Biomedical subjects
Publications and source records attributed to K P Chan.
We provide an analytic theory to explain Anghel et al's recent numerical finding whereby a maximum in the global performance emerges for a sparsely connected competitive population [Phys. Rev. Lett. 92, 058701 (2004)]. We show that the effect originates in the highly correlated dynamics of strategy choice, and can be significantly enhanced using a simple modification to the model.
A two-dimensional heterodyne detection technique based on the frequency-synchronous detection method [Jpn. J. Appl. Phys. 39, 1194 (2000)] is demonstrated for full-field optical coherence tomography. This technique, which employs a pair of CCD cameras to detect the in-phase and quadrature components of the heterodyne signal simultaneously, offers the advantage of phase-drift suppression in interferometric measurement. Horizontal cross-sectional images are acquired at the rate of 100 frames/s in a single longitudinal scan, with a depth interval of 6 microm, making the rapid reconstruction of three-dimensional images possible.
During 1999-2000, a sustained mumps outbreak in the highly vaccinated population in Singapore was attributed to vaccine failure associated with the Rubini vaccine strain. To explain this phenomenon, the complete nucleotide and amino acid sequences of the hemagglutinin-neuraminidase (HN) gene of eight mumps virus isolates from patients with parotitis in Singapore were determined and compared with those of known vaccine strains. Phylogenetic trees constructed on the basis of HN nucleotide and amino acid sequences showed that the Singapore mumps virus isolates were more closely related to the Urabe strain and belonged to a different cluster from the Rubini and Jeryl-Lynn strains. The Rubini vaccine showed only approximately 93% nucleotide and approximately 96% amino acid sequence similarity to Urabe and Singapore isolates. Compared with the vaccine strains, six of the eight isolates lacked the extracellular glycosylation site at residues 400-402. Other significant amino acid disparities (e.g., at residue 354) may also affect the antigenic properties of the HN protein. These findings suggest that the evolution and adaptation of the currently circulating mumps virus strains in the community has led to the emergence of genetically distinct viral strains. The low vaccine efficacy of the Rubini strain represents a major reason for the recent mumps resurgence and failure of mumps immunization in Singapore.
BACKGROUND: The search for biologically relevant gene-environment interactions has been facilitated by technological advances in genotyping. The design of studies to detect interactions on continuous traits such as blood pressure and insulin sensitivity is attracting increasing attention. We have previously described power calculations for such studies, and this paper describes the extension of those calculations to take account of measurement error. METHODS: The model considered in this paper is a simple linear regression relating a continuous outcome to a continuously distributed exposure variable in which the ratio of slopes for each genotype is considered as the interaction parameter. The classical measurement error model is used to describe the uncertainty in measurement in the outcome and the exposure. The sample size to detect differing magnitudes of interaction with varying frequencies of the minor allele are calculated for a given main effect observed with error both in the exposure and the outcome. The sample size to detect a given interaction for a given minor allele frequency is calculated for differing degrees of measurement error in the assessment of the exposure and the outcome. RESULTS: The required sample size is dependent upon the magnitude of the interaction, the allele frequency and the strength of the association in those with the common allele. As an example, we take the situation in which the effect size in those with the common allele was a quarter of a standard deviation change in the outcome for a standard deviation change in the exposure. If a minor allele with a frequency of 20% leads to a doubling of that effect size, then the sample size is highly dependent upon the precision with which the exposure and outcome are measured. rho(Tx) and rho(Ty) are the correlation between the measured exposure and outcome, respectively and the true value. If poor measures of the exposure and outcome are used, (e.g. rho(Tx) = 0.3, rho(Ty) = 0.4), then a study size of 150 989 people would be required to detect the interaction with 95% power at a significance level of 10(-4). Such an interaction could be detected in study samples of under 10 000 people if more precise measurements of exposure and outcome were made (e.g. rho(Tx) = 0.7, rho(Ty) = 0.7), and possibly in samples of under 5000 if the precision of estimation were enhanced by taking repeated measurements. CONCLUSIONS: The formulae for calculating the sample size required to study the interaction between a continuous exposure and a genetic factor on a continuous outcome variable in the face of measurement error will be of considerable utility in designing studies with appropriate power. These calculations suggest that smaller studies with repeated and more precise measurement of the exposure and outcome will be as powerful as studies even 20 times bigger, which necessarily employ less precise measures because of their size. Even though the cost of genotyping is falling, the magnitude of the effect of measurement error on the power to detect interaction on continuous traits suggests that investment in studies with better measurement may be a more appropriate strategy than attempting to deal with error by increasing sample sizes.
