Gluteal Tendinopathy: A Review of Mechanisms, Assessment and Management.
Tendinopathy of the gluteus medius and gluteus minimus tendons is now recognized as a primary local source of lateral hip pain. The condition mostly occurs in mid-life both in athletes and in subjects who do not regularly exercise. Females are afflicted more than males. This condition interferes with sleep (side lying) and common weight-bearing tasks, which makes it a debilitating musculoskeletal condition with a significant impact. Mechanical loading drives the biological processes within a tendon and determines its structural form and load-bearing capacity. The combination of excessive compression and high tensile loads within tendons are thought to be most damaging. The available evidence suggests that joint position (particularly excessive hip adduction), together with muscle and bone elements, are key factors in gluteal tendinopathy. These factors provide a basis for a clinical reasoning process in the assessment and management of a patient presenting with localized lateral hip pain from gluteal tendinopathy. Currently, there is a lack of consensus as to which clinical examination tests provide best diagnostic utility. On the basis of the few diagnostic utility studies and the current understanding of the pathomechanics of gluteal tendinopathy, we propose that a battery of clinical tests utilizing a combination of provocative compressive and tensile loads is currently best practice in its assessment. Management of this condition commonly involves corticosteroid injection, exercise or shock wave therapy, with surgery reserved for recalcitrant cases. There is a dearth of evidence for any treatments, so the approach we recommend involves managing the load on the tendons through exercise and education on the underlying pathomechanics.


Risk for depression tripled during the COVID-19 pandemic in emerging adults followed for the last 8 years.
The coronavirus disease 2019 (COVID-19) pandemic has significantly increased depression rates, particularly in emerging adults. The aim of this study was to examine longitudinal changes in depression risk before and during COVID-19 in a cohort of emerging adults in the U.S. and to determine whether prior drinking or sleep habits could predict the severity of depressive symptoms during the pandemic. Participants were 525 emerging adults from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a five-site community sample including moderate-to-heavy drinkers. Poisson mixed-effect models evaluated changes in the Center for Epidemiological Studies Depression Scale (CES-D-10) from before to during COVID-19, also testing for sex and age interactions. Additional analyses examined whether alcohol use frequency or sleep duration measured in the last pre-COVID assessment predicted pandemic-related increase in depressive symptoms. The prevalence of risk for clinical depression tripled due to a substantial and sustained increase in depressive symptoms during COVID-19 relative to pre-COVID years. Effects were strongest for younger women. Frequent alcohol use and short sleep duration during the closest pre-COVID visit predicted a greater increase in COVID-19 depressive symptoms. The sharp increase in depression risk among emerging adults heralds a public health crisis with alarming implications for their social and emotional functioning as this generation matures. In addition to the heightened risk for younger women, the role of alcohol use and sleep behavior should be tracked through preventive care aiming to mitigate this looming mental health crisis.


Variability of rRNA Operon Copy Number and Growth Rate Dynamics of Bacillus Isolated from an Extremely Oligotrophic Aquatic Ecosystem.
The ribosomal RNA (rrn) operon is a key suite of genes related to the production of protein synthesis machinery and thus to bacterial growth physiology. Experimental evidence has suggested an intrinsic relationship between the number of copies of this operon and environmental resource availability, especially the availability of phosphorus (P), because bacteria that live in oligotrophic ecosystems usually have few rrn operons and a slow growth rate. The Cuatro Ciénegas Basin (CCB) is a complex aquatic ecosystem that contains an unusually high microbial diversity that is able to persist under highly oligotrophic conditions. These environmental conditions impose a variety of strong selective pressures that shape the genome dynamics of their inhabitants. The genus Bacillus is one of the most abundant cultivable bacterial groups in the CCB and usually possesses a relatively large number of rrn operon copies (6-15 copies). The main goal of this study was to analyze the variation in the number of rrn operon copies of Bacillus in the CCB and to assess their growth-related properties as well as their stoichiometric balance (N and P content). We defined 18 phylogenetic groups within the Bacilli clade and documented a range of from six to 14 copies of the rrn operon. The growth dynamic of these Bacilli was heterogeneous and did not show a direct relation to the number of operon copies. Physiologically, our results were not consistent with the Growth Rate Hypothesis, since the copies of the rrn operon were decoupled from growth rate. However, we speculate that the diversity of the growth properties of these Bacilli as well as the low P content of their cells in an ample range of rrn copy number is an adaptive response to oligotrophy of the CCB and could represent an ecological mechanism that allows these taxa to coexist. These findings increase the knowledge of the variability in the number of copies of the rrn operon in the genus Bacillus and give insights about the physiology of this bacterial group under extreme oligotrophic conditions.


Reds are more important than greens: how UK supermarket shoppers use the different information on a traffic light nutrition label in a choice experiment.
Colour coded front-of-pack nutrition labelling ('traffic light labelling') has been recommended for use in the UK since 2006. The voluntary scheme is used by all the major retailers and some manufacturers. It is not clear how consumers use these labels to make a single decision about the relative healthiness of foods. Our research questions were: Which of the four nutrients on UK traffic light labels (total fat, saturated fat, sugar and salt) has the most influence on decisions? Do green lights or red lights have a greater influence? Are there age and gender differences in how people use the colour and nutrient information? We recruited participants from a UK supermarket chain membership list to conduct an online choice experiment in May 2014. We analysed data using multilevel logisitic models with food choices (n = 3321) nested in individuals (n = 187) as the unit of analysis. A food with more reds was 11.4 (95% confidence intervals: 10.3, 12.5) times less likely to be chosen as healthy, whereas a food with more greens was 6.1 (5.6, 6.6) times more likely to be chosen as healthy. Foods with better colours on saturated fat and salt were 7.3 (6.7, 8.0) and 7.1 (6.5, 7.8) times more likely to be chosen as healthy - significantly greater than for total fat (odds ratio 4.8 (4.4, 5.3)) and sugar (5.2 (4.7, 5.6)). Results were broadly similar for different genders and age groups. We found that participants were more concerned with avoiding reds than choosing greens, and that saturated fat and salt had a greater influence on decisions regarding healthiness than total fat and sugar. This could influence decisions about food reformulation and guidance on using nutrition labelling.


Paleopathology of human tuberculosis and the potential role of climate.
Both origin and evolution of tuberculosis and its pathogens (Mycobacterium tuberculosis complex) are not fully understood. The paleopathological investigation of human remains offers a unique insight into the molecular evolution and spread including correlative data of the environment. The molecular analysis of material from Egypt (3000-500 BC), Sudan (200-600 AD), Hungary (600-1700 AD), Latvia (1200-1600 AD), and South Germany (1400-1800 AD) urprisingly revealed constantly high frequencies of tuberculosis in all different time periods excluding significant environmental influence on tuberculosis spread. The typing of various mycobacteria strains provides evidence for ancestral M. tuberculosis strains in Pre- to early Egyptian dynastic material (3500-2650 BC), while typical M. africanum signatures were detected in a Middle Kingdom tomb (2050-1650 BC). Samples from the New Kingdom to Late Period (1500-500 BC) indicated modern M. tuberculosis strains. No evidence was seen for M. bovis in Egyptian material while M. bovis signatures were first identified in Siberian biomaterial dating 2000 years before present. These results contraindicates the theory that M. tuberculosis evolved from M. bovis during early domestication in the region of the "Fertile Crescent," but supports the scenario that M. tuberculosis probably derived from an ancestral progenitor strain. The environmental influence of this evolutionary scenario deserves continuing intense evaluation.


Developing drugs for treatment of atopic dermatitis in children (≥3 months to <18 years of age): Draft guidance for industry.
Atopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high-level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for "the Agency's current thinking on a particular subject." Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices).


Favorable ecological circumstances promote life expectancy in chimpanzees similar to that of human hunter-gatherers.
Demographic data on wild chimpanzees are crucial for understanding the evolution of chimpanzee and hominin life histories, but most data come from populations affected by disease outbreaks and anthropogenic disturbance. We present survivorship data from a relatively undisturbed and exceptionally large community of eastern chimpanzees (Pan troglodytes schweinfurthii) at Ngogo, Kibale National Park, Uganda. We monitored births, deaths, immigrations, and emigrations in the community between 1995 and 2016. Using known and estimated ages, we calculated survivorship curves for the whole community, for males and females separately, and for individuals ≤2 years old when identified. We used a novel method to address age estimation error by calculating stochastic survivorship curves. We compared Ngogo life expectancy, survivorship, and mortality rates to those from other chimpanzee communities and human hunter-gatherers. Life expectancy at birth for both sexes combined was 32.8 years, far exceeding estimates of chimpanzee life expectancy in other communities, and falling within the range of human hunter-gatherers (i.e., 27-37 years). Overall, the pattern of survivorship at Ngogo was more similar to that of human hunter-gatherers than to other chimpanzee communities. Maximum lifespan for the Ngogo chimpanzees, however, was similar to that reported at other chimpanzee research sites and was less than that of human-hunter gatherers. The absence of predation by large carnivores may contribute to some of the higher survivorship at Ngogo, but this cannot explain the much higher survivorship at Ngogo than at Kanyawara, another chimpanzee community in the same forest, which also lacks large carnivores. Higher survivorship at Ngogo appears to be an adaptive response to a food supply that is more abundant and varies less than that of Kanyawara. Future analyses of hominin life history evolution should take these results into account.


Dimensionality reduction by UMAP to visualize physical and genetic interactions.
Dimensionality reduction is often used to visualize complex expression profiling data. Here, we use the Uniform Manifold Approximation and Projection (UMAP) method on published transcript profiles of 1484 single gene deletions of Saccharomyces cerevisiae. Proximity in low-dimensional UMAP space identifies groups of genes that correspond to protein complexes and pathways, and finds novel protein interactions, even within well-characterized complexes. This approach is more sensitive than previous methods and should be broadly useful as additional transcriptome datasets become available for other organisms.


