Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication

Microdeletions encompassing 14q11.2 locus, involving SUPT16H and CHD8, were shown to cause developmental delay, intellectual disability, autism spectrum disorders and macrocephaly. Variations leading to CHD8 haploinsufficiency or loss of function were also shown to lead to a similar phenotype. Recently, a 14q11.2 microduplication syndrome, encompassing CHD8 and SUPT16H, has been described, highlighting the importance of a tight control of at least CHD8 gene-dosage for a normal development. There have been only a few reports of 14q11.2 microduplications. Patients showed variable neurodevelopmental issues of variable severity. Breakpoints of the microduplications were non-recurrent, making interpretation of the CNV and determination of their clinical relevance difficult. Here, we report on two patients with 14q11.2 microduplication encompassing CHD8 and SUPT16H, one of whom had normal intelligence. Review of previous reports describing patients with comparable microduplications allowed for a more precise delineation of the condition and widening of the phenotypic spectrum.

     

African-American Adolescents’ Weight Loss Skills Utilization: Effects on Weight Change in a Sequential Multiple Assignment Randomized Trial

Objective

Successful weight loss interventions for African-Americans adolescents are lacking. Cognitive-behavioral interventions seek to develop weight loss skills (e.g., counting calories, goal setting, managing one's environment). Little is known about how well adolescents implement such skills in their daily lives. Study aims were to (1) examine weight loss skills utilization at midpoint and end of a 6-month cognitive-behavioral/motivational interviewing weight loss sequential multiple assignment randomized trial (SMART), and (2) determine if greater skill utilization predicted weight loss at treatment end and 3 months post-treatment.

Genotoxicity of synthetic amorphous silica nanoparticles in rats following short‐term exposure. Part 1: Oral route

Synthetic amorphous silica (SAS) in its nanosized form is now used in food applications although the potential risks for human health have not been evaluated. In this study, genotoxicity and oxidative DNA damage of two pyrogenic (NM‐202 and 203) and two precipitated (NM‐200 and ‐201) nanosized SAS were investigated in vivo in rats following oral exposure. Male Sprague Dawley rats were exposed to 5, 10, or 20 mg/kg b.w./day for three days by gavage. DNA strand breaks and oxidative DNA damage were investigated in seven tissues (blood, bone marrow from femur, liver, spleen, kidney, duodenum, and colon) with the alkaline and the (Fpg)‐modified comet assays, respectively. Concomitantly, chromosomal damage was investigated in bone marrow and in colon with the micronucleus assay. Additionally, malondialdehyde (MDA), a lipid peroxidation marker, was measured in plasma. When required, a histopathological examination was also conducted. The results showed neither obvious DNA strand breaks nor oxidative damage with the comet assay, irrespective of the dose and the organ investigated. Similarly, no increases in chromosome damage in bone marrow or lipid peroxidation in plasma were detected. However, although the response was not dose‐dependent, a weak increase in the percentage of micronucleated cells was observed in the colon of rats treated with the two pyrogenic SAS at the lowest dose (5 mg/kg b.w./day). Additional data are required to confirm this result, considering in particular, the role of agglomeration/aggregation of SAS NMs in their uptake by intestinal cells. Environ. Mol. Mutagen. 56:218–227, 2015. © 2014 Wiley Periodicals, Inc.     

Antidepressant and other centrally acting drugs regulate glucocorticoid receptor messenger RNA levels in rat brain

The effect of imipramine, desipramine, ketanserin and lithium on Type II glucocorticoid receptor (GR) mRNA levels was studied in rat brain regions involved in the control of the hypothalamo-pituitary-adrenal (HPA) axis, the dysregulation of which has been implicated in the pathophysiology of major depression. Northern blot analysis of Type II GR mRNA showed that treatment of male rats with either desipramine or imipramine increased hypothalamic and hippocampal GR mRNA levels. Upregulation of GR mRNA following administration of imipramine was found in brain regions of female rats, while desipramine had no effect. Ketanserin increased levels of GR mRNA in hippocampus of male, but not female, rats. Lithium also was able to induce important increases rat brain GR mRNA; this effect was particularly marked in females.

We conclude that desipramine, imipramine, ketanserin and lithium can modulate GR mRNA in regions of rat brain involved in the control of the HPA axis and may have a common mechanism of action at the level of the GR gene. Sexual dimorphism for drug regulation of brain GR mRNA content was shown and may be related to sex differences in the prevalence of certain affective disorders.     

