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.

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.

Non-restricted immunoglobulin-G subclass islet cell antibodies in Chinese.

Islet cell antibodies (ICAs) in Chinese (23 IDDM, 13 NIDDM and 6 non-diabetic) were characterized for immunoglobulin isotypes and light chain specificity. All ICAs were IgG-type and none were IgM- or IgA-type (median titre: 20 JDF units; range 10-160). Light chain specificity showed that 25/36 (69.4%) of the diabetic patients had lambda and kappa chains. Half of the non-diabetic subjects had both lambda and kappa chains. The rest had only lambda chains. Isotyping for ICA-IgG subclass combination with IUIS/WHO reference monoclonal antibodies in the diabetic patients gave the following: IgG1 alone-9 (25%), IgG1+2+3-8 (22.2%), IgG1+2-11 (30.6%), IgG1+3-6 (16.7%), IgG2+3-2 (5.6%). No ICA-IgG4 was detected. The frequency of the subclasses would be: IgG1-94.4%, IgG2-58.3% and IgG3-44.4%. The distribution of ICA-IgG subclasses was not affected by diabetes type (IDDM or NIDDM) or duration of disease. Of the 6 non-diabetic subjects only one had a single ICA-IgG subclass (IgG1). Serum levels of IgG subclasses in a subgroup of the patients (n = 16) were not significantly different from normal individuals. Biochemical modification of pancreatic tissue prior to ICA testing showed that acetylneuraminic acid residues, lipid and protein components were associated with binding of ICAs. The co-existence of other autoantibodies was also tested in these 42 ICA-positive sera. Twelve individuals (1 non-diabetic) had thyroid autoantibodies. Antibodies to thyrotrophin receptor, gastric parietal cell and rheumatoid factor were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbohydrate and lipid metabolism during human labor: free fatty acids, glucose, insulin, and lactic acid metabolism during normal and oxytocin-induced labor for postmaturity.

This investigation was performed to study the metabolism of the major body fuels (viz. glucose and free fatty acids), insulin, and lactic acid during the stress of human labor. In addition, the role of the normal placenta in the transport of these substances between mother and the fetus was evaluated by measuring them in the mother and cord blood at delivery. To study possible alterations of this role in the placenta which had exceeded the normal period of gestation, a second comparable group of women had labor induced with oxytocin 16-18 days beyond the expected date of delivery. A dramatic twofold increase in maternal plasma free fatty acids was observed during labor. There was a lesser but definite increase in blood glucose concentrations. No rise in serum insulin levels was noted which coincided with the changes in blood glucose. Lactic acid concentrations during the course of labor were variable from baseline but at delivery, the concentrations rose to very significant levels. Free fatty acids and blood glucose levels were significantly higher in the maternal than in the fetal side. A significantly positive correlation was noted between the maternal and cord blood values except for free fatty acids in the postmature group. No significant difference, nor a correlation was found between the two compartments in the insulin nor lactic acid levels. These results suggest that during human labor free fatty acids are the principal metabolic fuel. This increase in maternal free fatty acids may serve to spare glucose as a metabolic fuel in the fetus. The mechanism responsible for the increase maternal free fatty acid mobilization remains to be determined. It is not possible to discern any consistant alteration in placental function as a consequence of prolonged gestation.

Cardiovascular diseases in Chinese, Malays, and Indians in Singapore. II. Differences in risk factor levels.

STUDY OBJECTIVE: The aim of the study was to examine cardiovascular risk factors to see how these might explain differences in cardiovascular disease mortality among Chinese, Malays, and Indians in the Republic of Singapore. DESIGN: The study was a population based cross sectional survey. Stratified systematic sampling of census districts, reticulated units, and houses was used. The proportions of Malay and Indian households were increased to improve statistical efficiency, since about 75% of the population is Chinese. SETTING: Subjects were recruited from all parts of the Republic of Singapore. SUBJECTS: 2143 subjects aged 18 to 69 years were recruited (representing 60.3% of persons approached). There were no differences in response rate between the sexes and ethnic groups. MEASUREMENTS AND MAIN RESULTS: Data on cardiovascular risk factors were collected by questionnaire. Measurements were made of blood pressure, serum cholesterol, low and high density lipoprotein cholesterol, fasting triglycerides and plasma glucose. In males the age adjusted cigarette smoking rate was higher in Malays (53.3%) than in Chinese (37.4%) or Indians (44.5%). In both sexes, Malays had higher age adjusted mean systolic blood pressure: males 124.6 mm Hg v 121.2 mm Hg (Chinese) and 121.2 mm Hg (Indians); females 122.8 mm Hg v 117.3 mm Hg (Chinese) and 118.4 mm Hg (Indians). Serum cholesterol, low density lipoprotein cholesterol and triglyceride showed no ethnic differences. Mean high density lipoprotein cholesterol in males (age adjusted) was lower in Indians (0.69 mmol/litre) than in Chinese (0.87 mmol/litre) and Malays (0.82 mmol/litre); in females the mean value of 0.95 mmol/litre in Indians was lower than in Chinese (1.05 mmol/litre) and Malays (1.03 mmol/litre). Rank prevalence of diabetes for males was Indians (highest), Malays and then Chinese; for females it was Malays, Indians, Chinese. CONCLUSIONS: The higher mortality from ischaemic heart disease found in Indians in Singapore cannot be explained by the major risk factors of cigarette smoking, blood pressure and serum cholesterol; lower high density lipoprotein cholesterol and higher rates of diabetes may be part of the explanation. The higher systolic blood pressures in Malays may explain their higher hypertensive disease mortality.

Thyrotoxic myopathy: a clinical and quantitative analytic electromyographic study.

