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Biomedical subjects

S Fernando

Publications and source records attributed to S Fernando.

At least 19 recordsLinked to original sources
PubMed2006

Patterns of disease among adults hospitalized with dengue infections.

BACKGROUND: Recent years have seen an increase in dengue infections among adults in Sri Lanka, with similar trends seen in many other countries. Data on the natural history and outcome of dengue in adults are quite limited. AIM: To study clinical and laboratory findings in adult dengue patients hospitalized in Sri Lanka during a recent major dengue epidemic. DESIGN: Prospective observational study. METHODS: Clinical, laboratory and demographic information were collected from adult patients with confirmed dengue infections (n = 108) treated in a general medical ward in Sri Lanka from 24 April to 31 July 2004. RESULTS: There were 68 male and 40 female patients, mean age 26.6 years. Dengue fever (DF) was seen in 33 (30.6%) and dengue haemorrhagic fever (DHF) in 75 (69.4%). Of the 37 (34.3%) with primary dengue infections, 19 (51.4%) developed DF and 18 (48.6%) developed DHF. Overall, 42 patients (38.9%) had bleeding manifestations. These adults showed differences in clinical and laboratory findings, disease severity and mortality, compared to children seen during the same epidemic. Secondary dengue infections were significantly associated with development of severe disease (OR 5.0, 95%CI 1.9-13.5, p < 0.001). Mortality was 3.7%. DISCUSSION: Pooling data on adult dengue patients from different regions should help us to understand the natural history of disease in this group. It would also help in developing evidence-based treatment guidelines and allocating limited and scarce health resources. Our data contribute towards this goal.

Adolescent↗
PubMed2006

Patterns of disease in Sri Lankan dengue patients.

BACKGROUND: Dengue is the most important mosquito borne viral infection in the world. Nearly 90% of infections occur in children. At present, prospective information on clinical and laboratory findings in South Asian children with dengue is generally lacking. AIM: To describe patterns of clinical disease in a cohort of children hospitalised with dengue during a major dengue epidemic in Sri Lanka. RESULTS: A total of 104 children were studied during a three month period. Eighteen had dengue fever (DF) and 86 had dengue haemorrhagic fever (DHF). Of those with DHF, 34, 23, 27, and 2 had DHF grade I, II, III, and IV respectively. Based on dengue serology testing, 13 of the DF patients had a primary infection and 5 had secondary dengue infections. In contrast, 68 of the children with DHF had secondary and 18 had primary dengue infections. Oral candidiasis was seen in 19 children. The odds ratio for children with secondary dengue infection to develop DHF was 9.8 (95% CI 3.1 to 31.2). CONCLUSION: Studies on patterns of paediatric dengue disease in different regions should help clinicians and health administrators make more informed and evidence based health planning decisions. It should also help towards mapping out dengue trends on a global scale. Oral candidiasis has not been previously documented in children suffering with acute dengue in Sri Lanka or elsewhere. Studying underlying reasons for this manifestation during future dengue epidemics may provide useful leads in understanding overall dengue pathogenesis.

Acute Disease↗
PubMed2004

Dengue viral infections.

Dengue viral infections are one of the most important mosquito borne diseases in the world. They may be asymptomatic or may give rise to undifferentiated fever, dengue fever, dengue haemorrhagic fever (DHF), or dengue shock syndrome. Annually, 100 million cases of dengue fever and half a million cases of DHF occur worldwide. Ninety percent of DHF subjects are children less than 15 years of age. At present, dengue is endemic in 112 countries in the world. No vaccine is available for preventing this disease. Early recognition and prompt initiation of appropriate treatment are vital if disease related morbidity and mortality are to be limited. This review outlines aspects of the epidemiology of dengue infections, the dengue virus and its mosquito vector, clinical features and pathogenesis of dengue infections, and the management and control of these infections.

Africa↗
PubMed2003

Linkage disequilibrium mapping provides further evidence of a gene for reading disability on chromosome 6p21.3-22.

Linkage disequilibrium (LD) mapping was used to follow up reports of linkage between reading disability (RD) and an 18 cM region of chromosome 6p21.3-22. Using a two-stage approach, we tested for association between RD and 22 microsatellite markers in two independent samples of 101 (Stage 1) and 77 (Stage 2) parent/proband trios in which RD was rigorously defined. The most significant replicated associations were observed between combinations of markers D6S109/422/1665 (Stage 1, P=0.002 (adjusted for multiple testing); Stage 2, P=0.0001) and D6S506/1029/1660 (Stage 1, P=0.02 (adjusted), Stage 2, P=0.0001). The only two-marker association observed in both samples was with D6S422/1665 (P=0.01, 0.04). No single marker showed replicated association but D6S506 produced values of P=0.01 and 0.08 which were significant when combined (P=0.02). We observed weaker and less consistent evidence of association in a region of confirmed linkage to RD in previous studies. The most consistently significant haplotypic association D6S109/422/1665, showed association with single-word reading, spelling, phonological awareness, phonological decoding, orthographic accuracy and random automised naming, but not with vocabulary or Attention Deficit Hyperactivity Disorder. Our findings strongly support the presence of a gene contributing to RD in a region of chromosome 6 between markers D6S109 and D6S1260, but do not rule out the presence of a gene between D6S1556 and MOG.

Adolescent↗
PubMed2001

Attention deficit hyperactivity disorder (ADHD) and the dopamine D4 receptor gene: evidence of association but no linkage in a UK sample.

Recent studies report association and linkage between attention deficit hyperactivity disorder (ADHD) and the 7-repeat allele of a 48 base-pair repeat in the dopamine D4 receptor gene (DRD4). We examined the frequency of this allele in a sample of probands with DSM-IV ADHD using a case-control design, as well as the transmission disequilibrium test (TDT) and haplotype-based haplotype relative risk (HHRR) in the subset of probands with DNA available from both parents. One hundred and thirty-two ADHD probands were compared with 189 controls (chi(2) = 6.17, 1 df, P = 0.01, OR = 1.73, 95% CI = 1.11--2.71). A total of 85 complete trios were available for within-family tests of association and linkage. Fifty-two heterozygous parents carrying one copy of the 7-repeat were informative for the TDT (29 transmitted vs 23 non-transmitted, chi(2) = 0.69). Analysis of the entire sample of 132 probands using TRANSMIT provided no additional evidence for excess transmission of the 7-repeat allele (58 transmitted vs 54 non-transmitted). HHRR gave similar results. We conclude that the case-control findings are likely to be falsely positive, resulting from genetic stratification. However we can not rule out alternative explanations of low statistical power and gene-environment correlation.

Alleles↗
PubMed2001

Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples.

Molecular genetic studies in attention deficit hyperactivity disorder (ADHD) have focussed on candidate genes within the dopamine system, which is thought to be the main site of action of stimulant drugs, the primary pharmacological treatment of the disorder. Of particular interest are findings with the dopamine transporter gene (DAT1), since stimulant drugs interact directly with the transporter protein. To date, there have been eight published association studies of ADHD with a 480 base-pair allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the gene, five that support an association and three against. We have analysed the same VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children with DSM-IV ADHD, using the transmission disequilibrium test (TDT). Results from the UK (chi(2) = 8.97, P = 0.001, OR = 1.95), but not the Turkish sample (chi(2) = 0.93, P = 0.34) support association and linkage between genetic variation at the DAT1 locus and ADHD. When considered alongside evidence from other published reports, there is only modest evidence for the association, consistent with a very small main effect for the 480-bp allele (chi(2) = 3.45, P = 0.06, OR = 1.15), however we find significant evidence of heterogeneity between the combined dataset (chi(2) = 22.64, df = 8, P = 0.004).

3' Untranslated Regions↗
PubMed2001

Limitations of conventional methods of self-monitoring of blood glucose: lessons learned from 3 days of continuous glucose sensing in pediatric patients with type 1 diabetes.

OBJECTIVE: Children with type 1 diabetes are usually asked to perform self-monitoring of blood glucose (SMBG) before meals and at bedtime, and it is assumed that if results are in target range, along with HbA(1c) measurements, then overall glycemic control is adequate. However, the brief glimpses in the 24-h glucose profile provided by SMBG may miss marked glycemic excursions. The MiniMed Continuous Glucose Monitoring System (CGMS) has provided a new method to obtain continuous glucose profiles and opportunities to examine limitations of conventional monitoring. RESEARCH DESIGN AND METHODS: A total of 56 children with type 1 diabetes (age 2-18 years) wore the CGMS for 3 days. Patients entered four fingerstick blood samples into the monitor for calibration and kept records of food intake, exercise, and hypoglycemic symptoms. Data were downloaded, and glycemic patterns were identified. RESULTS: Despite satisfactory HbA(1c) levels (7.7 +/- 1.4%) and premeal glucose levels near the target range, the CGMS revealed profound postprandial hyperglycemia. Almost 90% of the peak postprandial glucose levels after every meal were >180 mg/dl (above target), and almost 50% were >300 mg/dl. Additionally, the CGMS revealed frequent and prolonged asymptomatic hypoglycemia (glucose <60 mg/dl) in almost 70% of the children. CONCLUSIONS: Despite excellent HbA(1c) levels and target preprandial glucose levels, children often experience nocturnal hypoglycemia and postprandial hyperglycemia that are not evident with routine monitoring. Repeated use of the CGMS may provide a means to optimize basal and bolus insulin replacement in patients with type 1 diabetes.

