Changing the perspective on early development of Rett syndrome

We delineated the achievement of early speech-language milestones in 15 young children with Rett syndrome (MECP2 positive) in the first two years of life using retrospective video analysis. By contrast to the commonly accepted concept that these children are normal in the pre-regression period, we found markedly atypical development of speech-language capacities, suggesting a paradigm shift in the pathogenesis of Rett syndrome and a possible approach to its early detection.     

Early socio-communicative forms and functions in typical Rett syndrome

Rett syndrome (RTT) is a severe neurological disorder characterized by a developmental regression in motor and speech-language domains. There is, however, limited research on socio-communicative development of affected children before the onset of regression. We analyzed audio–video recordings made by parents of six 9- to 12-month old girls later diagnosed with typical RTT, applying the Inventory of Potential Communicative Acts (IPCA) to identify early communicative forms and functions. Each girl used at least one communicative form (e.g., body movement, eye gaze, or vocalizations) to gain attention and answer, but none were observed to make choices or request information. Varying numbers of children were observed to perform other communicative functions according to the IPCA including social convention, rejecting or requesting an object. Non-verbal forms (e.g., reaching, moving closer, eye contact, smiling) were more common than non-linguistic verbal forms (e.g., unspecified vocalizations, pleasure vocalizations, crying). (Pre-)linguistic verbal forms (e.g., canonical or variegated babbling, proto-words) were not used for communicative purposes. These data suggest that atypical developmental patterns in the socio-communicative domain are evident prior to regression in young individuals later diagnosed with RTT.     

The use of liquid latex for detecting traces of blood following thermal exposure

International Journal of Legal Medicine - In cases of crimes involving blood, the perpetrators often attempt to remove the traces they have left behind. Setting fire to the crime scene, aside from...     

Hearing protector fit testing with off-shore oil-rig inspectors in Louisiana and Texas

Objective: This field study aimed to assess the noise reduction of hearing protection for individual workers, demonstrate the effectiveness of training on the level of protection achieved, and measure the time required to implement hearing protector fit testing in the workplace. Design: The National Institute for Occupational Safety and Health (NIOSH) conducted field studies in Louisiana and Texas to test the performance of HPD Well-Fit. Study sample: Fit tests were performed on 126 inspectors and engineers working in the offshore oil industry. Results: Workers were fit tested with the goal of achieving a 25-dB PAR. Less than half of the workers were achieving sufficient protection from their hearing protectors prior to NIOSH intervention and training; following re-fitting and re-training, over 85% of the workers achieved sufficient protection. Typical test times were 6–12?minutes. Conclusions: Fit testing of the workers’ earplugs identified those workers who were and were not achieving the desired level of protection. Recommendations for other hearing protection solutions were made for workers who could not achieve the target PAR. The study demonstrates the need for individual hearing protector fit testing and addresses some of the barriers to implementation.     

BURDEN 2020—Burden of disease in Germany at the national and regional level

Background

Evidence-based policy measures need non-interest-guided information about the health status of a population and the diseases that affect the population the most. In such cases, a national burden of disease study can provide reliable insights at the regional level.

Aim

This article presents the potential of the BURDEN 2020 project and its expected outcome for Germany at the national and regional level.

Methods

The BURDEN 2020 project uses several indicators including years of life lost (YLL) to cover the impact of mortality and years lived with disability (YLD) to cover morbidity. The sum of both is the measure of population health called disability adjusted life years (DALY).

Results

The study ranks individual diseases and risk factors based on their impact on population health. The burden of disease approach is assumed to be sensitive to subnational differences and may generate immediate benefits for regional planning. The BURDEN 2020 study will pilot a national burden of disease study for Germany that will later be transformed into a continuous data processing and visualization tool. This is done by using, modifying and supplementing the methodology employed by the Global Burden of Disease (GBD) study to better fit the needs of health policy in Germany. This study is aimed at calculating the disease burden for up to 17 preselected diseases. Furthermore, the estimates of burden of disease are attributed to a selected set of risk factors.

Conclusion

The Burden 2020 study will provide the results of a new, health-related data processing system to the public. This includes a noninterest-guided presentation of the burden of disease (DALY) in Germany at the national and regional level.

