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Biomedical subjects

S Yap

Publications and source records attributed to S Yap.

At least 19 recordsLinked to original sources
PubMed2005

DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice.

Type 1 diabetes (T1D), a T-cell-mediated autoimmune disease, could be attributed to many defects in nonobese diabetic (NOD) mice, including deficient expressions of costimulatory molecules that impair antigen presentation. Thus, this deficient antigen presentation may result in a reduced ability to induce a tolerogenic response through negative selection/regulation of autoreactive T cells. Improperly activated T cells seem to be able to induce autoimmune responses causing diabetes. To re-establish tolerance to autoantigens by modulating costimulation, we constructed and tested a new type of DNA vaccine encoding a membrane-bound preproinsulin (mbPPI) and a chimeric gene vector encoding mutant B7.1/CD40L (mB7.1/CD40L) fusion protein. This mutant B7.1 binds CTLA4 but not CD28. We report that young NOD mice immunized with mbPPI along with mB7.1/CD40L DNA vectors significantly reduced diabetes incidence while treatment with CTLA4/IgG1 exacerbated diabetes. In conclusion, the combination of mbPPI and mB7.1/CD40L was able to protect against autoimmunity and diabetes in NOD mice possibly by promoting a more efficient presentation of autoantigen PPI and inducing specific tolerance to PPI by negatively regulating autoreactive T cells.

Animals↗
PubMed2004

Public attitudes to emergency medical services in Singapore: EMS day 2002.

INTRODUCTION: In the year 2002, the Society for Emergency Medicine in Singapore Chapter of Paramedics organised the first emergency medical services (EMS) day, to educate the public about basic emergency response skills and to increase public awareness of the local EMS System. METHODS: This was an observational, cross-sectional study. A survey was conducted to find out about the knowledge and attitudes of the public and paramedic volunteer instructors towards the local EMS System. RESULTS: Two hundred and six (81.4 percent) out of 253 members of the public and 70 paramedics (100 percent) responded. For the public, the majority were females (86 percent), mean age (standard deviation [sd]) was 15.9 (7.9) years, range 11.0 to 67.0 years. For the paramedics, mean (sd) age was 26.6 (3.8) years. 61.9 percent were females. The public showed good knowledge of the emergency ambulance number and the indications for calling an ambulance. Public expectations of ambulance response times were significantly shorter than paramedics. They were also less comfortable with ambulance crews performing advanced life support interventions compared with the paramedics. CONCLUSION: Continuing efforts should be made to increase public awareness of the EMS system as well as to manage public expectations regarding response times and the roles of paramedics. EMS day represents one such opportunity.

Adolescent↗
PubMed2003

Classical homocystinuria: vascular risk and its prevention.

Homocystinuria due to cystathionine beta-synthase deficiency is the second most treatable aminoacidopathy. The reported incidence varies from 1 in 344,000 worldwide to 1 in 65,000 in Ireland. Untreated patients with homocystinuria have severe hyperhomocysteinaemia. Amongst its pathological sequelae, which include mental retardation, ectopia lentis and osteoporosis, vascular events remain the major cause of morbidity and mortality in untreated patients. Recognized modalities of treatment include pyridoxine, in combination with folic acid and vitamin B12; methionine-restricted, cystine-supplemented diet; and betaine. The natural history of vascular events is such that half will have an event before age 30 years and there is a predicted one event per 25 years at the time of maximal risk. In 158 patients with 2822 patient-years of treatment, there would be a predicted 112 events if left untreated, but instead only 17 vascular events were recorded during treatment (relative risk 0.09, 95% CI 0.036 to 0.228; p < 0.0001). Appropriate chronic treatment to lower hyperhomocysteinaemia is effective in reducing the potentially life-threatening vascular risk in patients with homocystinuria. These findings may also have relevance to the significance of mild hyperhomocysteinaemia that is commonly found in patients with premature vascular disease.

Homocystine↗
PubMed2001

The intellectual abilities of early-treated individuals with pyridoxine-nonresponsive homocystinuria due to cystathionine beta-synthase deficiency.

