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K P McAdam

Publications and source records attributed to K P McAdam.

At least 19 recordsLinked to original sources
PubMed2005

Mycobacterium tuberculosis genome-wide screen exposes multiple CD8 T cell epitopes.

Mounting evidence suggests human leucocyte antigen (HLA) class I-restricted CD8(+) T cells play a role in protective immunity against tuberculosis yet relatively few epitopes specific for the causative organism, Mycobacterium tuberculosis, are reported. Here a total genome-wide screen of M. tuberculosis was used to identify putative HLA-B*3501 T cell epitopes. Of 479 predicted epitopes, 13 with the highest score were synthesized and used to restimulate lymphocytes from naturally exposed HLA-B*3501 healthy individuals in cultured and ex vivo enzyme-linked immunospot (ELISPOT) assays for interferon (IFN)-gamma. All 13 peptides elicited a response that varied considerably between individuals. For three peptides CD8(+) T cell lines were expanded and four of the 13 were recognized permissively through the HLA-B7 supertype family. Although further testing is required we show the genome-wide screen to be feasible for the identification of unknown mycobacterial antigens involved in immunity against natural infection. While the mechanisms of protective immunity against M. tuberculosis infection remain unclear, conventional class I-restricted CD8(+) T cell responses appear to be widespread throughout the genome.

CD8-Positive T-Lymphocytes↗
PubMed2001

Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial.

BACKGROUND: RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a new adjuvant (AS02). We did a randomised trial of the efficacy of RTS,S/AS02 against natural P. falciparum infection in semi-immune adult men in The Gambia. METHODS: 306 men aged 18-45 years were randomly assigned three doses of either RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxine/pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P. falciparum. Analysis was per protocol. FINDINGS: 250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/AS02 was safe and well tolerated. P. falciparum infections occurred significantly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's test p=0.018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8.0-53, p=0.014). Protection seemed to wane: estimated efficacy during the first 9 weeks of follow-up was 71% (46-85), but decreased to 0% (-52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circumsporozoite protein and strong T-cell responses. Protection was not limited to the NF54 parasite genotype from which the vaccine was derived. 158 men received a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4-71, p=0.037). INTERPRETATION: RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P. falciparum infection.

Adult↗
PubMed2001

The influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental transfer of antibodies and IgG subclasses in a rural West African population.

Two hundred thirteen mother-baby pairs in The Gambia were studied to determine the influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental antibody transfer. Antibody transfer for herpes simplex virus 1 (HSV-1), respiratory syncytial virus (RSV), and varicella-zoster virus (VZV) was significantly reduced by placental malaria infection by 69%, 58%, and 55%, respectively. Maternal hypergammaglobulinemia was associated with a significant reduction in antibody transfer for HSV-1, RSV, VZV, and pneumococcus by 89%, 90%, 91%, and 88%, respectively. In addition, placental malaria infection was associated with a significant reduction in transfer of IgG1, IgG2, and IgG4 (P<.01, P=.01, and P=.03, respectively) but not of IgG3 (P=.59). Maternal hypergammaglobulinemia significantly impaired the transfer of IgG1 and IgG2 (P=.01) but not of IgG3 or IgG4 (P=.62 and P=.59, respectively). Placental malaria infection and maternal hypergammaglobulinemia were associated with reduction in the transplacental transfer of these specific antibodies, IgG1, and IgG2 in this Gambian population.

Adult↗
PubMed2001

HLA-B*35-restricted CD8 T cell epitopes in the antigen 85 complex of Mycobacterium tuberculosis.

