Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes

The challenge of comprehensively mapping children's health in a nation-wide health survey: Design of the German KiGGS-Study

<p>Abstract</p> <p>Background</p> <p>From May 2003 to May 2006, the Robert Koch Institute conducted the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Aim of this first nationwide interview and examination survey was to collect comprehensive data on the health status of children and adolescents aged 0 to 17 years.</p> <p>Methods/Design</p> <p>Participants were enrolled in two steps: first, 167 study locations (sample points) were chosen; second, subjects were randomly selected from the official registers of local residents. The survey involved questionnaires filled in by parents and parallel questionnaires for children aged 11 years and older, physical examinations and tests, and a computer assisted personal interview performed by study physicians. A wide range of blood and urine testing was carried out at central laboratories. A total of 17 641 children and adolescents were surveyed – 8985 boys and 8656 girls. The proportion of sample neutral drop-outs was 5.3%. The response rate was 66.6%.</p> <p>Discussion</p> <p>The response rate showed little variation between age groups and sexes, but marked variation between resident aliens and Germans, between inhabitants of cities with a population of 100 000 or more and sample points with fewer inhabitants, as well as between the old West German states and the former East German states. By analysing the short non-responder questionnaires it was proven that the collected data give comprehensive and nationally representative evidence on the health status of children and adolescents aged 0 to 17 years.</p

Influence of Miscibility of Protein-Sugar Lyophilizates on Their Storage Stability

For sugars to act as successful stabilizers of proteins during lyophilization and subsequent storage, they need to have several characteristics. One of them is that they need to be able to form interactions with the protein and for that miscibility is essential. To evaluate the influence of protein-sugar miscibility on protein storage stability, model protein IgG was lyophilized in the presence of various sugars of different molecular weight. By comparing solid-state nuclear magnetic resonance spectroscopy relaxation times of both protein and sugar on two different timescales, i.e., H-1 T-1 and H-1 T-1 rho, miscibility of the two components was established on a 2-5- and a 20-50-nm length scale, respectively, and related to protein storage stability. Smaller sugars showed better miscibility with IgG, and the tendency of IgG to aggregate during storage was lower for smaller sugars. The largest sugar performed worst and was phase separated on both length scales. Additionally, shorter protein H-1 T-1 relaxation times correlated with higher aggregation rates during storage. The enzyme-linked immunosorbent assay (ELISA) assay showed overlapping effects of aggregation and chemical degradation and did not correspond as well with the miscibility. Because of the small scale at which miscibility was determined (2-5 nm) and the size of the protein domains (similar to 2.5 x 2.5 x 5 nm), the miscibility data give an indirect measure of interaction between protein and sugar. This reduced interaction could be the result of steric hindrance, providing a possible explanation as to why smaller sugars show better miscibility and storage stability with the protein

Three-dimensional cometary dust coma modelling in the collisionless regime: strengths and weaknesses

Inverse coma and tail modelling of comets based on the method developed by Finson & Probstein is commonly used to analyse cometary coma images. Models of this type often contain a large number of assumptions that may not be constrained unless wide temporal or spectral coverage is available and the comets are bright and at relatively small geocentric distance. They are used to predict physical parameters, such as the mass distribution of the dust, but rarely give assessments of the accuracy of the estimate. A three-dimensional cometary dust coma model in the collisionless regime has been developed to allow the effectiveness of such models to constrain dust coma properties to be tested. The model is capable of simulating the coma morphology for the following input parameters: the comet nucleus shape, size, rotation, emission function (including active fraction and jets), grain velocity distribution (and dispersion), size distribution, dust production rate, grain material and light scattering from the cometary dust. Characterization of the model demonstrates that the mass distribution cannot be well constrained as is often assumed; the cumulative mass distribution index ? can only be constrained to within ±0.15. The model is highly sensitive to the input grain terminal velocity distribution so model input can be tested with a large degree of confidence. Complex secondary parameters such as jets, rotation and grain composition all have an effect on the structure of the coma in similar ways, so unique solutions for these parameters cannot be derived from a single optical image alone. Multiple images at a variety of geometries close in time can help constrain these effects. The model has been applied to photometric observations of comets 126P/IRAS and 46P/Wirtanen to constrain a number of physical properties including the dust production rate and mass distribution index. The derived dust production rate (Qdust) for 46P/Wirtanen was 3+7/1.5 kg s1 at a pre-perihelion heliocentric distance of 1.8 au, and for P/IRAS was 50+100/20 kg s1 at a pre-perihelion heliocentric distance of 1.7 au; both comets exhibited a mass distribution index ? = 0.8 ± 0.15

Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium

Source at http://doi.org/10.1371/journal.pone.0170791Background:Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality.Methods:In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488.Findings:We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and Interpretation:In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths

Beef in an Optimal Lean Diet study: effects on lipids, lipoproteins, and apolipoproteins123

Background: A Step I diet with lean beef compared with lean white meat both decrease LDL cholesterol. To our knowledge, no studies have evaluated a low–saturated fatty acid (SFA) (<7% calories) diet that contains lean beef

Evaluation of a health promotion program in children: Study protocol and design of the cluster-randomized Baden-Württemberg primary school study [DRKS-ID: DRKS00000494]

<p>Abstract</p> <p>Background</p> <p>Increasing prevalences of overweight and obesity in children are known problems in industrialized countries. Early prevention is important as overweight and obesity persist over time and are related with health problems later in adulthood. "Komm mit in das gesunde Boot - Grundschule" is a school-based program to promote a healthier lifestyle. Main goals of the intervention are to increase physical activity, decrease the consumption of sugar-sweetened beverages, and to decrease time spent sedentary by promoting active choices for healthy lifestyle. The program to date is distributed by 34 project delivery consultants in the state of Baden-Württemberg and is currently implemented in 427 primary schools. The efficacy of this large scale intervention is examined via the Baden-Württemberg Study.</p> <p>Methods/Design</p> <p>The Baden-Württemberg Study is a prospective, stratified, cluster-randomized, and longitudinal study with two groups (intervention group and control group). Measurements were taken at the beginning of the academic years 2010/2011 and 2011/2012. Efficacy of the intervention is being assessed using three main outcomes: changes in waist circumference, skinfold thickness and 6 minutes run. Stratified cluster-randomization (according to class grade level) was performed for primary schools; pupils, teachers/principals, and parents were investigated. An approximately balanced number of classes in intervention group and control group could be reached by stratified randomization and was maintained at follow-up.</p> <p>Discussion</p> <p>At present, "Komm mit in das Gesunde Boot - Grundschule" is the largest school-based health promotion program in Germany. Comparative objective main outcomes are used for the evaluation of efficacy. Simulations showed sufficient power with the existing sample size. Therefore, the results will show whether the promotion of a healthier lifestyle in primary school children is possible using a relatively low effort within a school-based program involving children, teachers and parents. The research team anticipates that not only efficacy will be proven in this study but also expects many other positive effects of the program.</p> <p>Trial registration</p> <p>German Clinical Trials Register (DRKS), DRKS-ID: DRKS00000494</p