Genome-wide scan identifies novel modifier loci of acromegalic phenotypes for isolated familial somatotropinoma.

Isolated familial somatotropinoma (IFS) accounts for 18% of familial isolated pituitary adenoma (FIPA) cases. Recently, germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have been found in families with pituitary adenoma predisposition, FIPA, and IFS. In this study, we investigate the AIP mutation status and perform a genome-wide scan to search for the modifier regions of acromegalic phenotypes in an IFS family of 31 aborigines from Borneo. Complete endocrine diagnosis and data could not be collected due to logistical and cultural reasons. AIP mutation screening was carried out by direct sequencing and the genome-wide scan was performed using 400 microsatellites. Non-parametric linkage analysis was performed to obtain the logarithm of odds (LOD) scores. A novel AIP frameshift mutation in exon 4 (c.500delC) (p.P167HfsX3) was identified in all members with acromegalic features, as well as in 15 members without acromegalic features, revealing incomplete penetrance of AIP. The data showed that patients with the same mutation may express acromegalic features of differing severity, suggesting the existence of modifier genes. The highest LOD score of 2.2 was obtained near D19S571 (19q13.41). We also found weak linkages on chromosomes 3q28, 8q12.1, and 21q22.13, with LOD scores of 1.1, 1.8, and 1.4 respectively. Our results show the first genome-wide scan that identifies novel modifier loci for acromegalic phenotypes in an IFS family. Identification of modifier loci may provide further insight into the disease mechanism and explain the clinical variability observed in its patients.

Comparative bioavailability study of two salbutamol tablets in healthy adult volunteers.

This study was carried out to compare the rate and extent of absorption of a generic salbutamol in oral dosage form (Brethmol, 4 mg) with the proprietary equivalent product (Ventolin, 4 mg), in healthy adult subjects, under fasting conditions. The study was a single dose, randomized, two way crossover study with a four-week washout period. It involved 22 healthy volunteers who received a single dose (4 mg) of the test and the reference products after an overnight fast of at least 10 hours. Blood samples were collected at pre-dose and a serial of 14 samples were collected from each of the subject from 1 h until 48 h post-dose. Plasma concentrations of salbutamol were analyzed using GCMS method. The mean AUC(0-yen) values were 91.26 and 96.45 h.ng/ml for reference and test product, respectively. The mean C(max) values were 12.26 and 12.38 ng/ml and the mean t(max) values were 2.80 and 2.33 hours for reference and test product, respectively. Analysis of variance showed that the 90% confidence intervals on the relative difference of the ratio for the AUC(0-yen) and the C(max) for the test and reference products were contained within the bioequivalence limit (80 - 125%) (C(max): 89.8 - 110.5% and AUC(0-yen): 91.6 - 121.5%). There was no statistically significant difference for the t(max) between the test and reference formulations (p = 0.30). The test formulation was found to be bioequivalent to the reference formulation with regard to AUC(0-yen) and C(max). There was no statistically significant difference in Brethmol and Ventolin t(max). In conclusion, Brethmol and Ventolin are bioequivalent in healthy subjects.

Phytoestrogens levels determination in the cord blood from Malaysia rural and urban populations.

This study is a result of an analysis of free and conjugated phytoestrogens daidzein, genistein, daidzin, genistin and coumesterol in human cord blood plasma using LCMS. Cord blood was collected from urban and rural populations of Malaysia (n=300) to establish a simple preliminary database on the levels of the analyzed compounds in the collected samples. The study also aimed to look at the levels of phytoestrogens in babies during birth as this may have a profound effect on the developmental process. The sample clean up was carried out by solid-phase extraction using C18 column and passed through DEAE sephadex gel before analysis by LCMS. The mean concentrations of total phytoestrogens were daidzein (1.4+/-2.9 ng/ml), genistein (3.7+/-2.8 ng/ml), daidzin (3.5+/-3.1 ng/ml), genistin (19.5+/-4.2 ng/ml) and coumesterol (3.3+/-3.3 ng/ml). Distribution of phytoestrogen was found to be higher in samples collected from rural areas compared to that of urban areas.

Sociodemographic determinants of glycaemic control in young diabetic patients in peninsular Malaysia.

Recent studies have shown that good glycaemic control can prevent the development of diabetic complications in type 1 and type 2 diabetes. We wished to observe the glycaemic control in patients from different centres in Peninsular Malaysia and the factors that determine it. We recruited 926 patients with diabetes diagnosed before age 40 years from seven different centres, with proportionate representation from the three main ethnic groups. Clinical history and physical examination were done and blood taken for HbA1c and fasting glucose. The overall glycaemic control was poor with geometric mean HbA1c of 8.6% whilst 61.1% of the patients had HbA1c greater than 8%. Glycaemic control in patients with type 2 diabetes varied between various centres and ethnic groups, with the best control obtained in Chinese patients. Significant predictors of HbA1c in both type 1 and type 2 diabetes include access to nurse educators, ethnic background and WHR. In type 2 diabetes, use of insulin was a significant predictor, while in type 1 diabetes, household income was a significant predictor. Socioeconomic status did not have a significant effect in type 2 diabetes. There were no significant differences in the glycaemic control in patients with different educational status. In conclusion, glycaemic control in big hospitals in Malaysia was poor, and was closely related to the availability of diabetes care facilities and ethnic group, rather than socioeconomic status.