A clinical trial of combined anti-androgen and anti-heavy metal therapy in autistic disorders.
A medical hypothesis has suggested that some autism spectrum disorders (ASDs) may result from interactions between the methionine cycle-transsulfuration and androgen pathways following exposure to mercury. The IRB of the Institute for Chronic Illnesses approved the present study. A novel treatment was utilized combining LUPRON (leuprolide acetate, TAP Pharmaceuticals, Inc.) and CHEMET (meso-2, 3-dimercaptosuccinic acid--DMSA, McNeil Consumer Products Company) on 11 consecutive children with ASDs. A significant (p<0.01) overall improvement from the 70-79th percentile of severity (median baseline score=87) at baseline to the 40-49th percentile of severity (median end of study period score=63) at the end of the study was observed for patients treated for a median of approximately 4 months. Significant improvements in sociability, cognitive awareness, behavior, and clinical symptoms/behaviors of hyperandrogenemia were also observed. Significant decreases in blood androgens and increases in urinary heavy metal concentrations were observed. Minimal drug adverse effects were found. This study provides the first clinical evidence for the benefit that combined anti-androgen and anti-heavy metal therapy may have on some children with ASDs. Additional studies should examine androgen and heavy metal mechanisms of action in ASDs, and future ASD treatment protocols should consider androgens and heavy metals.


Kilovoltage cone-beam computed tomography imaging dose estimation and optimization: Need of daily cone-beam computed tomography.
The aim of the present study was to access the need of daily cone-beam computed tomography (CBCT) and the requirement of in-house protocols of image acquisition frequency to reduce unnecessary exposure to the patients undergoing radiotherapy treatment. The dose delivered during CBCT procedure (On-Board Imager, Trilogy, Varian medical system, Inc., Palo Alto, California) was assessed for pelvic and head and neck region. For dose estimation, cylindrical polymethyl methacrylate phantoms of 15 cm length, 16 cm, and 32 cm diameter were used to simulate the patient's head and neck and pelvic region thickness, respectively. More than 10 cm scatterer was added on either end of this phantom. Calibrated Ionization chamber DCT10 LEMO SN 1685 iba, dosimetry, Germany (10 cm active length) was used to measure the dose Index. The doses known as cone-beam dose index (CBDI100) were estimated for all the scanning protocols (kV and mAs setting) available on the machine. In this study, image acquisition frequency to correct the setup error was optimized. In-house protocol for image acquisition frequency during treatment has been suggested to reduce the dose. It was based on the principle of as low as reasonable achievable. Optimized dose protocol observed was the "standard dose head" for which the CBDI100 was 2.43 mGy. Whereas for pelvic imaging, single protocol of 125 kV, 80 mA was available by which a dose of 7.61 mGy is likely to be received by the patient during scan. Maximum shift of 6 mm in lateral direction was observed to the patient of Pelvis region and 5 mm was observed in the longitudinal direction for the H and N patients. Angular shift measured in patient position was 3.8° and 3.1° for H and N and pelvic region, respectively. Three consecutive-day CBCT-imaging at the beginning of the treatment followed by once weekly CBCT and two-dimensional (2D) imaging in remaining days of treatment can be an optimized way of imaging for the patient having malignancy in the region of pelvic and abdomen. For H and N, once in a week, CBCT with standard dose head protocol, followed by 2D-imaging in remaining days can be an optimized way of imaging.


Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms.
Forty two Crohn's disease patients were followed up after ileocolic resection with regard to symptoms and endoscopic appearance of the ileocolic anastomosis. Twenty eight patients resected because of colonic neoplasm served as controls. In all the Crohn's disease patients the ileal resection margin was disease free macroscopically at operation. In addition, intraoperative ileoscopy was performed in 13 and no sign of residual inflammation in the neoterminal ileum was seen. Endoscopy soon after surgery often showed preanastomotic ileal ulceration before symptoms appeared, whereas no anastomotic lesions were observed in the controls. Thus, 22 of 30 Crohn's disease patients examined had ulceration of the anastomotic area after three months, but only 10 had developed symptoms indicating relapse (73 v 33%). Corresponding figures in the 30 patients examined after one year were 93 v 37%, and in 14 patients after three years they were 100 and 86% respectively. The inflammatory lesions in all cases were preanastomotic, in the neoterminal ileum, and showed time related progression from aphthae to larger ulcers and stricture. The study suggests that endoscopically observed inflammatory lesions that appear soon after ileocolic resection for Crohn's disease signify new inflammation and not residual, persistent disease or incomplete anastomotic healing. The data further suggest that despite clinical remission after apparently radical intestinal resection, the bowel is permanently inflamed in Crohn's disease.


Long lasting increase in neuropeptide Y gene expression in rat adrenal gland with reserpine treatment: positive regulation of transsynaptic activation and membrane depolarization.
To elucidate how the neuropeptide Y (NPY) gene is regulated by physiological/pharmacological changes in neural functions, the expression and regulation of the NPY gene were studied by measuring changes in the abundances of NPY and NPY mRNA in the adrenal gland and brain regions of rats in vivo and in PC12 rat pheochromocytoma cells after reserpine treatment. Long term treatment with reserpine in vivo, which causes hypotension and increased splanchnic nerve activity, induced prolonged increases in the abundance of NPY mRNA and putative NPY pre-mRNA, with concomitant increases in NPY, in the adrenal gland in a tissue-dependent manner but caused no changes in the abundance of beta-actin mRNA. Transection of the splanchnic nerves almost completely (76%) prevented the reserpine-induced increases in the abundance of NPY mRNA and NPY pre-mRNA, but denervation alone did not affect their steady state levels. These results suggested that increased activity of the splanchnic nerves regulates NPY gene expression positively in the adrenal gland, probably at the level of transcription. In PC12 cells, reserpine decreased the abundance of NPY mRNA directly, but nicotinic receptor activation increased its abundance transiently and the persistent membrane depolarization increased its abundance markedly. Thus, NPY gene expression is positively regulated by membrane depolarization via increased transsynaptic activation with reserpine.


A Photoactivatable Formaldehyde Donor with Fluorescence Monitoring Reveals Threshold To Arrest Cell Migration.
Controlled light-mediated delivery of biological analytes can enable the investigation of highly reactivity molecules within living systems. As many biological effects are concentration dependent, it is critical to determine the location, time, and quantity of analyte donation. In this work, we have developed the first photoactivatable donor for formaldehyde (FA). Our optimized photoactivatable donor, photoFAD-3, is equipped with a fluorescence readout that enables monitoring of FA release with a concomitant 139-fold fluorescence enhancement. Tuning of photostability and cellular retention enabled quantification of intracellular FA release through cell lysate calibration. Application of photoFAD-3 uncovered the concentration range necessary for arresting wound healing in live cells. This marks the first report where a photoactivatable donor for any analyte has been used to quantify intracellular release.


Curcumin ameliorates high glucose-induced acute vascular endothelial dysfunction in rat thoracic aorta.
1. The aims of the present study were to explore the protective effect of curcumin against the acute vascular endothelial dysfunction induced by high glucose and to investigate the possible role of heme oxygenase (HO)-1 in this protective action. 2. Thoracic aortic rings, with or without endothelium, obtained from male Sprague-Dawley rats were mounted in an organ bath. Isometric contraction of the rings was recorded. After completion of the organ bath studies, rings were homogenized and centrifuged (30,000 g, 4 degrees C, 15 min) and HO activity was determined in the supernatant. 3. After 2 h incubation of aortic rings in the presence of high glucose (44 mmol/L), the relaxation evoked by acetylcholine (3 x 10(-8) to 3 x 10(-5) mol/L) was significantly decreased only in rings with an intact endothelium. When rings were coincubated in the presence of curcumin (10(-13) to 10(-11) mol/L) and high glucose, curcumin reversed the vasodilator dysfunction induced by high glucose dose dependently. 4. Curcumin (10(-11) mol/L) increased HO activity in the aortic rings compared with activity in control rings (63.1 +/- 3.6 vs control 43.2 +/- 2.9 pmol/mg per h, respectively; P < 0.01). Protoporphyrin IX zinc (10(-6) mol/L), an inhibitor of HO-1, offset the protective effects of curcumin. In addition, the non-selective guanylate cyclase (GC) inhibitor methylene blue (10(-6) mol/L) completely abolished the protective effects of curcumin. 5. In conclusion, the results of the present study show that curcumin alleviates the acute endothelium-dependent vasodilator dysfunction induced by high glucose in rat aortic rings. Increased HO-1 activity and stimulation of GC may be involved in the protective effects of curcumin.


Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug.
Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4+ and CD8+ T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. This required direct contact and was inhibited by blocking adhesion molecules on CLL B cells. In T cells from patients with CLL and in T cells from healthy individuals that had been in contact with CLL cells, recruitment of key regulatory proteins to the immune synapse was inhibited. Treatment of autologous T cells and CLL cells with the immunomodulating drug lenalidomide resulted in improved synapse formation. These results define what we believe to be a novel immune dysfunction in T cells from patients with CLL that has implications for both autologous and allogeneic immunotherapy approaches and identifies repair of immune synapse defects as an essential step in improving cancer immunotherapy approaches.


Flexible organofunctional aerogels.
Flexible inorganic-organic silica aerogels based on methyltrimethoxysilane (MTMS, CH3Si(OCH3)3) can overcome the drawbacks of conventional silica aerogels by introducing high mechanical strength, elastic recovery and hydrophobicity to monolithic materials. In this work, MTMS is co-condensed with organofunctional alkoxysilanes RSi(OMe)3 (R = vinyl, chloropropyl, mercaptopropyl, methacryloxypropyl, etc.) yielding aerogels that are not only flexible but also contain reactive functional groups. Sol-gel parameters, such as the MTMS/RSi(OMe)3 ratio, have been systematically investigated in terms of gelation behavior, complete/incomplete incorporation of the functional organic groups (confirmed by FTIR-ATR and Raman spectroscopy) and flexibility of the resulting gel. Sterically more demanding functional moieties lead to macroscopic phase separation; however, this problem was overcome by the employment of surfactants. Functional aerogels dried by supercritical extraction with carbon dioxide showed promising results in uniaxial compression tests and had an elastic recovery up to 60%. Furthermore, the accessibility of the functional groups was demonstrated by simple reactions, e.g. conversion of the chloro into azido groups via a nucleophilic substitution reaction with NaN3 followed by click reactions.


