Why Are Lipid Rafts Not Observed In Vivo?

The existence of lipid rafts in live cells remains a topic of lively debate. Although large, micrometer-sized rafts are readily observed in artificial membranes, attempts to observe analogous domains in live cells place an upper limit of approximately 5 nm on their size. We suggest that integral membrane proteins attached to the cytoskeleton act as obstacles that limit the size of lipid domains. Computer simulations of a binary lipid mixture show that the presence of protein obstacles at only 5-10% by area dramatically reduces the tendency of the lipids to phase separate. These calculations emphasize the importance of spatial heterogeneity in cell membranes, which limits the transferability of conclusions drawn from artificial membranes to live cells.     

Why Are Clinicians Not Embracing the Results from Pivotal Clinical Trials in Severe Sepsis? A Bayesian Analysis

Background

Five pivotal clinical trials (Intensive Insulin Therapy; Recombinant Human Activated Protein C [rhAPC]; Low-Tidal Volume; Low-Dose Steroid; Early Goal-Directed Therapy [EGDT]) demonstrated mortality reduction in patients with severe sepsis and expert guidelines have recommended them to clinical practice. Yet, the adoption of these therapies remains low among clinicians.

Objectives

We selected these five trials and asked: Question 1-What is the current probability that the new therapy is not better than the standard of care in my patient with severe sepsis? Question 2-What is the current probability of reducing the relative risk of death (RRR) of my patient with severe sepsis by meaningful clinical thresholds (RRR >15%; >20%; >25%)?

Methods

Bayesian methodologies were applied to this study. Odds ratio (OR) was considered for Question 1, and RRR was used for Question 2. We constructed prior distributions (enthusiastic; mild, moderate, and severe skeptic) based on various effective sample sizes of other relevant clinical trials (unfavorable evidence). Posterior distributions were calculated by combining the prior distributions and the data from pivotal trials (favorable evidence).

Main Findings

Answer 1-The analysis based on mild skeptic prior shows beneficial results with the Intensive Insulin, rhAPC, and Low-Tidal Volume trials, but not with the Low-Dose Steroid and EGDT trials. All trials'' results become unacceptable by the analyses using moderate or severe skeptic priors. Answer 2-If we aim for a RRR>15%, the mild skeptic analysis shows that the current probability of reducing death by this clinical threshold is 88% for the Intensive Insulin, 62–65% for the Low-Tidal Volume, rhAPC, EGDT trials, and 17% for the Low-Dose Steroid trial. The moderate and severe skeptic analyses show no clinically meaningful reduction in the risk of death for all trials. If we aim for a RRR >20% or >25%, all probabilities of benefits become lower independent of the degree of skepticism.

Conclusions

Our clinical threshold analysis offers a new bedside tool to be directly applied to the care of patients with severe sepsis. Our results demonstrate that the strength of evidence (statistical and clinical) is weak for all trials, particularly for the Low-Dose Steroid and EGDT trials. It is essential to replicate the results of each of these five clinical trials in confirmatory studies if we want to provide patient care based on scientifically sound evidence.     

Why Are Autism Spectrum Conditions More Prevalent in Males?

Autism Spectrum Conditions (ASC) are much more common in males, a bias that may offer clues to the etiology of this condition. Although the cause of this bias remains a mystery, we argue that it occurs because ASC is an extreme manifestation of the male brain. The extreme male brain (EMB) theory, first proposed in 1997, is an extension of the Empathizing-Systemizing (E-S) theory of typical sex differences that proposes that females on average have a stronger drive to empathize while males on average have a stronger drive to systemize. In this first major update since 2005, we describe some of the evidence relating to the EMB theory of ASC and consider how typical sex differences in brain structure may be relevant to ASC. One possible biological mechanism to account for the male bias is the effect of fetal testosterone (fT). We also consider alternative biological theories, the X and Y chromosome theories, and the reduced autosomal penetrance theory. None of these theories has yet been fully confirmed or refuted, though the weight of evidence in favor of the fT theory is growing from converging sources (longitudinal amniocentesis studies from pregnancy to age 10 years old, current hormone studies, and genetic association studies of SNPs in the sex steroid pathways). Ultimately, as these theories are not mutually exclusive and ASC is multi-factorial, they may help explain the male prevalence of ASC.     

Tuberculosis and Poverty: Why Are the Poor at Greater Risk in India?

Background

Although poverty is widely recognized as an important risk factor for tuberculosis (TB) disease, the specific proximal risk factors that mediate this association are less clear. The objective of our study was to investigate the mechanisms by which poverty increases the risk of TB.

Methods

Using individual level data from 198,754 people from the 2006 Demographic Health Survey (DHS) for India, we assessed self-reported TB status, TB determinants and household socioeconomic status. We used these data to calculate the population attributable fractions (PAF) for each key TB risk factor based on the prevalence of determinants and estimates of the effect of these risk factors derived from published sources. We conducted a mediation analysis using principal components analysis (PCA) and regression to demonstrate how the association between poverty and TB prevalence is mediated.

Results

The prevalence of self-reported TB in the 2006 DHS for India was 545 per 100,000 and ranged from 201 in the highest quintile to 1100 in the lowest quintile. Among those in the poorest population, the PAFs for low body mass index (BMI) and indoor air pollution were 34.2% and 28.5% respectively. The PCA analysis also showed that low BMI had the strongest mediating effect on the association between poverty and prevalent TB (12%, p = 0.019).

Conclusion

TB control strategies should be targeted to the poorest populations that are most at risk, and should address the most important determinants of disease—specifically low BMI and indoor air pollution.     

Are most species small? Not within species-level phylogenies.

The robust macro-ecological observation that there are more small-bodied species implies that small-bodied organisms have experienced elevated net rates of diversification. We investigate the role of body size in creating non-random differences in rates of cladogenesis using a set of 38 species-level phylogenies drawn from a range of animal groups. We use independent contrasts to explore the relationship between body size and species richness within individual phylogenies and across related sets of phylogenies. We also carry out a meta-analysis looking for associations between body size and species richness across the taxa. We find little evidence for increased cladogenesis among small-bodied organisms within taxa, and no evidence for any consistent differences between taxa. We explore possible explanations for the inconsistency of our findings with macro-ecological patterns.