The clinical entity of chronic thyrotoxic myopathy was considered rare by Waldenström in 1945. Forty eight consecutive patients with thyrotoxicosis were studied clinically and by electromyography for muscle involvement. Quantitative electromyographic techniques were used to analyse both the electromyographic activity of the muscle at a standard tension and also the single motor potential obtained in isolation at minimal effort. The interference pattern was described in simple numerical terms such as the number of potential changes/s and the mean amplitude. All cases that were thyrotoxic (both clinically and on thyroid function tests) showed the changes of myopathy on electromyography, though only 68% of the cases showed clinical myopathy consisting of muscle weakness and/or atrophy.

Neuromuscular transmission in thyrotoxicosis.

The occurrence of thyrotoxicosis in myasthenia gravis is estimated as 5.3% (Osserman et al. 1967) but the incidence of myasthenia in the course of thyrotoxicosis is only 0.2% (Simpson 1968). The association between these two diseases is not a chance one and there are two possible basic mechanisms viz. the action of thyroid hormone on the neuromuscular junction or the existence of a cause common to both. The fatigability seen clinically in thyrotoxic myopathy could be partly attributed to myasthenia. With these possibilities in mind, a search for electromyographic stigmata of latent myasthenia was done on 48 consecutive cases of hyperthyroidism who also had chronic myopathy by performing repeated nerve stimulation. Eight cases had abnormal neuromuscular transmission as in myasthenia gravis and one of these cases later developed clinical myasthenia involving the ocular muscles. Three other cases showed abnormal facilitation as in the Eaton-Lambert syndrome.

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.

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.

Sino-atrial Wenckebach conduction in thyrotoxic periodic paralysis: a case report.

A 28-year-old male presented with thyrotoxic periodic paralysis. On admission to hospital the serum potassium level was 1.4 mmol/l. The ECG showed classical features of hypokalaemia. In addition, sino-atrial block with Wenckebach conduction was also present. With the normalization of the serum potassium, the ECG became completely normal and showed no evidence of any arrhythmia.

The light and electron microscopic changes in the skeletal muscles during paralysis in thyrotoxic periodic paralysis.

Light microscopy of the biopsied quadriceps muscles during paralysis in 17 patients with thyrotoxic periodic paralysis (TPP) showed no abnormalities in 23.5 per cent, sarcolemmal nuclear proliferation in 35.5 per cent, atrophy of muscle fibers in 29.4 per cent, central nuclei in 23.5 per cent, fatty infiltration in 17.6 per cent, vacuolation in 11.8 per cent, and sarcoplasmic masses in 11.8 per cent. The muscle specimens were also examined by electron microscopy in ten of these patients; the main changes observed were vacuolation (90 per cent), mitochondrial abnormalities (100 per cent), glycogen granules accumulation (100 per cent), disruption of the myofibers (50 per cent), and changes in the T-system (40 per cent). The light and electron microscopic changes in the skeletal muscles during paralysis were not well correlated with the severity of the muscle weakness of hypokalemia.

Ultrastructure of the skeletal muscles in acromegaly--before and after hypophysectomy.

Electron microscopic examination of the skeletal muscles in a patient with acromegaly and marked elevation of the serum growth hormone reveals altered mitochondria (pleomorphism, elongation, matrical pallor, and cristae abnormalities), glycogen granules infiltration, inclusion bodies, and vesicular dilatations. Nine months after surgical removal of the pituitary tumor, the serum growth hormone levels were markedly diminished. A repeat examination of the skeletal muscle shows that the previous ultrastructural changes in the muscles are related to the growth hormone levels.

Current management of obesity.

Obesity is common and its prevalence is rising. In Singapore, a national health survey in 1992 showed that 5% of the adult population were obese and 21% were overweight. Obesity causes much morbidity and mortality and treatment is desirable. The majority of obese patients have no known cause but it is essential to exclude any underlying cause before treatment. Antiobesity drugs should be used as an adjunct to an adequate programme of dietary restriction, exercise and behavior modification. Serotonergic drugs and adrenergic agents are available in the treatment of obesity. The short-term efficacy and safety of antiobesity drugs such as fenfluramine and d-fenfluramine are proven. The long-term use of antiobesity drugs used singly or in combination remains to be established. Many peptides (cholecystokinin, glucagon, bombesin, neurotensin, etc) with weight reduction properties are undergoing extensive studies: their clinical applications are experimental. The treatment of obesity is difficult and frustrating and antiobesity drugs have an established short-term role. In morbid obesity where the life of the patient is in danger, surgery such as gastric plication may be life-saving. The recent discovery of leptin (1994) and neuropeptide Y (1995) are important breakthrough in obesity research; hopefully further research may produce more effective treatment of obesity in man.

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.

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.

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.

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).

Medical treatment of Cushing's syndrome with aminoglutethimide and ketoconazole.

We report a 54-year-old Chinese man with Cushing's syndrome from bilateral adrenal adenomata in whom surgery was contraindicated because of his intercurrent medical conditions. Instead, he was successfully treated with aminoglutethimide 0.75 gm/day (which reduced his 24-hour urinary free cortisol from 628 nmol/day to 177 nmol/day in 4 weeks), followed by ketoconazole 0.6 gm/day which continued to suppress the urinary free cortisol level. We conclude that aminoglutethimide or ketoconazole offers a viable non-surgical alternative to the treatment of Cushing's syndrome.

Fatal lactic acidosis from imported phenformin--report of two cases.

This report describes two diabetic patients who presented with severe lactic acidosis. Both patients had been taking a medicine (phenformin) which they had obtained from China, and which has been withdrawn from Singapore since 1977. Both cases were admitted with severe metabolic acidosis and were treated with intravenous sodium bicarbonate and intensive care support with unsuccessful outcomes.