Stent graft management of stable, uncomplicated type B aortic dissection.
Aortic dissection has an incidence of 2.6 to 3.5 per 100,000 person years. Although the traditional approach has focused on surgical and medical intervention, several studies demonstrate the efficacy of endovascular repair for aortic dissection. Bolstered by a high technical success rate and improved morbidity and mortality relative to its surgical counterpart, endovascular repair has become a first-line treatment for complicated type B aortic dissection. The debate over the optimal approach to uncomplicated type B dissection is more contentious. The consensus remains in support of medical therapy tailored for tight control of hypertension. The poor long-term results of this regimen, with up to 50% mortality at 5 years, have shifted attention to endovascular stent grafting as an alternative. This article reviews the latest research on uncomplicated type B dissection and its treatment, concentrating on endovascular technique, anatomic considerations, timing of intervention, and outcomes. Early research indicates endovascular stent grafting is a promising modality for these patients.


Factors affecting response to an invitation to attend for a health check.
To describe the characteristics of general practice patients who fail to respond to an invitation to attend for a health check, in relation to demographic variables, risk factor status, health status, and attitudes to behaviour modification. Postal questionnaire before invitation to attend a health check and subsequent record of attendance. Five urban general practices in Bedfordshire, UK. A total of 2678 patients aged 35-64 years were invited for a health check in 1989-90. The number of patients who did not attend was low overall but was higher among men than women (21 v 15%, p < 0.001), and in unmarried than married patients (24 v 16%, p < 0.001). Failure to attend was also higher among people in manual than in non-manual occupations (21 v 15%, p < 0.001), in people living in rented accommodation than in homeowners (29 v 16%, p < 0.001), and in those without access to a car than in car users (27 v 16%, p < 0.001). There was no difference in non-attendance rate according to age at completion of full time education. After adjustment for age, sex, marital state, and social class, the odds ratio for non-attendance was 1.74 (95% confidence interval (CI) 1.41, 2.14) for smokers; 1.07 (95% CI 0.76, 1.51) for heavy drinkers; 1.91 (95% CI 1.41, 2.58) for those with a less healthy diet; and 1.50 (95% CI 1.09, 2.07) for those who were obese. Patients who had visited their general practice more frequently and those who indicated a willingness to change their behaviour were significantly more likely to attend the health check. Health check attendance was lowest among patients who rarely attended the surgery and those who reported higher risk behaviour. Attendance was not, however, confined to the 'worried well'. Equal numbers of those with and without chest pain attended, as did at least three quarters of those in each risk group. This high rate of attendance reflects the time and effort invested in systematic recruitment. The development of a robust recruiting strategy is essential if substantial numbers, and particularly those at highest risk, are to be reached.


Damage control resuscitation in combination with damage control laparotomy: a survival advantage.
Damage control laparotomy (DCL) improves outcomes when used in patients with severe hemorrhage. Correction of coagulopathy with close ratio resuscitation while limiting crystalloid forms a new methodology known as damage control resuscitation (DCR). We hypothesize a survival advantage in DCL patients managed with DCR when compared with DCL patients managed with conventional resuscitation efforts (CRE). This study is a 4-year retrospective study of all DCL patients who required >or=10 units of packed red blood cells (PRBC) during surgery. A 2-year period after institution of DCR (DCL and DCR) was compared with the preceding 2 years (DCL and CRE). Univariate analysis of continuous data was done with Student's t test followed by multiple logistic regression. One Hundred twenty-four and 72 patients were managed during the DCL and CRE and DCL and DCR time periods, respectively. Baseline patient characteristics of age, Injury Severity Score, % penetrating, blood pressure, hemoglobin, base deficit, and INR were similar between groups. There was no difference in quantity of intraoperative PRBC utilization between DCL and CRE and DCL and DCR study periods: 21.7 units versus 25.5 units (p = 0.53); however, when compared with DCL and CRE group, patients in the DCL and DCR group received less intraoperative crystalloids, 4.7 L versus 14.2 L (p = 0.009); more fresh frozen plasma (FFP), 18.2 versus 6.4 (p = 0.002); a closer FFP to PRBC ratio, 1 to 1.2 versus 1 to 4.2 (p = 0.002); platelets to PRBC ratio, 1:2.3 versus 1:5.9 (0.002); shorter mean trauma intensive care unit length of stay, 11 days versus 20 days (p = 0.01); and greater 30-day survival, 73.6% versus 54.8% (p < 0.009). The addition of DCR to DCL conveyed a survival benefit (odds ratio; 95% confidence interval: 0.19 (0.05-0.33), p = 0.005). This is the first civilian study that analyses the impact of DCR in patients managed with DCL. During the DCL and DCR study period more PRBC, FFP, and platelets with less crystalloid solution was used intraoperatively. DCL and DCR were associated with a survival advantage and shorter trauma intensive care unit length of stay in patients with severe hemorrhage when compared with DCL and CRE.


Dinosaur evolution. Sustained miniaturization and anatomical innovation in the dinosaurian ancestors of birds.
Recent discoveries have highlighted the dramatic evolutionary transformation of massive, ground-dwelling theropod dinosaurs into light, volant birds. Here, we apply Bayesian approaches (originally developed for inferring geographic spread and rates of molecular evolution in viruses) in a different context: to infer size changes and rates of anatomical innovation (across up to 1549 skeletal characters) in fossils. These approaches identify two drivers underlying the dinosaur-bird transition. The theropod lineage directly ancestral to birds undergoes sustained miniaturization across 50 million years and at least 12 consecutive branches (internodes) and evolves skeletal adaptations four times faster than other dinosaurs. The distinct, prolonged phase of miniaturization along the bird stem would have facilitated the evolution of many novelties associated with small body size, such as reorientation of body mass, increased aerial ability, and paedomorphic skulls with reduced snouts but enlarged eyes and brains.


Plant competition for light analyzed with a multispecies canopy model : I. Model development and influence of enhanced UV-B conditions on photosynthesis in mixed wheat and wild oat canopies.
Competition for light among species in a mixed canopy can be assessed quantitatively by a simulation model which evaluates the importance of different morphological and photosynthetic characteristics of each species. A model was developed that simulates how the foliage of all species attenuate radiation in the canopy and how much radiation is received by foliage of each species. The model can account for different kinds of foliage (leaf blades, stems, etc.) for each species. The photosynthesis and transpiration for sunlit and shaded foliage of each species is also computed for different layers in the canopy. The model is an extension of previously described single-species canopy photosynthesis simulation models. Model predictions of the fraction of foliage sunlit and interception of light by sunlit and shaded foliage for monoculture and mixed canopies of wheat (Triticum aestivum) and wild oat (Avena fatua) in the field compared very well with measured values. The model was used to calculate light interception and canopy photosynthesis for both species of wheat/wild oat mixtures grown under normal solar and enhanced ultraviolet-B (290-320 nm) radiation (UV-B) in a glasshouse experiment with no root competition. In these experiments, measurements showed that the mixtures receiving enhanced UV-B radiation had a greater proportion of the total foliage area composed of wheat compared to mixtures in the control treatments. The difference in species foliage area and its position in the canopy resulted in a calculated increase in the portion of total canopy radiation interception and photosynthesis by wheat. This, in turn, is consistent with greater canopy biomass of wheat reported in canopies irradiated with supplemental UV-B.


Effects of resistance to Bt cotton on diapause in the pink bollworm, Pectinophora gossypiella.
Fitness costs associated with resistance to Bacillus thuringiensis (Bt) crops are expected to delay the evolution of resistance. In a previous study where pink bollworm, Pectinophora gossypiella (Lepidoptera: Gelechiidae), larvae overwintered in outdoor insectaries, individuals from Bt-resistant strains had lower survival than individuals from Bt-susceptible strains or F1 progeny from crosses between resistant and susceptible adults. To investigate the physiological basis of such recessive cost, diapause duration was experimentally manipulated in the laboratory. Compared to a Bt-susceptible strain and F1 progeny, we hypothesized that Bt-resistant strains could exhibit a lower propensity or intensity of diapause, faster weight loss during overwintering, lower initial weight of diapausing larvae, and reduced longevity of moths emerging from diapause. Results were as expected for initial weight of diapausing larvae and longevity of overwintered male moths or female moths remaining in diapause for a short period. However, a higher diapause induction and intensity and slower weight loss occurred in F1 progeny and Bt-resistant strains than in a Bt-susceptible strain. Moreover, F1 progeny had greater overwintering survival than the Bt-resistant and Bt-susceptible strains, and F1 female moths had the greatest longevity after sustaining long diapausing periods. All of these unexpected results may be explained by pleiotropic effects of resistance to Bt cotton that increased the strength of diapause in the F1 progeny and Bt-resistant strains. Incomplete resistance was reflected in disadvantages suffered by Bt-resistant individuals feeding on a Bt diet instead of a non-Bt diet, including lower diapause propensity, lower diapause intensity and reduced longevity of overwintered male moths. While this study suggests that the evolution of resistance to Bt cotton and feeding on a Bt diet in Bt-resistant individuals have pervasive effects on several traits associated with diapause, further field experiments are needed to elucidate the basis of the overwintering cost in the pink bollworm.


