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Biomedical subjects

T N Williams

Publications and source records attributed to T N Williams.

At least 19 recordsLinked to original sources
PubMed2005

Cytokine mRNA expression and iron status in children living in a malaria endemic area.

Iron deficiency has been reported to affect both malaria pathogenesis and cell-mediated immune responses; however, it is unclear whether the protection afforded by iron deficiency is mediated through direct effects on the parasite, through immune effector functions or through both. We have determined cytokine mRNA expression levels in 59 children living in a malaria endemic area on the coast of Kenya who we selected on the basis of their biochemical iron status. Real-time quantitative reverse transcriptase polymerase chain reaction analysis of cytokine mRNA levels of peripheral blood mononuclear cells (PBMC) obtained from these children showed an association between interleukin-4 (IL-4) mRNA levels and all the biochemical indices of iron that we measured. Furthermore, IL-10 mRNA was higher in parasite blood smear-positive children than in blood smear-negative children irrespective of their iron status. This study suggests that IL-4 expression by PBMC may be affected by iron status.

Anemia, Iron-Deficiency↗
PubMed2004

HLA class-I and class-II allele frequencies and two-locus haplotypes in Melanesians of Vanuatu and New Caledonia.

HLA class-I and class-II allele frequencies and two-locus haplotypes were examined in 367 unrelated Melanesians living on the islands of Vanuatu and New Caledonia. Diversity at all HLA class-I and class-II loci was relatively limited. In class-I loci, three HLA-A allelic groups (HLA-A*24, HLA-A*34 and HLA-A*11), seven HLA-B alleles or allelic groups (HLA-B*1506, HLA-B*5602, HLA-B*13, HLA-B*5601, HLA-B*4001, HLA-B*4002 and HLA-B*2704) and four HLA-C alleles or allelic groups (HLA-Cw*04, HLA-Cw*01, HLA-Cw*0702 and HLA-Cw*15) constituted more than 90% of the alleles observed. In the class-II loci, four HLA-DRB1 alleles (HLA-DRB1*15, HLA-DRB1*11, HLA-DRB1*04 and HLA-DRB1*16), three HLA-DRB3-5 alleles (HLA-DRB3*02, HLA-DRB4*01 and HLA-DRB5*01/02) and five HLA-DQB1 alleles (HLA-DQB1*0301, HLA-DQB1*04, HLA-DQB1*05, HLA-DQB1*0601 and HLA-DQB1*0602) constituted over 93, 97 and 98% of the alleles observed, respectively. Homozygosity showed significant departures from expected levels for neutrality based on allele frequency (i.e. excess diversity) at the HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB3/5 loci on some islands. The locus with the strongest departure from neutrality was HLA-DQB1, homozygosity being significantly lower than expected on all islands except New Caledonia. No consistent pattern was demonstrated for any HLA locus in relation to malaria endemicity.

Ethnicity↗
PubMed2003

Reevaluation of flow cytometry for investigating antibody binding to the surface of Plasmodium falciparum trophozoite-infected red blood cells.

BACKGROUND: The acquisition of antibodies directed toward variant surface antigens (VSAs) expressed on the surface of the trophozoite-infected red blood cell is an important determinant of natural immunity to Plasmodium falciparum malaria. In recent years, flow cytometry has been used increasingly to investigate these responses, but few systematic assessments of this method are available in the published literature. METHODS: We developed a highly standardized experimental protocol and used parasites of the A4 laboratory clone, a monoclonal antibody to the VSA expressed by this clone (monoclonal antibody BC6), and a single pool of hyperimmune plasma to explore the parameters responsible for variations in VSA antibody responses measured by flow cytometry. RESULTS: Despite strenuous efforts to standardize our flow cytometric assay, we found marked variability in our assay readout, even between repeat experiments using identical antibody and parasite combinations. We found no remediable cause for much of this variability. However, we identified three major factors that we considered important contributors: antibody concentration, nonspecific antibody binding to uninfected red blood cells, and parasite agglutination. CONCLUSIONS: A number of potential pitfalls should be considered when designing and interpreting studies using this technique. In particular, we suggest that comparisons between assays conducted on different occasions can be made only through reference to carefully selected standards. We anticipate that a better appreciation of the factors that lead to assay variation will assist the design of improved experimental protocols.

