Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms

Mutations in the melanocortin-4 receptor gene (MC4R) represent the commonest monogenic cause of human obesity. However, information regarding the precise effects of such mutations on receptor function is very limited. We examined the functional properties of 12 different mutations in human MC4R that result in severe, familial, early-onset obesity. Of the nine missense mutants studied, four were completely unable to generate cAMP in response to ligand and five were partially impaired. Four showed evidence of impaired cell surface expression and six of reduced binding affinity for ligand. One mutation in the C-terminal tail, I316S, showed reduced affinity for alpha-MSH but retained normal affinity for the antagonist AgRP. None of the mutations inhibited signaling through co-transfected wild-type receptors. Thus, in the most comprehensive study to date of the functional properties of naturally occurring MC4R mutations we have (1) established that defective expression on the cell surface is a common mechanism impairing receptor function, (2) identified mutations which specifically affect ligand binding affinity thus aiding the definition of receptor structure-function relationships, (3) provided evidence against the notion that these receptor mutants act as dominant-negatives, and (4) identified a potentially novel molecular mechanism of receptor dysfunction whereby a mutation alters the relative affinities of a receptor for its natural agonist versus antagonist.     

A de novo mutation affecting human TrkB associated with severe obesity and developmental delay

An 8-year-old male with a complex developmental syndrome and severe obesity was heterozygous for a de novo missense mutation resulting in a Y722C substitution in the neurotrophin receptor TrkB. This mutation markedly impaired receptor autophosphorylation and signaling to MAP kinase. Mutation of NTRK2, which encodes TrkB, seems to result in a unique human syndrome of hyperphagic obesity. The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system.     

Rural and urban variation in psychological distress among adults: results of the 2014–2015 Eastern Townships Population Health Survey (ETPHS)

ObjectiveA growing number of people live in urban areas. Urbanization has been associated with an increased prevalence of mental disorders, but which mechanisms cause this increase is unknown. Psychological distress is a good indicator of mental health. This study sought to examine the relationship between urbanization and distress among adults in the Eastern Townships (southern region of Quebec, Canada).MethodIn the 2014–2015 Eastern Townships Population Health Survey (N = 10,687 adults living in one of the 96 Eastern Townships communities), distress was measured with the K6 distress scale (≥ 7). Urbanization was estimated by the residential density of the community treated in quintiles. Logistic regression analyses were carried out with adjustments for individual and environmental characteristics.ResultsWomen, young people aged 18–24, single parents, those without diplomas, those without a job, those with < $20,000 in income, adults with two or more chronic physical illnesses, adults with bad perceived health, or those living in disadvantaged neighbourhoods exhibited more distress. The unadjusted estimate between density and distress is only significant for the fifth quintile when compared with the first quintile (OR 1.23; 95% CI: 1.06–1.42). The relationship is practically the same after controlling for individual characteristics but decreases considerably after controlling for environmental characteristics (lack of trees, social deprivation, intersection density, vegetation index, and land use mix).ConclusionThis study was the first to examine an association between urbanization and distress by considering individual and environmental characteristics. The latter seem to explain the relationship between these concepts.     

Association between epstein barr virus and tongue squamous cell carcinoma in iranian patients

Detection of Epstein-Barr virus in oral squamous cell carcinoma suggests its involvement in the carcinogenesis of oral cavity. But, there are few studies on the incidence of EBV genome in squamous cell carcinomas at specific locations in the oral cavity like tongue and with different tumor progression. In this study the presence of EBV genome in tongue Squamous Cell Carcinoma (TSCC) in Iranian patients were investigated. Accordingly, a total of 94 cases with TSCC were firstly analyzed for the presence of viral genome through Nested PCR. Patients were divided into different groups based on their gender and the size, nodal involvement, grade and stage of their tumor. Results showed the presence of EBV genome in 72.3% of TSCCs with no significant difference between two genders, although slightly higher in females. Interestingly, PCR products of EBV genome showed a statistically significant higher distribution in TSCCs at IVa stage (p = 0.04), while a considerable low involvement of EBV genome was seen in T1-sized tumors. The result of this study further emphasizes the role of EBV in oral SCCs – mainly at tongue. This is the first investigation to clarify the association between EBV genome and different tumor size and stage in TSCCs; however, more studies in different regions and larger populations should be performed to be able to draw a firmed conclusion.     

Investigation of white blood cell characteristics in cerebrospinal fluid samples at pediatric brain tumor diagnosis

Journal of Neuro-Oncology - The role of white blood cells (WBC) in the pediatric central nervous system (CNS) tumor microenvironment is incompletely defined. We hypothesized that the WBC profile in...