Effects of the DPP-4 inhibitor, linagliptin, in diet-induced obese rats: a comparison in naive and exenatide-treated animals.
To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period. In a subsequent study, rats received exenatide (either 3 or 30 microg/kg/day) or vehicle by osmotic mini-pump for 28 days. In addition, groups of animals were dosed orally with linagliptin either alone or in combination with a 3 microg/kg/day exenatide dose for the study duration. In a final study, rats were administered exenatide (30 microg/kg/day) or vehicle by osmotic mini-pump for eleven days. Subsequently, exenatide-treated animals were transferred to vehicle or continued exenatide infusion for a further ten days. Animals transferred from exenatide to vehicle were also dosed orally with either vehicle or linagliptin. In all studies, body weight, food and water intake were recorded daily and relevant plasma parameters and carcass composition were determined. In contrast to exenatide, linagliptin did not significantly reduce body weight or carcass fat in DIO rats versus controls. Linagliptin augmented the effect of exenatide to reduce body fat when given in combination but did not affect the body weight response. In rats withdrawn from exenatide, weight regain was observed such that body weight was not significantly different to controls. Linagliptin reduced weight regain after withdrawal of exenatide such that a significant difference from controls was evident. These data demonstrate that linagliptin does not significantly alter body weight in either untreated or exenatide-treated DIO rats, although it delays weight gain after exenatide withdrawal. This finding may suggest the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain.


Dental materials and their performance for the management of screw access channels in implant-supported restorations.
Unsuccessfully sealed screw access channels of prosthetic implant abutments may lead to malodor or peri-implant diseases in gingival tissues adjacent to implant-supported restorations. Therefore, 72 sets of screw channel analogs with six different materials incorporated (Polytetrafluoroethylene (PTFE), wax, gutta-percha, cavit, endofrost-pellets and cotton pellets) were exposed (2.5 h, 37°C) to Streptococcus mutans, oralis and Candida albicans suspensions. Bacterial adherence was quantified by using the fluorescence dye, Alamar Blue/resazurin, and an automated multifunctional reader. For quantification of fungal adherence the ATP-based bioluminescence approach was used. High relative fluorescence and luminescence intensities (>10,000), indicating high adhesion of streptococci and fungi were found for cotton and endofrost-pellets and low intensities (<5,000) for wax, gutta-percha, cavit and PTFE. The quantity of bacterial and fungal adhesion differed significantly between the assessed various sealing materials. In conclusion and within the limitations of this study, wax, gutta-percha, cavit and PTFE should be preferred as sealing materials.


Capillary Filling at the Microscale: Control of Fluid Front Using Geometry.
We propose an experimental and theoretical framework for the study of capillary filling at the micro-scale. Our methodology enables us to control the fluid flow regime so that we can characterise properties of Newtonian fluids such as their viscosity. In particular, we study a viscous, non-inertial, non-Washburn regime in which the position of the fluid front increases linearly with time for the whole duration of the experiment. The operating shear-rate range of our apparatus extends over nearly two orders of magnitude. Further, we analyse the advancement of a fluid front within a microcapillary in a system of two immiscible Newtonian liquids. We observe a non-Washburn regime in which the front can accelerate or decelerate depending on the viscosity contrast between the two liquids. We then propose a theoretical model which enables us to study and explain both non-Washburn regimes. Furthermore, our theoretical model allows us to put forward ways to control the emergence of these regimes by means of geometrical parameters of the experimental set-up. Our methodology allows us to design and calibrate a micro-viscosimetre which works at constant pressure.


Adverse life events and coping skills in panic disorder.
Research literature and clinical experience shows that panic patients are often able to identify stressors that preceded the onset of their first attacks. In this study we investigated the relation between life events, coping skills, and panic disorder. Forty-tree panic patients were compared with 29 control subjects regarding the occurrence and the impact of stressful life events in a 1-year period preceding the onset of panic attacks using the Social Readjustment Rating Scale and London Life Event and Difficulty Schedule. Coping skills were measured using the Ways of Coping Questionnaire. No differences were observed between panic patients and controls regarding the number of reported stressful life events in the previous year. Panic patients compared to controls reported loss of social support as the most meaningful class of events significantly more often. In response to stressful situations, panic patients more often used coping skills judged as ineffective. The present study suggests that the type of life event and the coping skills used in response to them, more than the occurrence of stressful events itself, may be associated with the onset of panic disorder.


Amnesic trace locked into the benzodiazepine state of memory.
Rats were trained in a food-rewarded lever-pressing task until they could complete an FR10 requirement within the first 120 s of the session, and were tested for the retention of this response requirement after having reached this criterion. The pharmacological treatment instituted at the time of tests was either the same as or different from that used during acquisition. In this state-dependency (StD) procedure, saline-to-drug as well as drug-to-saline state changes produced robust failures to transfer with chlordiazepoxide (CDP) and also with yohimbine. Diazepam substituted for, while Ro 15-1788 antagonised, CDP; none of several non-benzodiazepine compounds substituted for CDP. Neither food deprivation nor extensive overtraining after CDP prevented the failure of transfer when animals were tested for drug-to-saline transfer. Another series of experiments evaluated the effects of CDP and diazepam in a rat conflict procedure. The doses at which CDP and diazepam produced anti-conflict effects were similar to those at which failure to transfer occurred in saline-to-drug state changes, and higher than those at which such failure occurred in drug-to-saline state changes. With benzodiazepines, StD of memory retrieval conceivably constitutes a parsimonious explanation of the anxiolytic and untoward (amnesic, drug dependence) actions of these drugs.


Amino-functionalized polystyrene nanoparticles activate the NLRP3 inflammasome in human macrophages.
Specifically designed and functionalized nanoparticles hold great promise for biomedical applications. Yet, the applicability of nanoparticles is critically predetermined by their surface functionalization. Here we demonstrate that amino-functionalized polystyrene nanoparticles (PS-NH(2)) of ∼100 nm in diameter, but not carboxyl- or nonfunctionalized particles, trigger NLRP3 inflammasome activation and subsequent release of proinflammatory interleukin 1β (IL-1β) by human macrophages. PS-NH(2) induced time-dependent proton accumulation in lysosomes associated with lysosomal destabilization, release of cathepsin B, and damage of the mitochondrial membrane. Accumulation of mitochondrial reactive oxygen species was accompanied by oxidation of thioredoxin, a protein playing a central role in maintaining the cellular redox balance. Upon oxidation, thioredoxin dissociated from the thioredoxin-interacting protein (TXNIP). Liberated TXNIP, in turn, interacted with the NLRP3 protein, resulting in a conformational change of the pyrin domain of the NLRP3 protein, as was predicted by molecular modeling. Consequently, this prompted assembly of the NLRP3 inflammasome complex with recruitment and activation of caspase-1, inducing IL-1β release by cleavage of pro-IL-1β. The central role of the NLRP3 inflammasome for cytokine production was confirmed by in vitro knockdown of NLRP3 and of the adaptor protein ASC, confirming that other inflammasomes were not activated by PS-NH(2). The PS-NH(2)-mediated proinflammatory macrophage activation could be antagonized by the radical scavenger N-acetyl-L-cysteine, which prevented mitochondrial damage, caspase-1 activation, and the subsequent release of IL-1β. Our study reveals the molecular mechanism of NLRP3 inflammasome activation by amino-functionalized nanoparticles and suggests a strategy as to how such adverse effects could be antagonized.


How 'arm-twisting' by the inducer triggers activation of the MalT transcription factor, a typical signal transduction ATPase with numerous domains (STAND).
Signal transduction ATPases with numerous domains (STAND) get activated through inducer-dependent assembly into multimeric platforms. This switch relies on the conversion of their nucleotide-binding oligomerization domain (NOD) from a closed, ADP-bound form to an open, ATP-bound form. The NOD closed form is stabilized by contacts with the arm, a domain that connects the NOD to the inducer-binding domain called the sensor. How the inducer triggers NOD opening remains unclear. Here, I pinpointed the NOD-arm interface of the MalT STAND transcription factor, and I generated a MalT variant in which this interface can be covalently locked on demand, thereby trapping the NOD in the closed state. By characterizing this locked variant, I found that the inducer is recognized in two steps: it first binds to the sole sensor with low affinity, which then triggers the recruitment of the arm to form a high-affinity arm-sensor inducer-binding site. Strikingly, this high-affinity binding step was incompatible with arm-NOD contacts maintaining the NOD closed. Through this toggling between two mutually exclusive states reminiscent of a single-pole double-throw switch, the arm couples inducer binding to NOD opening, shown here to precede nucleotide exchange. This scenario likely holds for other STANDs like mammalian NLR innate immunity receptors.


Clinically relevant quality measures for risk factor control in primary care: a retrospective cohort study.
Assessment of the proportion of patients with well controlled cardiovascular risk factors underestimates the proportion of patients receiving high quality of care. Evaluating whether physicians respond appropriately to poor risk factor control gives a different picture of quality of care. We assessed physician response to control cardiovascular risk factors, as well as markers of potential overtreatment in Switzerland, a country with universal healthcare coverage but without systematic quality monitoring, annual report cards on quality of care or financial incentives to improve quality. We performed a retrospective cohort study of 1002 randomly selected patients aged 50-80 years from four university primary care settings in Switzerland. For hypertension, dyslipidemia and diabetes mellitus, we first measured proportions in control, then assessed therapy modifications among those in poor control. "Appropriate clinical action" was defined as a therapy modification or return to control without therapy modification within 12 months among patients with baseline poor control. Potential overtreatment of these conditions was defined as intensive treatment among low-risk patients with optimal target values. 20% of patients with hypertension, 41% with dyslipidemia and 36% with diabetes mellitus were in control at baseline. When appropriate clinical action in response to poor control was integrated into measuring quality of care, 52 to 55% had appropriate quality of care. Over 12 months, therapy of 61% of patients with baseline poor control was modified for hypertension, 33% for dyslipidemia, and 85% for diabetes mellitus. Increases in number of drug classes (28-51%) and in drug doses (10-61%) were the most common therapy modifications. Patients with target organ damage and higher baseline values were more likely to have appropriate clinical action. We found low rates of potential overtreatment with 2% for hypertension, 3% for diabetes mellitus and 3-6% for dyslipidemia. In primary care, evaluating whether physicians respond appropriately to poor risk factor control, in addition to assessing proportions in control, provide a broader view of the quality of care than relying solely on measures of proportions in control. Such measures could be more clinically relevant and acceptable to physicians than simply reporting levels of control.


Caregiver determinants of patient clinical event risk in heart failure.
Preventing hospitalization and improving event-free survival are primary goals of heart failure (HF) treatment according to current European Society of Cardiology guidelines; however, substantial uncertainty remains in our ability to predict risk and improve outcomes. Although caregivers often assist patients to manage their HF, little is known about their influence on clinical outcomes. To quantify the influence of patient and caregiver characteristics on patient clinical event risk in HF. This was a secondary analysis of data using a sample of Italian adults with HF and their informal caregivers ( n = 183 patient-caregiver dyads). HF patients were followed over 12 months for the following clinical events: hospitalization for HF, emergency room visit for HF or all-cause mortality. Influence of baseline caregiver- and patient-level factors (patient and caregiver age; dyad relationship type; patient New York Heart Association (NYHA) Class, cognition, and comorbidities; and caregiver strain, mental health status, and contributions to HF self-care) on patient risk of death or hospitalization/emergency room use was quantified using Cox proportional hazards regression. Over the course of follow up, 32.8% of patients died, 19.7% were hospitalized for HF and 10.4% visited the emergency room. Higher caregiver strain, better caregiver mental health status and greater caregiver contributions to HF self-care maintenance were associated with significantly better event-free survival. Worse patient functional class and greater caregiver contributions to patient self-care management were associated with significantly worse patient event-free survival. Considering caregiving factors together with patient factors significantly increases our understanding of patient clinical event risk in HF.


Reduced facial emotion recognition in overweight and obese children.
Emotional problems often co-occur in overweight or obese children. However, questions of whether emotion recognition deficits are present and how they are reflected have only been sparsely investigated to date. Therefore, the present study included 33 overweight and obese as well as 33 normal weight elementary school children between six and ten years that were matched for sex, age and socioeconomic status. Participants were shown different emotional faces of a well-validated set of stimuli on a computer screen, which they categorized and then rated on an emotional intensity level. Key measures were categorization performance along with reaction times and emotional intelligence as well as emotional eating questionnaire ratings. Overweight children exhibited lower categorization accuracy as well as longer reaction times as compared to normal weight children, while no differences in intensity ratings occurred. Reaction time to neutral facial expressions was negatively related to intrapersonal and interpersonal emotional intelligence and emotional eating correlated negatively with accuracy for recognizing sad expressions. Facial emotion decoding difficulties seem to be of importance in overweight and obese children and deserve further consideration in terms of their exact impact on social functioning as well as on the maintenance of elevated body weight during child development.


Intact memory for irrelevant information impairs perception in amnesia.
Memory and perception have long been considered separate cognitive processes, and amnesia resulting from medial temporal lobe (MTL) damage is thought to reflect damage to a dedicated memory system. Recent work has questioned these views, suggesting that amnesia can result from impoverished perceptual representations in the MTL, causing an increased susceptibility to interference. Using a perceptual matching task for which fMRI implicated a specific MTL structure, the perirhinal cortex, we show that amnesics with MTL damage including the perirhinal cortex, but not those with damage limited to the hippocampus, were vulnerable to object-based perceptual interference. Importantly, when we controlled such interference, their performance recovered to normal levels. These findings challenge prevailing conceptions of amnesia, suggesting that effects of damage to specific MTL regions are better understood not in terms of damage to a dedicated declarative memory system, but in terms of impoverished representations of the stimuli those regions maintain.


Creating a safe haven-women's experiences of the midwife's professional skills during planned home birth in four Nordic countries.
The midwife assisting a birth has a considerable influence on the woman's experience of the birth. The aim of this study was to investigate the experience of the midwife's professional skills among women in Norway, Denmark, Iceland, and Sweden who chose a planned home birth. All known home birth midwives were asked to inform the mothers about the project and invite them to complete a questionnaire about different aspects of their home birth experience. The women were asked to assess 10 different aspects of the midwives' professional skills on a 4-graded scale below the main question: What was your experience of the midwife who assisted the labor? Furthermore, the mothers' experiences with the attending midwives were identified in the free text birth stories. The chosen method was a mixed method design. The home birth midwives' professional skills were generally high scored. No statistically significant differences were found with respect to the assessment of the midwife. The content analyses yielded one overarching theme: The competence and presence of the midwife creates a safe haven, and three categories, midwife's safe hand, midwife's caring approach, and midwife's peaceful presence. Women choosing a home birth in the four Nordic countries experienced that their midwives were highly skilled and they found the presence of the midwives valuable in helping them to feel safe and confident during birth. Despite differences in organization and guidelines for home births, the women's experience of the midwife's professional skills did not differ between the four countries.


A novel chemopreventive mechanism of selenomethionine: enhancement of APE1 enzyme activity via a Gadd45a, PCNA and APE1 protein complex that regulates p53-mediated base excision repair.
Organic selenium compounds have been documented to play a role in cancer prevention. Our previous study showed that selenomethionine (SeMet) induces p53 activation without genotoxic effects including apoptosis and cell cycle arrest. In this study, we investigated the mechanism by which organic selenium compounds promote p53-mediated base excision repair (BER) activity. Our data demonstrated for the first time that the interaction between growth arrest and DNA damage-inducible protein 45A (Gadd45a), which is a p53-activated downstream gene, and two BER-mediated repair proteins, proliferating cell nuclear antigen (PCNA) and apurinic/apyrimidinic endonuclease (APE1/Ref-1), was significantly increased in a p53-dependent manner following treatment with organic selenium compounds. Furthermore, we observed that the activity of APE1 was significantly increased in a p53-dependent manner in response to the organic selenium compounds. These results suggest that BER activity is dependent on wild-type p53 activity and is mediated by the modulation of protein interactions between Gadd45a and repair proteins in response to organic selenium compounds. We propose that p53-dependent BER activity is a distinct chemopreventive mechanism mediated by organic selenium compounds, and that this may provide insight into the development of effective chemopreventive strategies against various oxidative stresses that contribute to a variety of human diseases, particularly cancer.


Physiologic Specialization of Puccinia triticina on Wheat in the United States in 2009.
Collections of Puccinia triticina were obtained from rust-infected leaves provided by cooperators throughout the United States and from surveys of wheat (Triticum aestivum) fields and wheat breeding plots by United States Department of Agriculture-Agricultural Research Service personnel in the Great Plains, Ohio River Valley, southeast, California, and Washington State in order to determine the virulence of the wheat leaf rust population in 2009. Single uredinial isolates (591 in total) were derived from the collections and tested for virulence phenotype on lines of Thatcher wheat that are near-isogenic for leaf rust resistance genes Lr1, Lr2a, Lr2c, Lr3a, Lr9, Lr16, Lr24, Lr26, Lr3ka, Lr11, Lr17a, Lr30, LrB, Lr10, Lr14a, Lr18, Lr21, and Lr28 and a winter wheat line with Lr39/41. Forty-one virulence phenotypes were described. Virulence phenotypes MLDSD, TCRKG, and TDBGG were the three most common phenotypes. Phenotype MLDSD is virulent to Lr17 and Lr39/Lr41 and was widely distributed throughout the United States. Phenotype TCRKG is virulent to Lr11, Lr18, and Lr26 and is found mostly in the soft red winter wheat region in the eastern United States. TDBGG is virulent to Lr24 and was found in both the soft red winter wheat and hard red winter wheat regions. Virulence to Lr21 was not found in any of the tested isolates. Virulence to Lr11, Lr18, and Lr26 increased in 2009 in the soft red winter wheat regions. Virulence to Lr17 and Lr39/Lr41 increased in the Great Plains region. Two separate epidemiological zones of P. triticina in the soft red winter wheat region of the southern and eastern states and in the hard red wheat region of the Great Plains were described.


Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability.
The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro- and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro- and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.


African experience with sperm morphology training courses.
This paper reports on the results of a 6-year ongoing training and quality control programme for sperm morphology. The programme consists of a 5-day semenology workshop, during which participants receive intensive training on issues such as sperm concentration, motility, vitality and morphology. Following the workshop, all the participants are enrolled in a continuous quality control (CQC) programme for sperm morphology. These workshops and quality control programmes are presented by the Department of Obstetrics and Gynaecology at Tygerberg Hospital (South Africa) in conjunction with the World Health Organization's (WHO) Special Programme for Research Development and Research Training. Seventy individuals from 11 countries in sub-Saharan Africa have been trained since 1997; 58 of these are still participating in the quality control programme. Using the results from the quality control programme, participants were classified according to their sperm morphology reading skills recorded over an extended period. It is concluded that an external quality control programme can be highly successful, on condition that it is presented continuously with a 3-4 month interval between tests.


Fizeau interferometer-fringe sharpening.
A vector representation of the formation of fringe profiles in a Fizeau (wedge) interferometer shows that, under certain conditions, off-axis illumination may lead to fringe sharpening. The incident angle is such that the beam is first reflected toward the apex of the wedge and, following a certain controllable number of reflections, is reflected away from the apex. A typical example is shown.