The pathological sequelae of untreated homocystinuria due to cystathionine beta-synthase deficiency include ectopia lentis, osteoporosis, thromboembolic events and mental retardation. They occur at a significantly higher rate with poorer mental capabilities (mean IQ = 57) in the untreated pyridoxine-nonresponsive individuals. The mental capabilities of 23 pyridoxine-nonresponsive individuals with 339 patient-years of treatment were assessed using age-appropriate psychometric tests and were compared to those of 10 unaffected siblings (controls). Of the 23 individuals, 19 were diagnosed through newborn screening with early treatment, two were late-detected and two were untreated at the time of assessment. Thirteen of the newborn, screened group who were compliant with treatment had no complications, while the remaining 6, who had poor compliance, developed complications. Good compliance was defined by a lifetime plasma free homocystine median < 11 micromol/L. The newborn screened, good compliance group (n = 13) with a mean age of 14.4 years (range 4.4-24.9) had mean full-scale IQ (FIQ) of 105.8 (range 84-120), while the poorly compliant group (n = 6) with a mean age of 19.9 years (range 13.8-25.5) had a mean FIQ of 80.8 (range 40-103). The control group (n = 10) with mean age of 19.4 years (range 9.7-32.9) years had a mean FIQ of 102 (range 76-116). The two late-detected patients aged 18.9 and 18.8 years had FIQ of 80 and 102, while the two untreated patients aged 22.4 and 11.7 years had FIQ of 52 and 53, respectively. There was no statistical evidence of significant differences between the compliant, early-treated individuals and their unaffected siblings (controls) except for the FIQ, which was significantly higher than that of the unaffected siblings (p = 0.0397). These data, despite the relatively small numbers, suggest that early treatment with good biochemical control (lifetime plasma free homocystine median < 11 micromol/L) seems to prevent mental retardation.

Adolescent↗
PubMed2001

Ocular findings among patients with late-diagnosed or poorly controlled homocystinuria compared with a screened, well-controlled population.

INTRODUCTION: Untreated homocystinuria (HCU) leads to systemic and ocular complications preventable by early treatment. METHODS: This study describes the ocular features in HCU patients who had late diagnosis or were noncompliant with treatment compared with a control group of early-diagnosed and well-controlled subjects. RESULTS: Fourteen late-diagnosed HCU patients with a median age at diagnosis of 4 years (range, 1.25-28 years) were studied. Five patients were born outside of Ireland or before screening began. All 14 patients had lens subluxation or dislocation at diagnosis. Only 28.6% of eyes had 20/40 vision or better. Three patients were tested for HCU following the diagnosis in a sibling. Four patients attended ophthalmology departments for a median of 12.8 years (range, 4-23 years) prior to diagnosis of HCU; all had steadily progressive myopic astigmatism and lens subluxation. Six patients who became poorly controlled in their teens or early twenties showed significant progression of their myopia, and 3 had phacodonesis or lens subluxation develop. All eyes in this group had 20/40 vision or better. Fifteen patients who were detected in the newborn period and remained well controlled had no evidence of lens subluxation. All of the control group patients had 20/20 vision bilaterally. The difference in visual acuity between late-diagnosed patients and the control group was highly significant (P =.0002). The differences in refractive errors between the groups were also highly significant (P =.0001). CONCLUSIONS: Lens subluxation is a principal feature of untreated HCU, yet we found a median lag period of 5.5 years in 4 cases before diagnosis. Young persons with marked and progressive myopia or idiopathic lens subluxation should be screened for HCU.

Adult↗
PubMed2001

Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study.

