Autistic behavior in boys with fragile X syndrome: social approach and HPA-axis dysfunction

The primary goal of this study was to examine environmental and neuroendocrine factors that convey increased risk for elevated autistic behavior in boys with Fragile X syndrome (FXS). This study involves three related analyses: (1) examination of multiple dimensions of social approach behaviors and how they vary over time, (2) investigation of mean levels and modulation of salivary cortisol levels in response to social interaction, and (3) examination of the relationship of social approach and autistic behaviors to salivary cortisol. Poor social approach and elevated baseline and regulation cortisol are discernible traits that distinguish boys with FXS and ASD from boys with FXS only and from typically developing boys. In addition, blunted cortisol change is associated with increased severity of autistic behaviors only within the FXS and ASD group. Boys with FXS and ASD have distinct behavioral and neuroendocrine profiles that differentiate them from those with FXS alone and typically developing boys

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

Nitric oxide sustains IL-1β expression in human dendritic cells enhancing their capacity to induce IL-17-producing T-cells

The role played by lung dendritic cells (DCs) which are influenced by external antigens and by their redox state in controlling inflammation is unclear. We studied the role played by nitric oxide (NO) in DC maturation and function. Human DCs were stimulated with a long-acting NO donor, DPTA NONOate, prior to exposure to lipopolysaccharide (LPS). Dose-and time-dependent experiments were performed with DCs with the aim of measuring the release and gene expression of inflammatory cytokines capable of modifying T-cell differentiation, towardsTh1, Th2 and Th17 cells. NO changed the pattern of cytokine release by LPS-matured DCs, dependent on the concentration of NO, as well as on the timing of its addition to the cells during maturation. Addition of NO before LPS-induced maturation strongly inhibited the release of IL-12, while increasing the expression and release of IL-23, IL-1β and IL-6, which are all involved in Th17 polarization. Indeed, DCs treated with NO efficiently induced the release of IL-17 by T-cells through IL-1β. Our work highlights the important role that NO may play in sustaining inflammation during an infection through the preferential differentiation of the Th17 lineage

Epidemiology of multimorbidity in China and implications for the healthcare system: cross-sectional survey among 162,464 community household residents in southern China

<b>Background</b> China, like other countries, is facing a growing burden of chronic disease but the prevalence of multimorbidity and implications for the healthcare system have been little researched. We examined the epidemiology of multimorbidity in southern China in a large representative sample. The effects of multimorbidity and other factors on usual source of healthcare were also examined. <p></p> <b>Methods</b> We conducted a large cross-sectional survey among approximately 5% (N = 162,464) of the resident population in three prefectures in Guangdong province, southern China in 2011. A multistage, stratified random sampling was adopted. The study population had many similar characteristics to the national census population. Interviewer-administered questionnaires were used to collect self-report data on demographics, socio-economics, lifestyles, healthcare use, and health characteristics from paper-based medical reports. <p></p> <b>Results</b> More than one in ten of the total study population (11.1%, 95% confidence interval (CI) 10.6 to 11.6) had two or more chronic conditions from a selection of 40 morbidities. The prevalence of multimorbidity increased with age (adjusted odds ratio (aOR) = 1.36, 95% CI 1.35 to 1.38 per five years). Female gender (aOR = 1.70, 95% CI 1.64 to 1.76), low education (aOR = 1.26, 95% CI 1.23 to 1.29), lack of medical insurance (aOR = 1.79, 95% CI 1.71 to 1.89), and unhealthy lifestyle behaviours were independent predictors of multimorbidity. Multimorbidity was associated with the regular use of secondary outpatient care in preference to primary care. <p></p> <b>Conclusions</b> Multimorbidity is now common in China. The reported preferential use of secondary care over primary care by patients with multimorbidity has many major implications. There is an urgent need to further develop a strong and equitable primary care system