Dynamic Stability of Passive Dynamic Walking Following Unexpected Perturbations.
Mitigating the risk of falling is an area of significant interest among clinicians due to the often profound health-related consequences of falls. Consequently, there is acute interest in characterizing the biomechanical conditions associated with increased fall risk, and in methods for quantifying gait stability under those conditions toward predicting and ultimately preventing falls. Considerable insights into the biomechanics of fall risk have been provided by examining the passive dynamic walking (PDW) model under nominal and perturbed conditions. This work aims to expand upon prior efforts and develop the PDW model as a model of tripping and slipping by simulating and analyzing the behavior of the model during transient perturbations. We show that fall risk increases with increasing perturbation magnitude, yet stable walking may be found even with fairly large perturbations. In cases where transient perturbations result in a fall, a nontrivial portion exhibit a substantial period of stumbling before the fall, indicating an opportunity for developing early fall-risk detection and intervention techniques. In such cases, we show that widely used kinematic metrics are able to predict whether or not a fall will occur with up to 82% balanced accuracy, even when a variety of gait kinematics are considered.


Using nutritional survey data to inform the design of sugar-sweetened beverage taxes in low-resource contexts: a cross-sectional analysis based on data from an adult Caribbean population.
Sugar-sweetened beverage (SSB) taxes have been implemented widely. We aimed to use a pre-existing nutritional survey data to inform SSB tax design by assessing: (1) baseline consumption of SSBs and SSB-derived free sugars, (2) the percentage of SSB-derived free sugars that would be covered by a tax and (3) the extent to which a tax would differentiate between high-sugar SSBs and low-sugar SSBs. We evaluated these three considerations using pre-existing nutritional survey data in a developing economy setting. We used data from a nationally representative cross-sectional survey in Barbados (2012-2013, prior to SSB tax implementation). Data were available on 334 adults (25-64 years) who completed two non-consecutive 24-hour dietary recalls. We estimated the prevalence of SSB consumption and its contribution to total energy intake, overall and stratified by taxable status. We assessed the percentage of SSB-derived free sugars subject to the tax and identified the consumption-weighted sugar concentration of SSBs, stratified by taxable status. Accounting for sampling probability, 88.8% of adults (95% CI 85.1 to 92.5) reported SSB consumption, with a geometric mean of 2.4 servings/day (±2 SD, 0.6, 9.2) among SSB consumers. Sixty percent (95% CI 54.6 to 65.4) of SSB-derived free sugars would be subject to the tax. The tax did not clearly differentiate between high-sugar beverages and low-sugar beverages. Given high SSB consumption, targeting SSBs was a sensible strategy in this setting. A substantial percentage of free sugars from SSBs were not covered by the tax, reducing possible health benefits. The considerations proposed here may help policymakers to design more effective SSB taxes.


Changes in body composition, hormonal status, and physical fitness in 11-, 13-, and 15-year-old Finnish regional youth soccer players during a two-year follow-up.
Vänttinen, T, Blomqvist, M, Nyman, K, and Häkkinen, K. Changes in body composition, hormonal status, and physical fitness in 11-, 13-, and 15-year-old Finnish regional youth soccer players during a two-year follow-up. J Strength Cond Res 25(12): 3342-3351, 2011-The purpose of this study was to examine the changes in body composition, hormonal status, and physical fitness in 10.8 ± 0.3-year-old (n = 13), 12.7 ± 0.2-year-old (n = 14), and 14.7 ± 0.3-year-old (n = 12) Finnish regional youth soccer players during a 2-year monitoring period and to compare physical fitness characteristics of soccer players with those of age-matched controls (10.7 ± 0.3 years, n = 13; 14.7 ± 0.3 years, n = 10) not participating in soccer. Body composition was measured in terms of height, weight, muscle mass, percentage of body fat, and lean body weight of trunk, legs, and arms. Hormonal status was monitored by concentrations of serum testosterone and cortisol. Physical fitness was measured in terms of sprinting speed, agility, isometric maximal strength (leg extensors, abdominal, back, grip), explosive strength, and endurance. Age-related development was detected in all other measured variables except in the percentage of body fat. The results showed that the physical fitness of regional soccer players was better than that of the control groups in all age groups, especially in cardiovascular endurance (p < 0.01-0.001) and in agility (p < 0.01-0.001). In conclusion, playing in a regional level soccer team seems to provide training adaptation, which is beyond normal development and which in all likelihood leads to positive health effects over a prolonged period of time.


Impaired Epstein-Barr virus-specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family-positive B-cell targets.
X-linked lymphoproliferative disease (XLP) is a condition associated with mutations in the signaling lymphocytic activation molecule (SLAM)-associated protein (SAP; SH2D1A). SAP functions as an adaptor, binding to and recruiting signaling molecules to SLAM family receptors expressed on T and natural killer cells. XLP is associated with extreme sensitivity to primary Epstein-Barr virus (EBV) infection, often leading to a lethal infectious mononucleosis. To investigate EBV-specific immunity in XLP patients, we studied 5 individuals who had survived EBV infection and found CD8(+) T-cell responses numerically comparable with healthy donors. However, further investigation of in vitro-derived CD8(+) T-cell clones established from 2 of these donors showed they efficiently recognized SLAM ligand-negative target cells expressing EBV antigens, but showed impaired recognition of EBV-transformed, SLAM ligand-positive, lymphoblastoid cell lines (LCLs). Importantly, LCL recognition was restored when interactions between the SLAM receptors CD244 and natural killer-, T-, and B-cell antigen (NTBA) and their ligands on LCLs were blocked. We propose that XLP patients' particular sensitivity to EBV, and not to other viruses, reflects at least in part EBV's strict tropism for B lymphocytes and the often inability of the CD8(+) T-cell response to contain the primary infection of SLAM ligand-expressing target cells.


Association Between Side Effects and Blood microRNA Expression Levels and Their Targeted Pathways in Patients With Major Depressive Disorder Treated by a Selective Serotonin Reuptake Inhibitor, Escitalopram: A CAN-BIND-1 Report.
Antidepressant drugs are effective therapies for major depressive disorder; however, they are frequently associated with side effects. Although there is some evidence for a relationship between genetic variation and side effects, little is known regarding the role of dynamic molecular factors as moderators of side effects. The aim of this study was to assess microRNA (miRNA) changes associated with side effects during escitalopram treatment and their downstream effects on target gene expression. A total 160 patients with major depressive disorder from the CAN-BIND-1 cohort were included. Side effects were assessed with the Toronto Side Effect Scale after 2 weeks of treatment with escitalopram. We assessed the relationship between side effects and changes in peripheral expression of miRNAs between baseline and week 2. For miRNA whose expression changed, we used target prediction algorithms to identify putative messenger RNA (mRNA) targets and assessed their expression. Nausea was experienced by 42.5% of patients. We identified 45 miRNAs whose expression changed on initiation of escitalopram treatment, of which 10 displayed a negative association with intensity of nausea (miR15b-5p, miR17-5p, miR20a-5p, miR20b-5p, miR103a-3p, miR103b, miR106a-5p, miR182-5p, miR185-5p, and miR660-5p). Additionally, we found negative associations between 4 microRNAs (miR20a-5p, miR106a-5p, miR185-5p, miR660-5p) and mRNA targets. The expression of the miR185-5p target, CAMK2δ was significantly decreased [log 2 mean = -0.048 (0.233)] between weeks 0 and 2 (P = .01)]. We identified an overexpression of miR185-5p during escitalopram treatment of major depressive disorder, which was negatively associated with intensity of nausea, and identified a potential mRNA target that may mediate this effect.


Amphotericin B concentrations in healthy mallard ducks (Anas platyrhynchos) following a single intratracheal dose of liposomal amphotericin B using an atomizer.
Aspergillosis is a fungal infection that primarily affects the respiratory tract. Amphotericin B has broad antifungal activity and is commonly used to treat aspergillosis, a fungal pneumonia that is a common sequela in oiled waterfowl as well as other birds in wildlife rehabilitation. Pharmacokinetic parameters of nebulized amphotericin B in an avian model have been reported, but those of direct intratracheal delivery have yet to be established. The objective of this study was to evaluate if a single 3 mg/kg dose of liposomal amphotericin B delivered intratracheally using a commercial atomizer would achieve plasma and lung tissue concentrations exceeding targeted minimum inhibitory concentrations (MIC) for Aspergillus species in adult mallard ducks (Anas platyrhynchos). Following intratracheal delivery, amphotericin B was present in lung parenchyma at concentrations above the targeted MIC of 1 μg/g for up to 9 days post-administration; however, distribution of the drug was uneven, with the majority of the drug concentrated in one lung lobe. Concentrations in the contralateral lung lobe and the kidneys were above the targeted MIC 1 day after administration but declined exponentially with a half-life of approximately 2 days. Plasma concentrations were never above the targeted MIC. Histological examination of the trachea, bronchi, lungs, heart, liver, and kidneys did not reveal any toxic changes. Using a commercial atomizer, intratracheal delivery of amphotericin B at 3 mg/kg resulted in lung parenchyma concentrations above 1 μg/ml with no discernable systemic effects. Further studies to establish a system of drug delivery to both sides of the pulmonary parenchyma need to be performed, and the efficacy of this treatment for disease prevention remains to be determined.


Vedolizumab in Japanese patients with ulcerative colitis: A Phase 3, randomized, double-blind, placebo-controlled study.
Vedolizumab safety and efficacy have been established in many populations all over the world, but have never been studied in Japan. We report results from a Phase 3, randomized, double-blind, placebo-controlled study of vedolizumab in Japanese patients with active ulcerative colitis (UC). Patients with moderate-to-severe UC were enrolled into Cohort 1 (double-blinded) or Cohort 2 (open-label) in the induction phase. Cohort 1 was randomized 2:1 to receive 300 mg vedolizumab or placebo, while Cohort 2 received vedolizumab 300 mg only, at Weeks 0, 2, and 6. Patients from Cohorts 1 and 2 showing a clinical response to vedolizumab at Week 10 were randomized 1:1 to receive vedolizumab or placebo (double-blinded) at Week 14 and then every 8 weeks up to Week 54 as the maintenance phase. The primary endpoint was clinical response at Week 10, for the induction phase, and clinical remission at Week 60, for the maintenance phase. A total of 292 patients were enrolled into the induction phase (246 in Cohort 1, 46 in Cohort 2); 83 patients achieved response to vedolizumab and were subsequently enrolled into the maintenance phase. Clinical response rates at Week 10 were 39.6% (65/164) and 32.9% (27/82) in the vedolizumab and placebo groups in Cohort 1, respectively (adjusted odds ratio [AOR] = 1.37, 95% CI 0.779-2.399; p = 0.2722). In the maintenance phase, clinical remission rate at Week 60 was significantly higher in the vedolizumab group, at 56.1% (23/41), versus 31.0% (13/42) for placebo (AOR = 2.88, 95% CI 1.168-7.108; p = 0.0210). Most adverse events were mild to moderate in intensity, and no deaths occurred during the study period. Vedolizumab showed numerically greater efficacy compared with placebo as induction therapy, but the difference was not statistically significant. Vedolizumab was significantly superior to placebo as maintenance therapy in Japanese patients with UC. Vedolizumab has favourable safety and tolerability in these patients. ClinicalTrials.gov: NCT02039505.