The Nipah virus is a newly identified paramyxovirus responsible for an outbreak of fatal encephalitis in Malaysia and Singapore. This paper reports the follow up clinical and magnetic resonance imaging findings in 22 affected subjects. Of 13 patients with encephalitis, one died, one was lost to follow up, and seven recovered. Among the four remaining patients, one had residual sixth nerve palsy, another suffered from severe clinical depression, and a third patient had evidence of retinal artery occlusion. One patient with delayed onset Horner syndrome had a single lesion in the cervical spinal cord. The brain magnetic resonance findings were stable or improved in nine patients over 18 months of follow up. Among a second group of nine asymptomatic seropositive abattoir workers, magnetic resonance examination in seven subjects revealed discrete small lesions in the brain; similar to those detected in encephalitis patients. These findings suggest that in addition to encephalitis, the newly discovered Nipah virus affects the spinal cord and the retina. Late clinical and radiological findings can occur in Nipah virus infections as with other paramyxoviruses.
BACKGROUND: We experienced a hand, foot and mouth disease (HFMD) outbreak in late year 2000 in Singapore. Between 14 September 2000 and 14 November 2000, a total of 3526 cases of HFMD were notified. There were 652 patients clinically suspected to have HFMD, who were seen at the Children's Emergency department of KK Women's and Children's Hospital of Singapore. OBJECTIVE OF THE STUDY: To study the clinical profile and virologic isolates of children admitted with HFMD during the outbreak. STUDY DESIGN: A prospective observational study. METHODS: Analysis of clinical features and virologic studies of 129 selected cases of HFMD and herpangina. RESULTS: The median age was 25 months with a range of between 4 months and 11 years. The majority were less than 5 years old (87%). The male-to-female ratio was 1.3:1. The median numbers of day of illness to presentation to the hospital was 3 days. Poor feeding and loss of appetite accounted for 76.7% of the admissions. Symptoms of vomiting were present in 37.2% of the cases. Oral ulcers were found in 96.1%, rashes over hands in 87.6%, over feet in 86.8% and over buttocks in 54.3%. Only 4.7% exhibited no rashes other than oral ulcers and were labelled as herpangina. The median duration of fever was 3 days, ranging from 2 to 7 days. An intravenous drip was required in 68.2% due to poor feeding. Viral cultures were sent in 89.1% of patients of whom 61.7% of patients were positive for viruses. Of the positive cultures, types of viruses isolated were EV71 (enterovirus 71) in 59/71 (83%), Coxsackievirus (A16, A24, A2 B3, B4) in 6/71 (8.4%), EV Untypable in 4/71 (5.6%) and mixed [EV71, echo25, cytomegalovirus (CMV)] in 2/71 (2.8%). EV71 was isolated mostly from stool samples followed by vesicle fluid culture and throat swabs. Two siblings aged 14 months and 2.5 years died during this period at day 5 of illness, their post-mortem examinations showed interstitial pneumonitis of the lungs. EV71 was isolated from the brain, heart, tonsils, intestines, throat and rectal swabs. A raised total white cell count of 14,000/L versus 12,000/L was significantly associated with complicated HFMD (P = 0.04). There was no difference in clinical characteristics of EV71 versus non-EV71 infections. Other viral illnesses, e.g. measles and CMV, may be mistaken for HFMD in the outbreak setting. CONCLUSIONS: HFMD tends to occur in younger children less than 5 years old due to low herd immunity. Poor feeding due to mouth ulcers accounts for admission to hospital requiring intravenous drip. EV71 accounted for the majority (75%) of the positive isolations, followed by coxsackievirus and untypable EV, mixed infection of echovirus or CMV. The yield of virus isolation was highest from stool, followed by vesicles and throat swabs. There is no difference in clinical characteristics of EV71 and non-EV71 virus infections. Enterovirus can cause mild symptoms to fatal death. Two infants died of interstitial pneumonitis and encephalitis.
