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The impact of mental illness on cardiac outcomes: a review for the cardiologist.
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Traditional cardiac risk factors, such as smoking, hypertension and obesity, are widely accepted contributors to the onset and progression of cardiovascular disease (CVD), one of the foremost causes of morbidity and mortality worldwide. Largely overlooked, however, is the impact of mental health on cardiac disease. From extensive MEDLINE and PsycINFO searches, we have reviewed the association between specific psychiatric disorders and CVD-related morbidity and mortality, the efficacy and safety of their treatments, and plausible behavioral and biological mechanism through which these associations may occur. The preponderance of evidence suggests that depression, anxiety disorders, bipolar disorder and schizophrenia are all important cardiac risk factors, and patients with these disorders are at significantly higher risk for cardiac morbidity and mortality than are their counterparts in the general population. Antidepressants, antipsychotics, mood stabilizers and benzodiazepines are effective therapeutic interventions, and many are safe to use in cardiac populations. Some, such as selective serotonin reuptake inhibitors and atypical antipsychotics, may even improve cardiac outcomes in healthy individuals and patients with CVD, although more work is needed to confirm this hypothesis. A combination of behavioral and biological mechanisms underlies the association between cardiac disease and mental illness, many of which are shared across disorders. With further research, it may be learned that psychiatric treatments definitively reverse the detrimental effects of mental illness on cardiac health. Currently, however, the challenge lies in raising awareness of mental health issues in cardiac patients, so that basic but critical treatments may be initiated in this population.
| 19,004,512
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Effects of initial iron corrosion rate on long-term performance of iron permeable reactive barriers: column experiments and numerical simulation.
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Column experiments and numerical simulation were conducted to test the hypothesis that iron material having a high corrosion rate is not beneficial for the long-term performance of iron permeable reactive barriers (PRBs) because of faster passivation of iron and greater porosity loss close to the influent face of the PRBs. Four iron materials (Connelly, Gotthart-Maier, Peerless, and ISPAT) were used for the column experiments, and the changes in reactivity toward cis-dichloroethene (cis-DCE) degradation in the presence of dissolved CaCO3 were evaluated. The experimental results showed that the difference in distribution of the accumulated precipitates, resulting from differences in iron corrosion rate, caused a difference in the migration rate of the cis-DCE profiles and a significant difference in the pattern of passivation, indicating a faster passivation in the region close to the influent end for the material having a higher corrosion rate. For the numerical simulation, the accumulation of secondary minerals and reactivity loss of iron were coupled using an empirically-derived relationship that was incorporated into a multi-component reactive transport model. The simulation results provided a reasonable representation of the evolution of iron reactivity toward cis-DCE treatment and the changes in geochemical conditions for each material, consistent with the observed data. The simulations for long-term performance were also conducted to further test the hypothesis and predict the differences in performance over a period of 40 years under typical groundwater conditions. The predictions showed that the cases of higher iron corrosion rates had earlier cis-DCE breakthrough and more reduction in porosity starting from near the influent face, due to more accumulation of carbonate minerals in that region. Therefore, both the experimental and simulation results appear to support the hypothesis and suggest that reactivity changes of iron materials resulting from evolution of geochemical conditions should be considered in the design of iron PRBs.
| 19,004,521
|
Plaque and tangle imaging and cognition in normal aging and Alzheimer's disease.
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Amyloid plaques and tau neurofibrillary tangles, the pathological hallmarks of Alzheimer's disease (AD), begin accumulating in the healthy human brain decades before clinical dementia symptoms can be detected. There is great interest in how this pathology spreads in the living brain and its association with cognitive deterioration. Using MRI-derived cortical surface models and four-dimensional animation techniques, we related cognitive ability to positron emission tomography (PET) signal from 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([(18)F]FDDNP), a molecular imaging probe for plaques and tangles. We examined this relationship at each cortical surface point in 23 older adults (10 cognitively intact, 6 with amnestic mild cognitive impairment, 7 with AD). [(18)F]FDDNP-PET signal was highly correlated with cognitive performance, even in cognitively intact subjects. Animations of [(18)F]FDDNP signal growth with decreased cognition across all subjects (http://www.loni.ucla.edu/ approximately thompson/FDDNP/video.html) mirrored the classic Braak and Braak trajectory in lateral temporal, parietal, and frontal cortices. Regions in which cognitive performance was significantly correlated with [(18)F]FDDNP signal include those that deteriorate earliest in AD, suggesting the potential utility of [(18)F]FDDNP for early diagnosis.
| 19,004,525
|
Synthesis, evaluation and 3D QSAR analysis of novel estradiol-RGD octapeptide conjugates with oral anti-osteoporosis activity.
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To enhance the potency, reduce the side effects and improve oral property of estradiol in estrogen replacement therapy (ERT), 6 novel estradiol-RGD octapeptide conjugates have been prepared. In an ovariectomized mouse osteoporotic model, at an oral dosage of 110.3 nmol/kg per day, their anti-osteoporosis activity was significantly higher than that of estradiol and estradiol-RGD tetrapeptide conjugates, and their risks of thrombogenesis and endometrial hyperplasia were significantly lower than that of estradiol and estradiol-RGD tetrapeptide conjugates. Using QSAR module of Cerius2, the 3D QSAR was performed for both femur weights and femur ash weights of estradiol-RGD peptide conjugates receiving mice. The r(2) of the 3D QSAR equations up to 0.995 and 0.988 indicates that they are capable of predicting a comparatively exact anti-osteoporosis activity for a conjugate.
| 19,004,530
|
Podocalyxin selectively marks erythroid-committed progenitors during anemic stress but is dispensable for efficient recovery.
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Podocalyxin expression on Ter119(+) erythroblasts is induced following administration of erythropoietin (Epo) or phenylhydrazine treatment, but is notably absent on committed erythroid progenitors during homeostatic red cell turnover. Following high-dose Epo administration in vivo, podocalyxin surface expression is upregulated, in part, via a signal transducers and activators of transcription 5-dependent pathway and this expression has been postulated to play a role in the release of reticulocytes from hematopoietic organs into the periphery under conditions of increased erythropoietic rate. Here we have thoroughly addressed this hypothesis and further examined the expression profile of podocalyxin during Epo-induced erythroblast expansion and stress erythropoiesis. Following Epo induction, progenitor cells were sorted to characterize podocalyxin expression during stress. In addition, as podocalyxin-deficient mice die perinatally, we used chimeric mice reconstituted with wild-type or podocalyxin-deficient hematopoietic cells to analyze differences in response to high dose Epo administration and chemically induced anemia. Podocalyxin surface expression is rapidly upregulated in response to stress and marks early erythroid progenitors and erythroblasts. Despite loss of podocalyxin, chimeras exhibit normal basal erythropoiesis and no differences in erythroid progenitor proportions in the spleen and marrow in response to Epo. Further, podocalyxin is dispensable for efficient recovery from models of anemia. We demonstrate that podocalyxin is a highly specific marker of stress-induced blast-forming unit erythroid and colony-forming unit erythroid progenitors in mouse bone marrow and spleen. In addition, our findings suggest that podocalyxin is not necessary for efficient erythroblast expansion, erythroid differentiation, or reticulocyte release in response to Epo stimulation in vivo.
| 19,004,540
|
Assessing college students' perceptions of tolerance to alcohol using social cues: the Social Tolerance Index.
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Increased tolerance to alcohol is considered a risk factor for developing future problems. While college students are considered a high-risk population in relation to alcohol use it is suggested that tolerance operates differently in this population than in chronic drinking samples. Individuals' perceptions about their level of tolerance measured by social cues and comparisons to peers may influence drinking behavior. The present study evaluated the Social Tolerance Index (STI), a measure designed to examine perceptions about personal tolerance to alcohol using social cues in college students. College students (n = 177) completed measures of social tolerance, social desirability, drinking rates, and demographic information at baseline, 2-week, and 4-week follow-up assessments to assess test-retest reliability. A confirmatory factor analysis was conducted on the STI. In addition, tests of discriminant, construct and predictive validities were also conducted. The STI demonstrated good reliability and validity for use in a college student population.
| 19,004,562
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Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer.
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Preoperative chemoradiotherapy followed by surgery represents the standard of care for locally advanced rectal cancer (LARC). Cetuximab has proved activity in advanced colorectal cancer, and its incorporation in preoperative treatment may increase tumor downstaging. After biopsy and staging, uT3/uT4 N0/+ LARC received single-agent cetuximab in three doses, followed by weekly cetuximab plus 5-fluorouracil (5-FU), concomitantly with RT. Sample size was calculated according to Bryant and Day test, a two-stage design with at least 10 pathologic complete remissions observed in 60 patients (pts) able to complete the treatment plan. Forty pts with LARC were entered: male/female = 34/6; median age: 61 (range, 28-77); 12 uT3N0 Ed(30%); 25 uT3N1 (62%); 3 uT4N1 (8%); all Eastern Cooperative Oncology Group = 0. Thirty-five pts completed neoadjuvant treatment; 5 (12%) withdrew therapy after one cetuximab administration: three for hypersensitivity reactions, one for rapid progression, and one for purulent arthritis. They continued 5-FU in continuous infusion in association with RT. Thirty-one pts (77%) presented with acnelike rash; dose reduction/interruption of treatment was necessary in six pts (15%): two for Grade 3 acnelike rash, two for Grade 3 gastrointestinal toxicity, and two for refusal. Thirty-eight pts were evaluable for pathological response (one patient refused surgery, and one was progressed during neoadjuvant treatment). Pathological staging was: pT0N0 three pts (8%), pT1N0 1 pt (3%); pT2N0 13 pts (34%), and pT3 19 pts (50%) (N0:9, N1:5; N2:5); pT4 2 pts (5%). Preoperative treatment with 5-FU, cetuximab, and pelvic RT is feasible with acceptable toxicities; however, the rate of pathologic responses is disappointingly low.
| 19,004,567
|
Treatment Cost Analysis Tool (TCAT) for estimating costs of outpatient treatment services.
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A Microsoft Excel-based workbook designed for research analysts to use in a national study was retooled for treatment program directors and financial officers to allocate, analyze, and estimate outpatient treatment costs in the U.S. This instrument can also be used as a planning and management tool to optimize resources and forecast the impact of future changes in staffing, client flow, program design, and other resources. The Treatment Cost Analysis Tool (TCAT) automatically provides feedback and generates summaries and charts using comparative data from a national sample of non-methadone outpatient providers. TCAT is being used by program staff to capture and allocate both economic and accounting costs, and outpatient service costs are reported for a sample of 70 programs. Costs for an episode of treatment in regular, intensive, and mixed types of outpatient treatment were $882, $1310, and $1381 respectively (based on 20% trimmed means and 2006 dollars). An hour of counseling cost $64 in regular, $85 intensive, and $86 mixed. Group counseling hourly costs per client were $8, $11, and $10 respectively for regular, intensive, and mixed. Future directions include use of a web-based interview version, much like some of the commercially available tax preparation software tools, and extensions for use in other modalities of treatment.
| 19,004,576
|
Departments of corrections as purchasers of community-based treatment: a national study.
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Community-based substance abuse treatment for offenders has been shown to reduce both substance use and recidivism. One strategy to ensure treatment availability for offenders is to have each state's Department of Corrections (DOC) fund treatment directly. Purchasing treatment implies regulation, but DOC as both a purchaser and regulator of community-based services has been underexamined. This national survey of administrators from the Single State Authority (SSA) and DOC in each state found DOCs purchase treatment in 35 states, with most states purchasing it directly from community-based providers utilizing a variety of funding sources. Fewer states reported DOCs purchased ancillary services than SSAs (68% vs. 81%). Although both DOCs and SSAs had workforce and program requirements, there were differences within and between states. Most (41/42) SSA administrators reported a strong relationship with DOC. This report represents the first step in describing the availability, mechanisms, and regulations of these two publicly funded community-based treatment systems.
| 19,004,602
|
Metastasis of oral cancer to the parotid node.
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The parotid node is an uncommon site of metastasis in head and neck cancer. This study was intended to clarify the incidence and indicators of oral cancer metastases to the parotid node. We reviewed the records of 253 patients with oral carcinomas who had undergone a total of 289 neck dissections between April 2001 and December 2006. The histologic diagnoses of the primary tumors were squamous cell carcinoma in 239 patients, mucoepidermoid carcinoma in 5, adenoid cystic carcinoma in 4, and miscellaneous others in 5. In all neck dissections, the tail of the parotid gland below the marginal mandibular branch of the facial nerve was resected. The cervical and parotid lymph nodes were isolated from the surgical specimens. One section through the maximum cross-sectional area of each node was examined histologically. From 183 of the 289 neck specimens, we collected 539 parotid nodes: 222 extraglandular and 317 intraglandular. Of the 253 patients, 10 (4.0%) had 19 parotid node metastases, of which 4 were extraglandular and 15 intraglandular. Parotid node involvement occurred in 2.5% of oral squamous cell carcinoma cases. For the other cancers, there were too few cases to determine a meaningful frequency. In terms of indicators, the likelihood of metastasis to the parotid nodes increased with the number of cancer-positive cervical nodes. Metastasis to the parotid nodes should be considered in patients with oral cancer. Resection of the tail of the parotid gland is warranted during the neck dissection.
| 19,004,605
|
Do sex differences affect prefrontal cortex associated cognition in schizophrenia?
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Cognitive deficits in schizophrenia, especially those related to prefrontal cortex (PFC) functions, influence functional outcome. There is evidence for sex differences in cognition in schizophrenia, but the results in the literature are still controversial. This study evaluated different modalities of working memory (WM) and executive control (EC), functions that are both associated with the PFC, between sexes in schizophrenic patients and controls. We used a battery of neuropsychological tests for assessing auditory, spatial, and visual-matching WM and used a dual task for assessing EC. The study included 50 inpatients (25 female) partially remitted and taking atypical neuroleptics, as well as 40 controls (20 female) matched for age and education. Significant sex differences were found in the dual task; female patients detected fewer correct trials than male patients and controls did. Moreover, female patients performed significantly worse in the single visual subtest of the dual task. For the controls, no sex differences were found. Males showed higher positive symptoms than females, but no other differences in psychopathology, disease characteristics, or extrapyramidal symptoms were found between sexes. The present study shows an absence of sex differences in WM in healthy subjects and in patients with schizophrenia. However, in the dual task and in the single visual subtest, female patients performed worse than males. This finding suggests that in contrast to males, nonacute female inpatients show an underlying attentional deficit that may contribute to impairment in higher-order functions such as EC.
| 19,004,617
|
The adsorption behavior of cationic surfactant onto human hair fibers.
