Microarray analysis of multiple candidate genes and associated plasma proteins for nephropathy secondary to type 2 diabetes among Chinese individuals.

AIMS/HYPOTHESIS: Evolving research suggests that common and rare alleles jointly constitute the genetic landscape of complex disease. We studied the association between 43 pathway-related candidate genes with 'intermediate phenotype' (i.e. corresponding plasma protein) and diabetic nephropathy in a customised microarray of 1,536 SNPs. METHODS: In this case-control study of type 2 diabetic Chinese individuals with and without diabetic nephropathy, cases (n = 545) were defined on the basis of a spot urinary albumin/creatinine ratio (ACR) > 113 mg/mmol; the value for controls (n = 503) was ACR < 3.3 mg/mmol. Genotyping was performed using Illumina GoldenGate assay. RESULTS: No single nucleotide polymorphism (SNP) remained significant in single locus analysis after correction for multiple testing. Therefore, we explored the best approximately 1% SNPs. Of these 13 SNPs, four clustered to a 5' end NADPH oxidase homologue 4 (NOX4) haplotype (GGCC frequency = 0.776) with estimated OR for diabetic nephropathy of 2.05 (95% CI 1.04-4.06) (heterozygous) and 2.48 (1.27-4.83) (homozygous) (p = 0.0055). The haplotype was correlated with plasma Cu/Zn superoxide dismutase (SOD) concentration, suggesting increased oxidative burden. Endothelin-1 SNP (rs1476046G>A, frequency = 0.252) was correlated with plasma C-terminal pro-endothelin-1 concentrations with an estimated OR for diabetic nephropathy of (heterozygous) 1.26 (0.96-1.66) and (homozygous) 1.87 (1.13-3.12) (p = 0.0072). Nitric oxide synthase 1 (NOS1) 5' haplotype (TGTC frequency = 0.38) also revealed a suggestive association with diabetic nephropathy: heterozygous 1.26 (0.95-1.67), homozygous 1.57 (1.04-2.35) (p = 0.0073). A rare NADPH oxidase homologue 1 (NOX1)-coding non-synonymous SNP (Arg315His, frequency = 0.006) was found exclusively among cases. CONCLUSIONS/INTERPRETATION: Our preliminary observations suggest that common haplotypes from NOX4 and endothelin-1 SNP correlated with plasma Cu/Zn SOD and C-terminal pro-endothelin-1 concentrations, respectively, and might have conferred diabetic nephropathy susceptibility. Common NOS1 and rare NOX1 variants also revealed a suggestive association with diabetic nephropathy. Future studies to validate our observation are needed.

Auto-antibodies in the hospitalised Oriental elderly.

Aches and pains are a common problem in the elderly and often a positive auto-antibody result is difficult to interpret in the given clinical setting. We studied 96 unselected hospitalised Oriental elderly aged 65 years and above to determine the prevalence of auto-antibodies and their clinical significance. Anti-nuclear antibody (ANA) was positive in 33%; commonest titres were low (i.e. 1:40); commonest patterns were speckled and homogeneous; 44% had no known cause for a positive result apart from their age; 37% were taking drugs known to be associated with a positive ANA and 19% had both a disease and a drug known to be associated with a positive ANA. Rheumatoid factor (RF) was positive in 16%; 47% had titres < or = 40 IU/ml and 87% had no known cause of positive RF. Other auto-antibodies tested were negative. We conclude that the prevalence of auto-antibodies in the hospitalised Oriental elderly are common and of no clinical significance if accompanying features of an auto-immune disease are absent.

A window on the current status of diabetes mellitus in Singapore--the Diabcare-Singapore 1998 study.

