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.     

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.     

Dose-dependent effect of histamine on liver function markers in immunized rabbits

ObjectiveThe present study was designed to delineate the hepatotoxicological roles of histamine dose-dependently in immunized rabbits.MethodsThe cohort comprised of three groups (II, III and IV), containing 18 rabbits each, and received subcutaneous histamine 50 μg/kg, 100 μg/kg and 200 μg/kg, respectively for 10 days (b.i.d., starting from 3 days prior to immunization until 7 days after immunization). Group I (control, n = 18) received subcutaneous sterile distilled water for 10 days. They were subsequently immunized at day 3 with intravenous injection of SRBC (1 × 10⁹ cells/ml). Blood samples were collected on pre-immunization (pre-I) day 0, as well as on days 7-, 14-, 21-, 28- and 58-post-immunization (post-I). Biochemical parameters aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin [total bilirubin (TB), direct bilirubin (DB) and indirect bilirubin (IB)] were determined.ResultsGroups II and IV revealed a significant decrease (on day 0-pre-I) and a significant increase (on days 7-, 14-, 21-, 28- and 58-post-I) in ALT and AST levels, when compared with the corresponding values of groups I and III while group II showed a significant increase in ALT and AST levels as compared to group IV. ALP levels in groups II, III and IV showed a significant enhancement when compared with group I. Moreover, results of TB, DB and IB demonstrated increased levels in group III when compared with groups I, II and IV. The results were found statistically significant (p < 0.05).ConclusionShort-term treatment of histamine produces dose-dependent differential patterns of hepatic dysfunctions suggestive mild liver degeneration warranting further long-term studies.     

Both HCV and HBV are Major Causes of Liver Cancer in Southeast Asians

The incidence of hepatocellular carcinoma (HCC) is higher in Asian Americans than in other ethnicities. While hepatitis B virus (HBV) is common, hepatitis C virus (HCV) is more prevalent in some subgroups. Our goal was to determine the etiology of liver disease associated with HCC in subgroups of Asian Americans. This was an analysis of 510 Asian HCC patients at a US medical center. Patients were identified using ICD9 diagnosis. Multivariate logistic regression was used to study predictors of HCV as the cause of HCC. Patients were Southeast Asian, Chinese, and Korean, with similar gender, age, and foreign-born status. Southeast Asians had a similar proportion of HBV- and HCV-related HCC, while Chinese and Korean patients had a higher proportion of HBV-related HCC. HCC was usually associated with HBV in Chinese and Korean patients, but both HCV and HBV were important associations in Southeast Asians.     

Changes in body weight and physical performance after receiving dietary advice in patients with chronic obstructive pulmonary disease (COPD): 1-year follow-up

Nutritional studies in patients with chronic obstructive pulmonary disease (COPD) are often based on oral nutritional supplementation and are of short duration. Our aim was to study the changes in body weight and physical performance in COPD patients after receiving the dietary advice for 1 year. Thirty-six patients with COPD as a primary diagnosis (mean age: 68.5 ± 7.8 years), referred to a pulmonary rehabilitation program were studied. Each patient received dietary advice individually. Body weight had increased significantly by 1.3 kg (p = 0.02) and walking distance by 83.2 m (p = 0.007) after 1 year. There was an increase in mean handgrip strength after 1 year (1.6 kg, p = 0.07). The mean intake of energy and protein expressed as percent of energy and protein requirement had increased after 1 year (15%, p < 0.001, and 5.6%, p = 0.09, respectively). Handgrip strength correlated significantly with energy (r = 0.53, p = 0.002), fat (r = 0.50, p = 0.02) and protein intake (r = 0.41, p = 0.002) after 1 year. In conclusion, positive effects on body weight, handgrip strength and walking distance in patients with COPD were seen after receiving dietary advice with a 1-year follow-up.