmetic products.
1. They use human stem cells. It baffles me that companies use apple or rose stem cells and expect that they will do anything on human skin.
2. Their results are modest. They make no claims that they’ve cured baldness or any other condition people would love to solve. Researchers are almost always (as they should be) reserved about the meaning of any experiment. This could just be a fluke that they can’t repeat.
This is a very promising result though and it will be interesting to see where this technology goes. Animal and then human trials are probably the next thing required. But it won’t be as simple as just rinsing your head in a stream of human stem cells or topically applying some stem cell cream. They have to actually do a tissue transplant to get it to work.
Stem cell technology is promising and I believe in the future there really will be some amazing things done with it. Just don’t believe the hype of stem cell containing creams that you see for sale now. The stem cells aren’t doing anything.
2 comments
1. Yuni So
Hi Perry,
Thanks for enlighting us about the supposingly non-working stem cell ingredients if they are applied topically.
Surprisingly, the rating on those Swiss Botany brand and Peter Thomas Roth are very high 4.5/5 +
How would it be possible to have so many happy customers that claimed those product work?
1. Perry Romanowski
Well, people are prone to be happy with their products when they spend a lot of money on them. Also, I’m sure the products are fine moisturizers. They just aren’t better than less expensive versions you could buy.
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1a01aa77535b9ecfb87b9fc36adbcd2f
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7,671,412,215,822,529,000
|
Does the sex of one's co-twin affect height and BMI in adulthood? A study of dizygotic adult twins from 31 cohorts.
Biol Sex Differ 2017 27;8:14. Epub 2017 Apr 27.
Institute for Molecular Medicine FIMM, University of Helsinki, P.O. Box 20, FI-00014 Helsinki, Finland.
Background: The comparison of traits in twins from opposite-sex (OS) and same-sex (SS) dizygotic twin pairs is considered a proxy measure of prenatal hormone exposure. To examine possible prenatal hormonal influences on anthropometric traits, we compared mean height, body mass index (BMI), and the prevalence of being overweight or obese between men and women from OS and SS dizygotic twin pairs.
Methods: The data were derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) database, and included 68,494 SS and 53,808 OS dizygotic twin individuals above the age of 20 years from 31 twin cohorts representing 19 countries. Zygosity was determined by questionnaires or DNA genotyping depending on the study. Multiple regression and logistic regression models adjusted for cohort, age, and birth year with the twin type as a predictor were carried out to compare height and BMI in twins from OS pairs with those from SS pairs and to calculate the adjusted odds ratios and 95% confidence intervals for being overweight or obese.
Results: OS females were, on average, 0.31 cm (95% confidence interval (CI) 0.20, 0.41) taller than SS females. OS males were also, on average, taller than SS males, but this difference was only 0.14 cm (95% CI 0.02, 0.27). Mean BMI and the prevalence of overweight or obesity did not differ between males and females from SS and OS twin pairs. The statistically significant differences between OS and SS twins for height were small and appeared to reflect our large sample size rather than meaningful differences of public health relevance.
Conclusions: We found no evidence to support the hypothesis that prenatal hormonal exposure or postnatal socialization (i.e., having grown up with a twin of the opposite sex) has a major impact on height and BMI in adulthood.
Download full-text PDF
Source
http://dx.doi.org/10.1186/s13293-017-0134-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408365PMC
June 2018
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Neurosci Biobehav Rev 2002
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Horm Behav 1986
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Personal Individ Differ 1994
CC Cohen-Bendahan et al.
Neurosci Biobehav Rev 2005
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Which phase of the nursing process includes care that can be delegated?
Which phase of the nursing process includes care that can be delegated?