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Quaternary ammonium surfactants are important ingredients that are frequently formulated into hair care products to modify the properties of hair surface. The adsorption kinetics, isotherms and association structures of cationic surfactants on hair surface, however, are not fully understood due to the heterogeneous nature of human hair fibers. In this work, a quaternary ammonium of surfactant, dimethylpabamidopropyl laurdimonium tosylate (DDABDT) was chosen as a probe to investigate the adsorption behavior of cationic surfactant on cuticles of scalp hair. The results reveal that the adsorption kinetics fit to a pseudo-second-order kinetic model and the adsorption isotherms fit to the Freundlich adsorption model. With the increase of DDABDT adsorption, the wettability of hair fibers changes from hydrophobic to hydrophilic. The association structure could be monolayer or bilayer depending on the initial concentration of the surfactant. In the monolayer structure, the 'anchor' surfactant molecules are believed to adsorb vertically on the surface of hair fibers through electrostatic interaction. In the bilayer structure, the second layer molecules may then pile up on top of the first layer with charged groups orienting outward. The thickness of DDABDT film on hair fibers treated with 5 x 10(-4) mol/l DDABDT solution is measured to be 5.42 nm on average with a force-distance method. This figure is very close to the two times of the theoretical molecular size of the DDABDT molecule.
| 19,004,622
|
Equipment failure: causes and consequences in endoscopic gynecologic surgery.
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To determine the incidence of equipment failure in gynecologic endoscopy and investigate causes and consequences. A prospective observational single-center study between January and April 2006. Gynecologic surgery department of a university hospital. In all, 116 endoscopic interventions were included: 62 laparoscopies, 51 operative hysteroscopies, and 3 fertiloscopies. Emergency and equipment testing procedures were excluded. Equipment malfunctions were divided into 4 categories with regard to imaging, transmission of fluids and light, the electric circuit, and surgical instruments. We also found cases with faulty connections between elements. Factors including human error, loss of time, and actual or potential consequences were analyzed. At least 1 equipment failure was noted in 38.8% of operative procedures, 41.9% of laparoscopies, and 37.3% of hysteroscopies. Fluid, gas, and light transmission was faulty in 36.2%, surgical instruments in 29.3%, the electric circuit in 22.4%, and imaging in 12.1%. Of malfunctions, 46.6% were a result of faulty connection between 2 elements. The most common cause for concern was bipolar forceps and cables in laparoscopy (42.3%) and the assembly of small parts in hysteroscopy (47.4%). Personnel were implicated in 43% of cases (nurses in 72%, surgeons in 12%, both in 16%). One equipment failure increased the total duration of laparoscopy by 7% and of hysteroscopy by 20%. The mean delay was 5.6+/-4.0minutes by equipment failure. Of the incidences, 19% could have led to serious complications for the patient; however, no morbidity or mortality actually occurred in this series. Equipment malfunction is common in endoscopic surgery and concerns both laparoscopy and hysteroscopy. Consequences are potentially serious. It is mandatory to identify and rectify causes of equipment failure so as to optimize the daily use of endoscopic instruments and improve patient safety. The implementation of systematic checklists is currently under evaluation.
| 19,004,670
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Mad science in art.
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Cover artist Mike Butler discusses how he's influenced by science fiction and artists to create his unique digital art.
| 19,004,678
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From cells to cell processors: the integration of health and video games.
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Healthcare offers special opportunities for the application of game research and technology. This was evident in the presentations at the 2007 Games for Health Conference.
| 19,004,688
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A multiresolution stochastic level set method for Mumford-Shah image segmentation.
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The Mumford-Shah model is one of the most successful image segmentation models. However, existing algorithms for the model are often very sensitive to the choice of the initial guess. To make use of the model effectively, it is essential to develop an algorithm which can compute a global or near global optimal solution efficiently. While gradient descent based methods are well-known to find a local minimum only, even many stochastic methods do not provide a practical solution to this problem either. In this paper, we consider the computation of a global minimum of the multiphase piecewise constant Mumford-Shah model. We propose a hybrid approach which combines gradient based and stochastic optimization methods to resolve the problem of sensitivity to the initial guess. At the heart of our algorithm is a well-designed basin hopping scheme which uses global updates to escape from local traps in a way that is much more effective than standard stochastic methods. In our experiments, a very high-quality solution is obtained within a few stochastic hops whereas the solutions obtained with simulated annealing are incomparable even after thousands of steps. We also propose a multiresolution approach to reduce the computational cost and enhance the search for a global minimum. Furthermore, we derived a simple but useful theoretical result relating solutions at different spatial resolutions.
| 19,004,702
|
Reliability estimation for statistical shape models.
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One of the drawbacks of statistical shape models is their occasional failure to converge. Although visually this fact is usually easy to recognize, there is no automatic way to detect it. In this paper, we introduce a generic reliability measure for statistical shape models. It is based on a probabilistic framework and uses information extracted by the model itself during the matching process. The proposed method was validated with two variants of Active Shape Models in the context facial image analysis. Experimental results on more than 3700 facial images showed a high degree of correlation between the segmentation accuracy and the estimated reliability metric.
| 19,004,714
|
Detection and segmentation of concealed objects in terahertz images.
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Terahertz imaging makes it possible to acquire images of objects concealed underneath clothing by measuring the radiometric temperatures of different objects on a human subject. The goal of this work is to automatically detect and segment concealed objects in broadband 0.1-1 THz images. Due to the inherent physical properties of passive terahertz imaging and associated hardware, images have poor contrast and low signal to noise ratio. Standard segmentation algorithms are unable to segment or detect concealed objects. Our approach relies on two stages. First, we remove the noise from the image using the anisotropic diffusion algorithm. We then detect the boundaries of the concealed objects. We use a mixture of Gaussian densities to model the distribution of the temperature inside the image. We then evolve curves along the isocontours of the image to identify the concealed objects. We have compared our approach with two state-of-the-art segmentation methods. Both methods fail to identify the concealed objects, while our method accurately detected the objects. In addition, our approach was more accurate than a state-of-the-art supervised image segmentation algorithm that required that the concealed objects be already identified. Our approach is completely unsupervised and could work in real-time on dedicated hardware.
| 19,004,716
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[The design of new protocols/what place for the pathology departments?].
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The pathologist's role in 2008 includes diagnosic, prognostic and predictive implications. Histopathologic criteria are still essential to manage the disease of cancer patients. They need to be based on standardized pathology reports and can use ancillary techniques such as immunohistochemistry and molecular biology. However, all the criteria used are not sufficient enough to provide accurate prognostic and predictive parameters for every patient and disease. This is the reason why translational studies more often involve the pathologist in prospective trials. The modern pathology is really integrated in this strategy, in terms of multidisciplinary approach, tumor banking, tissue microarray, molecular biology and new fixatives developments. All these subjects are discussed in this review article.
| 19,004,732
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[Principles of intensive care in severe acute pancreatitis in 2008].
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Acute pancreatitis is a dynamic, often progressive disease; 14-20% require intensive care in its severe form due to multiorgan dysfunction and/or failure. This review was created using systematic literature review of articles published on this subject in the last 5 years. The outcome of severe acute pancreatitis is determined by the inflammatory response and multiorgan dysfunction - the prognostic scores (Acute Physiology and Chronic Health Evaluation, Glasgow Prognostic Index, Sepsis-related Organ Failure Assessment, Multi Organ Dysfunction Syndrome Scale, Ranson Scale) can be used to determine outcome. Clinical signs (age, coexisting diseases, confusion, obesity) and biochemistry values (serum amylase, lipase, C-reactive protein, procalcitonin, creatinine, urea, calcium) have important prognostic roles as well. Early organ failure increases the risk of late abdominal complications and mortality. Intensive care can provide appropriate multi-function patient monitoring which helps in early recognition of complications and appropriate target-controlled treatment. Treatment of severe acute pancreatitis aims at reducing systemic inflammatory response and multiorgan dysfunction and, on the other side, at increasing the anti-inflammatory response. Oral starvation for 24-48 hours is effective in reducing the exocrine activity of the pancreas; the efficacy of protease inhibitors is questionable. Early intravascular volume resuscitation and stable haemodynamics improve microcirculation. Early oxygen therapy and mechanical ventilation provide adequate oxygenation. Electrolyte and acid-base control can be as important as tight glucose control. Adequate pain relief can be achieved by thoracic epidural catheterization. Early enteral nutrition with immunonutrition should be used. There is evidence that affecting the coagulation cascade by activated protein C can play a role in reducing the inflammatory response. The complex therapy of acute pancreatitis includes appropriate antibiotics, thrombo-embolic prophylaxis and in certain cases plasmapheresis and/or haemofiltration. Reducing intraabdominal pressure may be necessary in the acute phase. Intensive care multidisciplinary teamwork can reduce the mortality of severe acute pancreatitis from 30% to 10%.
| 19,004,743
|
[The history, ingredients and effects of energy drinks].
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The market and the degree of the consumption of energy drinks is increasing every year, but only a few have global knowledge of their ingredients and actual physiological effects. Furthermore, the number of available publications that really go into the details in this topic is also rather poor. After a short historical introduction, this article reviews the contents of energy drinks, lists a few products distributed in Hungary and abroad as a comparison, and provides information on their physical and mental effects on the human body. In the end of the article the authors word the limitations of energy drink consumption.
| 19,004,746
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[Hemodynamic effects of N-acetylcysteine and ischemic preconditioning in a liver ischemia-reperfusion model].
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The aim of the study was to investigate whether repeated ischemic preconditioning or N-acetylcysteine (NAC) prevents ischemic-reperfusion injury as determined by having favourable hemodynamic effects during reperfusion in canine livers. The control group ( n = 10) underwent 60 minutes of hepatic ischemia followed by 180 minutes reperfusion. In the NAC group ( n = 5) 150 mg kg -1 of NAC was administered intravenously before inducing ischemia. In the preconditioned group ( n = 5) animals received ischemic preconditioning (10 minutes of ischemia followed by 10 minutes of reperfusion repeated three times) before clamping the portal triad. 18 dogs survived the study period. One dog in the NAC group died due to circulatory failure unresponsive to inotropic drugs. The cardiac index and the intrathoracic blood volume index were significantly higher in the preconditioning group compared to the controls throughout the study period. Repeated ischemic preconditioning might improve hemodynamic parameters, whereas we were unable to find any significant differences between the groups regarding N-acetylcysteine.
| 19,004,747
|
Reproductive constraint is a developmental mechanism that maintains social harmony in advanced ant societies.
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A hallmark of eusociality in ants is the reproductive division of labor between queens and workers. Yet, nothing is known about the molecular mechanisms underlying reproduction in this group. We therefore compared the developmental genetic capacity of queens and workers to reproduce in several eusocially advanced species from the two largest subfamilies of ants, the Myrmicinae and Formicinae. In flies, the asymmetric localization of maternally encoded determinants (mRNAs and proteins) during oogenesis establishes oocyte polarity and subsequently ensures proper embryonic development. Vasa and nanos, two key maternal determinants, are properly localized in the posterior of queen oocytes, but their localization is impaired in those of the workers. This mislocalization leads to severe embryonic defects in worker progeny, and therefore, represents a constraint on worker reproduction that we call 'reproductive constraint.' We show that reproductive constraint is phylogenetically widespread, and is at high levels in most species tested. Reproductive constraint can simultaneously reduce or eliminate the workers' ability to produce viable eggs for reproduction, while preserving their ability to produce trophic eggs for nutrition, and thus, may have been the basis for the evolutionary retention of worker ovaries in the majority of ants. We propose that high levels of reproductive constraint has most likely evolved as a consequence of selection at the colony level to reduce or eliminate any potential conflict over worker reproduction, therefore maintaining harmony and colony efficiency in advanced ant societies.
| 19,004,767
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Enhanced optical properties of chemical vapor deposited single crystal diamond by low-pressure/high-temperature annealing.
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Single crystal diamond produced by chemical vapor deposition (CVD) at very high growth rates (up to 150 microm/h) has been successfully annealed without graphitization at temperatures up to 2200 degrees C and pressures <300 torr. Crystals were annealed in a hydrogen environment by using microwave plasma techniques for periods of time ranging from a fraction of minute to a few hours. This low-pressure/high-temperature (LPHT) annealing enhances the optical properties of this high-growth rate CVD single crystal diamond. Significant decreases are observed in UV, visible, and infrared absorption and photoluminescence spectra. The decrease in optical absorption after the LPHT annealing arises from the changes in defect structure associated with hydrogen incorporation during CVD growth. There is a decrease in sharp line spectral features indicating a reduction in nitrogen-vacancy-hydrogen (NVH(-)) defects. These measurements indicate an increase in relative concentration of nitrogen-vacancy (NV) centers in nitrogen-containing LPHT-annealed diamond as compared with as-grown CVD material. The large overall changes in optical properties and the specific types of alterations in defect structure induced by this facile LPHT processing of high-growth rate single-crystal CVD diamond will be useful in the creation of diamond for a variety of scientific and technological applications.
| 19,004,770
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Interactions between amino acid side chains in cylindrical hydrophobic nanopores with applications to peptide stability.
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Confinement effects on protein stability are relevant in a number of biological applications ranging from encapsulation in the cylindrical cavity of a chaperonin, translocation through pores, and structure formation in the exit tunnel of the ribosome. Consequently, free energies of interaction between amino acid side chains in restricted spaces can provide insights into factors that control protein stability in nanopores. Using all-atom molecular dynamics simulations, we show that 3 pair interactions between side chains--hydrophobic (Ala-Phe), polar (Ser-Asn) and charged (Lys-Glu)--are substantially altered in hydrophobic, water-filled nanopores, relative to bulk water. When the pore holds water at bulk density, the hydrophobic pair is strongly destabilized and is driven to large separations corresponding to the width and the length of the cylindrical pore. As the water density is reduced, the preference of Ala and Phe to be at the boundary decreases, and the contact pair is preferred. A model that accounts for the volume accessible to Phe and Ala in the solvent-depleted region near the pore boundary explains the simulation results. In the pore, the hydrogen-bonded interactions between Ser and Asn have an enhanced dependence on their relative orientations, as compared with bulk water. When the side chains of Lys and Glu are restrained to be side by side, parallel to each other, then salt bridge formation is promoted in the nanopore. Based on these results, we argue and demonstrate that for a generic amphiphilic sequence, cylindrical confinement is likely to enhance thermodynamic stability relative to the bulk.
| 19,004,772
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Environmental and anthropogenic controls over bacterial communities in wetland soils.