Use of ototopical antibiotics in treating 3 common ear diseases.
Prompted by rising rates of antibiotic resistance, lack of standardized treatment regimens, and new treatment alternatives, the American Academy of Otolaryngology-Head and Neck Surgery convened an expert consensus panel to consider recommendations for the responsible use of antibiotics in chronic suppurative otitis media, tympanostomy tube otorrhea, and otitis externa. The Panel concluded that in the absence of systemic infection or serious underlying disease, topical antibiotics alone constitute first-line treatment for most patients with these conditions, finding no evidence that systemic antibiotics alone or in combination with topical preparations improve treatment outcomes compared with topical antibiotics alone. Topical preparations should be selected on the basis of expected bacteriology and informed knowledge of the risk-benefit of each available preparation. The use of nonototoxic preparations in treating acute otitis externa (when the tympanic membrane is perforated or its status is unknown), chronic suppurative otitis media, and tympanostomy tube otorrhea should be considered.


Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA.
We previously demonstrated that the frequency of birth defects among children of residents of the Red River Valley (RRV), Minnesota, USA, was significantly higher than in other major agricultural regions of the state during the years 1989-1991, with children born to male pesticide applicators having the highest risk. The present, smaller cross-sectional study of 695 families and 1,532 children, conducted during 1997-1998, provides a more detailed examination of reproductive health outcomes in farm families ascertained from parent-reported birth defects. In the present study, in the first year of life, the birth defect rate was 31.3 births per 1,000, with 83% of the total reported birth defects confirmed by medical records. Inclusion of children identified with birth or developmental disorders within the first 3 years of life and later led to a rate of 47.0 per 1,000 (72 children from 1,532 live births). Conceptions in spring resulted in significantly more children with birth defects than found in any other season (7.6 vs. 3.7%). Twelve families had more than one child with a birth defect (n = 28 children). Forty-two percent of the children from families with recurrent birth defects were conceived in spring, a significantly higher rate than that for any other season. Three families in the kinships defined contributed a first-degree relative other than a sibling with the same or similar birth defect, consistent with a Mendelian inheritance pattern. The remaining nine families did not follow a Mendelian inheritance pattern. The sex ratio of children with birth defects born to applicator families shows a male predominance (1.75 to 1) across specific pesticide class use and exposure categories exclusive of fungicides. In the fungicide exposure category, normal female births significantly exceed male births (1.25 to 1). Similarly, the proportion of male to female children with birth defects is significantly lower (0.57 to 1; p = 0.02). Adverse neurologic and neurobehavioral developmental effects clustered among the children born to applicators of the fumigant phosphine (odds ratio [OR] = 2.48; confidence interval [CI], 1.2-5.1). Use of the herbicide glyphosate yielded an OR of 3.6 (CI, 1.3-9.6) in the neurobehavioral category. Finally, these studies point out that (a) herbicides applied in the spring may be a factor in the birth defects observed and (b) fungicides can be a significant factor in the determination of sex of the children of the families of the RRV. Thus, two distinct classes of pesticides seem to have adverse effects on different reproductive outcomes. Biologically based confirmatory studies are needed.


Pioglitazone and Deoxyribonucleoside Combination Treatment Increases Mitochondrial Respiratory Capacity in m.3243A>G MELAS Cybrid Cells.
The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that aim to stimulate mitochondrial biogenesis to boost ATP generation above a critical disease threshold. Here, we examine the effects of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), on mitochondrial biogenesis in cybrid cells containing >90% of the m.3243A>G mutation associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PioG + dNs combination treatment increased mtDNA copy number and mitochondrial mass in both control (CON) and m.3243A>G (MUT) cybrids, with no adverse effects on cell proliferation. PioG + dNs also increased mtDNA-encoded transcripts in CON cybrids, but had the opposite effect in MUT cybrids, reducing the already elevated transcript levels. Steady-state levels of mature oxidative phosphorylation (OXPHOS) protein complexes were increased by PioG + dNs treatment in CON cybrids, but were unchanged in MUT cybrids. However, treatment was able to significantly increase maximal mitochondrial oxygen consumption rates and cell respiratory control ratios in both CON and MUT cybrids. Overall, these findings highlight the ability of PioG + dNs to improve mitochondrial respiratory function in cybrid cells containing the m.3243A>G MELAS mutation, as well as their potential for development into novel therapies to treat mitochondrial disease.


Chemical genomics of cancer chemopreventive dithiolethiones.
3H-1,2-dithiole-3-thione (D3T) and its analogues 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (OLT) and 5-tert-butyl-3H-1,2-dithiole-3-thione (TBD) are chemopreventive agents that block or diminish early stages of carcinogenesis by inducing activities of detoxication enzymes. While OLT has been used in clinical trials, TBD has been shown to be more efficacious and possibly less toxic than OLT in animals. Here, we utilize a robust and high-resolution chemical genomics procedure to examine the pharmacological structure-activity relationships of these compounds in livers of male rats by microarray analyses. We identified 226 differentially expressed genes that were common to all treatments. Functional analysis identified the relation of these genes to glutathione metabolism and the nuclear factor, erythroid derived 2-related factor 2 pathway (Nrf2) that is known to regulate many of the protective actions of dithiolethiones. OLT and TBD were shown to have similar efficacies and both were weaker than D3T. In addition, we identified 40 genes whose responses were common to OLT and TBD, yet distinct from D3T. As inhibition of cytochrome P450 (CYP) has been associated with the effects of OLT on CYP expression, we determined the half maximal inhibitory concentration (IC(50)) values for inhibition of CYP1A2. The rank order of inhibitor potency was OLT >> TBD >> D3T, with IC(50) values estimated as 0.2, 12.8 and >100 microM, respectively. Functional analysis revealed that OLT and TBD, in addition to their effects on CYP, modulate liver lipid metabolism, especially fatty acids. Together, these findings provide new insight into the actions of clinically relevant and lead dithiolethione analogues.


Geometric control of human stem cell morphology and differentiation.
During tissue morphogenesis, stem cells and progenitor cells migrate, proliferate, and differentiate, with striking changes in cell shape, size, and acting mechanical stresses. The local cellular function depends on the spatial distribution of cytokines as well as local mechanical microenvironments in which the cells reside. In this study, we controlled the organization of human adipose derived stem cells using micro-patterning technologies, to investigate the influence of multi-cellular form on spatial distribution of cellular function at an early stage of cell differentiation. The underlying role of cytoskeletal tension was probed through drug treatment. Our results show that the cultivation of stem cells on geometric patterns resulted in pattern- and position-specific cell morphology, proliferation and differentiation. The highest cell proliferation occurred in the regions with large, spreading cells (such as the outer edge of a ring and the short edges of rectangles). In contrast, stem cell differentiation co-localized with the regions containing small, elongated cells (such as the inner edge of a ring and the regions next to the short edges of rectangles). The application of drugs that inhibit the formation of actomyosin resulted in the lack of geometrically specific differentiation patterns. This study confirms the role of substrate geometry on stem cell differentiation, through associated physical forces, and provides a simple and controllable system for studying biophysical regulation of cell function.


Comprehensive evaluation of bone health using DXA and pQCT in an Indian boy with osteogenesis imperfecta.
We present a 9-year-old male child having history of fractures on trivial trauma with a family history of the same. He was treated for osteogenesis imperfecta (OI; zolendronate, calcium and vitamin D) and showed clinical improvement. On evaluating his bone health using dual energy X-ray absorptiometry and peripheral quantitative CT, we found that the child had bone density within the reference range but a smaller bone mass for his height, low muscle mass and thin bones with a lower strength strain index in comparison with healthy children. Our case suggests that treatment with bisphosphonates results in increase in bone density; however, bones remain thin and the lean body mass in these children may also be low. Controlled physical activity to improve muscle health and newer approaches to improve bone geometry would result in better bone health in children with OI.


Environmental risk factors for the incidence of American cutaneous leishmaniasis in a sub-Andean zone of Colombia (Chaparral, Tolima).
Environmental risk factors for cutaneous leishmaniasis were investigated for the largest outbreak recorded in Colombia. The outbreak began in 2003 in Chaparral, and in the following five years produced 2,313 cases in a population of 56,228. Candidate predictor variables were land use, elevation, and climatic variables such as mean temperature and precipitation. Spatial analysis showed that incidence of cutaneous leishmaniasis was higher in townships with mean temperatures in the middle of the county's range. Incidence was independently associated with higher coverage with forest or shrubs (2.6% greater for each additional percent coverage, 95% credible interval [CI] = 0.5-4.9%), and lower population density (22% lower for each additional 100 persons/km(2), 95% CI = 7-41%). The extent of forest or shrub coverage did not show major changes over time. These findings confirmed the roles of climate and land use in leishmaniasis transmission. However, environmental variables were not sufficient to explain the spatial variation in incidence.


