TGF beta type II receptor signaling controls Schwann cell death and proliferation in developing nerves

During development, Schwann cell numbers are precisely adjusted to match the number of axons. It is essentially unknown which growth factors or receptors carry out this important control in vivo. Here, we tested whether the type II transforming growth factor (TGF)beta receptor has a role in this process. We generated a conditional knock-out mouse in which the type II TGF beta receptor is specifically ablated only in Schwann cells. Inactivation of the receptor, evident at least from embryonic day 18, resulted in suppressed Schwann cell death in normally developing and injured nerves. Notably, the mutants also showed a strong reduction in Schwann cell proliferation. Consequently, Schwann cell numbers in wild-type and mutant nerves remained similar. Lack of TGF beta signaling did not appear to affect other processes in which TGF beta had been implicated previously, including myelination and response of adult nerves to injury. This is the first in vivo evidence for a growth factor receptor involved in promoting Schwann cell division during development and the first genetic evidence for a receptor that controls normal developmental Schwann cell death

Revisiting the impact of Schistosoma mansoni regulating mechanisms on transmission dynamics using SchiSTOP, a novel modelling framework

BACKGROUND: The transmission cycle of Schistosoma is remarkably complex, including sexual reproduction in human hosts and asexual reproduction in the intermediate host (freshwater snails). Patterns of rapid recrudescence after treatment and stable low transmission are often observed, hampering the achievement of control targets. Current mathematical models commonly assume regulation of transmission to occur at worm level through density-dependent egg production. However, conclusive evidence on this regulating mechanism is weak, especially for S. mansoni. In this study, we explore the interplay of different regulating mechanisms and their ability to explain observed patterns in S. mansoni epidemiology. METHODOLOGY/PRINCIPAL FINDINGS: We developed SchiSTOP: a hybrid stochastic agent-based and deterministic modelling framework for S. mansoni transmission in an age-structured human population. We implemented different models with regulating mechanisms at: i) worm-level (density-dependent egg production), ii) human-level (anti-reinfection immunity), and iii) snail-level (density-dependent snail dynamics). Additionally, we considered two functional choices for the age-specific relative exposure to infection. We assessed the ability of each model to reproduce observed epidemiological patterns pre- and post-control, and compared successful models in their predictions of the impact of school-based and community-wide treatment. Simulations confirmed that assuming at least one regulating mechanism is required to reproduce a stable endemic equilibrium. Snail-level regulation was necessary to explain stable low transmission, while models combining snail- and human-level regulation with an age-exposure function informed with water contact data were successful in reproducing a rapid rebound after treatment. However, the predicted probability of reaching the control targets varied largely across models. CONCLUSIONS/SIGNIFICANCE: The choice of regulating mechanisms in schistosomiasis modelling largely determines the expected impact of control interventions. Overall, this work suggests that reaching the control targets solely through mass drug administration may be more challenging than currently thought. We highlight the importance of regulating mechanisms to be included in transmission models used for policy.</p

Multiple testing in orthopedic literature: a common problem?

BACKGROUND: Performing multiple tests in primary research is a frequent subject of discussion. This discussion originates from the fact that when multiple tests are performed, it becomes more likely to reject one of the null hypotheses, conditional on that these hypotheses are true and thus commit a type one error. Several correction methods for multiple testing are available. The primary aim of this study was to assess the quantity of articles published in two highly esteemed orthopedic journals in which multiple testing was performed. The secondary aims were to determine in which percentage of these studies a correction was performed and to assess the risk of committing a type one error if no correction was applied. METHODS: The 2010 annals of two orthopedic journals (A and B) were systematically hand searched by two independent investigators. All articles on original research in which statistics were applied were considered. Eligible publications were reviewed for the use of multiple testing with respect to predetermined criteria. RESULTS: A total of 763 titles were screened and 127 articles were identified and included in the analysis. A median of 15 statistical inference results were reported per publication in both journal A and B. Correction for multiple testing was performed in 15% of the articles published in journal A and in 6% from journal B. The estimated median risk of obtaining at least one significant result for uncorrected studies was calculated to be 54% for both journals. CONCLUSION: This study shows that the risk of false significant findings is considerable and that correcting for multiple testing is only performed in a small percentage of all articles published in the orthopedic literature reviewed

Formal and informal social participation of the 'young-old' in the Netherlands in 1992 and 2002

The study compares the formal and informal social participation of 60-69 year olds in The Netherlands in 1992 and 2002, and examines which attributes of the two cohorts favour social participation. Using data from the Longitudinal Aging Study Amsterdam, it was found that cohort differences in formal participation (as members of organisations, in volunteer work and in religious organisations) and in informal participation (having a large social network, and in cultural and recreational activities) associated with cohort differences in individual characteristics (level of education, health, employment status and marital status). Descriptive analyses showed an increase between 1992 and 2002 in all forms of participation except religious involvement. The 2002 cohort members were more educated and more engaged in employment, but in worse health and had a higher prevalence of divorce than the 1992 cohort members. Logistic regression analyses showed that the positive effect on social participation of the recent cohort's higher educational level was suppressed by the negative effect of their worse health. Being divorced had mixed effects on formal and informal participation, but the difference in the number of divorcees did not explain cohort differences in social participation. Interaction effects showed that the influence of sex and health on volunteer work and religious involvement changed over time. The paper concludes with a discussion of the prospects for higher levels of formal and informal social participation among future cohorts of young-older people. © 2010 Cambridge University Press