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Soil bacteria regulate wetland biogeochemical processes, yet little is known about controls over their distribution and abundance. Bacteria in North Carolina swamps and bogs differ greatly from Florida Everglades fens, where communities studied were unexpectedly similar along a nutrient enrichment gradient. Bacterial composition and diversity corresponded strongly with soil pH, land use, and restoration status, but less to nutrient concentrations, and not with wetland type or soil carbon. Surprisingly, wetland restoration decreased bacterial diversity, a response opposite to that in terrestrial ecosystems. Community level patterns were underlain by responses of a few taxa, especially the Acidobacteria and Proteobacteria, suggesting promise for bacterial indicators of restoration and trophic status.
| 19,004,771
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F-pili dynamics by live-cell imaging.
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Bacteria have evolved numerous mechanisms for cell-cell communication, many of which have important consequences for human health. Among these is conjugation, the direct transfer of DNA from one cell to another. For gram-negative bacteria, conjugation requires thin, flexible filaments (conjugative pili) that are elaborated by DNA donor cells. The structure, function, and especially the dynamics of conjugative pili are poorly understood. Here, we have applied live-cell imaging to characterize the dynamics of F-pili (conjugative pili encoded by the F plasmid of Escherichia coli). We establish that F-pili normally undergo cycles of extension and retraction in the absence of any obvious triggering event, such as contact with a recipient cell. When made, such contacts are able to survive the shear forces felt by bacteria in liquid media. Our data emphasize the role of F-pilus flexibility both in efficiently sampling a large volume surrounding donor cells in liquid culture and in establishing and maintaining cell-cell contact. Additionally and unexpectedly, we infer that extension and retraction are accompanied by rotation about the long axis of the filament.
| 19,004,777
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Crystal structures of the organomercurial lyase MerB in its free and mercury-bound forms: insights into the mechanism of methylmercury degradation.
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Bacteria resistant to methylmercury utilize two enzymes (MerA and MerB) to degrade methylmercury to the less toxic elemental mercury. The crucial step is the cleavage of the carbon-mercury bond of methylmercury by the organomercurial lyase (MerB). In this study, we determined high resolution crystal structures of MerB in both the free (1.76-A resolution) and mercury-bound (1.64-A resolution) states. The crystal structure of free MerB is very similar to the NMR structure, but important differences are observed when comparing the two structures. In the crystal structure, an amino-terminal alpha-helix that is not present in the NMR structure makes contact with the core region adjacent to the catalytic site. This interaction between the amino-terminal helix and the core serves to bury the active site of MerB. The crystal structures also provide detailed insights into the mechanism of carbon-mercury bond cleavage by MerB. The structures demonstrate that two conserved cysteines (Cys-96 and Cys-159) play a role in substrate binding, carbon-mercury bond cleavage, and controlled product (ionic mercury) release. In addition, the structures establish that an aspartic acid (Asp-99) in the active site plays a crucial role in the proton transfer step required for the cleavage of the carbon-mercury bond. These findings are an important step in understanding the mechanism of carbon-mercury bond cleavage by MerB.
| 19,004,822
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The stability and transactivation potential of the mammalian MafA transcription factor are regulated by serine 65 phosphorylation.
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The level of the MafA transcription factor is regulated by a variety of effectors of beta cell function, including glucose, fatty acids, and insulin. Here, we show that phosphorylation at Ser(65) of mammalian MafA influences both protein stability and transactivation potential. Replacement of Ser(65) with Glu to mimic phosphorylation produced a protein that was as unstable as the wild type, whereas Asp or Ala mutation blocked degradation. Analysis of MafA chimeric and deletion constructs suggests that protein phosphorylation at Ser(65) alone represents the initial degradation signal, with ubiquitinylation occurring within the C terminus (amino acids 234-359). Although only wild type MafA and S65E were polyubiquitinylated, both S65D and S65E potently stimulated transactivation compared with S65A. Phosphorylation at Ser(14) also enhanced activation, although it had no impact on protein turnover. The mobility of MafA S65A was profoundly affected upon SDS-PAGE, with the S65E and S65D mutants influenced less due to their ability to serve as substrates for glycogen synthase kinase 3, which acts at neighboring N-terminal residues after Ser(65) phosphorylation. Our observations not only illustrate the sensitivity of the cellular transcriptional and degradation machinery to phosphomimetic mutants at Ser(65), but also demonstrate the singular importance of phosphorylation at this amino acid in regulating MafA activity.
| 19,004,825
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Identification of the active site of DS-epimerase 1 and requirement of N-glycosylation for enzyme function.
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Dermatan sulfate is a highly sulfated polysaccharide and has a variety of biological functions in development and disease. Iduronic acid domains in dermatan sulfate, which are formed by the action of two DS-epimerases, have a key role in mediating these functions. We have identified the catalytic site and three putative catalytic residues in DS-epimerase 1, His-205, Tyr-261, and His-450, by tertiary structure modeling and amino acid conservation to heparinase II. These residues were systematically mutated to alanine or more conserved residues, which resulted in complete loss of epimerase activity. Based on these data and the close relationship between lyase and epimerase reactions, we propose a model where His-450 functions as a general base abstracting the C5 proton from glucuronic acid. Subsequent cleavage of the glycosidic linkage by Tyr-261 generates a 4,5-unsaturated hexuronic intermediate, which is protonated at the C5 carbon by His-205 from the side of the sugar plane opposite to the side of previous proton abstraction. Concomitant recreation of the glycosidic linkage ends the reaction, generating iduronic acid. In addition, we show that proper N-glycosylation of DS-epimerase 1 is required for enzyme activity. This study represents the first description of the structural basis for epimerization by a glycosaminoglycan epimerase.
| 19,004,833
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Differential interactions of thrombospondin-1, -2, and -4 with CD47 and effects on cGMP signaling and ischemic injury responses.
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Thrombospondin-1 regulates nitric oxide (NO) signaling in vascular cells via CD47. Because CD47 binding motifs are conserved in the C-terminal signature domains of all five thrombospondins and indirect evidence has implied CD47 interactions with other family members, we compared activities of recombinant signature domains of thrombospondin-1, -2, and -4 to interact with CD47 and modulate cGMP signaling. Signature domains of thrombospondin-2 and -4 were less active than that of thrombospondin-1 for inhibiting binding of radiolabeled signature domain of thrombospondin-1 or SIRPalpha (signal-regulatory protein) to cells expressing CD47. Consistent with this binding selectivity, the signature domain of thrombospondin-1 was more potent than those of thrombospondin-2 or -4 for inhibiting NO-stimulated cGMP synthesis in vascular smooth muscle cells and downstream effects on cell adhesion. In contrast to thrombospondin-1- and CD47-null cells, primary vascular cells from thrombospondin-2-null mice lack enhanced basal and NO-stimulated cGMP signaling. Effects of endogenous thrombospondin-2 on NO/cGMP signaling could be detected only in thrombospondin-1-null cells. Furthermore, tissue survival of ischemic injury and acute recovery of blood flow in thrombospondin-2-nulls resembles that of wild type mice. Therefore, thrombospondin-1 is the dominant regulator of NO/cGMP signaling via CD47, and its limiting role in acute ischemic injury responses is not shared by thrombospondin-2.
| 19,004,835
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Tackling antibiotic resistance: a dose of common antisense?
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Resistance to antimicrobial agents undermines our ability to treat bacterial infections. It attracts intense media and political interest and impacts on personal health and costs to health infrastructures. Bacteria have developed resistance to all licensed antibacterial agents, and their ability to become resistant to unlicensed agents is often demonstrated during the development process. Conventional approaches to antimicrobial development, involving modification of existing agents or production of synthetic derivatives, are unlikely to deliver the range or type of drugs that will be needed to meet all future requirements. Although many companies are seeking novel targets, further radical approaches to both antimicrobial design and the reversal of resistance are now urgently required. In this article, we discuss 'antisense' (or 'antigene') strategies to inhibit resistance mechanisms at the genetic level. These offer an innovative approach to a global problem and could be used to restore the efficacy of clinically proven agents. Moreover, this strategy has the potential to overcome critical resistances, not only in the so-called 'superbugs' (methicillin-resistant Staphylococcus aureus, glycopeptide-resistant enterococci and multidrug-resistant strains of Acinetobacter baumannii, and Pseudomonas aeruginosa), but in resistant strains of any bacterial species.
| 19,004,840
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Fomepizole: a critical assessment of current dosing recommendations.
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Fomepizole, 4-methylpyrazole (4-MP), is a competitive antagonist of alcohol dehydrogenase with a binding affinity >8000 times that of ethanol. The drug is currently labeled by the United States Food and Drug Administration for the treatment of adult patients with known or suspected ethylene glycol or methanol poisoning. Fomepizole's wide therapeutic dose range and safety profile confer several advantages over standard ethanol therapy for the treatment of toxic alcohol exposures, including the lack of ethanol-associated side effects. Published data and data obtained from the drug's manufacturer implies that the dose escalation after 48 hours is to compensate for fomepizole-induced increased body clearance resulting from autoinduction of the cytochrome P450 (CYP) drug metabolizing enzyme CYP2E1. However, we were unable to identify any evidence of fomepizole's metabolism occurring via CYP2E1 in humans while the data most frequently cited as evidence for induction do not appear to support this claim. Based on this data along with the apparent zero-order kinetics, the current dose increase recommendations may be unnecessary and considering the safety margin described for fomepizole, an extremely conservative constant higher dose administered every 12 hours would appear to assure efficacy and tolerability. Despite the evidence, dose changes should only be implemented after careful clinical trials.
| 19,004,845
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Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers.
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In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.
| 19,004,846
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Directing pathfinding along the dorsolateral path - the role of EDNRB2 and EphB2 in overcoming inhibition.
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Neural crest cells that become pigment cells migrate along a dorsolateral route between the ectoderm and the somite, whereas most other neural crest cells are inhibited from entering this space. This pathway choice has been attributed to unique, cell-autonomous migratory properties acquired by neural crest cells when they become specified as melanoblasts. By shRNA knockdown and overexpression experiments, we investigated the roles of three transmembrane receptors in regulating dorsolateral pathfinding in the chick trunk. We show that Endothelin receptor B2 (EDNRB2) and EphB2 are both determinants in this process, and that, unlike in other species, c-KIT is not. We demonstrate that the overexpression of EDNRB2 can maintain normal dorsolateral migration of melanoblasts in the absence of EphB2, and vice versa, suggesting that changes in receptor expression levels regulate the invasion of this pathway. Furthermore, by heterotopic grafting, we show that neural crest cell populations that do not rely on the activation of these receptors can migrate dorsolaterally only if this path is free of inhibitory molecules. We conclude that the requirement for EDNRB2 and EphB2 expression by melanoblasts is to support their migration by helping them to overcome repulsive or non-permissive cues in the dorsolateral environment.
| 19,004,859
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Unusual aortic stent complication after endovascular repair of the descending thoracic aorta in type B dissection in a patient with giant-cell arteritis.
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The advent of endovascular prostheses to treat descending thoracic aortic lesions offers an alternative approach in patients who are poor candidates for surgery. We present a case of a type B descending thoracic aortic dissection with rapid aneurysmal evolution in a woman with a giant-cell arteritis, treated by endovascular repair: 26 months after, we observed the anterior dislocation of the distal segment of the stent. The dislocation required a second treatment in order to avoid the aortic wall rupture and to restore the axis of the prosthesis. This report emphasizes the difficulty of the endovascular repair in the giant-cell arteritis, because of the vascular fragility confirmed by the rapid aneurysmal evolution after the type B dissection and the appearance of the stenting complication.
| 19,004,862
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Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice.
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Previously we demonstrated that upstream stimulatory factor 2 (USF2) transgenic (Tg) mice developed nephropathy including albuminuria and glomerular hypertrophy, accompanied by increased transforming growth factor (TGF)-beta and fibronectin accumulation in the glomeruli. However, the mechanisms by which overexpression of USF2 induces kidney injury are unknown. USF has been shown to regulate renin expression. Moreover, the renin-angiotensin system (RAS) plays important roles in renal diseases. Therefore, in the present studies the effects of USF2 on the regulation of RAS in the kidney as well as in mesangial cells from USF2 (Tg) mice were examined. The role of USF2-mediated regulation of RAS in TGF-beta production in mesangial cells was also determined. Our data demonstrate that USF2 (Tg) mice exhibit increased renin and angiotensin (ANG) II levels in the kidney. In contrast, renal expression of other components of RAS such as renin receptor, angiotensinogen, angiotensin-converting enzyme (ACE), ACE2, angiotensin type 1a (AT(1a)) receptor, and AT(2) receptor was not altered in USF2 (Tg) mice. Similarly, mesangial cells isolated from USF2 (Tg) mice had increased renin and ANG II levels. Mesangial cells overexpressing USF2 also had increased TGF-beta production, which was blocked by small interfering RNA-mediated renin gene knockdown or RAS blockade (enalapril or losartan). Collectively, these results suggest that USF2 promotes renal renin expression and stimulates ANG II generation, leading to activation of the intrarenal RAS. In addition, renin-dependent ANG II generation mediates the effect of USF2 on TGF-beta production in mesangial cells, which may contribute to the development of nephropathy in USF2 (Tg) mice.
| 19,004,931
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Human cytomegalovirus-encoded immune modulators partner to downregulate major histocompatibility complex class I molecules.
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Throughout the course of natural evolution with its host, the human cytomegalovirus (HCMV) has developed a variety of strategies to avoid immune recognition and clearance. The major histocompatibility complex (MHC) class I antigen presentation pathway is a major target of the virus. HCMV encodes at least six gene products that modulate the processing of endoplasmic reticulum (ER)-resident MHC class I molecules. Here, we show that two virus-encoded proteins, US2 and US3, coordinate their functions toward the common goal of attenuating class I protein surface expression. In cells stably expressing both US2 and US3, class I molecules were almost completely downregulated from the cell surface. In addition, pulse-chase analysis revealed that the proteasome-dependent turnover of class I molecules occurs more rapidly in cells expressing both US2 and US3 than either US2 or US3 alone. The ability of US3 to retain class I molecules in the ER produces a target-rich environment for US2 to mediate the destruction of class I heavy chains. In fact, expression of US3 enhanced the association between US2 and class I molecules, thus encouraging their dislocation and degradation. This immune evasion strategy ensures that viral antigens are not presented on the cell surface during the early phase of HCMV infection, a critical time of replication and viral proliferation.
| 19,004,944
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Analysis of the differential host cell nuclear proteome induced by attenuated and virulent hemorrhagic arenavirus infection.
