Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity.

Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans1-3. Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity4,5. ADCY3 localizes to the primary cilia of neurons 6 , organelles that function as hubs for select signaling pathways. Mutations that disrupt the functions of primary cilia cause ciliopathies, rare recessive pleiotropic diseases in which obesity is a cardinal manifestation 7 . We demonstrate that MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons, that obesity-associated MC4R mutations impair ciliary localization and that inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight. These data suggest that impaired signaling from the primary cilia of MC4R neurons is a common pathway underlying genetic causes of obesity in humans

Age at menarche and the menstrual pattern of secondary school adolescents in northwest Ethiopia

<p>Abstract</p> <p>Background</p> <p>Population studies on normal and dysfunctional characteristics of menstrual cycles are scarce in Ethiopia. In addition variability in menarcheal age and menstrual characteristics are common. Knowledge on this variability is necessary for patient education and to guide clinical evaluation.</p> <p>Methods</p> <p>A cross sectional study was conducted in two small towns called Dabat and Kola Diba, northwest Ethiopia between April and May 2007. Systematic sampling method was used to select 622 school girls from two secondary schools. A pretested questionnaire prepared in Amharic was used to gather data. Selected girls cooperated in answering the questionnaire in their classrooms under the supervision of the research team. Only 612 of the adolescent females were included in the final analysis, of which 305 were from Koladiba High School and 307 from Dabat.</p> <p>Results</p> <p>The age of the study subjects ranges between 14 and 19 with a mean (standard deviation) of 16.9 ± 1 years. About 92.2% had attained menarche by the time the survey was conducted. The probit analysis of the <it>status quo </it>data yielded a median (CI) age at menarche of 14.8 (13.9-15.3) years. The average age at menarche by recall method was 15.8 ± 1 years. The mean age at menarche was 0.3 years younger for urban females compared with rural ones (p < 0.001). A cycle length between 21 and 35 days was observed in 70.3% of the girls. The mean duration of flow was 4 ± 1.3 days with a range of 2-7 days. The menstrual cycles were irregular in 42.8% of the subjects. The overall prevalence of dysmenorrhoea was 72% among these subjects. Premenstrual symptoms were present in 435 of the females (75.4%). The leading sources of menarcheal information to the adolescents were mothers (39.7%), followed by their friends (26.6%) and teachers (21.8%).</p> <p>Conclusion</p> <p>In this study age of menarche was found to be delayed which is even higher than the findings indicated similar studies conducted in Ethiopia and other African countries. A significant number of students complain of abnormal menstrual cycle, dysmenorrhoea and premenstrual symptoms which call for appropriate counselling and management.</p

OPERATIONS RESEARCH PROCEEDINGS 2011

This study is an empirical analysis of the productive efficiency of public forestry firms in Switzerland. Because of the available database, the period under examination extends from 1998 to 2006, and is based on a balanced panel of 100 firms. We inquire whether public subsidies exert any significant impact on the efficiency of these firms. In order to determine the productive efficiency, a nonparametric method (DEA) is applied. Panel unit root tests and panel cointegration technique are employed to establish the long-run relationship between efficiency and selected variables. Results show that subsidies had a positive influence on technical efficiency

Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in pa-tatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepa-tocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericel-lular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases