Choice of antihypertensive drug in the diabetic patient.

The hypertensive patient with type 2 diabetes is especially at risk of adverse cardiovascular events. The United Kingdom Prospective Diabetes Study (UKPDS) and Hypertension Optimal Treatment (HOT) studies suggested that treatment to a lower target blood pressure resulted in better prevention of clinical disease in these patients. Most trials comparing antihypertensive drugs have shown only minimal differences between the various agents. The evidence from the trials suggests that diuretics, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and the angiotensin-receptor antagonists (ARBs) will all successfully reduce adverse clinical events. The largest of the comparative hypertensive drug trials, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), demonstrated that a diuretic has a better hypotensive effect, and was more successful in preventing many aspects of cardiovascular disease compared with CCBs and ACE inhibitors. The importance of good blood pressure control and the general equivalence of antihypertensive drugs were again shown in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, which compared an ARB with a CCB. Choice of antihypertensive agent should be individualized and guided by the presence of concomitant clinical disease and the need to protect any specific target organ system in the diabetic hypertensive. Diuretics, being potent hypotensive drugs with clearly demonstrated clinical benefit, should form part of the antihypertensive regimen of most diabetic hypertensives. ACE inhibitors and ARBs are especially useful in preventing nephropathy. Most patients will require a combination of antihypertensive drugs to achieve tight blood pressure control of under 130/80 mm Hg in the diabetic hypertensive. The clinician should concentrate on seeking this lower target blood pressure rather than be excessively concerned about which is the best antihypertensive agent.

Milestones of the medical school and medical progress of Singapore over the past 100 years.

The Medical School started off in an old female lunatic asylum on the site of the general hospital at Sepoy Lines. It was founded on 3 July 1905 and was called the Straits and Federated Malay States Government Medical School. In 1916, the Licentiate in Medicine and Surgery (LMS) was recognised fully by the General Medical Council of Britain as a registrable qualification. In 1921, the medical school was renamed King Edward VII College of Medicine to reflect its academic status. In 1926, the College and its hospitals were inspected by Sir Richard Needham, who had been sent by the General Medical Council of Great Britain. In his report, he told the Council that in his opinion, the graduates should be given the MBBS degree because of the high standard of the Medical School. The medical school was closed by the Japanese on 16 February 1942. After the end of World War II, the College of Medicine resumed classes in June 1946. In 1962, the medical faculty became the Faculty of Medicine of the University of Singapore. From 1984 to 1986, following the university's move to Kent Ridge, the Faculty's clinical school also moved to the National University Hospital. In 2004, plans were well underway for the opening of the country's second medical school on the grounds of the Singapore General Hospital.

The first graduates in 1910.

The Medical School in Singapore was founded on 3 July 1905 and named the Straits and Federated Malay States Government Medical School. There were 23 students in the first enrollment; 16 students attended the full course, while 7 attended a 2-year course for hospital assistants. The pioneer group of 7 that graduated in May 1910 (the Magnificent Seven) consisted of Drs Chen Su Lan, Edwin Williborod deCruz, and John Gnanapragasam from Singapore; Drs Willie Carnegie and Mark W Chill from Penang; Dr SR Krishnan from Seramban and Dr John Scott Lee from Ipoh. In December 1910, a further 6 students graduated. Of this first batch of 13 graduates in 1910, we describe the careers of 6; no records exist of the remaining 7.

Absence of ion channels CACN1AS and SCN4A mutations in thyrotoxic hypokalemic periodic paralysis.