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Arenaviruses are important emerging pathogens and include a number of hemorrhagic fever viruses classified as NIAID category A priority pathogens and CDC potential biothreat agents. Infection of guinea pigs with the New World arenavirus Pichindé virus (PICV) has been used as a biosafety level 2 model for the Lassa virus. Despite continuing research, little is known about the molecular basis of pathogenesis, and this has hindered the design of novel antiviral therapeutics. Modulation of the host response is a potential strategy for the treatment of infectious diseases. We have previously investigated the global host response to attenuated and lethal arenavirus infections by using high-throughput immunoblotting and kinomics approaches. In this report, we describe the differential nuclear proteomes of a murine cell line induced by mock infection and infection with attenuated and lethal variants of PICV, investigated by using two-dimensional gel electrophoresis. Spot identification using tandem mass spectrometry revealed the involvement of a number of proteins that regulate inflammation via potential modulation of NF-kappaB activity and of several heterogeneous nuclear ribonuclear proteins. Pathway analysis revealed a potential role for transcription factor XBP-1, a transcription factor involved in major histocompatibility complex II (MHC-II) expression; differential DNA-binding activity was revealed by electrophoretic mobility shift assay, and differences in surface MHC-II expression were seen following PICV infection. These data are consistent with the results of several previous studies and highlight potential differences between transcriptional and translational regulation. This study provides a number of differentially expressed targets for further research and suggests that key events in pathogenesis may be established early in infection.
| 19,004,951
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Does an altered leptin axis play a role in obesity among children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency?
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Congenital adrenal hyperplasia (CAH) patients are at a higher risk to develop obesity. The role of leptin in CAH is still controversial. Our study aimed to evaluate serum levels of leptin, the soluble leptin receptor (sOB-R), and the sOB-R: leptin molar ratios in a cohort of CAH children and adolescents, and their associations with clinical and metabolic parameters. We studied 51 CAH patients, aged 5.6-19.6 years (median 11.8, n=30 females) cross-sectionally. All patients had genetically proven CAH and received standard steroid substitution therapy. Blood specimens were taken after overnight fasting between 0800 and 1000 h. For the analyses of leptin and sOB-R, matched pairs were built with healthy Caucasian patients for sex, Tanner stage (TS), chronologic age (CA), and body mass index (BMI). BMI and SDS were significantly elevated compared with the reference population. Leptin levels were not different between matched pairs, whereas sOB-R levels were significantly lower in CAH. Consequently, the sOB-R: leptin molar ratios were significantly decreased in CAH. Correlation analyses in CAH patients revealed significant relationship between leptin and CA, TS, BMI, and homeostasis model assessment of insulin resistance. Similar results were obtained for the matched control group. For sOB-R, we found no significant correlation for CA, TS, or BMI in CAH, but we did in the controls. There were significant correlations for androgens within the CAH group. Additional analyses revealed no correlation with steroid medication or metabolic control. Our data show that an altered leptin axis with normal serum leptin concentrations but decreased sOB-R serum levels may contribute to the increased risk of overweight and obesity in CAH.
| 19,004,982
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Is the olfactory bulb computationally similar to the retina?
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The computational role of the olfactory bulb remains a mystery after 60 yr of physiological research. Recently, Fantana and colleagues proposed a new model of bulb function based on sparse inhibitory connections between glomeruli, the functional units of the bulb, rather than the existing lateral inhibition model. I present a summary of their model here and its implications along with comparison to recent work in the very similar Drosophila olfactory system.
| 19,004,990
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Random stimulation of spider mechanosensory neurons reveals long-lasting excitation by GABA and muscimol.
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gamma-Aminobutyric acid type A (GABA(A)) receptor activation inhibits many primary afferent neurons by depolarization and increased membrane conductance. Deterministic (step and sinusoidal) functions are commonly used as stimuli to test such inhibition. We found that when the VS-3 mechanosensory neurons innervating the spider lyriform slit-sense organ were stimulated by randomly varying white-noise mechanical or electrical signals, their responses to GABA(A) receptor agonists were more complex than the inhibition observed during deterministic stimulation. Instead, there was rapid excitation, then brief inhibition, followed by long-lasting excitation. During the final excitatory phase, VS-3 neuron sensitivity to high-frequency signals increased selectively and their linear information capacity also increased. Using experimental and simulation approaches we found that the excitatory effect could also be achieved by depolarizing the neurons without GABA application and that excitation could override the inhibitory effect produced by increased membrane conductance (shunting). When the VS-3 neurons were exposed to bumetanide, an antagonist of the Cl(-) transporter NKCC1, the GABA-induced depolarization decreased without any change in firing rate, suggesting that the effects of GABA can be maintained for a long time without additional Cl(-) influx. Our results show that the VS-3 neuron's response to GABA depends profoundly on the type of signals the neuron is conveying while the transmitter binds to its receptors.
| 19,004,993
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Adjustments differ among low-threshold motor units during intermittent, isometric contractions.
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We investigated the changes in muscle fiber conduction velocity, recruitment and derecruitment thresholds, and discharge rate of low-threshold motor units during a series of ramp contractions. The aim was to compare the adjustments in motor unit activity relative to the duration that each motor unit was active during the task. Multichannel surface electromyographic (EMG) signals were recorded from the abductor pollicis brevis muscle of eight healthy men during 12-s contractions (n = 25) in which the force increased and decreased linearly from 0 to 10% of the maximum. The maximal force exhibited a modest decline (8.5 +/- 9.3%; P < 0.05) at the end of the task. The discharge times of 73 motor units that were active for 16-98% of the time during the first five contractions were identified throughout the task by decomposition of the EMG signals. Action potential conduction velocity decreased during the task by a greater amount for motor units that were initially active for >70% of the time compared with that of less active motor units. Moreover, recruitment and derecruitment thresholds increased for these most active motor units, whereas the thresholds decreased for the less active motor units. Another 18 motor units were recruited at an average of 171 +/- 32 s after the beginning of the task. The recruitment and derecruitment thresholds of these units decreased during the task, but muscle fiber conduction velocity did not change. These results indicate that low-threshold motor units exhibit individual adjustments in muscle fiber conduction velocity and motor neuron activation that depended on the relative duration of activity during intermittent contractions.
| 19,004,996
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Topography and response timing of intact cerebellum stained with absorbance voltage-sensitive dye.
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Physiological activity of the turtle cerebellar cortex (Cb), maintained in vitro, was recorded during microstimulation of inferior olive (IO). Previous single-electrode responses to such stimulation showed similar latencies across a limited region of Cb, yet those recordings lacked spatial and temporal resolution and the recording depth was variable. The topography and timing of those responses were reexamined using photodiode optical recordings. Because turtle Cb is thin and unfoliated, its entire surface can be stained by a voltage-sensitive dye and transilluminated to measure changes in its local absorbance. Microstimulation of the IO evoked widespread depolarization from the rostral to the caudal edge of the contralateral Cb. The time course of responses measured at a single photodiode matched that of single-microelectrode responses in the corresponding Cb locus. The largest and most readily evoked response was a sagittal band centered about 0.7 mm from the midline. Focal white-matter (WM) microstimulation on the ventricular surface also activated sagittal bands, whereas stimulation of adjacent granule cells evoked a radial patch of activation. In contrast, molecular-layer (ML) microstimulation evoked transverse beams of activation, centered on the rostrocaudal stimulus position, which traveled bidirectionally across the midline to the lateral edges of the Cb. A timing analysis demonstrated that both IO and WM microstimulation evoked responses with a nearly simultaneous onset along a sagittal band, whereas ML microstimulation evoked a slowly propagating wave traveling about 25 cm/s. The response similarity to IO and WM microstimulation suggests that the responses to WM microstimulation are dominated by activation of its climbing fibers. The Cb's role in the generation of precise motor control may result from these temporal and topographic differences in orthogonally oriented pathways. Optical recordings of the turtle's thin flat Cb can provide insights into that role.
| 19,004,999
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Thermodynamics and density of binding of a panel of antibodies to high-molecular-weight capsular polysaccharides.
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The interaction between antipolysaccharide (anti-PS) antibodies and their antigens was investigated by the use of isothermal titration calorimetry to determine the thermodynamic binding constant (K), the change in the enthalpy of binding (DeltaH), and the binding density (N) to high-molecular-weight PSs. From these values, the change in the entropy of binding (DeltaS) was calculated. The thermodynamic parameters of binding to high-molecular-weight capsular PSs are reported for two monoclonal antibodies (MAbs) with different specificities for meningococcal serogroup C PS, five MAbs specific for different pneumococcal serotypes, and the Fab fragments of two antipneumococcal MAbs. The K values were in the range of 10(6) to 10(7) M(-1), and these values were 1 to 2 orders of magnitude greater than the previously reported K values derived from antibody-oligosaccharide interactions. The DeltaH associated with binding was favorable for each MAb and Fab fragment. The DeltaS associated with binding was also generally favorable for both the MAbs and the Fab fragments, with the exception of the anti-serotype 14 MAb and its Fab fragment. N provides information regarding how densely MAbs or Fabs can bind along PS chains and, as expressed in terms of monosaccharides, was very similar for the seven MAbs, with an average of 12 monosaccharides per bound MAb. The value of N for each Fab was smaller, with five or seven monosaccharides per bound Fab. These results suggest that steric interactions between antibody molecules are a major influence on the values of N of high-affinity MAbs to capsular PSs.
| 19,005,020
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Modes and mishaps of neuronal migration in the mammalian brain.
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The ability of neurons to migrate to their appropriate positions in the developing brain is critical to brain architecture and function. Recent research has elucidated different modes of neuronal migration and the involvement of a host of signaling factors in orchestrating the migration, as well as vulnerabilities of this process to environmental and genetic factors. Here we discuss the role of cytoskeleton, motor proteins, and mechanisms of nuclear translocation in radial and tangential migration of neurons. We will also discuss how these and other events essential for normal migration of neurons can be disrupted by genetic and environmental factors that contribute to neurological disease in humans.
| 19,005,035
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Protein kinase Cdelta regulates ethanol intoxication and enhancement of GABA-stimulated tonic current.
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Ethanol alters the distribution and abundance of PKCdelta in neural cell lines. Here we investigated whether PKCdelta also regulates behavioral responses to ethanol. PKCdelta(-/-) mice showed reduced intoxication when administered ethanol and reduced ataxia when administered the nonselective GABA(A) receptor agonists pentobarbital and pregnanolone. However, their response to flunitrazepam was not altered, suggesting that PKCdelta regulates benzodiazepine-insensitive GABA(A) receptors, most of which contain delta subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKCdelta overlapped with GABA(A) delta subunits in thalamus and hippocampus, and ethanol failed to enhance tonic GABA currents in PKCdelta(-/-) thalamic and hippocampal neurons. Moreover, using an ATP analog-sensitive PKCdelta mutant in mouse L(tk(-)) fibroblasts that express alpha4beta3delta GABA(A) receptors, we found that ethanol enhancement of GABA currents was PKCdelta-dependent. Thus, PKCdelta enhances ethanol intoxication partly through regulation of GABA(A) receptors that contain delta subunits and mediate tonic inhibitory currents. These findings indicate that PKCdelta contributes to a high level of behavioral response to ethanol, which is negatively associated with risk of developing an alcohol use disorder in humans.
| 19,005,054
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Neurotoxic activation of microglia is promoted by a nox1-dependent NADPH oxidase.
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Reactive oxygen species (ROS) modulate intracellular signaling but are also responsible for neuronal damage in pathological states. Microglia, the resident CNS macrophages, are prominent sources of ROS through expression of the phagocyte oxidase which catalytic subunit Nox2 generates superoxide ion (O2(.-)). Here we show that microglia also express Nox1 and other components of nonphagocyte NADPH oxidases, including p22(phox), NOXO1, NOXA1, and Rac1/2. The subcellular distribution and functions of Nox1 were determined by blocking Nox activity with diphenylene iodonium or apocynin, and by silencing the Nox1 gene in microglia purified from wild-type (WT) or Nox2-KO mice. [Nox1-p22(phox)] dimers localized in intracellular compartments are recruited to phagosome membranes during microglial phagocytosis of zymosan, and Nox1 produces O2(.-) in zymosan-loaded phagosomes. In microglia activated with lipopolysaccharide (LPS), Nox1 produces O2(.-), which enhances cell expression of inducible nitric oxide synthase and secretion of interleukin-1beta. Comparisons of microglia purified from WT, Nox2-KO, or Nox1-KO mice indicate that both Nox1 and Nox2 are required to optimize microglial production of nitric oxide. By injecting LPS in the striatum of WT and Nox1-KO mice, we show that Nox1 also enhances microglial production of cytotoxic nitrite species and promotes loss of presynaptic proteins in striatal neurons. These results demonstrate the functional expression of Nox1 in resident CNS phagocytes, which can promote production of neurotoxic compounds during neuroinflammation. Our study also shows that Nox1- and Nox2-dependent oxidases play distinct roles in microglial activation and that Nox1 is a possible target for the treatment of neuroinflammatory states.
| 19,005,069
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Contributions of the human temporoparietal junction and MT/V5+ to the timing of interception revealed by transcranial magnetic stimulation.
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To intercept a fast target at destination, hand movements must be centrally triggered ahead of target arrival to compensate for neuromechanical delays. The role of visual-motion cortical areas is unclear. They likely feed downstream parietofrontal networks with signals reflecting target motion, but do they also contribute internal timing signals to trigger the motor response? We disrupted the activity of human temporoparietal junction (TPJ) and middle temporal area (hMT/V5+) by means of transcranial magnetic stimulation (TMS) while subjects pressed a button to intercept targets accelerated or decelerated in the vertical or horizontal direction. Target speed was randomized, making arrival time unpredictable across trials. We used either repetitive TMS (rTMS) before task execution or double-pulse TMS (dpTMS) during target motion. We found that after rTMS and dpTMS at 100-200 ms from motion onset, but not after dpTMS at 300-400 ms, the button-press responses occurred earlier than in the control, with time shifts independent of target speed. This suggests that activity in TPJ and hMT/V5+ can feed downstream regions not only with visual-motion information, but also with internal timing signals used for interception at destination. Moreover, we found that TMS of hMT/V5+ affected interception of all tested motion types, whereas TMS of TPJ significantly affected only interception of motion coherent with natural gravity. TPJ might specifically gate visual-motion information according to an internal model of the effects of gravity.
| 19,005,072
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Evidence of dysregulated peripheral oxytocin release among depressed women.