Effect of lifestyle intervention plus rosiglitazone or placebo therapy on left ventricular mass assessed with cardiovascular magnetic resonance in the metabolic syndrome

<p>Abstract</p> <p>Background</p> <p>To evaluate the effect of lifestyle intervention in conjunction with rosiglitazone or placebo therapy on left ventricular (LV) mass, using cardiovascular magnetic resonance (CMR) in the metabolic syndrome.</p> <p>Methods</p> <p>The present study was a pre-specified substudy of a double-blind randomized controlled trial evaluating the effect of lifestyle intervention in conjunction with rosiglitazone or placebo therapy on carotid artery atherosclerosis in the metabolic syndrome. From this original study population, 10 subjects from the placebo group and 10 from the rosiglitazone group were randomly selected. At baseline and follow-up (52 weeks), clinical and laboratory measurements were assessed and a CMR-examination was performed to evaluate LV mass indexed for body surface area (LV mass-I). Subsequently, the effect of therapy (rosiglitazone vs. placebo) and clinical and laboratory variables on LV mass-I was evaluated.</p> <p>Results</p> <p>In both groups, body mass index, waist circumference, systolic and diastolic blood pressure significantly decreased during follow-up. Interestingly, LV mass-I significantly decreased in the placebo group (48.9 ± 5.3 g/m²vs. 44.3 ± 5.6 g/m², p < 0.001) indicating reverse remodeling, whereas LV mass-I remained unchanged in the rosiglitazone group (54.7 ± 9.9 g/m²vs. 53.7 ± 9.2 g/m², p = 0.3). After correction for systolic and diastolic blood pressure and triglyceride, the kind of therapy (rosiglitazone vs. placebo) remained the only significant predictor of LV mass-I reduction.</p> <p>Conclusions</p> <p>Lifestyle intervention resulted in a reduction of LV mass-I in the metabolic syndrome, indicating reverse remodeling. However, rosiglitazone therapy may have inhibited this positive reverse remodeling.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN54951661">ISRCTN54951661</a>.</p

Surfactants tailored by the class Actinobacteria

Globally the change towards the establishment of a bio-based economy has resulted in an increased need for bio-based applications. This, in turn, has served as a driving force for the discovery and application of novel biosurfactants. The class Actinobacteria represents a vast group of microorganisms with the ability to produce a diverse range of secondary metabolites, including surfactants. Understanding the extensive nature of the biosurfactants produced by actinobacterial strains can assist in finding novel biosurfactants with new potential applications. This review therefore presents a comprehensive overview of the knowledge available on actinobacterial surfactants, the chemical structures that have been completely or partly elucidated, as well as the identity of the biosurfactant-producing strains. Producer strains of not yet elucidated compounds are discussed, as well as the original habitats of all the producer strains, which seems to indicate that biosurfactant production is environmentally driven. Methodology applied in the isolation, purification and structural elucidation of the different types of surface active compounds, as well as surfactant activity tests, are also discussed. Overall, actinobacterial surfactants can be summarized to include the dominantly occurring trehalose-comprising surfactants, other non-trehalose containing glycolipids, lipopeptides and the more rare actinobacterial surfactants. The lack of structural information on a large proportion of actinobacterial surfactants should be considered as a driving force to further explore the abundance and diversity of these compounds. This would allow for a better understanding of actinobacterial surface active compounds and their potential for biotechnological application

Flexible modelling of risk factors on the incidence of pneumonia in young children in South Africa using piece-wise exponential additive mixed modelling

Introduction Recurrent episodes of pneumonia are frequently modeled using extensions of the Cox proportional hazards model with the underlying assumption of time-constant relative risks measured by the hazard ratio. We aim to relax this assumption in a study on the effect of factors on the evolution of pneumonia incidence over time based on data from a South African birth cohort study, the Drakenstein child health study. Methods We describe and apply two models: a time-constant and a time-varying relative effects model in a piece-wise exponential additive mixed model’s framework for recurrent events. A more complex model that fits in the same framework is applied to study the continuously measured seasonal effects. Results We find that several risk factors (male sex, preterm birth, low birthweight, lower socioeconomic status, lower maternal education and maternal cigarette smoking) have strong relative effects that are persistent across time. When time-varying effects are allowed in the model, HIV exposure status (HIV exposed & uninfected versus HIV unexposed) shows a strong relative effect for younger children, but this effect weakens as children grow older, with a null effect reached from about 15 months. Weight-for-length at birth shows a time increasing relative effect. We also find that children born in the summer have a much higher risk of pneumonia in the 3-to-8-month age period compared with children born in winter. Conclusion This work highlights the usefulness of flexible modelling tools in recurrent events models. It avoids stringent assumptions and allows estimation and visualization of absolute and relative risks over time of key factors associated with incidence of pneumonia in young children, providing new perspectives on the role of risk factors such HIV exposure