Dual oscillator model of the respiratory neuronal network generating quantal slowing of respiratory rhythm

We developed a dual oscillator model to facilitate the understanding of dynamic interactions between the parafacial respiratory group (pFRG) and the preBötzinger complex (preBötC) neurons in the respiratory rhythm generation. Both neuronal groups were modeled as groups of 81 interconnected pacemaker neurons; the bursting cell model described by Butera and others [model 1 in Butera et al. (J Neurophysiol 81:382–397, 1999a)] were used to model the pacemaker neurons. We assumed (1) both pFRG and preBötC networks are rhythm generators, (2) preBötC receives excitatory inputs from pFRG, and pFRG receives inhibitory inputs from preBötC, and (3) persistent Na+ current conductance and synaptic current conductances are randomly distributed within each population. Our model could reproduce 1:1 coupling of bursting rhythms between pFRG and preBötC with the characteristic biphasic firing pattern of pFRG neurons, i.e., firings during pre-inspiratory and post-inspiratory phases. Compatible with experimental results, the model predicted the changes in firing pattern of pFRG neurons from biphasic expiratory to monophasic inspiratory, synchronous with preBötC neurons. Quantal slowing, a phenomena of prolonged respiratory period that jumps non-deterministically to integer multiples of the control period, was observed when the excitability of preBötC network decreased while strengths of synaptic connections between the two groups remained unchanged, suggesting that, in contrast to the earlier suggestions (Mellen et al., Neuron 37:821–826, 2003; Wittmeier et al., Proc Natl Acad Sci USA 105(46):18000–18005, 2008), quantal slowing could occur without suppressed or stochastic excitatory synaptic transmission. With a reduced excitability of preBötC network, the breakdown of synchronous bursting of preBötC neurons was predicted by simulation. We suggest that quantal slowing could result from a breakdown of synchronized bursting within the preBötC

Scaled deployment of Wolbachia to protect the community from dengue and other Aedes transmitted arboviruses.

Background: A number of new technologies are under development for the control of mosquito transmitted viruses, such as dengue, chikungunya and Zika that all require the release of modified mosquitoes into the environment. None of these technologies has been able to demonstrate evidence that they can be implemented at a scale beyond small pilots. Here we report the first successful citywide scaled deployment of Wolbachia in the northern Australian city of Townsville. Methods: The wMel strain of Wolbachia was backcrossed into a local Aedes aegypti genotype and mass reared mosquitoes were deployed as eggs using mosquito release containers (MRCs). In initial stages these releases were undertaken by program staff but in later stages this was replaced by direct community release including the development of a school program that saw children undertake releases. Mosquito monitoring was undertaken with Biogents Sentinel (BGS) traps and individual mosquitoes were screened for the presence of Wolbachia with a Taqman qPCR or LAMP diagnostic assay. Dengue case notifications from Queensland Health Communicable Disease Branch were used to track dengue cases in the city before and after release. Results: Wolbachia was successfully established into local Ae. aegypti mosquitoes across 66 km 2 in four stages over 28 months with full community support.  A feature of the program was the development of a scaled approach to community engagement. Wolbachia frequencies have remained stable since deployment and to date no local dengue transmission has been confirmed in any area of Townsville after Wolbachia has established, despite local transmission events every year for the prior 13 years and an epidemiological context of increasing imported cases. Conclusion: Deployment of Wolbachia into Ae. aegypti populations can be readily scaled to areas of ~60km 2 quickly and cost effectively and appears in this context to be effective at stopping local dengue transmission

Physical activity, obesity and cardiometabolic risk factors in 9- to 10-year-old UK children of white European, South Asian and black African-Caribbean origin: the Child Heart And health Study in England (CHASE)