Muscle weakness in patients with thyrotoxicosis during hypokalemic episodes (thyrotoxic periodic paralysis [TPP]) occurs sporadically and mostly in males. It is treated by infusion or oral supplementation with potassium and with resolution of the thyrotoxicosis state. The clinical features of TPP resemble familial hypokalemic periodic paralysis (hypoKPP), which has been linked to two mutations in the gene encoding the skeletal muscle calcium channel alpha-1 subunit (CACN1AS; Arg528His and Arg1239His) and to the sodium channel alpha-subunit (SCN4A; Arg672His). We screened for the mutations (CACN1AS by polymerase chain reaction-restriction fragment length polymorphism [PCR-RFLP]; SCN4A by single-strand conformation polymorphism analysis) described in hypoKPP in 20 unrelated patients with documented episodes of TPP (mean age, 40.0 +/- 12.3 years 19 males). Forty-eight patients with hyperthyroidism resulting from Graves' disease (48.5 +/- 12.3 years; 13 males), 1 patient with idiopathic hypoKPP (a 32-year-old male) and 32 healthy subjects (41.0 +/- 19.1 years; 16 males) were included. We found none of the TPP patients carry CACN1AS and SCN4A mutations. The hyperthyroid patients and control subjects were also negative for the mutations. The patient with idiopathic hypoKPP was genotyped to have the Arg528His mutation. These results suggest that despite close similarities between TPP and hypoKPP, a likely genetic basis for TPP does not involve the same gene mutations associated with hypoKPP.

Hereditary spherocytosis, a pitfall in the assessment of glycaemic control.

The use of glycosylated haemoglobin in the assessment of diabetic control is ubiquitous. Hereditary spherocytosis is a haemolytic anaemia with shortened red blood cell lifespan, which can interfere with the methods of glycosylated haemoglobin measurement. We report a case of hereditary spherocytosis in a young man with type 1 diabetes, and illustrate the discrepancy in the measurements of glycosylated haemoglobin, which were inconsistent with the blood glucose profiles. Fructosamine, an alternative time-averaged indicator of blood glucose level, was advantageous in this particular situation. The awareness of the limitations of glycosylated haemoglobin is essential in the clinical care of patients with diabetes, which is a major health problem in Singapore.

IgG1 subclass dominates autoimmune response to tyrosine phosphatase-like molecule IA-2 in Chinese type 1 diabetes patients.

BACKGROUND AND AIMS: Islet autoantibodies are known markers for type 1 diabetes with an immune-mediated basis; their isotype or subclass profiles may also provide clues to changes in immune response during disease or after intervention. For ICAs and GADab, the IgG1 subclass consistently dominates in recent-onset disease. The aims of our study were to determine the isotype patterns for IA-2ab in Asian Chinese patients with autoimmune diabetes. MATERIALS AND METHODS: From an initial screening of over 400 diabetes patients, 40 subjects (mean age 22.2 +/- 15.8 years) with IA-2ab were enrolled for this study. IA-2ab was detected by radioimmunoassay of [35S]-labelled recombinant human IA-2 ic(605 - 979). Of them, 31 (median age 15 years, range 2 - 57 years; 16 children) had clinical type 1 diabetes (that is, they required insulin at onset or within 1 year) with the majority having been recently diagnosed (< 1 year). The other 9 patients had clinical type 2 diabetes phenotype. RESULTS: IA-2ab IgG subclasses determined with monospecific secondary antibodies showed that both type 1 diabetic adults and children had similarly non-restricted isotype patterns with a strong presence of IgG1-IA-2ab. The rank order was IgG1 > 3 > 2 > 4; 15 subjects had detectable IgG4-IA-2ab. Clonality of immune response determined with kappa/lambda chain-specific antibodies also showed a non-restricted pattern. Patients aged 38.2 +/- 15.2 years with type 2 diabetes had broad patterns of isotypes - IgG1/3 was detected more frequently (n = 8) than IgG2/4 (n = 5). Of three patients on insulin treatment, one was also positive for GADab. The remaining 6 patients were on oral hypoglycaemic treatment. IA-2ab in type 2 diabetes showed a low titre compared to type 1 diabetes. CONCLUSIONS: Isotype responses to IA-2 had a strong IgG1 presence, similar to ICAs and GADab. With IgG3 subclass representation, a predominant Th1 milieu in the systemic environment is likely. There is no suggestion of differences in immune response to IA-2 between adults and children with type 1 diabetes.

Systemic levels of cytokines and GAD-specific autoantibodies isotypes in Chinese IDDM patients.

It is not clear if a Th1/Th2 imbalance in Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) would lead to a particular antigen-specific IgG subclass dominant as had been shown in the mouse model. In new-onset Type 1 diabetics, an autoantibody response to glutamate decarboxylase (GADab) is frequently observed but the GADab subclass repertoire is not well-established. We determined the systemic levels of representative Th1 and Th2 cytokines and the GADab IgG subclass distribution in 41 Chinese IDDM patients of whom 26 were recently diagnosed (< or = 1 year) and 32 had GADab, to ascertain a likely association of antigen-specific antibody isotype and the Th1/Th2 dichotomy. With high-sensitivity ELISA systems that measure sub-picogram cytokine concentrations, 26 of the 41 patients (63.4%) had at least one of the pro-inflammatory Th1 cytokines (TNF-alpha, IFN-gamma and IL-12) detected. Fewer patients (4/41) had the anti-inflammatory Th2 cytokine IL-4 detected. For IL-10, all subjects had measurable quantities but only three diabetics had levels above the upper limit for healthy subjects (n = 20). Grouped according to the profile of detectable cytokines, there were 24 Th1, 2 Th2 and 2 Th0 patterns. GAD-specific IgG1 antibody was more frequently expressed; 22 of 32 GADab[+] patients. The rank order for the GADab subclasses was IgG1 > 4 > 3 > 2; IgG2 was found in 11 GADab[+] patients. Recent-onset diabetics have a similar ranking of the GAD-specific IgG subclasses. In human Type 1 diabetes, a predominance of GAD-specific IgG1 antibody response is observed together with a dominant Th1 cytokine pattern.

Management of obesity in NIDDM (non-insulin-dependent diabetes mellitus).

Obesity is common in NIDDM; in a cohort of 314 diabetics in Singapore, 44.3% are overweight. Management of obesity in diabetics differs from that in non-diabetics in that it is more urgent; weight maintenance is more difficult and hypoglycaemic medication may cause weight changes. Like in the non-diabetic, management of obesity in diabetic requires a pragmatic and realistic approach. A team approach is required: the help of the nurse educator, the dietitian, behaviour modification therapist, exercise therapist etc are required. A detailed history, careful physical examination and relevant investigations are required to assess the severity of the diabetic state and to exclude an occasional underlying cause of the obesity in the obese NIDDM. Weight loss is urgent in the obese NIDDM, especially those with android obesity. There must be a reduction in caloric intake. Weight loss leads to improvement in the glucose tolerance, insulin sensitivity, reduction in lipid levels and fall in blood pressure in the hypertensive. Exercise is of limited value except in the younger obese NIDDM. Metformin is the hypoglycaemic drug of choice as it leads to consistent weight reduction. The sulphonylureas may cause weight gain. Insulin should be avoided where possible as it causes further weight gain. Other hypoglycaemic agents include Glucobay (alpha-glucosidase inhibitor) and Troglitazone (insulin sensitizer) which do not alter the weight. Orlistat (lipase inhibitor) is promising as it causes reduction of weight, blood-glucose and lipid levels. Anti-obesity drugs (noradrenergic and serotonergic agents) have modest effects on weight reduction in the obese NIDDM; a widely use preparation, Dexfenfluramine (Adifax) has been withdrawn because of side effects. Surgery such as gastric plication is the last resort in treating the morbidly obese NIDDM. The discovery of leptin in 1994 has led to intense research into energy homeostasis in obesity; hopefully this will lead to better treatment of obesity in diabetics and non-diabetics.

The Malai Ika Daigaku (Syonan Medical College) in Malacca (1944 to 1945) during the Japanese occupation of Singapore and Malaya.

During the Japanese Occupation of Singapore and Malaya (1941-1945), Singapore was renamed Syonan (or Syonanto) and Malaya was called Malai (or Marai; Marei). On 27 April 2603 (1943) the Japanese Military Administration established. The Marai Ika Daigaku (Syonan Medical College) at the Tan Tock Seng Hospital (Hakuai Byoin), Syonan. The Medical College shifted to the General Hospital, Malacca in February 2604 (1944) where it functioned till the end of the Japanese Occupation in September 2605 (1945).

Management of obesity in non- insulin- dependent diabetes mellitus.

Obesity is common in non-insulin-dependent diabetes mellitus (NIDDM) patients; in Singapore in a cohort of 314 diabetics, 44.3% were overweight. Management of obesity in diabetics differs from that in non-diabetics in that it is more urgent; weight maintenance is more difficult and hypoglycaemic medication may cause weight changes. However, like in the non-diabetic, management of obesity in the diabetic requires a pragmatic and realistic approach. A team approach is required: the help of a nurse educator, a dietitian, behaviour modification therapist, exercise therapist and others are required. A detailed history, careful physical examination and relevant investigations are required to assess the severity of the diabetic state and to exclude an occasional underlying cause of the obesity in the obese NIDDM patient. Weight loss is urgent in the obese NIDDM patient, especially for those with android obesity. There must be a reduction in energy intake. Weight loss leads to an improvement in glucose tolerance and in insulin sensitivity, as well as to a reduction in lipid levels and to a fall in blood pressure in the hypertensive. Exercise is of limited short-term value measured in terms of weight reduction, except in the younger obese NIDDM patient; but it does allow improvement in overall metabolic control and, long-term, is critical for preferred weight maintenance. The biguanide, Metformin, is the hypoglycaemic drug of choice as it leads to consistent weight reduction. The sulphonylureas may cause weight gain. Insulin should be avoided where possible as it causes further weight gain. Other hypoglycaemic agents include Glucobay (alpha-glucosidase inhibitor) and Troglitazone (insulin sensitizer) which do not alter the weight. Orlistat (lipase inhibitor) is promising as it causes reduction of weight, blood glucose and lipid levels. Anti-obesity drugs (noradrenergic and serotonergic agents) have modest effects on weight reduction in the obese NIDDM patient; a widely-used preparation, Dexfenfluramine (Adifax), has been withdrawn because of side-effects. Surgery such as gastric plication is the last resort in treating the morbidly obese NIDDM patient. Against this background, the institution of life-long food and exercise habits which favour health, body composition and fat distribution are paramount in the prevention and minimization of expression of NIDDM. The discovery of leptin in 1994 has led to intense research into energy homeostasis in obesity; hopefully this will lead to better treatment of obesity in diabetics and non-diabetics.

Anti-GAD antibodies in Chinese patients with youth and adult-onset IDDM and NIDDM.

An autoimmune basis for the pathogenesis of insulin-dependent diabetes mellitus (IDDM) is supported by the frequent presence of autoantibodies - islet cell antibodies (ICAs) and GAD antibodies (GADab). However, in Chinese patients with clinical IDDM, a low prevalence of ICAs was observed. In non-insulin-dependent diabetic (NIDDM) patients, it has been suggested that the presence of GADab may identify a subset of latent autoimmune diabetes in adults (LADA). We determined the frequency of GADab in a large group of 134 IDDM and 168 NIDDM Chinese patients, and assessed the relation with ICAs status. Results showed that 39.6% IDDM and 16.1% NIDDM patients had GADab, and 20.1% and 4.8%, respectively had detectable ICAs. Frequency of GADab positivity was not influenced by whether the patients had youth or adult-onset IDDM or NIDDM, or by duration of diabetes. NIDDM patients seropositive for GADab shared similar clinical characteristics and fasting C-peptide levels with those who were GADab negative. Presence of GADab therefore did not serve to identify a subgroup of patients with latent or slow-onset IDDM. Half (53%) of our IDDM patients had neither GADab nor ICAs. The reason for this observation is unclear. One theory is that other autoantigens yet to be identified may be contributory. Alternatively, in the Chinese, autoimmunity may not be the major factor in the pathogenesis of IDDM.

The Marei Ika Daigaku (Syonan Medical College) during the Japanese occupation of Singapore (1942-1945).

During the Japanese Occupation of Singapore (1942-1945), Singapore was renamed Syonan (or Syonanto). The Japanese Military Administration established The Medical College on 27 April 2603 (1943) and it was known as The Marei Ika Daigaku or Syonan Medical College. It was sited at the Tan Tock Seng Hospital (Hakua Byoin). The Ika Daigaku relocated to the General Hospital, Malacca in February 2604 (1944) where it functioned till the end of the Japanese Occupation in September 1945. About 200 students from Singapore, Malaya, Sumatra and Java attended the Syonan Medical College; the students were taught mainly Japanese language and culture.