AIM: An epidemic of hand, foot and mouth disease (HFMD) occurred in Singapore between September and November 2000. During the epidemic, there were four HFMD-related deaths and after the epidemic, another three HFMD-related deaths. This study sought to determine the risk factors predictive of death from HFMD disease. METHODS: The risk factors for fatal HFMD were determined by comparing clinical and laboratory findings between fatal cases (n = 7) and non-fatal controls (n = 131) admitted between September 2000 and April 2001. Enterovirus 71 positive fatal cases (n = 4) and non-fatal controls (n = 63) were also compared. RESULTS: In total, 138 HFMD cases with a mean age of 32 mo were studied. The majority of fatal cases died from interstitial pneumonitis, of whom three also had brainstem encephalitis. Of the 131 non-fatal cases, 3 had concomitant infections (respiratory syncytial virus bronchiolitis, right-sided pneumonia, Haemophilus influenzae type b meningitis), 2 had aseptic meningitis, and 1 each had transient drowsiness, intravenous immunoglobulin-related complications and transverse myelitis. By multivariate logistic regression analysis, atypical physical findings (p = 0.0006), raised total white cell count (p = 0.0128), vomiting (p = 0.0116) and absence of mouth ulcers (p = 0.043) were predictive of a fatal course. Although previous epidemics have described neurogenic pulmonary oedema as the main cause of death, the fatal cases in this study died mainly from interstitial pneumonitis alone or with myocarditis or encephalitis. CONCLUSION: Although HFMD is generally a benign disease, risk factors such as vomiting, absence of mouth ulcers, atypical presentation and raised total white cell count should alert the physician of a fatal course of illness.
Following the Nipah virus (NV) outbreak in March 1999 in Singapore, a serological survey was undertaken to screen individuals potentially exposed to NV. Blood samples were tested for NV IgM, IgG and neutralizing antibodies. Twenty-two (1.5%) of 1469 people tested had antibodies suggesting NV infection. Although 12 of the 22 infected people (54.6%) were symptomatic, the remaining 10 (45.4%) were clinically well and had no past history of compatible pulmonary or neurological disease. Clinical and serological findings suggested three people had been infected with NV before the outbreak was recognized. All those who were infected were male abattoir workers. None of the people who had contact with horses, and no healthcare workers exposed to infected patients and their specimens had detectable antibodies. This study provides evidence that NV causes asymptomatic infection. All of the antibody positive individuals had direct contact with pigs and there was no evidence of human to human transmission.
A recent outbreak of hand, foot, and mouth disease in Singapore in 2000 affected several thousand children and resulted in four deaths. The aim of this study was to determine the applicability of reverse transcription-PCR (RT-PCR) with universal pan-enterovirus primers and enterovirus 71 (EV71) type-specific primers for the direct detection of enteroviruses in clinical specimens derived from this outbreak. With the universal primers, EV71 RNA sequences were successfully detected by RT-PCR and direct sequencing in 71% of positive specimens. Three pairs of EV71 type-specific primers were evaluated for rapid detection of EV71 directly from clinical specimens and cell culture isolates. By using a seminested RT-PCR strategy, specific identification of EV71 sequences directly in clinical specimens was achieved, with a detection rate of 53%. In contrast, cell culture could isolate EV71 in only 20% of positive specimens. EV71 was detected directly from brain, heart, and lung specimens of two deceased siblings. Although more than one type of enterovirus was identified in clinical specimens from this outbreak, 90% of the enteroviruses were confirmed as EV71. The data demonstrate the clinical applicability of pan-enterovirus and seminested RT-PCR for the detection of EV71 RNA directly from clinical specimens in an outbreak situation.