An Internship May Not Be Enough: Enhancing Bioscience Industry Job Readiness through Practicum Experiences.
In contrast to the narrowing of options in academic careers, the bioscience industry offers robust employment opportunities for STEM-trained workers, especially those who display both scientific and business talent. Unfortunately, traditional science programs typically lack curricular features that develop this type of worker. The North Carolina State University Master of Microbial Biotechnology (MMB) program facilitates industry-specific experiential learning to fill this training gap. Similar programs often rely on a single industry internship to provide students relevant work experience, but completion of one internship might not suffice to position students for employment in a highly competitive job market. The MMB program requires students to complete an internship and three practicum projects in an industry setting, to promote development of key skills in a variety of areas, to build confidence in the ability to perform initial job duties, and to establish a more extensive work history in industry. In this Perspective we discuss an unmet need in undergraduate and graduate STEM education that can be filled by incorporating a similar set of industry-specific work experiences for students who desire to transition from academe into the life science industry.


Using 10AFC to further improve the efficiency of the quick CSF method.
The contrast sensitivity function (CSF) provides a fundamental characterization of spatial vision, important for basic and clinical applications, but its long testing times have prevented easy, widespread assessment. The original quick CSF method was developed using a two-alternative forced choice (2AFC) grating orientation identification task (Lesmes, Lu, Baek, & Albright, 2010), and obtained precise CSF assessments while reducing the testing burden to only 50 trials. In this study, we attempt to further improve the efficiency of the quick CSF method by exploiting the properties of psychometric functions in multiple-alternative forced choice (m-AFC) tasks. A simulation study evaluated the effect of the number of alternatives m on the efficiency of the sensitivity measurement by the quick CSF method, and a psychophysical study validated the quick CS method in a 10AFC task. We found that increasing the number of alternatives of the forced-choice task greatly improved the efficiency of CSF assessment in both simulation and psychophysical studies. The quick CSF method based on a 10-letter identification task can assess the CSF with an averaged standard deviation of 0.10 decimal log unit in less than 2 minutes.


Continuously rotating chiral liquid crystal droplets in a linearly polarized laser trap.
The transfer of optical angular momentum to birefringent particles via circularly polarized light is common. We report here on the unexpected, continuous rotation of chiral nematic liquid crystal droplets in a linearly polarized optical trap. The rotation is non-uniform, occurs over a timescale of seconds, and is observed only for very specific droplet sizes. Synchronized vertical motion of the droplet occurs during the rotation. The motion is the result of photo-induced molecular reorganization, providing a micron sized opto-mechanical transducer that twists and translates.


Glutathione peroxidase-1 deficiency leads to increased nuclear light scattering, membrane damage, and cataract formation in gene-knockout mice.
Previous in vitro studies with transgenic and gene-knockout mice have shown that lenses with elevated levels of glutathione peroxidase (GPX)-1 activity are able to resist the cytotoxic effect of H(2)O(2), compared with normal lenses and lenses from GPX-1-deficient animals. The purpose of this study was to investigate the functional role of this enzyme in antioxidant mechanisms of lens in vivo by comparing lens changes of gene-knockout mice with age-matched control animals. In vivo lens changes were monitored by slit lamp biomicroscopy, and enucleated lenses were examined under a stereomicroscope in gene-knockout animals and age-matched control animals ranging in age from 3 weeks to 18 months. Transmission (TEM) and confocal microscopy were performed on different regions of lenses after the mice were killed at various times. Slit lamp images showed an increase in nuclear light scattering (NLS) in gene-knockout mice compared with control animals. TEM revealed changes in the nucleus as early as 3 weeks of age by the appearance of waviness of fiber membranes. With increasing age, there was greater distortion of fiber membranes and distension of interfiber space at the apex of fiber cells compared with control mice. The changes in nuclear fiber membranes were even more dramatic, as observed by confocal microscopy, which was performed on thicker sections. In contrast to the changes in the lens nucleus, the morphology of the epithelium and superficial cortex remained unchanged in knockout animals during the same experimental period, consistent with slit lamp observations. Stereomicroscopy of ex vivo lenses demonstrated a significant increase in opacification in gene-knockout mice relative to control animals of the same age. This effect became evident in mice aged 5 to 9.9 months and persisted thereafter in older animals, resulting in mature cataracts after 15 months. The results demonstrate the critical role of GPX-1 in antioxidant defense mechanisms of the lens nucleus. The increased NLS appears to be associated with damage to fiber membranes in the nucleus, which is particularly susceptible to oxidative challenge because of the deficiency of GPX-1. It is suggested that the lens membrane changes in the knockout animals may be due to the formation of lipid peroxides, which serve as substrates for GPX-1. Cataract development in gene-knockout mice appeared to progress from focal opacities, apparent at an earlier age, to lamellar cataracts between 6 and 10 months, and finally to complete opacification in animals older than 15 months. This is the first reported phenotype in GPX-1-knockout mice.


Pro-inflammatory and pro-oxidant status of pancreatic islet in vitro is controlled by TLR-4 and HO-1 pathways.
Since their isolation until implantation, pancreatic islets suffer a major stress leading to the activation of inflammatory reactions. The maintenance of controlled inflammation is essential to preserve survival and function of the graft. Identification and targeting of pathway(s) implicated in post-transplant detrimental inflammatory events, is mandatory to improve islet transplantation success. We sought to characterize the expression of the pro-inflammatory and pro-oxidant mediators during islet culture with a focus on Heme oxygenase (HO-1) and Toll-like receptors-4 signaling pathways. Rat pancreatic islets were isolated and pro-inflammatory and pro-oxidant status were evaluated after 0, 12, 24 and 48 hours of culture through TLR-4, HO-1 and cyclooxygenase-2 (COX-2) expression, CCL-2 and IL-6 secretion, ROS (Reactive Oxygen Species) production (Dihydroethidine staining, DHE) and macrophages migration. To identify the therapeutic target, TLR4 inhibition (CLI-095) and HO-1 activation (cobalt protoporphyrin,CoPP) was performed. Activation of NFκB signaling pathway was also investigated. After isolation and during culture, pancreatic islet exhibited a proinflammatory and prooxidant status (increase levels of TLR-4, COX-2, CCL-2, IL-6, and ROS). Activation of HO-1 or inhibition of TLR-4 decreased inflammatory status and oxidative stress of islets. Moreover, the overexpression of HO-1 induced NFκB phosphorylation while the inhibition of TLR-4 had no effect NFκB activation. Finally, inhibition of pro-inflammatory pathway induced a reduction of macrophages migration. These data demonstrated that the TLR-4 signaling pathway is implicated in early inflammatory events leading to a pro-inflammatory and pro-oxidant status of islets in vitro. Moreover, these results provide the mechanism whereby the benefits of HO-1 target in TLR-4 signaling pathway. HO-1 could be then an interesting target to protect islets before transplantation.


Faciobrachial dystonic seizures expressed as epileptic spasms, followed by focal seizures in anti-LGI1 encephalitis: a video-polygraphic study.
The origin of faciobrachial dystonic seizures in anti-LGI1 encephalitis is controversial due to a lack of neurophysiological characterization. We report a 68-year-old man with subacute anterograde memory loss and involuntary faciobrachial movements. Video-polygraphic recordings disclosed repetitive events characterized by sudden, short contraction of the upper limbs and ipsilateral hemiface. A focal contralateral EEG slow wave from frontal or central electrodes was accompanied by increased muscle activity, often with a diamond-shaped configuration, on the orbicularis oris muscle, deltoid muscle, and extensor muscle of the hand. This EEG/EMG pattern (resembling a tonic epileptic spasm) was always followed by oral and gestural automatisms with dystonic posturing of the upper limbs, compatible with a temporal lobe seizure. Brain MRI showed hyperintensity in the bilateral mesial temporal lobes, while 18FDG-PET revealed basal ganglia hypermetabolism with extensive cortical hypometabolism. Serum and CSF were both positive for anti-LGI antibodies. The patient was treated with intravenous methylprednisolone (1 g/day for five days) with seizure freedom within four days after initiation of the immunotherapy. In this case, a video-EEG/polygraphic study disclosed that faciobrachial dystonic seizures may resemble epileptic spasms, and the occurrence in close temporal association with focal seizures as a single ictal event is suggestive of a peculiar cortical-subcortical interaction. [Published with video sequence on www.epilepticdisorders.com].


Dendritic Integration of Sensory Evidence in Perceptual Decision-Making.
Perceptual decisions require the accumulation of sensory information to a response criterion. Most accounts of how the brain performs this process of temporal integration have focused on evolving patterns of spiking activity. We report that subthreshold changes in membrane voltage can represent accumulating evidence before a choice. αβ core Kenyon cells (αβc KCs) in the mushroom bodies of fruit flies integrate odor-evoked synaptic inputs to action potential threshold at timescales matching the speed of olfactory discrimination. The forkhead box P transcription factor (FoxP) sets neuronal integration and behavioral decision times by controlling the abundance of the voltage-gated potassium channel Shal (KV4) in αβc KC dendrites. αβc KCs thus tailor, through a particular constellation of biophysical properties, the generic process of synaptic integration to the demands of sequential sampling.


Parametric amplification and phase preserving amplitude regeneration of a 640 Gbit/s RZ-DPSK signal.
We report the first experimental demonstration of parametric amplification and all-optical phase-preserving amplitude regeneration for a 640 Gbit/s return-to-zero (RZ) differential phase-shift keying (DPSK) optical time division multiplexed (OTDM) signal. In the designed gain-flattened single-pump fiber optical parametric amplifier (FOPA), 620 fs short optical pulses are successfully amplified with 15 dB gain with error-free performance and less than 1 dB power penalty. Phase-preserving amplitude regeneration based on gain saturation in the FOPA is carried out for optical signals with degraded optical signal-to-noise ratio. An improvement of 2.2 dB in receiver sensitivity at a bit-error-ratio of 10(-9) has been successfully achieved after regeneration, together with 13.3 dB net gain.