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Oxytocin is a hypothalamic neuropeptide that plays a key role in mammalian female reproductive function. Animal research indicates that central oxytocin facilitates adaptive social attachments and modulates stress and anxiety responses. Major depression is prevalent among postpubertal females, and is associated with perturbations in social attachments, dysregulation of the hypothalamic-pituitary-adrenal stress axis, and elevated levels of anxiety. Thus, depressed women may be at risk to display oxytocin dysregulation. The current study was developed to compare patterns of peripheral oxytocin release exhibited by depressed and nondepressed women. Currently depressed (N = 17) and never-depressed (N = 17) women participated in a laboratory protocol designed to stimulate, measure, and compare peripheral oxytocin release in response to two tasks: an affiliation-focused Guided Imagery task and a Speech Stress task. Intermittent blood samples were drawn over the course of two, 1-hour sessions including 20-minute baseline, 10-minute task, and 30-minute recovery periods. The 10-minute laboratory tasks did not induce identifiable, acute changes in peripheral oxytocin. However, as compared with nondepressed controls, depressed women displayed greater variability in pulsatile oxytocin release over the course of both 1-hour sessions, and greater oxytocin concentrations during the 1-hour affiliation-focused imagery session. Oxytocin concentrations obtained during the imagery session were also associated with greater symptoms of depression, anxiety, and interpersonal dysfunction. Depressed women are more likely than controls to display a dysregulated pattern of peripheral oxytocin release. Further research is warranted to elucidate the clinical significance of peripheral oxytocin release in both depressed and nondepressed women.
| 19,005,082
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Differential response of gray poplar leaves and roots underpins stress adaptation during hypoxia.
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The molecular and physiological responses of gray poplar (Populus x canescens) following root hypoxia were studied in roots and leaves using transcript and metabolite profiling. The results indicate that there were changes in metabolite levels in both organs, but changes in transcript abundance were restricted to the roots. In roots, starch and sucrose degradation were altered under hypoxia, and concurrently, the availability of carbohydrates was enhanced, concomitant with depletion of sucrose from leaves and elevation of sucrose in the phloem. Consistent with the above, glycolytic flux and ethanolic fermentation were stimulated in roots but not in leaves. Various messenger RNAs encoding components of biosynthetic pathways such as secondary cell wall formation (i.e. cellulose and lignin biosynthesis) and other energy-demanding processes such as transport of nutrients were significantly down-regulated in roots but not in leaves. The reduction of biosynthesis was unexpected, as shoot growth was not affected by root hypoxia, suggesting that the up-regulation of glycolysis yields sufficient energy to maintain growth. Besides carbon metabolism, nitrogen metabolism was severely affected in roots, as seen from numerous changes in the transcriptome and the metabolome related to nitrogen uptake, nitrogen assimilation, and amino acid metabolism. The coordinated physiological and molecular responses in leaves and roots, coupled with the transport of metabolites, reveal important stress adaptations to ensure survival during long periods of root hypoxia.
| 19,005,089
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Primary prevention of violence against women: training needs of violence practitioners.
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Practitioners in domestic violence and sexual assault programs have been encouraged by the National Center for Injury Prevention and Control to enhance their activities in violence prevention; however, many practitioners have not been trained in prevention concepts and strategies. Therefore, a needs assessment was undertaken with practitioners in the Domestic Violence Prevention Enhancement and Leadership Through Alliances and the Rape Prevention and Education programs to determine training needs. Results show that practitioners are very interested in primary prevention. They want to learn about working at the community level (rather than the individual level), developing and evaluating prevention activities, and identifying effective primary prevention programs.
| 19,005,091
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Asymptomatic unruptured intracranial aneurysms: approach to screening and treatment.
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ABSTRACTOBJECTIVETo review the current knowledge of screening and treatment of asymptomatic unruptured intracranial aneurysms (AUIAs) using a case-based approach.SOURCES OF INFORMATIONPubMed was searched from January 1995 to January 2008 using the phrase unruptured intracranial aneurysm. Scientific statements of the Stroke Council of the American Heart Association pertaining to intracranial aneurysms were also reviewed.MAIN MESSAGEMost small AUIAs (</= 5 mm) do not rupture, and the risks of treatment are substantial. Most small AUIAs can therefore be managed conservatively. Endovascular coiling or surgical clipping of larger aneurysms (> 5 mm) should be considered on a case-by-case basis.CONCLUSIONThere is currently a lack of sound scientific evidence to support treatment of unruptured intracranial aneurysms. A prospective randomized controlled trial-Trial on Endovascular Aneurysm Management-is now under way to address this issue. It is expected to conclude in 2021.
| 19,005,121
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Complementary and alternative medicine use among Chinese and white Canadians.
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ABSTRACTOBJECTIVEThis study aimed to describe the level of complementary and alternative medicine (CAM) use and the factors associated with CAM use among Chinese and white Canadians.DESIGNA cross-sectional telephone survey conducted in English, Cantonese, and Mandarin.SETTINGCalgary, Alta.PARTICIPANTSChinese and white residents of Calgary aged 18 or older.MAIN OUTCOME MEASURESRates of use of 11 CAM therapies, particularly herbal therapy, massage, chiropractic care, and acupuncture; reasons for use of CAM therapies.RESULTSSixty percent of 835 Chinese respondents (95% confidence interval [CI] 56.5% to 63.2%) and 59% of 802 white respondents (95% CI 55.1% to 62.0%) had used CAM in the past year. Chinese respondents were more likely to use herbal therapy than white respondents were (48.7% vs 33.7%, P < .001), less likely to use massage (17.1% vs 30.4%, P < .001) and chiropractic care (8.4% vs 21.2%, P < .001), but equally likely to use acupuncture (8.3% vs 7.9%, P = .173). The common factor associated with herbal therapy, acupuncture, or massage use among Chinese and white respondents was receiving a CAM recommendation from a family member or friend. Factors unique to either Chinese or white CAM users varied by therapy. For example, herbal therapy use for Chinese respondents was associated with the presence of chronic disease (adjusted odds ratio [AOR] 2.15, 95% CI 1.09 to 4.24 for having 3 diseases compared with those without chronic disease), beliefs about the effectiveness of herbal therapy (AOR 1.56, 95% CI 1.12 to 2.17), and trust in herbal therapy practitioners (AOR 1.72, 95% CI 1.24 to 2.37). Herbal therapy use for white respondents was associated with the beliefs that herbal treatment had fewer side effects than prescription drugs (AOR 1.81, 95% CI 1.31 to 2.50) and that herbalists took a holistic approach (AOR 2.07, 95% CI 1.49 to 2.87).CONCLUSIONWhile the percentage of CAM use was similar in both groups, Chinese Canadians mainly used herbal therapy and white Canadians used a range of CAM therapies. Factors associated with CAM use varied with ethnicity and type of CAM therapy. Presence of chronic disease, however, was an important factor for Chinese Canadians. That finding suggests that Chinese Canadians use CAM for the treatment of chronic disease, while white Canadians use such therapies for disease treatment and health maintenance.
| 19,005,129
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Effect of ThinPrep preparation on human papillomavirus detection and genotyping in rectal samples by PCR.
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Specimen-to-specimen carryover during ThinPrep slide preparation was evaluated by comparing human papillomavirus genotypes detected prior and subsequent to the ThinPrep processing of 121 PreservCyt samples. Overall, 52 samples generated concordant genotypes and 38 had additional and 21 had fewer genotypes postprocessing. PreservCyt samples should be aliquoted for PCR testing prior to ThinPrep processing.
| 19,005,144
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Coiled-coil-mediated dimerization is not required for myosin VI to stabilize actin during spermatid individualization in Drosophila melanogaster.
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Myosin VI is a pointed-end-directed actin motor that is thought to function as both a transporter of cargoes and an anchor, capable of binding cellular components to actin for long periods. Dimerization via a predicted coiled coil was hypothesized to regulate activity and motor properties. However, the importance of the coiled-coil sequence has not been tested in vivo. We used myosin VI's well-defined role in actin stabilization during Drosophila spermatid individualization to test the importance in vivo of the predicted coiled coil. If myosin VI functions as a dimer, a forced dimer should fully rescue myosin VI loss of function defects, including actin stabilization, actin cone movement, and cytoplasmic exclusion by the cones. Conversely, a molecule lacking the coiled coil should not rescue at all. Surprisingly, neither prediction was correct, because each rescued partially and the molecule lacking the coiled coil functioned better than the forced dimer. In extracts, no cross-linking into higher molecular weight forms indicative of dimerization was observed. In addition, a sequence required for altering nucleotide kinetics to make myosin VI dimers processive is not required for myosin VI's actin stabilization function. We conclude that myosin VI does not need to dimerize via the predicted coiled coil to stabilize actin in vivo.
| 19,005,209
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A myopathy-linked desmin mutation perturbs striated muscle actin filament architecture.
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Desmin interacts with nebulin establishing a direct link between the intermediate filament network and sarcomeres at the Z-discs. Here, we examined a desmin mutation, E245D, that is located within the coil IB (nebulin-binding) region of desmin and that has been reported to cause human cardiomyopathy and skeletal muscle atrophy. We show that the coil IB region of desmin binds to C-terminal nebulin (modules 160-164) with high affinity, whereas binding of this desmin region containing the E245D mutation appears to enhance its interaction with nebulin in solid-phase binding assays. Expression of the desmin-E245D mutant in myocytes displaces endogenous desmin and C-terminal nebulin from the Z-discs with a concomitant increase in the formation of intracellular aggregates, reminiscent of a major histological hallmark of desmin-related myopathies. Actin filament architecture was strikingly perturbed in myocytes expressing the desmin-E245D mutant because most sarcomeres contained elongated or shorter actin filaments. Our findings reveal a novel role for desmin intermediate filaments in modulating actin filament lengths and organization. Collectively, these data suggest that the desmin E245D mutation interferes with the ability of nebulin to precisely regulate thin filament lengths, providing new insights into the potential molecular consequences of expression of certain disease-associated desmin mutations.
| 19,005,210
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Modeling single and repeated dose pharmacokinetics of PFOA in mice.
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Perfluorooctanoic acid (PFOA) displays complicated pharmacokinetics in that serum concentrations indicate long half-lives despite which steady state appears to be achieved rapidly. In this study, serum and tissue concentration time-courses were obtained for male and female CD1 mice after single, oral doses of 1 and 10 mg/kg of PFOA. When using one- and two-compartment models, the pharmacokinetics for these two dosages are not consistent with serum time-course data from female CD1 mice administered 60 mg/kg, or with serum concentrations following repeated daily doses of 20 mg/kg PFOA. Some consistency between dose regimens could be achieved using the saturable resorption model of Andersen et al. In this model PFOA is cleared from the serum into a filtrate compartment from which it is either excreted or resorbed into the serum by a process presumed transporter mediated with a Michaelis-Menten form. Maximum likelihood estimation found a transport maximum of T(m) = 860.9 (1298.3) mg/l/h and half-maximum concentration of K(T) = 0.0015 (0.0022) mg/l where the estimated standard errors (in parentheses) indicated large uncertainty. The estimated rate of flow into and out of the filtrate compartment, 0.6830 (1.0131) l/h was too large to be consistent with a biological interpretation. For these model parameters a single dose greater than 40 mg/kg, or a daily dose in excess of 5 mg/kg were necessary to observe nonlinear pharmacokinetics for PFOA in female CD1 mice. These data and modeling analyses more fully characterize PFOA in mice for purposes of estimating internal exposure for use in risk assessment.
| 19,005,225
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Nodular morphea.
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Scleroderma may present as being strictly limited to the skin, as in morphea, or within a multiorgan disease, as in systemic sclerosis. Accordingly, cutaneous manifestations vary clinically. In nodular or keloidal scleroderma, patients develop lesions that are clinically indistinguishable from a keloid; however, the histopathological findings are more variable. We describe a 16-year-old girl with morpheic lesions for 3-4 years and additional development of keloidal nodules within these lesions. The histological examination revealed a hypertrophic scar besides morphea.
| 19,005,241
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Reasons for hospital admissions in dementia patients in Birmingham, UK, during 2002-2007.
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There is a lack of evidence to explain why patients with dementia are admitted to a general hospital. Main reasons for hospitalisation were investigated in all patients admitted to a multi-ethnic general hospital during 2002-2007, by analysis of type of admission and primary diagnosis on admission. Anonymised data from the Hospital Activity Analysis Register was used to trace these patients; 505 were diagnosed with Alzheimer's disease (AD), 283 with vascular dementia (VD) and 1,773 patients were classified as unspecified dementia (UnD). Logistic regression analysis was used to compare these groups to 53,123 age-matched controls. Statistical significance of p < 0.001 was accepted. More dementia patients were admitted as emergency cases compared to controls (AD = 95.8%, VD = 95.4%, UnD = 96.7%, controls = 54.4%; p < 0.001 for all comparisons). The proportion of patients admitted for dementia as their primary diagnosis was small (AD = 5.9%, VD = 10.6%, UnD = 6.0%). Primary diagnoses such as syncope and collapse, bronchopneumonia, urinary tract infection and dehydration were more frequent in all dementia patients than controls. Dementia patients are frequently admitted as emergency cases, but dementia itself is often not the primary diagnosis. Earlier detection of the specific conditions mentioned above may reduce emergency hospital admissions amongst dementia patients.
| 19,005,254
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Change in morphology and oxytocin receptor expression in the uterine blood vessels during the involution process.
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The histological changes in uterine blood vessels during pregnancy have been well investigated, but there have been few reports focusing on the changes in blood vessels during the involution process, especially within the first 24 h. We observed the process of uterine involution, focusing on the vessels of the resected uterus. Paraffin-embedded uterine samples from 15 patients who underwent hysterectomy because of severe cervical laceration and uterine rupture were examined. The time between delivery and hysterectomy ranged from 15 min to 456 h. The specimens were stained with hematoxylin-eosin, elastica-van Gieson and an antioxytocin receptor antibody. Changes in the uterine vessels varied substantially based on their location. The intima in arteries of the endometrial side thickened within 5 h after delivery. On the serosal side, phlebosclerosis was demonstrated 6 weeks postpartum. Immunoreactivity for the oxytocin receptor (OTR) appeared in the muscular medias of arteries 5 h after delivery although it was not expressed before this period. Remodeling of uterine vessels involved thickening of the arterial intima and OTR expression in vessel walls during the first 5 h postpartum; the parameters normalized within 6 weeks. However, phlebosclerosis persisted for a long time on the serosal side.
| 19,005,262
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Patients presenting with AIDS in the HAART era: a collaborative cohort analysis.
