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.     

Perioperative circulatory side effects of topical 5% phenylephrine for mydriasis

PURPOSE: To study the systemic effects of topically applied 5% phenylephrine. To investigate intraoperative injection of epinephrine in the anterior chamber as an alternative. METHOD: 75 patients undergoing cataract surgery were randomized into three groups. In group 1, the pupil was dilated using topically 5% phenylephrine and 1% cyclopentolate, the patients blocked the lacrimal drainage system themselves by digital compression. Group 2 received the same drops, digital compression was performed by one of the investigators. In Group 3, no preoperative phenylephrine was used--instead, epinephrine 1:25,000 was injected in the anterior chamber at the beginning of surgery. Retrobulbar anesthesia was performed in a short narcosis with ketamine and propofol. RESULTS: Mean preoperative blood pressure values were higher than the day before. They fell during narcosis, to increase significantly after the injection of the local anesthetics. At the beginning of surgery they were back to prenarcotic values. Intraoperative blood pressure remained stable. Preoperative day values were found two hours postop. There was no significant difference in the circulatory behavior between the three groups. For mydriasis, intraoperative intracameral epinephrine was not as effective as preoperative phenylephrine. CONCLUSION: In normotonic or medically treated arterial hypertensive patients, preoperative mydriasis using 5% phenylephrine is safe--proceeding the way described above. Compression of the lacrimal drainage system can be performed by the patients effectively. Intraoperative intracameral epinephrine does not replace preoperative phenylephrine.     

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.     

Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19

Journal of NeuroVirology - As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis...