Recent advances in obstructive sleep apnea pathophysiology and treatment

Obstructive sleep apnea (OSA) is a sleep disorder characterized by recurring collapse of the pharyngeal airway leading to restricted airflow. OSA is becoming increasingly common with at least moderate disease now evident in 17% of middle aged men and 9% of women. The list of recognized adverse health consequences associated with OSA is growing and includes daytime symptoms of sleepiness, impaired cognition and risk of motor vehicle accidents as well as associations with hypertension, cardiovascular morbidity, malignancy and all-cause mortality. In this context adequate treatment of OSA is imperative; however, there are well-recognized pitfalls in the uptake and usage of the standard treatment modality, Continuous Positive Airway Pressure (CPAP). A broad range of pathophysiological mechanisms are now recognized beyond an anatomically smaller pharyngeal airway and impaired compensatory pharyngeal muscle responsiveness. Perturbations in ventilatory control stability, low arousal threshold, sleep-related decrease in lung volume and fluid redistribution as well as upper airway surface tension have all been shown to variously contribute to sleep-disordered breathing. Many new therapies are emerging from these advances in understanding of the mechanisms of OSA. Although many may not be universally effective, the promise of phenotyping patients according to their individual pathophysiology in order to target one or more therapies may prove highly effective and allow the treatment of OSA towards a personalized medicine approach.

     

pH-Dependent entry of chikungunya virus fusion into mosquito cells

Background

Millions of human infections caused by arthropod-borne pathogens are initiated by the feeding of an infected mosquito on a vertebrate. However, interactions between the viruses and the mosquito vector, which facilitates successful infection and transmission of virus to a subsequent vertebrate host, are still not fully understood.

Finding

Here we describe early chikungunya virus (CHIKV) infectious events in cells derived from one of the most important CHIKV vectors, Aedes albopictus. We demonstrated that CHIKV infection of mosquito cells depended on acidification of the endosome as indicated by significant inhibition following prophylactic treatment with the lysosomotropic drugs chloroquine, ammonium chloride, and monensin, which is consistent with observations in mammalian cells. While all three agents inhibited CHIKV infection in C6/36 cells, ammonium chloride was less toxic to cells than the other agents.

Conclusion

The observation of similar mechanisms for inhibition of CHIKV infection in mosquito and mammalian cell lines suggests that conserved entry pathways are utilized by CHIKV for vertebrate and invertebrate cell types.

     

The effect of disease on human cardiac protein expression profiles in paired samples from right and left ventricles

Background

Cardiac diseases (e.g. coronary and valve) are associated with ventricular cellular remodeling. However, ventricular biopsies from left and right ventricles from patients with different pathologies are rare and thus little is known about disease-induced cellular remodeling in both sides of the heart and between different diseases. We hypothesized that the protein expression profiles between right and left ventricles of patients with aortic valve stenosis (AVS) and patients with coronary artery disease (CAD) are different and that the protein profile is different between the two diseases. Left and right ventricular biopsies were collected from patients with either CAD or AVS. The biopsies were processed for proteomic analysis using isobaric tandem mass tagging and analyzed by reverse phase nano-LC-MS/MS. Western blot for selected proteins showed strong correlation with proteomic analysis.

Results

Proteomic analysis between ventricles of the same disease (intra-disease) and between ventricles of different diseases (inter-disease) identified more than 500 proteins detected in all relevant ventricular biopsies. Comparison between ventricles and disease state was focused on proteins with relatively high fold (±1.2 fold difference) and significant (P < 0.05) differences. Intra-disease protein expression differences between left and right ventricles were largely structural for AVS patients and largely signaling/metabolism for CAD. Proteins commonly associated with hypertrophy were also different in the AVS group but with lower fold difference. Inter-disease differences between left ventricles of AVS and CAD were detected in 9 proteins. However, inter-disease differences between the right ventricles of CAD and AVS patients were associated with differences in 73 proteins. The majority of proteins which had a significant difference in one ventricle compared to the other pathology also had a similar trend in the adjacent ventricle.

Conclusions

This work demonstrates for the first time that left and right ventricles have a different proteome and that the difference is dependent on the type of disease. Inter-disease differential expression was more prominent for right ventricles. The finding that a protein change in one ventricle was often associated with a similar trend in the adjacent ventricle for a large number of proteins suggests cross-talk proteome remodeling between adjacent ventricles.     

Effects of BMI,Fat Mass,and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study

Background

Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.

Methods and Findings

We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m², p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.

Conclusions

Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors'' Summary     

Assessing Causality in the Association between Child Adiposity and Physical Activity Levels: A Mendelian Randomization Analysis

Background

Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose–response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects.

Methods and Findings

The Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity.In observational analysis, a 3.3 kg/m² (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6×10⁻¹⁶), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7×10⁻²⁹), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0×10⁻⁴). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (∼5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI.

Conclusions

Our results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase childhood activity levels. Importantly, this does not exclude lower physical activity also leading to increased adiposity, i.e., bidirectional causation. Please see later in the article for the Editors'' Summary