Animals↗
PubMed2000

Genetic restriction of Plasmodium falciparum in an area of stable transmission: an example of island evolution?

To date, a high degree of polymorphism has been demonstrated at both the MSP1 and MSP2 loci in parasites from areas of stable malaria transmission. As a consequence, in such areas it is rare to find parasites of the same 2-locus genotype in more than 1 subject. We have studied MSP1 and MSP2 diversity in parasites collected from subjects with both symptomatic (n = 86) and asymptomatic (34) malaria living on the island of Santo, Vanuatu, an area of stable malaria transmission. Polymorphism at the MSP1 and MSP2 loci was considerably less than previously reported: only 5 MSP1 and 5 MSP2 alleles were detected and these showed no size variation within alleles. Santo is unique amongst the areas studied so far in that it is a small island at the limit of the malaria belt in the South Pacific. Thus, the evolution of the parasite population may have been affected by the small size and isolation of this island population. Moreover, limited parasite diversity may explain the unusually mild nature of Plasmodium falciparum disease on Santo. Islands have fascinated biologists for centuries and fuelled the advancement of evolutionary theory, since they are natural laboratories for the study of evolution. The simplicity of the Vanuatu P. falciparum population may facilitate the use and interpretation of sequence level analyses to address the mechanisms by which genetic diversity is generated and maintained in natural populations.

Adolescent↗
PubMed1999

Reduced soluble transferrin receptor concentrations in acute malaria in Vanuatu.

Soluble transferrin receptor (sTfR) concentration is a sensitive index of iron deficiency when used in conjunction with ferritin measurements in adults. One advantage of this assay is that unlike ferritin it does not appear to be affected by a range of infectious and inflammatory conditions or by pregnancy, rendering it a promising adjunct to the diagnosis of iron deficiency in tropical populations. We have measured plasma sTfR concentrations in a group of malaria patients (n = 21) and asymptomatic (18) and aparasitemic (76) controls in Vanuatu. Plasma sTfR concentration was significantly reduced in individuals with acute malaria (P = 0.003). While this observation provides evidence that erythropoeitic suppression may be an important etiologic component in malarial anemia, it also suggests that malaria may be a confounding factor when interpreting sTfR concentrations in such populations. The role of sTfR in the diagnosis of iron deficiency in tropical populations remains to be established.

Adolescent↗
PubMed1998

Alpha thalassaemia is associated with increased soluble transferrin receptor levels.

Although alpha+ thalassaemia is the commonest haemoglobinopathy in the world, it is not known if it is associated with significant ineffective erythropoiesis, a fact of importance in interpreting its complex interaction with malaria. To study this problem, we have measured the concentrations of soluble transferrin receptor (sTIR) and ferritin in 181 children from Vanuatu with heterozygous (68) and homozygous (46) alpha+ thalassaemia, and normal controls (67). sTfR concentrations were significantly higher in both homozygotes (mean 3.1 mg/l, range 2.8-3.4) and heterozygotes (2.86 mg/l, 2.6-3.2) compared to the normal controls (2.48 mg/l, 2.3-2.7), suggesting that although globin chain imbalance is minimal, there is ineffective erythropoiesis in both these conditions. Age was also shown to significantly affect sTfR, with peak levels occurring in the 5-9 years age group. Ferritin concentrations showed a similar trend, being higher in the thalassaemic groups, although this did not reach statistical significance. No individuals had low ferritin concentrations, although two had significantly elevated sTfR levels. These observations suggest that the alpha+ thalassaemia phenotype includes an expansion of the erythron, and may suggest possible mechanisms for the increased susceptibility in babies with alpha thalassaemia to both P. falciparum and P. vivax malaria.

Adolescent↗
PubMed1997

Plasma chloroquine concentrations in young and older malaria patients treated with chloroquine.