Pae nursing clinical case examples
Attribution – You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
The research was conducted through the review and analysis of documents and the positions of the authors of different theories that support and relate how the work of nursing develops over time
Vilar (1976) considers that nursing has represented in each culture and each era “the set of rules, roles, practices and relationships that condition its action and its image in society” (p.35); hence its necessary presence in terms of shaping favorable living conditions, referring to quality and quantity of aspects that contributed to boast a healthy body for much longer. In this sense, Siles (1999) makes an anthropological analysis of nursing and relates it to the Anglo-Saxon term nurse, which designates the task of raising, feeding and caring in a general way, but nursing is more than that, it broadens its missionary spectrum, because it combines the task of nursing with the caregiver of the sick. Despite the fact that the lives of patients depended precisely on this care, nursing was underestimated for a long time.
What was nursing care like in prehistoric times?
Both were carried out through anamnesis, observation and divination. Divination practices such as the use of cards, palm reading, dream interpretation to see where the illness came from were used.
What was nursing care like in the Middle Ages?
Nursing in the Middle Ages was dominated by religion. It was believed that illness was a punishment from God for sins committed, the only way to cure someone was to pray for forgiveness.
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What was nursing care like in prehistoric times?
Most of the men are shown hunting, fishing, carving stone, making metal tools, participating in religious or symbolic activities or in charge of politics and war. In front of them, the women take care, cook, weave or simply do nothing.
Nursing assessment pdf
At this stage, initial data collection is carried out in relation to the patient in order to learn about his or her situation. The sources of information for obtaining data are usually the following: the patient’s medical history, the patient himself, his family or someone related to him. This information will be the basis for subsequent decision-making.
At this stage, a conclusion is reached based on the nursing assessment of the data carried out in the previous phase. The nursing diagnosis may be different from the medical diagnosis.
In this third phase, once the information from the various sources mentioned above has been evaluated and a nursing diagnosis has been made, the nursing care to be provided is established.
This stage is decisive in the nursing care process and involves the implementation of the decisions taken in the previous stage, i.e., the care that has been decided to be applied is carried out. In this phase it is very important to collect data in order to be able to evaluate them in the following phase.
How is the valuation done?
The physical examination is the assessment made, either in a cephalocaudal order or by organs and systems, using four techniques: inspection, palpation, percussion and auscultation. 1 Careful and critical inspection or observation of the user to determine physical characteristics.
What are the types of nursing assessments?
The clinical examination involves obtaining observable and objective information from the patient. The physical examination should be performed in cephalo-caudal direction, considering the different regions; using the four main methods of exploration, which are inspection, palpation, percussion and auscultation.
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What is the nursing care process?
The nursing care process (NCP) is the application of the scientific method in nursing care practice, which allows us to provide care in a rational, logical and systematic way, which is of vital importance when working in the emergency department.
Subjective data in nursing
Author:Dr. Jacinto BátizHead of the Palliative Care Unit of the San Juan de Dios Hospital. Santurce. VizcayaDr. Pilar LoncanDirector of the Palliative Care Unit of the Santa Susana Residence Foundation. Barcelona
The principles of basic ethics are general criteria that serve as a basis for the standards of action of a social or professional group. Throughout history their essence has been maintained while adapting to new realities. At present, the principles to which we refer have been formulated by various philosophical currents and from different realities such as the Anglo-Saxon and Mediterranean worlds.
The term bioethics appeared in 1970 and quickly received a strong impulse through the Belmont reports (1978) and the Principles of Biomedical Ethics by Beauchamp and Childress (1979). Four principles were thus established:
The principles of beneficence and nonmaleficence are complementary and may conflict with the principle of autonomy through the competence and authority of the healthcare professional, due to the asymmetry in the doctor-patient relationship arising from the physician’s possession of knowledge and the patient’s need for the professional’s expertise. The concept of beneficence itself is a construct that clinical practice, professional judgment and patient judgment collaborate to elaborate dynamically and contemporaneously.
What is nursing care?
The Nursing Care Process (PAE) is a term applied to a system of nursing interventions for the health care of the individual, family and community, involving the use of the scientific method for the identification of needs.
What is the application of the Nursing Care Process called?
The application of the scientific method in nursing care practice is the method known as the Nursing Care Process (P.A.E.). This method allows nurses to provide care in a rational, logical and systematic manner as a result of nursing assessment.
What was nursing like in the Modern Age?
In the modern period, the emergence of nursing continued to be strongly marked by Christian morality, the submission of women and the addition of another element: military discipline, with which the first apprentice nurses were trained.
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Nursing Process
Supervision of delegated care, reassessment of the patient, determination of the need for nursing professional assistance, implementation of nursing interventions and recording of nursing activities determination of the need for nursing professional assistance, reassessment of the patient, implementation of nursing interventions, supervision of delegated care and recording of nursing activities Reassessment of the patient, determination of the need for nursing professional assistance, implementation of nursing interventions, supervision of delegated care and recording of nursing activities . When objectives have been partially met or not met The patient is to blame for the outcome We should not modify our plan of care We should review or modify our plan of care We should terminate our plan of care.At what point does assessment need to be performed? While, or immediately after the application of a nursing order and at specified intervals Continuously until he/she achieves the objectives and at discharge Only when the patient is admitted While, or immediately after the application of a nursing order and at specified intervals and continuously until he/she achieves the objectives and at discharge.1.
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Ketosis has recently become a hugely popular topic and has received its share of both praise and criticism by the peoples, experts. Is being healthy or harmful in ketosis? And if it is beneficial for you or not, should everyone do it? On this web page, we are going to share with a lot of essential; information about the ketosis and we also try to show why it’s so essential for your healthy physical-psychological fitness.
What Is The Ketosis?
Ketosis is a powerful metabolic level, where your body uses fat and ketone rather than glucose as its necessary fuel of sources. Glucose is stored in your liver and released as needed for energy. Otherside, after carb intake is deficient for one to two days, these glucose stores decrease.
Your liver can make some glucose from the amino acids in the protein that you eat through a process called gluconeogenesis; it is powerful fuel supply. However, ketosis can 100% provide you with an alternative source of energy. And here we would like to you that the keto diet allows you to achieve ketosis instantly.
What Are The Benefits Of Ketosis?
Weight Management Quickly: In addition to providing a robust energy level. Ketosis can help us to reduce inflammation and oxidative, stress, anxiety, weight-management. Suppose you are suffering from an obesity problem. In that case, you need to get a keto diet plan which allows you to achieve ketosis that will completely useful to eliminate your over-fat quickly. Moreover, it will help you to achieve a healthy slim-fit thin body shape naturally.
Improve Diabetes And Prediabetes: In many people with type 2 diabetes or prediabetes, ketosis can help normalize blood sugar and insulin response properly, potentially leading to the stop of diabetes medication. Ketosis can give an extremely long-lasting fuel, energy, and supply during sustained exercise in both high-level.
Other Health – Benefits Of Ketosis: Exciting early research also shows that ketosis can be beneficial or useful for many different conditions, such as reducing the frequency and severity of migraine headaches, reversing PCOS, perhaps exacerbating traditional brain cancer therapy, possibly potentially Alzheimer’s disease Slowing down the progress of. Helping people live longer, lead healthier lives. However, high-quality research is needed to confirm these effects. All the above benefits you may achieve by ketosis.
Is Ketosis Safe For You Or Not?
Undoubtedly, if you need to take above health-benefits, then ketosis is beneficial for you. When you are on the keto diet. So, at that time. Your body ultimately processes in the ketosis. Many experts, health-care doctors think that due to sugar and carbohydrate withdrawal. Moreover, it could be due to change or transfer your gut bacteria. You might notice a temporary side effect like Headache, Fatigue, Brain fog, Irritability, Constipation, Trouble sleeping, Nausea, Stomachache, Dizziness, Sugar cravings, Cramps, Sore muscles, Bad breath, also known as ketosis breath.
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