An inborn error of metabolism, homocystinuria due to cystathionine beta-synthase deficiency, results in markedly elevated levels of circulating homocysteine. Premature vascular events are the main life-threatening complication. Half of all untreated patients have a vascular event by 30 years of age. We performed a multicenter observational study to assess the effectiveness of long-term homocysteine-lowering treatment in reducing vascular risk in 158 patients. Vascular outcomes were analyzed and effectiveness of treatment in reducing vascular risk was evaluated by comparison of actual to predicted number of vascular events, with the use of historical controls from a landmark study of 629 untreated patients with cystathionine beta-synthase deficiency. The 158 patients had a mean (range) age of 29.4 (4.5 to 70) years; 57 (36%) were more than 30 years old, and 10 (6%) were older than 50 years. There were 2822 patient-years of treatment, with an average of 17.9 years per patient. Plasma homocysteine levels were markedly reduced from pretreatment levels but usually remained moderately elevated. There were 17 vascular events in 12 patients at a mean (range) age of 42.5 (18 to 67) years: pulmonary embolism (n=3), myocardial infarction (n=2), deep venous thrombosis (n=5), cerebrovascular accident (n=3), transient ischemic attack (n=1), sagittal sinus thrombosis (n=1), and abdominal aortic aneurysm (n=2). Without treatment, 112 vascular events would have been expected, for a relative risk of 0.09 (95% CI 0.036 to 0.228; P<0.0001). Treatment regimens designed to lower plasma homocysteine significantly reduce cardiovascular risk in cystathionine beta-synthase deficiency despite imperfect biochemical control. These findings may be relevant to the significance of mild hyperhomocysteinemia that is commonly found in patients with vascular disease.

Adolescent↗
PubMed2000

The prevalence of recurrent abdominal pain in 11- to 16-year-old Malaysian schoolchildren.

OBJECTIVE: To determine the prevalence of recurrent abdominal pain (RAP) among Malaysian school children aged from 11 to 16 years. METHODOLOGY: A preliminary cross-sectional survey in which three urban schools and three rural schools were selected randomly. Two classes were selected randomly from each year. A questionnaire was given to each child asking him or her about whether they had experienced abdominal pain occurring at least three times over a period of at least 3 months, interfering with normal daily activity. 1 Interfering with normal daily activity was defined as missing school and/or having to stop doing a routine daily activity on account of the pain. Girls whose pains were related to periods were excluded. After the forms had been completed, each child was again interviewed to ensure that Apley's criteria1 was fulfilled in cases of RAP. RESULTS: The overall prevalence of RAP among 1549 schoolchildren (764 boys; 785 girls) was 10.2% (95% confidence interval (CI), 8.8-11.8). There appeared to be a higher prevalence in rural schoolchildren (P = 0.008; odds ratio (OR) 1.58), in those with a lower family income (P < 0.001; OR 2.02) and in children whose fathers have a lower educational attainment (P = 0.002; OR 1. 92). There were no significant differences in the prevalence of RAP among children of different sex, age, ethnic group and family size. CONCLUSION: : In spite of differences in time and culture, the overall prevalence of 10.2% found in this study is similar to that determined by Apley.1 There are significant differences in the prevalence of RAP between children from rural and urban schools, among children with different family incomes and among children whose parents have different educational backgrounds.

Abdominal Pain↗
PubMed2000

Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta-synthase deficiency: effects of homocysteine-lowering therapy.

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency leads to severe hyperhomocysteinemia (HHcy). Vascular events (VE) remain the major cause of morbidity and mortality in the untreated patients with HCU. The study on the natural history of untreated HCU disclosed that, at the time of maximal risk, in other words beyond 10 years old, there was one event per 25 years. Recent studies from Australia (n = 32), The Netherlands (n = 28), and Ireland (n = 24) have documented the effects of long-term treatment on the vascular outcome of a total of 84 patients with 1314 patient-years of treatment for HCU. The mean (range) age was 27.8 (2.5 to 70) years. Five VE were recorded during treatment; one pulmonary embolism, two myocardial infarctions, and two abdominal aneurysms. All five VE occurred in B6-responsive patients at a mean (range) age of 48.8 (30 to 60) years. In 1314 patient-years of treatment, 53 VE would have been expected if they remained untreated; instead only 5 were documented, relative risk = 0.091 (95% confidence interval [CI] 0.043 to 0.190; p < 0.001). Appropriate homocysteine-lowering therapy for severe HHcy significantly reduced the vascular risk in patients with HCU. VE were rare with treatment despite the fact that the post-treatment homocysteine levels were several times higher than the cutoff point for homocysteine in the normal population. The present findings may have relevance to the current concept of "mild HHcy" as a risk factor for vascular disease, with elevated plasma homocysteine levels considerably lower than that of the post-treatment levels in this group of reported patients.