Plasma chloroquine (CQ) concentrations were measured by bioassay in young (0-4 years, n = 9) and older (5-60 years, n = 21) patients from Vanuatu infected with malaria following treatment with 25 mg/kg CQ over 3 days. CQ concentrations in young children tended to be lower than in older patients at days 2, 3, 4 and 7 after onset of treatment, with no drug present in two young children on day 3 and in one child on day 7. The greater difficulty experienced by young children to ingest all of their prescribed medication could have contributed to the lower CQ concentrations observed in the younger age group. The possibility that sub-therapeutic CQ concentrations are responsible for treatment failures in young children should be considered in areas where a high degree of CQ resistance has not yet been established. In such areas, the presence or prevalence of CQ-resistant infections should not be based on treatment failures observed in young children unless it can be confirmed that adequate blood CQ concentrations were achieved after treatment.

Adolescent↗
PubMed1997

Plasmodium vevax and P. falciparum: Biological interactions and the possibility of cross-species immunity.

The question of whether infection of humans with one species of malaria parasite alters the course of infection with another has been largely ignored because no such interaction was found during studies of induced malaria in patients with neurosyphilis. However, in animal model systems some degree of cross-species interaction is the rule rather than the exception. Furthermore, recent epidemiological observations in Vanuatu in the South Pacific have suggested a biological interaction between the dominant species, Plasmodium vivax, and P. falciparum. Kathryn Maitland, Tom Williams and Chris Newbold here speculate on the basis of these observations and other published findings that infection with P. vivax may result in the development of immunity sufficient to ameliorate the clinical course of subsequent infections with the potentially lethal parasite P. falciparum.

Journal Article↗
PubMed1997

Plasmodium vivax: a cause of malnutrition in young children.

We studied the aetiology of malnutrition in a cohort of 1511 children < 10 years old in Espiritu Santo, Vanuatu. Malnutrition was categorized using standard anthropometric criteria as: underweight [weight-for-age (WA) Z score < -2], wasting [weight-for-height (WH) Z < -2], or stunting [height-for-age (HA) Z < -2]. On multiple logistic regression analysis, the only factors significantly associated with wasting were age < 5 years [OR (95% CI) 1.8 (1.2-2.9), p = 0.01] and having suffered one or more episodes of clinical P. vivax malaria in the 6 months preceding nutritional assessment [OR 2.4 (1.3-4.4), p = 0.006]. The incidence of P. vivax infection was significantly higher during the 6 months preceding assessment in underweight vs. non-underweight children [incidence rate ratio (IRR) 2.6 (1.5-4.4), p < or = 0.0001). These groups had similar incidences of clinical P. falciparum infection during the same period [IRR 1.1 (0.57-2.1) p = 0.8] and of either species during the 6 months following assessment [IRR P. vivax 1.3 (0.9-2.0) p = 0.2; IRR P. falciparum 1.3 (0.9-1.9) p = 0.2]. In these children, P. vivax malaria was a major predictor of acute malnutrition; P. falciparum was not. Wasting neither predisposed to nor protected against malaria of either species. Although P. vivax malaria is generally regarded as benign, it may produce considerable global mortality through malnutrition.

Age Factors↗
PubMed1996

High incidence of malaria in alpha-thalassaemic children.

The alpha+-thalassaemias are the commonest known human genetic disorders, affecting up to 80 per cent of some populations. Although there is good evidence from both epidemiological and clinical studies that these gene frequencies reflect selection by, and protection from, malaria, the mechanism is unknown. We have studied the epidemiology of malaria in childhood on the southwestern Pacific island of Espiritu Santo in Vanuatu and here we report that, paradoxically, both the incidence of uncomplicated malaria and the prevalence of splenomegaly, an index of malaria infection, are significantly higher in young children with alpha+-thalassaemia than in normal children. Furthermore, this effect is most marked in the youngest children and for the non-lethal parasite Plasmodium vivax. The alpha+-thalassaemias may have been selected for their ability beneficially to increase susceptibility to P. vivax, which, by acting as a natural vaccine in this community, induces limited cross-species protection against subsequent severe P. falciparum malaria.