Adolescent↗
PubMed2001

Antibodies to hepatitis C virus in patients who have had multiple transfusions in Sri Lanka.

OBJECTIVE: To determine the prevalence of antibodies to hepatitis C virus (HCV) in patients who have had multiple transfusions in Sri Lanka. SETTING: University Medical Unit at the National Hospital, Colombo, the Cancer Institute, Maharagama, and the Lady Ridgeway Children's Hospital, Colombo. PATIENTS: One to 5 ml of blood for serology was collected from 200 multiply transfused patients (those who have received five or more blood transfusions). METHOD: The sera were tested for HCV specific antibodies using a third generation anti-HCV enzyme immuno-assay (EIA) kit. All sera giving positive or intermediate EIA results were re-tested by a commercial HCV Western blot confirmatory test. RESULTS: Of the 200 patients, 10 (5%) were repeatedly positive and confirmed by the Western blot. 33% (7/21) of haemophiliacs and 10% (3/31) of thalassaemics were positive for antibodies to HCV. Antibodies were not detected in other groups of multiply transfused patients (haemolytic disease, aplastic anemias, chronic renal failure, haematological and other malignancies). Of the 200 patients, those who have had more than 80 blood transfusions had a significantly higher prevalence of antibodies to HCV. The frequency of HCV infection was also higher among those who had received factor concentrates. CONCLUSION: 33% of haemophiliacs and 10% of thalassaemics who have received multiple transfusions were infected with HCV. These findings warrant a larger study among blood donors, and justify screening and decontamination of blood and blood products given to haemophiliacs and thalassaemics in Sri Lanka.

Blood Transfusion↗
PubMed2000

Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia.

Low blood folate levels result in hyperhomocysteinemia, which has been associated with increased risk for cardiovascular disease, neural tube defects and cognitive deficits. Intake of dietary folates is the chief determinant of blood folate levels. Molecular defects in the intestinal absorption of dietary folates that precipitate low blood folate levels and hyperhomocysteinemia have not been investigated previously. Dietary folates are a mixture of polyglutamylated folates which are digested to monoglutamyl folates by the action of folylpoly-gamma-glutamate carboxypeptidase (FGCP), an enzyme that is anchored to the intestinal brush border membrane and is expressed by the glutamate carboxypepidase II (GCPII) gene. We cloned GCPII cDNA from human intestine and identified both a full-length transcript and a 93 bp shorter transcript lacking exon 18, consistent with the presence of a splice variant. In addition, we identified an H475Y polymorphism in GCPII in DNA samples from a healthy Caucasian population (n = 75). We found that membranes of transfected COS-7 cells expressing the H475Y variant GCPII cDNA had 53% less FGCP activity than did cells expressing wild-type GCPII. The presence of the H475Y GCPII allele was significantly associated with lower folate and higher homocysteine levels in this population. These data suggest that the presence of the H475Y GCPII allele impairs the intestinal absorption of dietary folates, resulting in relatively low blood folate levels and consequent hyperhomocysteinemia.

Aged↗
PubMed2000

Family-based association mapping provides evidence for a gene for reading disability on chromosome 15q.

Family-based association mapping was used to follow up reports of linkage between reading disability (RD) and a genomic region on chromosome 15q. Using a two-stage approach, we ascertained 101 (stage 1) and 77 (stage 2) parent-proband trios, in which RD was characterized rigorously. In stage 1, a set of eight microsatellite markers spanning the region of putative linkage was used and a highly significant association was detected between RD and a three-marker haplotype (D15S994/D15S214/D15S146: P and empirical P < 0.001). A significant association with the same three-marker haplotype was also observed in the second-stage sample (P = 0.009, empirical P = 0.006). Our data therefore provide strong evidence for one or more genes contributing to RD being located in the vicinity of the region including D15S146 and D15S994. In addition, our results provide support for association analysis being a useful method to map susceptibility loci for complex disorders.

