Obesity-Associated GNAS Mutations and the Melanocortin Pathway.

BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).

Morbidity profile, prescribing patterns and working of the community drug programme in a health post in Western Nepal.

The study was carried out at the Naudanda Health Post over a two-month period (July 15, 2000, to September 15, 2000). The objectives were to obtain information on the demography of patients, morbidity, drug-prescribing patterns and the working of the Community Drug Programme. Acute respiratory infections were the most common illness. Paracetamol was most commonly prescribed and 80.6% of the drugs prescribed were essential drugs.

Investigation of antimicrobial use pattern in the intensive treatment unit of a teaching hospital in western Nepal.

BACKGROUND: Inappropriate use of antimicrobials is of special importance in the intensive treatment unit because of the large number of drugs prescribed, the chance for drug errors, and the likelihood of development of drug resistance. METHODS: A total of 297 records of patients admitted to the intensive treatment unit of the Manipal teaching hospital, a tertiary care hospital in Pokhara, western Nepal, were studied to determine the prescribing frequency and rationality of use of antimicrobials. Patient outcome, duration of stay in the intensive treatment unit, and the age and sex distribution of the patients were also studied. RESULTS: Mean+/-SD drugs per patient was 3.4+/-1.8. About half (50.2%) of the patients received an antimicrobial; 84.6% of the antimicrobials were used without obtaining bacteriologic evidence of infection. The commonest organisms isolated on culture were Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae, and Staphylococcus aureus. A total of 28.9% of the antimicrobials were prescribed for lower respiratory tract infections on the basis of the putative site of infection; 61.9% of the antimicrobials were prescribed by the parenteral route and mainly the older generation of antimicrobials were used. In 39 of the 149 patients prescribed an antimicrobial, the use was irrational. CONCLUSIONS: Prescriber education to improve prescribing patterns and regular auditing of antimicrobial prescriptions to prevent their inappropriate use and unnecessary cost to the patients are required. The high percentage of inappropriate use of antimicrobials raises concerns about the development and spread of drug resistance, which must be addressed.

Prescribing patterns of antibiotics and sensitivity patterns of common microorganisms in the Internal Medicine ward of a teaching hospital in Western Nepal: a prospective study.

BACKGROUND: Information about antibiotic use and resistance patterns of common microorganisms are lacking in hospitals in Western Nepal. Excessive and inappropriate use of antibiotics contributes to the development of bacterial resistance. The parameter: Defined daily dose/100 bed-days, provides an estimate of consumption of drugs among hospital in-patients. This study was carried out to collect relevant demographic information, antibiotic prescribing patterns and the common organisms isolated including their antibiotic sensitivity patterns. METHODS: The study was carried out over a 3-month period (01.04.2002 to 30.06.2002) at the Manipal Teaching Hospital, Western Nepal. The median number of days of hospitalization and mean +/- SD cost of antibiotics prescribed during hospital stay were calculated. The use of antibiotics was classified for prophylaxis, bacteriologically proven infection or non-bacteriologically proven infection. Sensitivity patterns of the common organisms were determined. Defined daily dose/100 bed-days of the ten most commonly prescribed antibiotics were calculated. RESULTS: 203 patients were prescribed antibiotics; 112 were male. Median duration of hospitalization was 5 days. 347 antibiotics were prescribed. The most common were ampicillin, amoxicillin, metronidazole, ciprofloxacin and benzylpenicillin. Mean +/- SD cost of antibiotics was 16.5 +/-13.4 US dollars. Culture and sensitivity testing was carried out in 141 patients. The common organisms isolated were H. influenzae, E. coli, K. pneumoniae and S. aureus. CONCLUSIONS: Antibiotic resistance is becoming a problem in the Internal Medicine ward. Formulation of a policy for hospital antibiotic use and an educational programme especially for junior doctors is required.