2,3-Dihydro-3-(4'-hydroxyphenyl)-1,1,3-trimethyl-1H-inden-5-ol, 1, is a chiral bisphenol useful for preparation of polymers. Previous screening of commercial hydrolases identified lipase from Chromobacterium viscosum (CVL) as a highly regio- and enantioselective catalyst for hydrolysis of diesters of 1. The regioselectivity was > or =30:1 favoring the ester at the 5-position, while the enantioselectivity varied with acyl chain length, showing the highest enantioselectivity (E = 48 +/- 20 S) for the dibutanoate ester. In this paper, we use a combination of nonsymmetrical diesters and computer modeling to identify that the remote ester group controls the enantioselectivity. First, we prepared nonsymmetrical diesters of (+/-)-1 using another regioselective, but nonenantioselective, reaction. Lipase from Candida rugosa (CRL) showed the opposite regioselectivity (>30:1), allowing removal of the ester at the 4'-position (the remote ester in the CVL-catalyzed reaction). Regioselective hydrolysis of (+/-)-1-dibutanoate (150 g) gave (+/-)-1-5-dibutanoate (89 g, 71% yield). Acylation gave nonsymmetrical diesters that varied at the 4'-position. With no ester at the 4'-position, CVL showed no enantioselectivity, while hindered esters (3,3-dimethylbutanoate) reacted 20 times more slowly, but retained enantioselectivity (E = 22). These results indicate that the remote ester group can control the enantioselectivity. Computer modeling confirmed these results and provided molecular details. A model of a phosphonate transition state analogue fit easily in the active site of the open conformation of CVL. A large hydrophobic pocket tilts to one side above the catalytic machinery. The tilt permits the remote ester at the 4'-position of only the (S)-enantiomer to bind in this pocket. The butanoate ester fits and fills this pocket and shows high enantioselectivity. Both smaller and larger ester groups show low enantioselectivity because small ester groups cannot fill this pocket, while longer ester groups extend beyond the pocket. An improved large-scale resolution of 1-dibutanoate with CVL gave (R)-(+)-1-dibutanoate (269 g, 47% yield, 92% ee) and (S)-(-)-1-4'-monobutanoate (245 g, 52% yield, 89% ee). Methanolysis yielded (R)-(+)-1 (169 g, 40% overall yield, >97% ee) and (S)-(-)-1 (122 g, 36% overall yield, >96% ee).
OBJECTIVE: The purpose of this study was to compare the psychologic impact and client satisfaction of routine surgical evacuation of the uterus with medical evacuation in cases of spontaneous abortion. STUDY DESIGN: This was a prospective, randomized controlled trial. Two hundred eighteen women who were admitted to a university teaching hospital after spontaneous abortion and who consented to the study were randomized to routine surgical evacuation or medical evacuation of the uterus with the use of misoprostol. General psychologic well-being, level of depression, fatigue symptoms, psychiatric morbidity, social functioning, client satisfaction, and acceptance were measured in the 2 groups. RESULTS: The 2 groups did not differ in any of the measured psychological outcomes. Significantly more participants who experienced successful evacuation of the uterus with the misoprostol protocol would choose the same mode of treatment if they were able to choose again. However, participants for whom the medical treatment failed to evacuate the uterus and subsequent surgical evacuation was required are significantly less satisfied with the treatment. CONCLUSION: Medical treatment of spontaneous abortion with misoprostol is psychologically safe and more compatible with the ethnomedical beliefs of our Chinese participants. Client satisfaction and acceptance should be taken into consideration in the evaluation of treatment outcomes.
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Enterovirus 71 (EV71) is a frequent cause of hand, foot, and mouth disease (HFMD) epidemics associated with severe neurological sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997. Recent HFMD epidemics in this region have been associated with a severe form of brainstem encephalitis associated with pulmonary edema and high case fatality rates. In this study, we show that four genetic lineages of EV71 have been prevalent in the Asia-Pacific region since 1997, including two previously undescribed genogroups (B3 and B4). Furthermore, we show that viruses belonging to genogroups B3 and B4 have circulated endemically in Southeast Asia during this period and have been the primary cause of several large HFMD or encephalitis epidemics in Malaysia, Singapore, and Western Australia.
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INTRODUCTION: The landmark Paediatric AIDS Clinical Trials Group (PACTG) trial 076 showed in 1994 that antiretroviral therapy (ART) was effective in reducing maternal-child transmission of human immunodeficiency virus (HIV). This trial included antenatal oral zidovudine (ZDV), intrapartum intravenous ZDV, 6 weeks of oral ZDV to the babies and no breastfeeding. MATERIALS AND METHODS: This study is an on-going, prospective, open-label trial conducted from 1995 in which we enrolled HIV-infected pregnant women using the above strategy. Since 1997, the antenatal component of the regimen was modified to include lamivudine with ZDV. All babies had serial HIV polymerase chain reaction (PCR) and antibody tests including enzyme-linked immunosorbent assay (EIA), particle agglutination (PA) and Western blot (WB) at day 1, 1 week, 1, 2, 3, 6, 12 and 18 months. RESULTS: A total of 16 out of 19 eligible women were recruited from 1995 to 1999. The median age was 26 years (range 22 to 38 years), 38% were Singaporeans, median CD4 was 421 cells/mL (range 18 to 713 cells/mL) and median baseline gestational age was 23.5 weeks (range 8 to 32 weeks). None of the 16 children was infected as evidenced by 2 negative HIV PCRs including 1 done > 4 months old with a follow-up of 6 months to 2 years. There was a statistically significant difference between the 3 HIV antibody tests at 12 months of age (P = 0.003), there being more negative results with WB as compared to PA (P = 0.02). However, the difference between the 3 tests at 18 months was not statistically significant. No long-term side effects in these children were seen. CONCLUSION: Although the number of patients in this study is small, the absolute prevention of transmission (95% confidence intervals 0%-17%) in this cohort supports the recommendation of antenatal HIV screening and treatment of those infected.
