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.     

Extraintestinal Seeding of Salmonella enterica Serotype Typhi,Pakistan

We evaluated Salmonella enterica serotype Typhi strains isolated from all body sites in Pakistan during 2013–2018. Despite an increase in overall number of localized, extensively drug-resistant Salmonella Typhi in organ infections during 2018, there was no increase in the proportion of such isolates in comparison with non–extensively drug-resistant isolates.     

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.     

Randomised controlled trial of reminders to enhance the impact of audit in general practice on management of patients who use benzodiazepines.

OBJECTIVE: To determine whether reminder cards in medical records enhance the effectiveness of audit with feedback in improving the care of patients taking long term benzodiazepine drugs. DESIGN: Randomised trial, practices receiving feedback only in one group and practices receiving feedback plus reminder cards in the other group. SETTING: 18 general practices in Leicestershire. SUBJECTS: Random samples of patients who had been taking a benzodiazepine anxiolytic or hypnotic drug for four weeks or longer. MAIN OUTCOME MEASURES: Entries in medical records indicating compliance with five criteria of care: assessment of suitability for withdrawal; being told about dependency; withdrawal being recommended; withdrawal or continuing medication; and a consultation with the general practitioner in the past year. Data were collected before and after feedback or feedback plus reminders. RESULTS: Of a total population of 125,846 registered with the 18 practices, 2409 (1.9%) had been taking a benzodiazepine for four weeks or longer. Of the 742 in the first samples, 543 (73.2%) were women, the mean (SD) age was 68.7 (14.9) years, and they had been taking a benzodiazepine for 10.1 (6.7) years. The number of patients whose care complied with the criteria rose after the interventions to implement change. The increase was greater in practices receiving feedback plus reminders for only two of the five criteria "told about dependency" increasing from 52 (11.1%) to 118 (25.8%) in the feedback only group, and from 27 (10.5%) to 184 (43.0%) in the feedback plus reminders group; odds ratio (OR) 1.46 (95% confidence interval (95% CI) 1.32 to 5.21); and "consulted in the past year" increasing from 434 (93.1%) to 411 (95.8%) in the feedback only group and 255 (96.6%) to 400 (99.8%) in the feedback plus reminders group, OR (95% CI) 13.5 (2.01 to 330.3). CONCLUSIONS: Reminder cards had only a limited effect and cannot be recommended for routine use. There were improvements in the care of patients of both groups of practices and further studies are indicated to determine the impact of both systematically developed criteria and reminders embedded into restructured medical records.