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Many patients infected with HIV still present with an AIDS diagnosis. The aim of this study was to evaluate the virological, immunological and clinical outcomes of HAART in these patients. The present study was a multi-cohort study. All patients with an AIDS diagnosis between 30 days before and 14 days after HIV diagnosis, recruited between 1997 and 2004 from eight hospital cohorts, were evaluated. A total of 760 patients were included [268 (35.3%) had pneumocystis and 168 (22.1%) tuberculosis]. Six hundred and twenty-four patients (82.1%) started HAART a median of 31 days after HIV diagnosis. One hundred and fifty-three patients started a nonnucleoside transcriptase inhibitor-based regimen (20.1%), 409 a protease inhibitor-based regimen (53.8%) and 62 other regimens (8.2%). In adjusted analyses, HAART was started sooner in more recent years, in patients with lower CD4 cell count and in those with Kaposi's sarcoma, whereas it was started later in those with tuberculosis. Five hundred and five patients (89%) attained a viral load of less than 500 copies/ml. The factors associated with a better virological response were later calendar year, lower initial viral load and cytomegalovirus disease. Virological rebound was more common in those receiving nucleoside reverse transcriptase inhibitor-based regimens, in those with tuberculosis and in earlier calendar years. One hundred and twenty-five (16%) patients died; 61 had received HAART (48.6%). Mortality was more likely in those who were older, those with a higher viral load at diagnosis, those with nonsexual HIV risks and those with lower CD4 cell count and haemoglobin levels over follow-up. Virological suppression was achieved in most AIDS patients, though mortality remains high in these individuals.
| 19,005,269
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Recurrent tuberculosis in HIV-infected patients in Rio de Janeiro, Brazil.
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The risk of recurrent tuberculosis may increase in HIV-infected patients due to exogenous reinfection. We measured the frequency of and determined risk factors for recurrent tuberculosis in a cohort of HIV-infected patients in Rio de Janeiro, Brazil. Data were abstracted from medical records of HIV-infected patients attending 29 HIV clinics between 1998 and 2007. Patients analyzed were those who had no tuberculosis history prior to their first HIV clinic visit and who had at least one episode of tuberculosis after entry. Incidence rate ratios compared incidence rates between risk groups and Cox proportional hazards regression models evaluated unadjusted and adjusted associations. Among 1080 HIV-infected patients with tuberculosis, 96 (8.9%) developed a recurrent diagnosis. The median time between diagnoses was 2.4 years. Fewer patients with recurrent tuberculosis had completed their initial 6-month course of tuberculosis treatment compared with patients without recurrence (78 versus 86%; P = 0.02). For patients who completed therapy, the incidence rate of recurrence was 2.5/100 versus 9.0/100 person-years for noncompleters (incidence rate ratio, 3.60; 95% confidence interval, 1.92-6.32). In multivariate modeling, initial tuberculosis treatment completion, receipt of antiretroviral therapy, and CD4 cell count more than 200 mm any time after the initial diagnosis were associated with a significantly decreased hazard of recurrence. Tuberculosis recurrence rates were high in this HIV-infected population. Completion of initial tuberculosis therapy, use of antiretroviral therapy, and increases in CD4 cell counts were associated with lower recurrence rates. Use of secondary preventive therapy might be warranted to reduce the burden of tuberculosis in patients with HIV infection.
| 19,005,276
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The relationships between PON1 activity as well as oxLDL levels and coronary artery lesions in CHD patients with diabetes mellitus or impaired fasting glucose.
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Lower paraoxonase (PON1) activity and higher oxidized low-density lipoprotein (oxLDL) levels are main risk factors of coronary heart disease (CHD). The aim of this study is to observe the characteristics of coronary artery lesions in CHD patients with or without hyperglycemia and relationships between coronary artery lesions and oxLDL levels as well as PON1 activity. Two hundred and eighty-four participants were divided into four groups according to their coronary angiographies and fasting plasma glucose levels: CHD+diabetes mellitus (DM) (n=46); CHD+impaired fasting glucose (n=62); CHD+normal fasting glucose (NFG) (n=86); healthy control group (n=90). The CHD+DM group had more diffuse lesions, higher frequency of severe coronary stenoses or total occlusions and more multivessel lesions than those with NFG. PON1 activity in the CHD+NFG group was lower than that in control participants (P<0.05), and much lower in the CHD patients with hyperglycemia (DM and impaired fasting glucose) (P<0.01). OxLDL levels in the CHD+DM group were higher than in the CHD+NFG group (P<0.05). In the CHD patients with hyperglycemia, the patients of multivessel lesions had higher oxLDL levels than those of single-vessel lesions (P<0.05) and the patients of severe stenosed vessels had obviously lower PON1 activity than those of mild and moderate stenosed vessels (P<0.01), whereas oxLDL levels were higher in the patients with diffuse lesions than those with focal lesions(P<0.05). In the multivariate analysis, the patients in the highest quartile of oxLDL level had an increased likelihood of having multivessel lesions or diffuse lesions compared with those in the lowest quartile [odds ratio (OR)=49.46, P=0.001; OR=34.30, P<0.001, respectively] whereas there was a negative correlation between two upper quartiles of serum PON1 activity and the likelihood of severe stenoses or total occlusions among the CHD patients with hyperglycemia (the top quartile, OR=0.14, P=0.008; the third quartile, OR=0.22, P=0.033). Lower PON1 activity and higher oxLDL levels may be predicting factors that denote diffuse, severe or multivessel disease in CHD patients with hyperglycemia.
| 19,005,291
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Cholesterol composition of erythrocyte membranes and its association with clinical presentation of coronary artery disease.
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Presence of free cholesterol in atherosclerotic plaques is a major determinant of plaque instability. It is hypothesized that extravasated erythrocytes may contribute to free cholesterol accumulation in atherosclerotic plaques through their rich in cholesterol membrane. In this study we assessed whether cholesterol in erythrocyte membranes (CEMs), that is, free (FCEM) versus esterified (ECEM), differs in patients with chronic stable angina (CSA) compared with patients presenting with acute coronary syndromes (ACSs). Consecutive angina patients were prospectively assessed; 154 had CSA (118 men, 63 years, 56-69 years) and 164 ACS (124 men, 63 years, 55-71 years). FCEM and ECEM were measured using an enzymatic assay, and protein content was assessed by the Bradford method. FCEM was significantly higher (P<0.001) in the ACS patients group (94.1 microg/mg, IQ 71-116.5 microg/mg) compared with patients with CSA (61.9 microg/mg, IQ 49.3-73.1 microg/mg). ECEM levels were also significantly higher (P<0.001) in ACS patients (23.3 microg/mg, IQ 14.9-47.7 microg/mg) compared with CSA patients (10.8 microg/mg, IQ 8-22.3 microg/mg). In contrast, ratio of free-to-esterified cholesterol (P=0.110) as well as ratio of free-to-total CEM (P=0.109) were not different among CSA and ACS patients. Findings of this study show that although free cholesterol is the prevailing form of CEMs, both FCEM and ECEM levels are increased in patients with ACS compared with CSA patients. These findings suggest that it is the quantity of CEM rather than the type of cholesterol present in the erythrocyte membrane that determines plaque progression.
| 19,005,293
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Postinjury immune monitoring: can multiple organ failure be predicted?
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Multiple organ failure is the main cause of late morbidity and mortality after severe injury. This disease state is driven by a dysfunctional immune system. Prediction of multiple organ failure on the basis of clinical parameters appears to be insufficient. A better understanding of immunological pathogenesis underlying multiple organ failure may lead to better prediction and innovation in treatment strategy in order to increase the survival of trauma patients. Immune monitoring has increased the knowledge of the pathogenesis of multiple organ failure, but many mechanisms underlying its cause and development remain to be elucidated. Consequently, adequate predictive markers for diagnosis and monitoring still need to be developed. General markers of inflammation including cytokines are correlated with posttraumatic complications with a low sensitivity and specificity and are, therefore, of little use as prognostic markers. Current findings regarding the functionality of immune cells are promising and might be of prognostic value in the near future.
| 19,005,307
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The timing of spinal stabilization in polytrauma and in patients with spinal cord injury.
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Despite improved care of multiple injured patients, controversial data about the best time point for decompression and stabilization of spine fractures and spinal cord injuries are published. Some studies even question the value of surgical management. In several mostly retrospective studies and a meta-analysis, there is growing evidence that early decompression and stabilization of spine injuries seems to be beneficial, especially in more severely injured patients. Early stabilization seems to reduce length of stay and pulmonary complications. Some studies report on improved neurological outcome and improved survival; however, other new studies add controversial data. Most studies support the hypothesis that early decompression and stabilization of spine injuries is beneficial in terms of reducing length of stay at the ICU, as well as improving neurological and overall outcome. Good prospective clinical trials are still missing, thus the level of evidence remains low.
| 19,005,310
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Return to physical activity after exertional rhabdomyolysis.
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Exertional rhabdomyolysis (ER) is a condition characterized by muscle pain, swelling, and weakness following some exertional stress, with or without concomitant heat stress. Athletes who experience ER often present to the emergency department, the training room, or the physician's office seeking guidance and care for this condition, often feeling it is simply normal delayed onset muscle soreness. The astute clinician must perform a thorough history and focused exam, in addition to ordering a serum creatine kinase (CK) and urinalysis. In this clinical setting, a CK equal to or greater than five times normal or a urine dipstick testing positive for blood with no demonstrable red blood cells upon microscopic assessment confirms the diagnosis. A urine or serum myoglobin is more definitive when expeditiously available. After treatment for ER, the provider must risk-stratify the athlete for risk of recurrence, consider further testing, and make the difficult decision on when, if, and under what conditions the athlete can safely return to play.
| 19,005,354
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Surgical management and outcome of scalp subcutaneous granuloma annulare in children: case report.
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Subcutaneous granuloma annulare (SGA) is a benign inflammatory disorder that rarely affects the scalp. We report 5 cases of children with SGA scalp lesions and discuss our clinical experience and the characteristic findings, diagnostic evaluation, method of treatment, and course of the disease. Five patients presented with multiple subcutaneous nodules at single or multiple sites overlying the scalp. A retrospective review of the medical, surgical, and pathology records of the 5 patients was conducted. All scalp lesions were excised and were confirmed histologically to be SGA nodules. In 4 of the 5 patients, the nodules were nontender and nonmobile. The mean number of lesions was 4.2. The mean age of patients at presentation was 3.8 years. Of the 5 patients, 4 experienced at least 1 recurrence of a solitary lesion at either the same site or a different site. In the 80% of patients who experienced a recurrence, all lesions recurred less than 1 year postoperatively, except in the case of 1 patient who continued to experience a disappearance and reappearance of lesions at 72 months. The ultimate diagnosis of all lesions was established through biopsy and subsequent microscopic evaluation. No postoperative complications were noted. Granuloma annulare should be included in the differential diagnosis whenever a scalp subcutaneous superficial nodule is observed. Although many modalities of treatment for SGA nodules are used, recurrence is common, even with surgical excision.
| 19,005,364
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Barbiturate infusion for intractable intracranial hypertension and its effect on brain oxygenation.
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Barbiturate-induced coma can be used in patients to treat intractable intracranial hypertension when other therapies, such as osmotic therapy and sedation, have failed. Despite control of intracranial pressure, cerebral infarction may still occur in some patients, and the effect of barbiturates on outcome remains uncertain. In this study, we examined the relationship between barbiturate infusion and brain tissue oxygen (PbtO2). Ten volume-resuscitated brain-injured patients who were treated with pentobarbital infusion for intracranial hypertension and underwent PbtO2 monitoring were studied in a neurosurgical intensive care unit at a university-based Level I trauma center. PbtO2, intracranial pressure (ICP), mean arterial pressure, cerebral perfusion pressure (CPP), and brain temperature were continuously monitored and compared in settings in which barbiturates were or were not administered. Data were available from 1595 hours of PbtO2 monitoring. When pentobarbital administration began, the mean ICP, CPP, and PbtO2 were 18 +/- 10, 72 +/- 18, and 28 +/- 12 mm Hg, respectively. During the 3 hours before barbiturate infusion, the maximum ICP was 24 +/- 13 mm Hg and the minimum CPP was 65 +/- 20 mm Hg. In the majority of patients (70%), we observed an increase in PbtO2 associated with pentobarbital infusion. Within this group, logistic regression analysis demonstrated that a higher likelihood of compromised brain oxygen (PbtO2 < 20 mm Hg) was associated with a decrease in pentobarbital dose after controlling for ICP and other physiological parameters (P < 0.001). In the remaining 3 patients, pentobarbital was associated with lower PbtO2 levels. These patients had higher ICP, lower CPP, and later initiation of barbiturates compared with patients whose PbtO2 increased. Our preliminary findings suggest that pentobarbital administered for intractable intracranial hypertension is associated with a significant and independent increase in PbtO2 in the majority of patients. However, in some patients with more compromised brain physiology, pentobarbital may have a negative effect on PbtO2, particularly if administered late. Larger studies are needed to examine the relationship between barbiturates and cerebral oxygenation in brain-injured patients with refractory intracranial hypertension and to determine whether PbtO2 responses can help guide therapy.
| 19,005,378
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Obesity and self-reported outcome after minimally invasive lumbar spinal fusion surgery.
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Many patients undergoing lumbar spine fusion are overweight or obese. The relationship between body habitus and outcome after lumbar spine fusion surgery is not well defined. We analyzed a prospectively maintained database of self-reported pain and quality of life measures, including Visual Analog Scale pain score, Short Form 36, and Oswestry Disability Index. We selected patients undergoing minimally invasive transforaminal lumbar interbody fusion between September 2002 and June 2006 at a single institution. We used linear regression models and mixed-effects linear models to examine the relationships between body habitus and self-reported outcomes. The analysis identified 110 patients meeting the study criteria, with a median follow-up period of 14.8 months. The mean age was 56 years, mean height was 169 cm, and mean weight was 82.2 kg. The mean body mass index (BMI) was 28.7 kg/m2; 31% of patients were overweight (BMI, 25-29.9), and 32% of patients were obese (BMI, >30). Linear regression analysis did not identify a correlation between weight or BMI and pre- and postsurgery changes in any of the outcome measures. The significant findings observed in the mixed-effects linear models were that the changing patterns of Short Form 36 Body Pain subscale and Short Form 36 Vitality subscale varied significantly by category of BMI (P = 0.01 and P = 0.002, respectively), but not significantly if continuous BMI was used (P = 0.53 and P = 0.46, respectively). BMI correlated marginally with estimated blood loss (P = 0.08), but not operative time, length of hospital stay, or complications. Among this cohort of minimally invasive lumbar fusion patients, body habitus measured by BMI, weight, or height did not have a significant relationship with most self-reported outcome measures, operative time, length of hospital stay, or complications. Obesity should not be considered a contraindication to minimally invasive lumbar spinal fusion surgery.
| 19,005,386
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Susceptibility of human mesenchymal stem cells to tacrolimus, mycophenolic acid, and rapamycin.