The Diabcare-Singapore project was carried out in 22 clinics (general hospitals, GH and primary healthcare centres, PHC) to provide an overview of diabetes management and metabolic control status. Data from 1697 diabetic patients were collected on paper forms and analysed centrally. Type 2 diabetes mellitus patients constituted 91.4% and type I patients constituted 8.1% of population. The proportion of type I patients was greater in GH (18.1%) vs PHC (3.4%). The mean age (+/- SD) was 58.1 +/- 14.4 years and mean duration of diabetes was 10.1 +/- 7.5 years. Mean body mass index (BMI) was 25.1 +/- 4.4 kg/m2 and more than half (53%) of patients were overweight (BMI >25 kg/m2). Mean HbA1c and FBG levels were 8.0 (1.9% and 9.1 +/- 3.1 mmol/l. A total of 51% of patients had HbA1c (1% above the Upper Limits of Normal (ULN). Fasting blood glucose (FBG) was >7.8 mmol/l in 61% of patients. The majority (70%) had satisfactory levels of fasting lipids (triglycerides, total cholesterol and HDL-cholesterol). Only 19.7% practised home blood glucose self-monitoring, while 99% reported receiving some diabetes education. Sixteen percent of patients had abnormal levels of protein (>500 mg/24 h) in the urine, 3% had elevated serum creatinine levels and 36% had microalbuminuria. Retinopathy (12%), cataract (16%) and neuropathy (12%) were commonly reported diabetic complications. The data revealed suboptimal glycaemic control in about half of patients studied.

The status of diabetes mellitus in primary care institution and restructured hospitals in Singapore.

The Diabcare-Asia Singapore 1998 project was carried out using data from 22 centres collected on paper forms to provide an overview of diabetes management and metabolic control status in 1697 diabetic patients from both primary health care clinic (PHC) (67%) and restructured hospital (RH) (33%) settings. PHC patients were on average older than RH patients (61.3 +/- 11.2 years vs 51.5 +/- 17.7 years), and had a shorter duration of diagnosed diabetes (9.2 +/- 6.8 years vs 12.0 +/- 8.5 years). The mean body mass index (BMI) for PHC patients was 25.5 +/- 4.4 kg/m2 vs 24.5 +/- 4.2 kg/m2 for RH patients. Proportionately more PHC than RH patients were overweight (BMI >25 kg/m2) (49% vs 42%). Patients with type I diabetes constituted 3.5% of PHC vs 18.1% of the RH cohort. HbA1c information was available for 92.5% of RH vs 69% of PHC patients. HbA1c measurements were <1% above ULN in 50% of PHC vs 37% of RH patients, while FBG was >7.8 mmol/l in >61% of all patients. Proteinuria (>500 mg/24 hrs) was reported in 13% of PHC vs 26% of RH patients tested. Microalbuminuria (20-300 mg/l) was noted in 36% of 171 RH patients tested. Oral hypoglycaemic agents were used as sole therapy in 83.5% of PHC vs 43% of RH patients. Eye, feet, renal and severe late complications were more commonly reported by RH than PHC patients. There is a variation in the patient profiles and care between PHC and RH patients.

Clinical features, investigations and pathology in surgically treated thyrotoxicosis.

A retrospective study was conducted on 41 thyrotoxic patients operated from January 1986 to June 1992 in Alexandra Hospital. One had multinodular goitre, and the rest had autoimmune thyroid diseases. Analysis of the histopathological features of the 40 patients with autoimmune thyroid diseases revealed that 32 had Graves' disease, four had Hashimoto's thyroiditis and four had a mixed form of Graves' disease and Hashimoto's thyroiditis. Only 14 out of 32 patients had eye and/or cutaneous manifestation of Graves' disease. None of the patients with Graves' disease developed hypothyroidism over a mean follow-up period of two years post-operatively, whereas one out of four Hashimoto's thyroiditis and two out of the four with the mixed form of Graves' and Hashimoto's thyroiditis had hypothyroidism after surgery. We conclude that it may be difficult to make a diagnosis of Hashimoto's thyroiditis in the early phase when it presents with thyrotoxicosis. Besides, there are cases with a mixed form of both Graves' and Hashimoto's thyroiditis. However, it is important that the diagnosis of Hashimoto's thyroiditis be made before surgery, otherwise progression to hypothyroidism would be accelerated.

Selection of patients for surgery in the management of thyrotoxicosis.