Adolescent↗
PubMed2000

Coronary artery bypass surgery on small patients.

Little research exists on the outcome of smaller patients who undergo coronary artery bypass graft surgery. The purpose of this study was to evaluate the outcomes of cardiac surgery in smaller patients (males with body surface area of 1.6 square meters or less, and women with 1.5 meters or less). A consecutive series of 4,358 patients undergoing bypass surgery was evaluated. Of these, 246 (5.6%) were classified as small patients. Smaller patients were more likely to be women, older and of Asian ethnicity. They were less likely to have undergone a prior cardiac surgery. Smaller patients were less likely to receive an arterial conduit (74% versus 99%; p<0.00001). Rates of post-surgery complications differed between small and normal size patients, with smaller patients more likely to require prolonged ventilator support (p <0.05), more likely to have acute renal failure (p<0.0001), more transfusions and re-operation for bleeding (p<0.05), higher death rate (5.7% versus 2.6%; p<0.01) and longer length of hospital stay (11.4 versus 8.3 days; p<0.00001). In multivariate analyses evaluating factors related to death, emergent surgery, poor ejection fraction and older patient age were independently related to mortality. Small body surface area was not an independent predictor. The results of this study indicate that smaller patients do have poorer outcomes associated with coronary artery bypass surgery. However, 90% of the smaller patients did have an event-free surgery. Surgeons may need to monitor these patients more closely and anticipate the increased risk and cost that is associated with this group.

Adult↗
PubMed1999

Factor V Leiden (Arg506Gln), a confounding genetic risk factor but not mandatory for the occurrence of venous thromboembolism in homozygotes and obligate heterozygotes for cystathionine beta-synthase deficiency.

Thrombosis is the major cause of morbidity and mortality in individuals with untreated classical homocystinuria (HCU) due to cystathionine beta-synthase deficiency and characterised by severe hyperhomocysteinaemia. In addition, mild and moderate hyperhomocysteinaemia and Factor V Leiden (FVL; Arg506Gln) have recently been identified as thrombotic risk factors. FVL. which renders resistance to activated Protein C, is the most common inherited genetic risk factor for thrombosis with a high allelic frequency amongst Caucasians. As thrombophilia is a multigenic disorder, 26 individuals with HCU (median age 17.6 years, range 3.5-32.8 years) and 36 obligate heterozygotes (median age 51.5 years, range 34-74 years) were screened for FVL. All the HCU individuals received treatment, except one, within 6 weeks of birth for those who were diagnosed at birth through the national newborn screening programme (n = 20) and at the time of diagnosis for those late detected (n = 5, mean age of starting treatment 4.9 years, range 1.4-11 years). All had been free from venous thrombosis, except one HCU individual and one HCU obligate heterozygote. Neither of the two individuals with venous thrombosis carried FVL. Two independent individuals with HCU (male 14.8 years; female 18.2 years) were heterozygous for FVL (allelic frequency 3.8%) and three independent HCU obligate heterozygotes (males 40 and 45.8 years; female 45.6 years) were also heterozygous for FVL (allelic frequency 4.16%). The findings in this small group suggest that FVL is not a mandatory but a significant confounding risk factor for the occurrence of thrombosis in HCU individuals and additional contributing factors may be required for thrombosis to occur in HCU obligate heterozygotes with FVL heterozygosity. Our data also suggest that treatment of HCU not only reduces the thrombotic risk in patients with isolated HCU but also in those with the additional FVL heterozygosity.

Adolescent↗
PubMed1998

Characterization of mutations in the cystathionine beta-synthase gene in Irish patients with homocystinuria.