Physical inactivity is implicated in unfavourable patterns of obesity and cardiometabolic risk in childhood. However, few studies have quantified these associations using objective physical activity measurements in children from different ethnic groups. We examined these associations in UK children of South Asian, black African-Caribbean and white European origin. This was a cross-sectional study of 2,049 primary school children in three UK cities, who had standardised anthropometric measurements, provided fasting blood samples and wore activity monitors for up to 7 days. Data were analysed using multilevel linear regression and allowing for measurement error. Overall physical activity levels showed strong inverse graded associations with adiposity markers (particularly sum of skinfold thicknesses), fasting insulin, HOMA insulin resistance, triacylglycerol and C-reactive protein; for an increase of 100 counts of physical activity per min of registered time, levels of these factors were 12.2% (95% CI 10.2-14.1%), 10.2% (95% CI 7.5-12.8%), 10.2% (95% CI 7.5-12.8%), 5.8% (95% CI 4.0-7.5%) and 19.2% (95% CI 13.9-24.2%) lower, respectively. Similar increments in physical activity levels were associated with lower diastolic blood pressure (1.0 mmHg, 95% CI 0.6-1.5 mmHg) and LDL-cholesterol (0.04 mmol/l, 95% CI 0.01-0.07 mmol/l), and higher HDL-cholesterol (0.02 mmol/l, 95% CI 0.01-0.04 mmol/l). Moreover, associations were broadly similar in strength in all ethnic groups. All associations between physical activity and cardiometabolic risk factors were reduced (albeit variably) after adjustment for adiposity. Objectively measured physical activity correlates at least as well with obesity and cardiometabolic risk factors in South Asian and African-Caribbean children as in white European children, suggesting that efforts to increase activity levels in such groups would have equally beneficial effect

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Cardiorespiratory fitness and adiposity in metabolically healthy overweight and obese youth

OBJECTIVE: Controversy exists surrounding the contribution of fitness and adiposity as determinants of the Metabolically Healthy Overweight (MHO) phenotype in youth. This study investigated the independent contribution of cardiorespiratory fitness and adiposity to the MHO phenotype among overweight and obese youth. METHODS: This cross-sectional study included 108 overweight and obese youth classified as MHO (no cardiometabolic risk factors) or non-MHO ($1 cardiometabolic risk factor), based on age- and genderspecific cut-points for fasting glucose, triglycerides, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and hepatic steatosis. RESULTS: Twenty-five percent of overweight and obese youth were classified as MHO. This phenotype was associated with lower BMI z-score (BMI z-score: 1.8 \ub1 0.3 vs 2.1 \ub1 0.4, P = .02) and waist circumference (99.7 \ub1 13.2 vs 106.1 \ub1 13.7 cm, P = .04) compared with non-MHO youth. When matched for fitness level and stratified by BMI z-score (1.6 \ub1 0.3 vs 2.4 \ub1 0.2), the prevalence of MHO was fourfold higher in the low BMI z-score group (27% vs 7%; P = .03). Multiple logistic regression analyses revealed that the best predictor of MHO was the absence of hepatic steatosis even after adjusting for waist circumference (odds ratio 0.57, 95% confidence interval 0.40- 0.80) or BMI z-score (odds ratio 0.59, 95% confidence interval 0.43- 0.80). CONCLUSIONS: The MHO phenotype was present in 25% of overweight and obese youth and is strongly associated with lower levels of adiposity, and the absence of hepatic steatosis, but not with cardiorespiratory fitness. Pediatrics 2013;132:e85-e92. Copyright \ua9 2013 by the American Academy of Pediatrics.Peer reviewed: YesNRC publication: Ye

Declines in Physical Activity and Higher Systolic Blood Pressure in Adolescence

The authors examined the potential association between changes in the number of moderate-to-vigorous physical activity (MVPA) sessions per week, adiposity, and systolic blood pressure (SBP) during adolescence. SBP and anthropometric factors were assessed biannually (1999/2000, 2002, and 2004) in a cohort of 1,293 Canadian adolescents aged 12-13 years in 1999. Self-reported 7-day recall data on MVPA sessions >or=5 minutes in duration were collected every 3 months over the 5-year period. Estimates of initial level and rate of decline in number of MVPA sessions per week from individual growth models were used as predictors of SBP in linear regression models. A decline of 1 MVPA session per week with each year of age was associated with 0.29-mm Hg and 0.19-mm Hg higher SBPs in girls and boys, respectively, in early adolescence (ages 12.8-15.1 years) and 0.40-mm Hg and 0.18-mm Hg higher SBPs, respectively, in late adolescence (ages 15.2-17.0 years). The associations were not attenuated by changes in body mass index, waist circumference, or skinfold thickness in girls during late adolescence. Although weaker, associations were evident in boys during late adolescence, as well as in both girls and boys during early adolescence. These results support prevention of declines in MVPA during adolescence to prevent higher blood pressure in youth.Katerina Maximova, Jennifer O’Loughlin, Gilles Paradis, James A. Hanley, and John Lync