Fisher information matrix for nonlinear mixed effects multiple response models: Evaluation of the appropriateness of the first order linearization using a pharmacokinetic/pharmacodynamic model

We focus on the Fisher information matrix used for design evaluation and optimization in nonlinear mixed effects multiple response models. We evaluate the appropriateness of its expression computed by linearization as proposed for a single response model. Using a pharmacokinetic–pharmacodynamic (PKPD) example, we first compare the computation of the Fisher information matrix with approximation to one derived from the observed matrix on a large simulation using the stochastic approximation expectation–maximization algorithm (SAEM). The expression of the Fisher information matrix for multiple responses is also evaluated by comparison with the empirical information obtained through a replicated simulation study using the first‐order linearization estimation methods implemented in the NONMEM software (first‐order (FO), first‐order conditional estimate (FOCE)) and the SAEM algorithm in the MONOLIX software. The predicted errors given by the approximated information matrix are close to those given by the information matrix obtained without linearization using SAEM and to the empirical ones obtained with FOCE and SAEM. The simulation study also illustrates the accuracy of both FOCE and SAEM estimation algorithms when jointly modelling multiple responses and the major limitations of the FO method. This study highlights the appropriateness of the approximated Fisher information matrix for multiple responses, which is implemented in PFIM 3.0, an extension of the R function PFIM dedicated to design evaluation and optimization. It also emphasizes the use of this computing tool for designing population multiple response studies, as for instance in PKPD studies or in PK studies including the modelling of the PK of a drug and its active metabolite. Copyright © 2009 John Wiley & Sons, Ltd.     

Dynamics of bacterial hand contamination during routine neonatal care.

OBJECTIVE: To evaluate the dynamics of bacterial contamination of healthcare workers' (HCWs) hands during neonatal care. SETTING: The 20-bed neonatal unit of a large acute care teaching hospital in Geneva, Switzerland. METHODS: Structured observation sessions were conducted. A sequence of care began when the HCW performed hand hygiene and ended when the activity changed or hand hygiene was performed again. Alcohol-based handrub was the standard procedure for hand hygiene. An imprint of the five fingertips of the dominant hand was obtained before and after hand hygiene and at the end of a sequence of care. Regression methods were used to model the final bacterial count according to the type and duration of care and the use of gloves. RESULTS: One hundred forty-nine sequences of care were observed. Commensal skin flora comprised 72.4% of all culture-positive specimens (n = 360). Other microorganisms identified were Enterobacteriaceae (n = 55, 13.8%); Staphylococcus aureus (n = 10, 2.5%); and fungi (n = 7, 1.8%). Skin contact, respiratory care, and diaper change were independently associated with an increased bacterial count; the use of gloves did not fully protect HCWs' hands from bacterial contamination. CONCLUSIONS: These data confirm that hands become progressively contaminated with commensal flora and potential pathogens during neonatal care, and identify activities at higher risk for hand contamination. They also reinforce the need for hand hygiene after a sequence of care, before starting a different task, and after glove removal.     

Polymères thiocarboxyliques, 5. Synthèse de poly(oxyéthylène)s à fonction dithioester terminale. Application au traitement de cellules d'électrophorèse

Poly(oxyethylene)s with dithioster end groups were obtained from mono- and dihydroxyl terminated commercial polymers by reaction with dimethyl chloroacetamide, subsequent thionation of the amide group, and usual conversion of the thioamides into the dithioesters 14, 15 and 20, 21 . The best results were obtained in the syntheses of the S-carboxymethyl dithioesters ( 15 and 21 ). The resulting reactive poly(oxyethylene)s were grafted upon silica tubes and electrophoresis cells, previously activated by aminopropylsilanization. These graftings result in lowering of the surface potential of the tubes and in suppression of the electro-osmosis flow in an electrophoresis cell tested with a TiO₂ standard sample.     

Features of the metabolic syndrome of "hypertriglyceridemic waist" and transplant coronary artery disease.

BACKGROUND: This study evaluated the prevalence of the atherogenic metabolic triad and the hypothesis that waist circumference and fasting triglyceride concentrations could be used as screening tools for identification of the atherogenic metabolic triad in a population of heart transplant men. It also evaluated the relationship between the atherogenic metabolic triad and coronary artery disease (CAD). METHODS: In the study group of 83 consecutive male heart transplant patients having their routine annual coronarography, 23 patients (28%) were characterized by the atherogenic metabolic triad defined by the presence of elevated fasting insulin and apolipoprotein B concentrations and by small low-density lipoprotein (LDL) particles. RESULTS: Seventy-seven per cent of patients with waist circumference values >/= 90 cm and with elevated triglyceride levels (>/=2.0 mmol/liter) were characterized by this atherogenic metabolic triad. Patients with the atherogenic metabolic triad were at markedly increased risk of CAD (odds ratio of 25.3, 95% CI: 1.11-577.3, p < 0.04) compared to heart transplant patients without the atherogenic metabolic triad. CONCLUSIONS: About 30% of heart transplant patients showed the features of the atherogenic metabolic triad. Measurement and interpretation of waist circumference and fasting triglycerides could be used among heart transplant patients to early identify men characterized by the presence of elevated fasting insulin and apolipoprotein B concentrations and small LDL particles. The presence of the atherogenic metabolic triad identified patients at high risk of CAD even in the heart transplant population.