There is at present no consensus as to what the best treatment for thyrotoxicosis is. If the patients are carefully selected, surgery offers a safe and effective cure for the disease over a short period of time. We reviewed the selection criteria of forty-one patients with thyrotoxicosis treated surgically in Alexandra Hospital. Over 90% of the patients were referred for surgery by physicians and general practitioners. The majority (95%) were young patients (under 40 years) and almost all were treated with antithyroid drugs before opting for surgery. The most common indication given for surgery was failure of conservative treatment (20/41). This was followed by patients who had difficulty adhering to the antithyroid drug regime (12/41) and patients who requested surgery for cosmetic reasons (5/41). Almost half of the patients had large glands (> 50g). One year after surgery, 84% of the patients remained euthyroid, 8% developed hypothyroidism and 8% had relapsed thyrotoxicosis. Three quarters of the patients tested positive for thyroid antibodies. This did not appear to increase the rate of hypofunction. There was no mortality from surgery.

Clinical utility of selective intra-arterial calcium-stimulated hepatic venous sampling in regionalisation of insulinomas--the Singapore experience.

INTRODUCTION: To evaluate the efficacy and safety of selective intra-arterial calcium-stimulated hepatic venous sampling (ASVS) as a preoperative regionalisation modality for insulinomas. DESIGN AND METHODS: Four patients with biochemically-proven endogenous hyperinsulinism and negative spiral computed tomographic (CT) pancreas were subjected to ASVS between October 1999 to May 2001. Results obtained from ASVS were compared with localisation studies using either magnetic resonance imaging (MRI) or endoscopic ultrasonography (EUS); and these were confirmed surgically whenever possible. RESULTS: ASVS led to a definitive regionalisation in all 4 patients evaluated; the predicted location of the insulinoma matched the findings intraoperatively in all 3 patients who were operated upon. These were all proven to be insulinoma histologically. However, 1 patient showed a positive ASVS result in samples obtained from the left hepatic vein only. In the patient who was unable to undergo surgical resection due to other co-morbid factors, his ASVS findings were corroborated by localisation obtained from the MRI study. Conversely, EUS was found to give an incorrect localisation of insulinoma in 1 patient. Adverse effects were encountered in 3 patients (2 with mild hypotension and 1 with transient atrial fibrillation); however, premature termination of the procedure was not necessary in any of the patients. CONCLUSION: ASVS is accurate and reliable for regionalisation of insulinoma, especially in patients who do not have an obvious, unequivocal tumour using high quality current-generation MRI scans.

Thyrotoxicosis and acute abdomen--still as defying and misunderstood today? Brief observations over the recent decade.

BACKGROUND: Clinicians managing thyrotoxic patients with acute abdomen face challenging diagnostic and risky therapeutic dilemmas. AIM: To analyse the frequency of medical vs. surgical acute abdomen, and to characterize the poorly understood thyrotoxic medical acute abdomen phenomenon. DESIGN: Retrospective review of case notes. METHODS: All case files with a simultaneous diagnosis of thyrotoxicosis and acute abdomen admitted between 1994 and 2004 were traced and audited. RESULTS: Thirteen had a history of thyrotoxicosis while 12 were newly diagnosed. The commonest cause was Graves' disease. Twenty-three (92%) cases were thyrotoxic, of whom six (24%) had thyroid crisis, while two (8%) had subclinical thyrotoxicosis. The provisional diagnosis of acute abdomen was correct in 14 cases (56%), but discordant with the final diagnosis in 11 cases (44%). Eight cases (32%) without any demonstrable pathology were medical, vs. four (16%) with surgical acute abdomen, while 11(44%) had gastritis, hepatobiliary-pancreatic disorders or diverticulitis conservatively managed. The epigastrium and/or central abdomen (72.7%) were the commonest affected regions in medical acute abdomen. CONCLUSION: Although the majority of acute abdomen in thyrotoxicosis was medical in nature, our experience indicates that surgical conditions were not uncommon. Thus, serious causes requiring life-saving surgery should be excluded before attributing it to medical acute abdomen.