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Mesenchymal stem cells (MSC) have multilineage differentiation and immunomodulatory capacities and are potentially useful for therapeutic applications, such as tissue regeneration and control of alloreactivity. MSC are present in most tissues including the transplantable organs. It is therefore unavoidable that MSC will be exposed to immunosuppressive drugs in a clinical transplantation setting. The molecular targets of these drugs are expressed in MSC, but the effect of their inhibition on MSC functioning is unknown. MSC were isolated and expanded from heart tissue and the effects of the calcineurin inhibitor tacrolimus, the cell cycle inhibitor mycophenolic acid (MPA), and the mammalian target of rapamycin inhibitor on MSC survival, proliferation, differentiation, and immunosuppressive capacity were examined. Short-term exposure to the immunosuppressants did not induce toxicity or apoptosis in MSC, but high-dose tacrolimus induced toxicity after 7 days. MPA and rapamycin inhibited MSC proliferation at therapeutic doses. The immunosuppressants had differential effects on the differentiation capacity of MSC. Tacrolimus reduced the expression of troponin T type 2 and desmin during cardiomyogenic differentiation of MSC, whereas MPA decreased the deposition of calcified minerals during osteogenic differentiation. Rapamycin stimulated lipid production during adipogenic differentiation. Unexpectedly, MSC had adverse effects on the immunosuppressive efficacy of tacrolimus and rapamycin. There was no such effect of MSC on the function of MPA. Preincubation of MSC with tacrolimus increased the immunosuppressive capacity of MSC. This study demonstrates that therapeutic concentrations of immunosuppressive drugs affect MSC function. MSC affect the efficacy of immunosuppressive medication. These findings are important for potential clinical use of MSC in combination with immunosuppressants.
| 19,005,411
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Dramatically reduced surface expression of NK cell receptor KIR2DS3 is attributed to multiple residues throughout the molecule.
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Using flow cytometry, fluorescent microscopy and examination of receptor glycosylation status, we demonstrate that an entire killer cell immunoglobulin-like receptor (KIR) locus (KIR2DS3)--assumed earlier to be surface expressed--appears to have little appreciable surface expression in transfected cells. This phenotype was noted for receptors encoded by three allelic variants including the common KIR2DS3*001 allele. Comparing the surface expression of KIR2DS3 with that of the better-studied KIR2DS1 molecule in two different cell lines, mutational analysis identified multiple polymorphic amino-acid residues that significantly alter the proportion of molecules present on the cell surface. A simultaneous substitution of five residues localized to the leader peptide (residues -18 and -7), second domain (residues 123 and 150) and transmembrane region (residue 234) was required to restore KIR2DS3 to the expression level of KIR2DS1. Corresponding simultaneous substitutions of KIR2DS1 to the KIR2DS3 residues resulted in a dramatically decreased surface expression. Molecular modeling was used to predict how these substitutions contribute to this phenotype. Alterations in receptor surface expression are likely to affect the balance of immune cell signaling impacting the characteristics of the response to pathogens or malignancy.
| 19,005,473
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Identifying genes for primary hypertension: methodological limitations and gene-environment interactions.
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Hypertension segregates within families, indicating that genetic factors explain some of the variance in the risk of developing the disease; however, even with major advances in genotyping technologies facilitating the discovery of multiple genetic risk markers for cardiovascular and metabolic diseases, little progress has been made in defining the genetic defects that cause elevations in blood pressure. Several plausible explanations exist for this apparent paradox, one of which is that the risk conveyed by genes involved in the development of hypertension is context dependent. This notion is supported by a growing number of published animal and human studies, although none has yet provided unequivocal evidence that genetic and environmental factors interact to influence the risk of primary hypertension in humans. In this review, an assumption is made that common genetic variation contributes meaningfully to the development of primary hypertension. The review focuses on (i) several methodological limitations of genetic association studies and (ii) the roles that gene-environment interactions might play in the development of primary hypertension. The proceeding sections of the review examine the design features necessary for future studies to adequately test the hypothesis that genes for primary hypertension act in a context-dependent manner. Finally, an outline of how knowledge of gene-environment interactions might be used to optimize the prevention or treatment of primary hypertension is provided.
| 19,005,475
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Telomere length is severely and similarly reduced in JAK2V617F-positive and -negative myeloproliferative neoplasms.
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Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by chronic proliferation of hematopoietic progenitors. We studied the telomere length (TL) of 335 MPN patients and 93 gender- and age-matched controls using a quantitative PCR method (relative TL calculated as the ratio of the amount of telomere DNA vs single-copy DNA: T/S ratio). TL was markedly reduced in MPN patients compared with controls (T/S 0.561 vs 0.990, P<0.001). In JAK2V617F MPN patients, TL correlated inversely with allelic burden (P<0.001). Patients homozygous for the mutation (allelic burden 90-100%) had the shortest TL, even when compared with patients with lower allele burdens consistent with a dominant heterozygous population (allelic burden 55-65%) (T/S 0.367 vs 0.497, P=0.037). This suggests that the high degree of proliferation of the MPN clone reduces TL and suggests the possibility that TL shortening may be indicative of progressive genomic instability during MPN progression. The TL of JAK2V617F-negative MPN patients was similar to JAK2V617F-positive counterparts (T/S 0.527 vs 0.507, P=0.603), suggesting that the yet-to-be-discovered causative mutation(s) impact the mutated stem cell similarly to JAK2V617F, and that TL measurement may prove useful in the diagnostic workup of JAK2V617F-negative MPN.
| 19,005,480
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The "caveolae brake hypothesis" and the epidermal barrier.
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Epidermal permeability barrier formation depends upon lamellar body (LB) secretion/fusion with the apical plasma membrane (APM) of outermost stratum granulosum (SG) cell, creating cholesterol/glycosphingolipid-enriched lipid rafts-like domains. We found that the dimensions of these domains are comparable to lipid raft in other cell types; and that acute barrier disruption regulates their size and dynamics. To assess the function of these LB-derived raft-like domains, we assessed APM dynamics and barrier recovery in methyl-beta-cyclodextrin (MbetaCD)-treated hairless mice and caveolin-1 knockouts (cav-1(-/-)). MbetaCD treatment impaired APM raft-like domain formation and barrier recovery. Accelerated barrier recovery is observed in cav-1(-/-) in parallel with expansion of raft-like domains. Barrier abrogation of normal epidermis resulted in translocation of cav-1 from the cytoplasm to raft-like membrane domains, restricting further raft-like domain formation and initiating terminal differentiation. Inhibition of LB secretion by monensin and absence of cav-1 delayed terminal differentiation. Furthermore, cav-1(-/-) mice exhibited an increased propensity to develop experimentally induced epidermal hyperplasia correlating with lipid raft persistence. Finally, the epidermal hyperplasia in psoriasis and Netherton syndrome is paralleled by increased lipid raft formation. These studies demonstrate that cav-1 delivery to the APM by LB trafficking to APM "brakes" further LB secretion, signals terminal differentiation, and regulates epidermal hyperproliferation.
| 19,005,485
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The role of microorganisms in coral bleaching.
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Coral bleaching is the disruption of the symbiosis between the coral host and its endosymbiotic algae. The prevalence and severity of the disease have been correlated with high seawater temperature. During the last decade, the major hypothesis to explain coral bleaching is that high water temperatures cause irreversible damage to the symbiotic algae resulting in loss of pigment and/or algae from the holobiont. Here, we discuss the evidence for an alternative but not mutually exclusive concept, the microbial hypothesis of coral bleaching.
| 19,005,495
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Protists are microbes too: a perspective.
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Our understanding of the composition and activities of microbial communities from diverse habitats on our planet has improved enormously during the past decade, spurred on largely by advances in molecular biology. Much of this research has focused on the bacteria, and to a lesser extent on the archaea and viruses, because of the relative ease with which these assemblages can be analyzed and studied genetically. In contrast, single-celled, eukaryotic microbes (the protists) have received much less attention, to the point where one might question if they have somehow been demoted from the position of environmentally important taxa. In this paper, we draw attention to this situation and explore several possible (some admittedly lighthearted) explanations for why these remarkable and diverse microbes have remained largely overlooked in the present 'era of the microbe'.
| 19,005,497
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Selective progressive response of soil microbial community to wild oat roots.
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Roots moving through soil induce physical and chemical changes that differentiate rhizosphere from bulk soil, and the effects of these changes on soil microorganisms have long been a topic of interest. The use of a high-density 16S rRNA microarray (PhyloChip) for bacterial and archaeal community analysis has allowed definition of the populations that respond to the root within the complex grassland soil community; this research accompanies compositional changes reported earlier, including increases in chitinase- and protease-specific activity, cell numbers and quorum sensing signal. PhyloChip results showed a significant change compared with bulk soil in relative abundance for 7% of the total rhizosphere microbial community (147 of 1917 taxa); the 7% response value was confirmed by16S rRNA terminal restriction fragment length polymorphism analysis. This PhyloChip-defined dynamic subset was comprised of taxa in 17 of the 44 phyla detected in all soil samples. Expected rhizosphere-competent phyla, such as Proteobacteria and Firmicutes, were well represented, as were less-well-documented rhizosphere colonizers including Actinobacteria, Verrucomicrobia and Nitrospira. Richness of Bacteroidetes and Actinobacteria decreased in soil near the root tip compared with bulk soil, but then increased in older root zones. Quantitative PCR revealed rhizosphere abundance of beta-Proteobacteria and Actinobacteria at about 10(8) copies of 16S rRNA genes per g soil, with Nitrospira having about 10(5) copies per g soil. This report demonstrates that changes in a relatively small subset of the soil microbial community are sufficient to produce substantial changes in functions observed earlier in progressively more mature rhizosphere zones.
| 19,005,498
|
Natural Killer Cell Receptor NKG2A/HLA-E Interaction Dependent Differential Thymopoiesis of Hematopoietic Progenitor Cells Influences the Outcome of HIV Infection.
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HIV infection and its outcome is complex because there is great heterogeneity not only in clinical presentation, incomplete clinical information of markers of immunodeficiency and in measurements of viral loads. Also, there many gene variants that control not only viral replication but immune responses to the virus; it has been difficult to study the role of the many AIDS restricting genes (ARGs) because their influence vary depending on the ethnicity of the populations studies and because the cost to follow infected individuals for many years. Nevertheless, at least genes of the major histocompatibility locus (MHC) such as HLA alleles have been informative to classify infected individuals following HIV infection; progression to AIDS and long-term-non-progressors (LTNP). For example, progressors could be defined as up to 5 years, up to 11 years or as we describe in this report up to 15 years from infection, and LTNP could be individuals with normal CD4+ T cell counts for more than 15 years with or without high viral loads. In this review, we emphasized that in the studies of ARGs the HLA alleles are important in LTNP; HLA-B alleles influencing the advantage to pathogens to produce immune defense mediated by CD8+ T cells (cognate immunuity). Our main point we make in this report is that contrary to recent reports claiming that this dominant effect was unlikely due to differences in NK activation through ligands such as HLA-Bw4 motif, we believe that cognate immunity as well as innate immunity conferred by NK cells are involved. The main problem is that HLA-Bw4 alleles can be classified according the aminoacid in position 80. Isoleucine determines LTNP, which is a ligand for 3DS1. Such alleles did not include HLA-B*44. B*13 and B*27 which have threonine at that position. The authors have not considered the fact that in addition to the NK immunoglobulin receptors, NK receptors can be of the lectin like such as NKG2A/HLA-E to influence the HIV infection outcome. HLA-Bw4 as well as HLA-Bw6 alleles can be classified into those with threonine or methionine in the second position of their leader peptides. These leader peptides are ligands for NKG2A in which methionine influences the inhibitory role of NKG2A for killing infected targets. Functional studies have not been done as well as studies of these receptors in infected individuals. However, analyses of the leader peptides of HLA-B alleles in published reports, suggested that threonine in the second position can explain the importance of HLA-B*57, B*13, B*44 as well as certain Bw6 alleles in LNTP. In addition, we analyzed the San Francisco database that was reported and found that the association of HLA-B alleles with LNTP or with progressors can be due to the presence of threonine or methionine in their second position. Therefore, studies of outcome of HIV infection should include not only mechanisms of cognate immunity mediated by peptides and CD8+ T cells but also, NK receptors of two types, NKG2A as well as 3DSI. We propose that the SCID mouse should be used to understand mechanisms mediated by many of the ARGs especially the importance of thymus derived cells as well as NK receptor interactions with their ligands in this experimental animal transplanted with human stem cells, thymus or NK cells obtained from individuals of known HLA genotypes.
| 19,005,583
|
Highly diastereo- and enantioselective construction of both central and axial chiralities by Rh-catalyzed [2 + 2 + 2] cycloaddition.
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The cationic Rh-SEGPHOS complex catalyzed an intermolecular [2 + 2 + 2] cycloaddition of enynes, possessing an ortho-substituted aryl group on their alkyne terminus, with acetylenedicarboxylates. Bicyclic cyclohexa-1,3-dienes with both central and axial chiralities were obtained in extremely highly diastereo- and enantioselective manner.
| 19,005,587
|
Rhodium catalysed conjugate addition of a chiral alkenyltrifluoroborate salt: the enantioselective synthesis of hermitamides A and B.
|
The concise enantioselective synthesis of hermitamides A and B is presented utilising a rhodium catalysed conjugate addition reaction to introduce the side chain and chiral information in a single step via an alkenyltrifluoroborate salt.
| 19,005,593
|
Development of a method for the parallel synthesis and purification of N-substituted pantothenamides, known inhibitors of coenzyme A biosynthesis and utilization.
|
N-Substituted pantothenamides are a class of pantothenic acid analogues which have been shown to act as inhibitors of coenzyme A biosynthesis and utilization, especially by blocking fatty acid metabolism through formation of inactive acyl carrier proteins. To fully explore the chemical diversity and inhibitory potential of these analogues we have developed a simple method for the parallel synthesis and purification of any number of pantothenamides from a single precursor, and subsequently evaluated a small library of these compounds as inhibitors of bacterial growth to demonstrate the potential and utility of the method.
| 19,005,594
|
Presence of a meningioma in a cervical myelomeningocele sac.
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An 11-year-old female, presented with a cervical myelomeningocele. Interestingly, the myelomeningocele sac was seen to contain a meningioma. There are no aetiological factors in the embryogenetic period that would lead to such a combination of lesions. In our opinion, the meningioma appeared in a later period because of local factors.
| 19,005,614
|
The self-thinning process in mangrove Kandelia obovata stands.
|
The self-thinning process was monitored in crowded Kandelia obovata Sheue, Liu & Yong stands over four years. The frequency distribution of tree phytomass was an L-shape, which was kept over the experimental period. Spearman's rank correlation coefficient for phytomass decreased as the time span of the comparison became longer, a result which indicates that the rank of phytomass changes as stands grow. Death of trees resulted from one-sided competition, i.e., death occurred in lower-rank trees. Surviving trees continued to grow. Whatever the current spatial distribution of the trees, death occurred randomly and the spatial distribution gradually became close to random as stands grew. The self-thinning exponent was 1.46, which can be regarded as evidence in favor of the 3/2 power law of self-thinning. Relative growth rate, RGR, decreased in proportion to decreasing relative mortality rate, RMR, with a proportionality constant of 1.57, which was not significantly different from the slope of the self-thinning exponent. This experimental result probably justifies the assumption that the ratio of RGR to RMR in the mean phytomass-density trajectory for any self-thinning population with different densities becomes constant as the growth stage progresses.
| 19,005,617
|
Oral cyclosporine A--the current picture of its liposomal and other delivery systems.
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The discovery of cyclosporine A was a milestone in organ transplantation and the treatment of autoimmune diseases. However, developing an efficient oral delivery system for this drug is complicated by its poor biopharmaceutical characteristics (low solubility and permeability) and the need to carefully monitor its levels in the blood. Current research is exploring various approaches, including those based on emulsions, microspheres, nanoparticles, and liposomes. Although progress has been made, none of the formulations is flawless. This review is a brief description of the main pharmaceutical systems and devices that have been described for the oral delivery of cyclosporine A in the context of the physicochemical properties of the drug and the character of its interactions with lipid membranes.
| 19,005,620
|
Ladder-like amplification of the type I interferon gene cluster in the human osteosarcoma cell line MG63.
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The organization of the type I interferon (IFN) gene cluster (9p21.3) was studied in a human osteosarcoma cell line (MG63). Array comparative genomic hybridization (aCGH) showed an amplification of approximately 6-fold which ended at both ends of the gene cluster with a deletion that extended throughout the 9p21.3 band. Spectral karyotyping (SKY) combined with fluorescence in-situ hybridization (FISH) identified an arrangement of the gene cluster in a ladder-like array of 5-7 'bands' spanning a single chromosome termed the 'IFN chromosome'. Chromosome painting revealed that the IFN chromosome is derived from components of chromosomes 4, 8 and 9. Labelling with centromeric probes demonstrated a ladder-like amplification of centromeric 4 and 9 sequences that co-localized with each other and a similar banding pattern of chromosome 4, as well as alternating with the IFN gene clusters. In contrast, centromere 8 was not detected on the IFN chromosome. One of the amplified centromeric 9 bands was identified as the functional centromere based on its location at the chromosome constriction and immunolocalization of the CENP-C protein. A model is presented for the generation of the IFN chromosome that involves breakage-fusion-bridge events.
| 19,005,637
|
Frontal analysis microchip capillary electrophoresis to study the binding of ligands to receptors derivatized on magnetic beads.
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The model binding of the glycopeptide antibiotic teicoplanin (Teic) from Actinoplanes teichomyceticus, immobilized on magnetic microspheres, to D-Ala-D-Ala terminus peptides was assessed using microchip capillary electrophoresis (MCE) with continuous frontal analysis (FA). Teic is closely related to vancomycin (Van), historically, the drug of last resort used to treat many gram-positive bacterial infections. Glycopeptide antibiotics inhibit bacterial growth by binding to the D-Ala-D-Ala terminus on the cell wall of gram-positive bacteria via hydrogen bonds, thereby preventing the enzyme-mediated cross-linking of peptidoglycan and eventual cell death. In this work direct and competitive bead-based assays in a microfluidic chip are demonstrated. The binding constants obtained using the technique are comparable with values reported in the literature.
| 19,005,646
|
Surfactant-induced conformational transition of amyloid beta-peptide.
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Accumulating evidence suggests that Abeta(1-42)-membrane interactions may play an important role in the pathogenesis of Alzheimer's disease. However, the mechanism of this structural transition remains unknown. In this work, we have shown that submicellar concentrations of sodium dodecyl sulfate (SDS) can provide a minimal platform for Abeta(1-42) self-assembly. To further investigate the relation between Abeta(1-42) structure and function, we analyzed peptide conformation and aggregation at various SDS concentrations using circular dichroism (CD), Fourier transform infrared spectroscopy, and gel electrophoresis. These aggregates, as observed via atomic force microscopy, appeared as globular particles in submicellar SDS with diameters of 35-60 nm. Upon sonication, these particles increased in disc diameter to 100 nm. Pyrene I (3)/I (1) ratios and 1-anilinonaphthalene-8-sulfonic acid binding studies indicated that the peptide interior is more hydrophobic than the SDS micelle interior. We have also used Forster resonance energy transfer between N-terminal labeled pyrene and tyrosine (10) of Abeta(1-42) in various SDS concentrations for conformational analysis. The results demonstrate that SDS at submicellar concentrations accelerates the formation of spherical aggregates, which act as niduses to form large spherical aggregates upon sonication.
| 19,005,650
|
Chick embryo chorioallantoic membrane model systems to study and visualize human tumor cell metastasis.
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Since their introduction almost a century ago, chick embryo model systems involving the technique of chorioallantoic grafting have proved invaluable in the in vivo studies of tumor development and angiogenesis and tumor cell dissemination. The ability of the chick embryo's chorioallantoic membrane (CAM) to efficiently support the growth of inoculated xenogenic tumor cells greatly facilitates analysis of human tumor cell metastasis. During spontaneous metastasis, the highly vascularized CAM sustains rapid tumor formation within several days following cell grafting. The dense capillary network of the CAM also serves as a repository of aggressive tumor cells that escaped from the primary tumor and intravasated into the host vasculature. This spontaneous metastasis setting provides a unique experimental model to study in vivo the intravasation step of the metastatic cascade. During experimental metastasis when tumor cells are inoculated intravenously, the CAM capillary system serves as a place for initial arrest and then, for tumor cell extravasation and colonization. The tissue composition and accessibility of the CAM for experimental interventions makes chick embryo CAM systems attractive models to follow the fate and visualize microscopically the behavior of grafted tumor cells in both spontaneous and experimental metastasis settings.
| 19,005,674
|
Sudden unexpected death in an infant with L-2-hydroxyglutaric aciduria.
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Inherited metabolic disorders are the cause of a small but significant number of sudden unexpected deaths in infancy. We report a girl who suddenly died at 11 months of age, during an intercurrent illness. Autopsy showed spongiform lesions in the subcortical white matter, in the basal ganglia, and in the dentate nuclei. Investigations in an older sister with developmental delay, ataxia, and tremor revealed L-2-hydroxyglutaric aciduria and subcortical white matter changes with hyperintensity of the basal ganglia and dentate nuclei at brain magnetic resonance imaging. Both children were homozygous for a splice site mutation in the L2HGDH gene. Sudden death has not been reported in association with L-2-hydroxyglutaric aciduria so far, but since this inborn error of metabolism is potentially treatable, early diagnosis may be important.
| 19,005,678
|
Cystic fibrosis, aminoglycoside treatment and acute renal failure: the not so gentle micin.
|
Aminoglycosides have a wide spectrum of gram-negative anti-bacterial activities and are available at low cost, which makes them commonly used drugs, especially for patients with cystic fibrosis (CF), who often suffer from chronic lung infections from Pseudomonas aeruginosa. Unfortunately, this treatment seems to have resulted in an increased incidence of acute renal failure (ARF) in patients with CF. A recent case-control study investigated risk factors for ARF in CF patients and suggested intravenous use of gentamicin as the prime culprit. Moreover, in most cases, at least one other risk factor, such as CF-related diabetes, pre-existing renal failure, dehydration or concurrent use of other nephrotoxic drugs, was present. We comment on the renal handling of aminoglycosides and the possible mechanisms of toxicity, as well as strategies for risk minimisation.
| 19,005,685
|
Resolving discogenic pain.
|
Recent basic science studies on discogenic low back pain have provided new knowledge about this condition. This paper reviews some of these results and presents an overview of the following findings. The rat lumbar intervertebral disk may be innervated non-segmentally through the paravertebral sympathetic nerve and segmentally through the sinuvertebral nerves, and also by dichotomizing sensory fibers. The exposure of the nucleus pulposus (NP) to the outer annulus fibrosus (AF) may induce nerve injury and ingrowth into the disk. Nerve growth factor (NGF)-sensitive neurons are predominant in the rat intervertebral disk, which indicates that hyperalgesic responses can be induced by inflammation. NGF in the NP may promote axonal growth. Lumbar fusion may inhibit nerve ingrowth into the degenerated disk and reduce the percentage of calcitonin gene related peptide (CGRP)-positive neurons.
| 19,005,695
|
A model for transcutaneous current stimulation: simulations and experiments.
|
Complex nerve models have been developed for describing the generation of action potentials in humans. Such nerve models have primarily been used to model implantable electrical stimulation systems, where the stimulation electrodes are close to the nerve (near-field). To address if these nerve models can also be used to model transcutaneous electrical stimulation (TES) (far-field), we have developed a TES model that comprises a volume conductor and different previously published non-linear nerve models. The volume conductor models the resistive and capacitive properties of electrodes, electrode-skin interface, skin, fat, muscle, and bone. The non-linear nerve models were used to conclude from the potential field within the volume conductor on nerve activation. A comparison of simulated and experimentally measured chronaxie values (a measure for the excitability of nerves) and muscle twitch forces on human volunteers allowed us to conclude that some of the published nerve models can be used in TES models. The presented TES model provides a first step to more extensive model implementations for TES in which e.g., multi-array electrode configurations can be tested.
| 19,005,714
|
Polymorphisms of Saccharomyces cerevisiae genes involved in wine production.
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The setting up of new molecular methods for Saccharomyces cerevisiae typing is valuable in enology. Actually, the ability to discriminate different strains in wine making can have a benefit both for the control of the fermentation process and for the preservation of wine typicity. This study focused on the screening of single-nucleotide polymorphisms in genes involved in wine production that could evolve rapidly considering the selective pressure of the isolation environment. Preliminary screening of 30 genes in silico was performed, followed by the selection of 10 loci belonging to 8 genes. The sequence analysis showed a low polymorphism and a degree of heterozygosity. However, a new potential molecular target was recognized in the TPS1 gene coding for the trehalose-6-phosphate synthase enzyme involved in the ethanol resistance mechanism. This gene showed a 1.42% sequence diversity with seven different nucleotide substitutions. Moreover, classic techniques were applied to a collection of 50 S. cerevisiae isolates, mostly with enologic origin. Our results confirmed that the wine making was not carried out only by the inoculated commercial starter because indigenous strains of S. cerevisiae present during fermentation were detected. In addition, a high genetic relationship among some commercial cultures was found, highlighting imprecision or fraudulent practices by starter manufacturers.
| 19,005,725
|
Argon plasma coagulation and gastric bypass--a novel solution to stomal dilation.
|
A patulous gastro-enterostomy after gastric bypass is a common cause of poor restriction and poor weight loss. Revisional surgery is an option but may be hazardous. This case report highlights the use of argon plasma coagulation by flexible endoscopy to reduce stomal size, improve restriction, and avoid revisional surgery.
| 19,005,735
|
Novel role of toll-like receptor 3, RIG-I and MDA5 in poly (I:C) RNA-induced mesothelial inflammation.
|
Viral inflammation and infection of mesothelial cells (MC) are a major problem in several organ systems including pleura, pericardium and peritoneum. Toll-like receptors (TLRs) are an essential part of the innate immune system for early recognition of pathogen-associated molecular patterns. TLRs recognise molecular patterns associated with microbial pathogens and induce an immune response. TLR3 recognises dsRNA of viral origin as exemplified by poly (I:C) RNA, a synthetic analogue of viral dsRNA. The helicases RIG-I and MDA5 may also act as sensors of viral infections. MC exhibit an expression of TLR3, RIG-I and MDA5. Poly (I:C) RNA stimulation resulted in an up-regulation of proinflammatory cytokines and chemokines as well as type I interferons. This novel finding of functional expression of viral sensors on human MC may indicate a novel link between viral infections and mesothelial inflammation and indicates a pathophysiologic role of viral receptors in these processes.
| 19,005,739
|
Cloning, characterization and localization of CHS gene from blood orange, Citrus sinensis (L.) Osbeck cv. Ruby.
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Chalcone synthase (CHS) is involved in the biosynthesis of anthocyanin. In this study, a full-length DNA of CHS gene (named as CsCHS-bo) was cloned from the blood orange, Citrus sinensis (L.) Osbeck cv. Ruby. The gene was 1,512 bp in size containing an open reading frame (1,176 bp) encoding 391 amino acids. Comparative and bioinformatic analyses revealed that the deduced protein of CsCHS-bo was highly homologous to CHS from other plant species. The protein of CsCHS-bo had four CHS-specific conserved motifs and a CHS-family signature sequence GFGPG. Phylogenetic analysis indicated that the protein of CsCHS-bo was in a subgroup with CHS of Ruta Palmatum. The CsCHS-bo was localized to the chromosomes 2p, 4p and 6p by an improved fluorescence in situ hybridization technique, indicating that at least three copies of CsCHS-bo were present in the genome.
| 19,005,777
|
Material suppliers and industrial metabolism.
|
Life Cycle Assessment (LCA) is not sufficiently tailored to the analysis of strategic environmental problems of material suppliers. Sustainable development calls for a reduction by a factor of 10 to 20 in the material intensity of the economy, a situation which leads to dramatic shifts in markets for raw materials. Furthermore, a material supplier might have major improvement options in the material's numerous downstream uses. LCAs, however, can't cover these two aspects. An adapted form of Substance Flow Analysis (SFA) may be an answer. This approach defines a system in relation to the flow of a specific material through society. All environmental interventions related to the material are inventoried. An emission evaluation indicates the dominant environmental bottlenecks, given the current market volume of each application of the material. This helps to identify improvement options and strategic choices in market portfolios. Scenario analysis on potential measures can further indicate changes of material flows - and thus markets - in the system. The approach is illustrated with a case study on chlorine.
| 19,005,794
|
Microbial phenol degradation of organic compounds in natural systems: Temperature-inhibition relationships.
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The combined influence of high phenol concentrations and low temperatures on aerobic and anaerobic phenol degradation kinetics was investigated in microbial enrichment cultures to evaluate temperature-inhibition relationships with respect to the ambient conditions in polluted habitats. The inhibition of microbial phenol degradation by excess substrate was found to be temperature-dependent. Substrate inhibition was intensified when temperatures were lower. This results in an elevated temperature sensitivity of phenol degradation at inhibitory substrate concentrations. The synergistic amplification of substrate inhibition at low temperatures may help to explain the limited self-purification potential of contaminated habitats such as soils, sediments and groundwater aquifers where high pollutant concentrations and low temperatures prevail.
| 19,005,802
|
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