The "medical model" is an insufficient explanation for the high suicide rates, but it does not mean that suicide is a different phenomenon in China. A multidimensional model (Fig. 6) is proposed to appreciate better the complexity of the problem, which can be applied to other countries. As in Figure 6, suicide and suicide attempts are conceptualized as a continuum of behaviors. The suicide method may modify the boundaries (i.e., the availability and choice of a lethal method may expand the size of completed suicides and vice versa). The spectrum of behaviors is also under the influence of individual factors, such as psychiatric disorders and personality, and local factors, such as local cultural norms, resources, and familial problems. All of these factors are subject to the influence of greater social forces. For example, psychiatric disorder increases the risk of suicide but is shaped by global forces. In the case of China, the importing of Western values influences the way Chinese people present their idioms of distress. Chinese people who tend to somatize start to psychologize more, [figure: see text] which in turn affects the rates of depression and subsequently the risk of suicide. The various factors also interact with one another. The diagnosis of disruptive and antisocial disorder illustrates how local factors modulate that of the individual. In Diagnostic and Statistical Manual of Mental Disorders, conduct disorder is defined by a series of "socially unacceptable behaviors," including aggression, destruction of property, theft, and violation of rules. Because biologic validity is lacking, the diagnosis (an individual factor) may vary widely in different cultural settings (a local factor). In China, conformity, self-control, and discipline are emphasized; subthreshold cases in the West already may be unacceptable in the Chinese setting and be labeled "disruptive." On the other hand, the cultural emphasis on conformity in the upbringing may reduce the display of such behaviors and lead to a lower prevalence of disruptive and antisocial disorders in China. With globalization, however, the "Chinese" values are more closely identified with the global culture, and a rising trend of personality disorders has been witnessed. The media are some of the powerful agents in transmitting these forces. The medical model of explaining the phenomenon of suicide with psychiatric disorders is not entirely satisfactory. The association of a high suicide rate with a low prevalence of psychiatric disorders in China challenges this conventional view. Rather than refuting this conventional model, the dynamic interaction with local sociocultural factors and global forces is emphasized. Empirical evidence is lacking, however, and should be the focus for future suicide research.
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A specific and sensitive method based on RT-PCR was developed to detect enterovirus 71 (EV71) from patients with hand, foot and mouth disease, myocarditis, aseptic meningitis and acute flaccid paralysis. RT-PCR primers from conserved parts of the VP1 capsid gene were designed on the basis of good correlation with sequences of EV71 strains. These primers successfully amplified 44 strains of EV71 including 34 strains isolated from Singapore in 1997 and 1998, eight strains from Malaysia isolated in 1997 and 1998, one Japanese strain and the neurovirulent strain EV71/7423/MS/87. RT-PCR of 30 strains of other enteroviruses including coxsackievirus A and B, and echoviruses failed to give any positive amplicons. Hence, RT-PCR with these primers showed 100% correlation with serotyping. Direct sequencing of the RT-PCR products of 20 EV71 strains revealed a distinct cluster with two major subgroups, thus enabling genetic typing of the viruses. The genetic heterogeneity of these strains culminated in amino acid substitutions within the VP1, VP2 and VP3 regions. The sequencing of a 2.9 kb fragment comprising the capsid region and the major part of 5' UTR of two Singapore strains revealed that they belonged to a group distinct from the prototype EV71/BrCr strain and the EV71/7423/MS/87 strain. The dendrogram generated from 341 bp fragments within the VP1 region revealed that the strains of Singapore, Malaysia and Taiwan belong to two entirely different EV71 genogroups, distinct from the three genogroups identified in another recent study.