     

Domains for activation and inactivation in G protein-coupled receptors – A mutational analysis of constitutive activity of the adenosine A2B receptor

G protein-coupled receptors (GPCRs) are a major drug target and can be activated by a range of stimuli, from photons to proteins. Most, if not all, GPCRs also display a basal level of biological response in the absence of such a stimulus. This level of so-called constitutive activity results from a delicate energy equilibrium that exists between the active and the inactive state of the receptor and is the first determinant in the GPCR activation mechanism. Here we describe new insights in specific regions of the adenosine A_2B receptor that are essential in activation and inactivation. We developed a new screening method using the MMY24 S. Cerevisiae strain by which we were able to screen for constitutively inactive mutants receptors (CIMs). We applied this screening method on a mutagenic library of the adenosine A_2B receptor, where random mutations were introduced in transmembrane domains four and five (TM4 and TM5) linked by extracellular loop 2 (EL2). The screen resulted in the identification of 22 single and double mutant receptors, all showing a decrease in constitutive activity as well as in agonist potency. By comparing these results with a previous screen of the same mutagenic library for constitutively active mutant receptors (CAMs), we discovered specific regions in this G protein-coupled receptor involved in either inactivation or activation or both. The results suggest the activation mechanism of GPCRs to be much less restricted to sites of high conservation or direct interaction with the ligand or G protein and illustrate how dynamic the activation process of GPCRs is.     

Effects of oral cisapride on interdigestive jejunal motor activity,psychomotor function,and side-effect profile in healthy man

Intravenous cisapride was shown to induce a phase-2-like pattern of human interdigestive jejunal motor activity containing an increased number of propagated contractions. This study investigated the effects of oral cisapride in 12 fasting healthy males. Jejunal pressures were recorded by a pneumohydraulic system and five catheter orifices positioned 10–30 cm aborad the ligament of Treitz. Single oral doses of 5 and 10mg cisapride, administered 5 min after an activity front under random double-blind conditions, induced a phase-2-like jejunal motor pattern with a significantly higher number and amplitude of contractions and significantly more aborally propagated waves than placebo (P<0.001), while the number of subjects with activity fronts decreased with increasing dose. Five and 10mg cisapride administered tid for three days affected psychomotor function, subjective feelings, and side-effect frequency, apart from increases in systolic blood pressure and heart rate, no more than placebo. It is concluded that in fasting man, oral cisapride induces a highly propagative phase-2-like jejunal motor pattern causing only minor side effects.     

Low dose aspirin is associated with plasma chemerin levels and may reduce adipose tissue inflammation

Chemerin is a peptide chemoattractant for macrophages and an adipokine regulating adipocyte differentiation and metabolism. Plasma chemerin is increased in chronic inflammatory diseases and in obesity. As inflammation and obesity are risk factors for coronary artery disease (CAD), we investigated possible associations of plasma chemerin with inflammatory markers and atherosclerosis in a CAD case–control study (n = 470). Chemerin levels were associated with C-reactive protein, BMI and LDL levels, and negatively associated with HDL levels. Mean plasma chemerin levels were similar in controls and CAD patients but significantly higher in CAD patients not taking low dose aspirin. To investigate the mechanism of chemerin reduction by aspirin, we analyzed chemerin expression in hepatocytes and adipocytes treated with aspirin in the presence and absence of inflammatory cytokines. Chemerin expression was upregulated by pro-inflammatory stimuli in adipocytes but not in hepatocytes. Treatment of stimulated hepatocytes and adipocytes with aspirin did not affect chemerin expression. However, treatment of inflammatory M1 macrophages with aspirin reduced secretion of the pro-inflammatory cytokines IL-1β and IL-6, and increased secretion of the anti-inflammatory IL-10. In summary, we show that plasma chemerin levels are associated with markers of inflammation and that they are significantly higher in CAD patients not treated with low dose aspirin. In addition, we show that low dose aspirin treatment reduces pro-inflammatory cytokine secretion by macrophages, which may lead to reduced chemerin secretion by adipocytes and may be a reason for the lower chemerin levels in the circulation of CAD patients on low dose aspirin.