Prevalence of glutamic acid decarboxylase antibodies amongst young Malaysian diabetics.

This study determined the prevalence of glutamic acid decarboxylase antibodies (GAD Ab) in a group of 926 young Malaysian diabetics of three ethnic groups, Malay, Chinese, and Indian. Patients were clinically diagnosed to be Type 1 or Type 2 before the age of 40 years. The overall GAD Ab positivity was 17.4% (161/926), significantly higher in the Type 1 than the Type 2 diabetics (35.5%, 116/329 vs. 7.5%, 45/597, P=0.0001). Compared to GAD Ab negative patients, seropositive diabetics were diagnosed at younger age (21.2+/-0.9 vs. 27.4+/-0.3 y, P=0.0001), had lower fasting (289+/-27.4 vs. 640+/-17.6 pmol/l, P=0.0001) and post-glucagon C-peptide levels (527+/-51.8 vs. 1030+/-28.9 pmol/l, P=0.0001). There were no racial differences in the prevalence of GAD Ab; of the total Type 1, 30.8, 36.4, and 39.4% were Malay, Chinese, and Indian diabetics, respectively and of the total Type 2, 8.8, 8.2, and 4.4% were Malay, Chinese, and Indian diabetics respectively. There was a curvilinear relationship between GAD Ab and the post-glucagon C-peptide levels, suggesting that GAD Ab do play a role in the beta-cells destruction and could be an important immune marker for the LADA group. This study reconfirmed previous reports that the autoimmune mechanisms in the Type 1 Asian diabetics are indeed different from the Caucasians, and further investigations should be carried out to explain the differences.

Prednisolone metasulphobenzoate foam retention enemas suppress the hypothalamo-pituitary-adrenal axis.

BACKGROUND: Corticosteroid enemas represent effective treatment for ulcerative proctitis, but absorption into the systemic circulation may have undesirable metabolic consequences. Prednisolone metasulphobenzoate, a lipophobic corticosteroid derivative, is designed to be absorbed poorly through the recto-sigmoid mucosa, but the effects of foam enema preparations upon the hypothalamo-pituitary-adrenal axis have not been examined. METHODS: Nine patients suffering from active ulcerative proctitis underwent four weeks of therapy with prednisolone metasulphobenzoate foam enemas. The hypothalamo-pituitary-adrenal axis, defined using the modified single-dose metyrapone test, glucose homeostasis and lipid profiles were studied before and after treatment. RESULTS: The hypothalamo-pituitary-adrenal axis was significantly depressed after the treatment period; mean stimulated plasma cortisol concentration fell from 384 +/- 244 (s.d.) to 288 +/- 252 nmol/L, P < 0.02; stimulated mean plasma 11-deoxycortisol concentration fell from 677 +/- 333 to 407 +/- 326 nmol/L, P < 0.01. Mean fasting plasma glucose, insulin, C-peptide, fructosamine and triglyceride concentration were unchanged, whilst the mean serum cholesterol concentrations rose from 5.6 +/- 1.1 to 6.0 +/- 1.2 mmol/L (not significant). CONCLUSION: Prednisolone metasulphobenzoate foam enemas have significant systemic and endocrine metabolic effects, which could assume importance with long-term therapy.

Apathetic thyrotoxicosis in adolescence.

We here describe a case of apathetic thyrotoxicosis in a 16-year-old female subject who presented with a range of non-specific symptoms. Apart from a history of significant weight loss, there were no other signs or symptoms indicative of hyperthyroidism. The diagnosis was made incidentally upon thyroid function testing, and there was a prompt clinical response to anti-thyroid therapy. The diagnostic pitfalls of this unusual presentation in the young are highlighted. A history of weight loss and a clinical index of suspicion will lead to the diagnosis, which is readily confirmed biochemically.

Culture-positive thoracic empyema in adults.

Twenty-nine adult patients with culture-positive thoracic empyema were seen at the University Hospital Kuala Lumpur from 1984 to 1988. Cough, fever, chest pain, dyspnoea and weight loss were the common presenting symptoms. The empyema in 16 patients was associated with primary bronchopulmonary infections, nine occurred following thoracentesis of culture-sterile pleural effusions, two occurred as post-thoracic surgery complications, one following a subdiaphragmatic abscess and one as a result of a stab wound. The most common culture isolates were Streptococcus milleri, Pseudomonas aeruginosa and Klebsiella pneumoniae. Closed tube thoracostomy, the most common form of drainage procedure employed, was able to effect a cure or control of the empyema in 11 out of 19 patients in whom it was used.