We used single-strand conformational polymorphism and nucleotide sequencing to characterize defective cystathionine beta-synthase gene alleles in 18 independent Irish patients with homocystinuria. Six mutations were detected, three of which have been reported previously and three of which were novel. The novel mutations include T302C (L101P), C684G (N228K), and G1063C (A354P). Of the three, only T302C (L101P) was somewhat prevalent, being found in 3 of 37 independent alleles.

Cystathionine beta-Synthase↗
PubMed1998

Newborn screening for homocystinuria: Irish and world experience.

Newborn screening for cystathionine beta-synthase deficiency (homocystinuria; HCU) was started in the late 1960s using a bacterial inhibition assay (BIA). At least seven countries have either national or regional screening programmes; 12 programmes are known to have discontinued. The worldwide incidence of HCU is approximately 1 in 335,000 but varies from 1:65,000 (Ireland) to 1:900,000 (Japan). Methodologies include the BIA, one-dimensional or thin-layer amino acid chromatography and, more recently, tandem mass spectrometry. The BIA diagnostic cut off concentration of blood methionine varies from 67 to 270 micromol/ (10-40 mg/l) with a median of 135 micromol/l (20 mg/l). In Ireland, 25 cases of HCU from 19 families have been identified from 1.58 million newborn infants since 1971; 21 cases were detected through the screening programme. Of the four missed cases, three were breast-fed at the time of blood collection and one was pyridoxine responsive. These findings were in broad agreement with the results from five other programmes, in which approximately one in every five cases was missed by the screening programme. Early hospital discharge, low protein intake, high blood methionine cut-off concentration and pyridoxine responsiveness were all identified as contributing to missed cases.

Homocystinuria↗
PubMed1998

Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control.

Homocystinuria (HCU) due to cystathionine beta-synthase deficiency (Mudd et al 1964) was independently described by Gerritsen and colleagues (USA) and Carson and colleagues (Northern Ireland) in 1962. The worldwide frequency of HCU has been reported as 1 in 344,000, while that in Ireland is much higher at 1 in 65,000, based on newborn screening and cases detected clinically. The national newborn screening programme for HCU in Ireland was started in 1971 using the bacterial inhibition assay. A total of 1.58 million newborn infants have been screened over a 25-year period up to 1996. Twenty-five HCU cases were diagnosed, 21 of whom were identified on screening. The remaining four HCU cases were missed and presented clinically; three of these were breast-fed and one was pyridoxine responsive. Twenty-four HCU cases were pyridoxine nonresponsive. Once the status of pyridoxine responsiveness was identified, all pyridoxine nonresponsive cases, but one, were started on a low methionine, cystine-enhanced diet supplemented with pyridoxine, vitamin B12 and folate. Dietary treatment commenced within 6 weeks of birth (range 8-42 days) for those cases detected by screening, while for the late-detected cases treatment was started upon presentation and diagnosis. Biochemical control was monitored measuring deproteinized plasma methionine, free homocystine and cystine at least once a month. Review of the clinical outcome of the 25 HCU cases with 365.7 patient-years of treatment revealed no HCU-related complications in 18 screened, dietary-treated cases. Fifteen of these had lifetime medians of free homocystine < or = 11 mumol/L (range 4-11). The remaining three cases with higher lifetime medians of free homocystine (18, 18 and 48 mumol/L) have developed increasing myopia recently. Among the three screened non-dietary-compliant cases, two have ectopia lentis, one has osteoporosis and two have mental handicap. Of the four cases missed on screening, three presented with ectopia lentis after the age of 2 years. There were no thromboembolic events in any of the 25 HCU cases. The lifetime medians for methionine ranged from 47 to 134 mumol/L. The Irish HCU clinical outcome data suggest that newborn screening, early commencement of dietary treatment and a lifetime median of free homocystine of < or = 11 mumol/L had significantly reduced the probability of developing complications when it was compared to the untreated HCU data (Mudd et al 1985).

Adolescent↗