Animals↗
PubMed1996

Red blood cell phenotypes in the alpha + thalassaemias from early childhood to maturity.

The alpha+ thalassaemias are the most common single gene disorders of humans, yet little is known about their haematological characteristics in childhood. Blood samples have been collected randomly from more than 2000 individuals in village communities in Vanuatu in the South West Pacific and analysed for alpha thalassaemia and associated haematological changes. Here we describe the haematological effects of the alpha+ thalassaemias from early childhood through to maturity in this population. Mean cell volume (MCV) and mean cell haemoglobin (MCH) levels in individuals of normal, heterozygous and homozygous genotype differed significantly from one another throughout the entire age range (2P < 0.05). In contrast, haemoglobin levels in heterozygous and homozygous individuals were well maintained throughout development. Adults of normal genotype attain Hb levels which are indistinguishable from Caucasian reference values, a finding made all the more remarkable given the high frequency of clinical malaria in this population. It is clear from these findings that haematological data are valuable in screening for carriers of alpha+ thalassaemia in this population. MCH is clearly the most sensitive discriminator. None of the homozygous adults tested had an MCH of > 27 pg, whereas < 10% of normals had a value of < 27 pg. These data provide reference values for areas in which the alpha+ thalassaemias are common and often confused with iron-deficiency anaemia.

Adolescent↗
PubMed1995

Thalassaemia in Vanuatu, south-west Pacific: frequency and haematological phenotypes of young children.

The archipelago of Vanuatu situated in the South-West Pacific has a high frequency of alpha + thalassaemia and additionally on some of the islands there is a high frequency of beta thalassaemia. As part of a large cohort study to investigate the clinical effect of thalassaemia on malaria on the islands of Espiritu Santo and Maewo in Vanuatu, the gene frequencies of the thalassaemias were determined and blood counts were performed on a cohort of infants from birth to 3 years. The haematological phenotypes of the different thalassaemic genotypes are compared, providing a detailed description of the clinical manifestations of alpha + thalassaemia during early development. In addition, cross-sectional surveys of the population of the two islands were performed to establish the frequency of thalassaemia and other red cell polymorphisms and their geographical distribution.

Child, Preschool↗
PubMed1992

A study of hepatitis B and C prevalence and liver function in multiply transfused thalassemic and their parents.

A series of clinics were conducted in Delhi, India, in January, 1990. Of 54 patients with beta thalassemia major (mean age 7.6 years), 11.1% (6 out of 54) tested positive for antibodies to hepatitis C virus (anti HCV antibodies) and 66.6% (36 out of 54) showed evidence of hepatitis B virus (HBV) infection. Only 7.4% (4 out of 54) were hepatitis B surface antigen (HBsAg) positive. Of their parents, 2.2% (2 out of 90) tested positive for anti HCV antibodies, 28.9% (26 out of 90) showed evidence of previous HBV infection and 11.1% (10 out of 90) were HBsAg positive. We argue that HCV constitutes a greater long term threat than HBV in these patients due to the higher incidence of chronic liver disease. We would advocate the introduction of HCV screening of donated blood as well as reinforcing the importance of HBV screening and immunization.

Adolescent↗
PubMed1978

Difunisal in general practice.

A large-scale, double-blind comparative study was carried out in general practice to assess the relative efficacy and tolerance of difunisal and aspirin in patients suffering from acute painful conditions such as sprains and trains, osteoarthritis, etc. Patients received either 250 mg or 500 mg difunisal twice daily, or 600 mg aspirin 4-times daily for 5 days. The results of subjective assessments of pain relief from the daily records of 1902 patients (967 on diflunisal, 935 on aspirin), and the overall assessment of response by both doctors and patients, showed that diflunisal was significantly better than aspirin. Gastric side-effects were more common and more severe in patients receiving aspirin, and more often led to withdrawal of treatment.

Analgesics↗