Chromosome Mapping↗
PubMed2000

Comparative genome sequence analysis of the Bpa/Str region in mouse and Man.

The progress of human and mouse genome sequencing programs presages the possibility of systematic cross-species comparison of the two genomes as a powerful tool for gene and regulatory element identification. As the opportunities to perform comparative sequence analysis emerge, it is important to develop parameters for such analyses and to examine the outcomes of cross-species comparison. Our analysis used gene prediction and a database search of 430 kb of genomic sequence covering the Bpa/Str region of the mouse X chromosome, and 745 kb of genomic sequence from the homologous human X chromosome region. We identified 11 genes in mouse and 13 genes and two pseudogenes in human. In addition, we compared the mouse and human sequences using pairwise alignment and searches for evolutionary conserved regions (ECRs) exceeding a defined threshold of sequence identity. This approach aided the identification of at least four further putative conserved genes in the region. Comparative sequencing revealed that this region is a mosaic in evolutionary terms, with considerably more rearrangement between the two species than realized previously from comparative mapping studies. Surprisingly, this region showed an extremely high LINE and low SINE content, low G+C content, and yet a relatively high gene density, in contrast to the low gene density usually associated with such regions.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

A high-resolution microsatellite map of the mouse genome.

The European Collaborative Interspecific Backcross (EUCIB) resource was constructed for the purposes of high-resolution genetic mapping of the mouse genome (). The large Mus spretus/C57BL/6 backcross of 982 progeny has a genetic resolution of 0.3 cM at the 95% confidence level ( approximately 500 kb in the mouse genome). We have used the EUCIB mapping resource to develop a genome-wide high-resolution genetic map incorporating 3368 microsatellites. The microsatellites are distributed among 2302 genetically separated bins with 1.46 markers per bin on average. Average bin separation is 0.61 cM. This high-resolution genetic map will aid the construction of a robust physical map of the mouse genome.

Animals↗
PubMed1997

High-throughput microsatellite analysis using fluorescent dUTPs for high-resolution genetic mapping of the mouse genome.

The use of fluorescent end-labeled primers has proved successful for rapid, semiautomated genotyping of microsatellite loci. However, custom synthesis is expensive and costs can be prohibitive when a wide range of markers is to be analyzed for only a few genotypings. This particularly applies to high-resolution genetic mapping in the mouse either in the construction of global maps or in the production of local high-resolution genetic maps for positional cloning. We demonstrate here the use of fluorescent dUTPs for cost-effective, high-throughput microsatellite genotyping in the mouse. This alternative to the use of fluorescent end-labeled primers for semiautomated genotyping is potentially applicable to the construction of linkage maps in other species.

Animals↗
PubMed1995

AM630, a competitive cannabinoid receptor antagonist.

AM630 (iodopravadoline), a novel aminoalkylindole, has been found to attenuate the ability of a number of cannabinoids to inhibit electrically-evoked twitches of the mouse isolated vas deferens. It did not block the inhibitory effects of morphine or clonidine on the twitch response. AM630 behaved as a competitive antagonist of CP 55,940, WIN 55,212-2, anandamide and (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (AM356), producing rightward shifts in the log concentration response curves of these cannabinoid receptor agonists that were concentration-dependent, essentially parallel and not accompanied by any decrease in the size of maximal response. AM630 also produced concentration-dependent, parallel rightward shifts in the log concentration-response curve of delta 9-THC. However, these shifts were accompanied by a decrease in the maximal response. AM630 was markedly more potent as an antagonist of delta 9-THC and CP 55,940 (Kd = 14.0 and 17.3 nM respectively) than as an antagonist of WIN 55,212-2, AM356 or anandamide (Kd = 36.5, 85.9 and 278.8 nM respectively). These differences in dissociation constant imply that the mouse vas deferens may contain more than one type of cannabinoid receptor. The data also indicate that the receptors for which AM630 has the highest affinity may not be CB1 cannabinoid receptors as the CB1 selective antagonist, SR141716A, is known to be equally potent in attenuating the inhibitory effects of CP 55,940 and anandamide on the twitch response of the mouse vas deferens.

Animals↗