Few target epitopes have been described for human CD8 T lymphocytes in antigens of Mycobacterium tuberculosis. By use of a reverse immunogenetics approach, 23 motif-bearing peptides of the Ag85 complex were tested for binding to HLA-B*35, one of the common B-types in West Africa. Three 9-mer peptides bound with high affinity to HLA-B*3501 and displayed low dissociation rates of peptide-major histocompatibility complexes (MHCs). IC(50) and half-life values of peptide-MHC class I complexes were in the same range as reported earlier for other immunogenic peptides. Immune responses against peptide Ag85C (aa 204-212) WPTLIGLAM were characterized in detail. Peptide-stimulated effector cells were able to kill macrophages infected with M. tuberculosis or bacille Calmette-Guérin. Peptide-specific CD8 T cells could be visualized by using HLA-B*3501 tetramers and were shown to produce interferon-gamma and tumor necrosis factor-alpha. Together with other published epitopes, these peptides can be used to study more closely the role of CD8 T cells in mycobacterial infection and tuberculosis.

Acyltransferases↗
PubMed2001

Neonatal bacillus Calmette-Guérin vaccination induces adult-like IFN-gamma production by CD4+ T lymphocytes.

The immaturity of the neonatal immune system in mice is associated with defective IFN-gamma production and Th2-biased immune responses. In this study, infants vaccinated at birth with BCG produced similar concentrations of IFN-gamma in response to PPD and showed similar frequencies of IFN-gamma-producing lymphocytes as compared to immune adults. Infants and adults produced only low concentrations of IL-4 and IL-5. CD4+ T lymphocytes were the main source of IFN-gamma. Similar proportions of Th1 and Th0 PPD-specific T cell clones were observed in infants and adults. This study demonstrates that the human neonatal immune response to BCG is not biased towards Th2 and is characterized by the predominant production of IFN-gamma by CD4+ T lymphocytes.

Adolescent↗
PubMed2001

Geographical variation in prevalence of hypertension within The Gambia.

Hypertension has become an important public health problem for sub-Sahara Africa. In a previous nationwide study, we observed a high degree of geographical variation in the prevalence of diastolic hypertension. Geographical variation provides essential background information for the development of community randomised trials could suggest aetiological mechanisms, inform control strategies and prompt further research questions. We designed a follow-up study from the nine high-prevalence communities, and from 18 communities where hypertension was found least prevalent (controls). In each community, 50 households were randomly selected. In each household, an (unrelated) man and woman were enrolled. The risk for hypertension (blood pressure > or =160/95 mm Hg) was higher in the high prevalence communities compared to the control villages (adjusted OR = 1.7, 95% CI 1.3-2.2). The observed coefficient of variation in hypertension prevalence, k, was 0.30. Thus we confirmed significant geographical variation in prevalence of hypertension over time, which has implications for planning of interventions.

Adolescent↗
PubMed2001

Atopy, intestinal helminth infection and total serum IgE in rural and urban adult Gambian communities.

BACKGROUND: The rarity of atopy in traditional societies has been attributed to high parasite-driven blocking IgE concentrations. Information is lacking on the relationship between atopy, IgE and intestinal helminth infection in African populations. OBJECTIVE: To determine the prevalence of atopy and intestinal helminth infection and to relate these to wheeze history and serum total IgE in a community sample of adults from an urban (Banjul) and a rural (Farafenni) area of the Gambia. METHODS: Six hundred and ninety-three adults were interviewed about respiratory symptoms using a modified version of the IUTLD questionnaire, and had skin prick testing using four allergens. Stools were examined after formol-ether concentration. Total serum IgE concentration was measured in a subset of participants. RESULTS: The prevalence of atopy (mean weal diameter > or = 3 mm) in the urban and rural area was 35.3% and 22.5% (P = 0.05); D. pteronyssinus and Mold mix being the common sensitizing allergens. Prevalence of wheeze in the previous 12 months was 4.4% and 3.5% for the urban and rural areas, respectively. Wheezing was not significantly associated with atopy. Seventeen per cent of urban and 8.2% of rural subjects had helminths detected in stools. There was an inverse association between atopy and intestinal helminth infection; 7% of atopic subjects had helminths, compared to 13% of non-atopic subjects (unadjusted odds ratio 0.51, 95%CI 0.24-1.1, P = 0.09; adjusted odds ratio 0.37, 95%CI 0.15-0.92, P = 0.03). Non-atopics had total serum IgE concentrations about 2.5 times the upper limit of the reference range in non-atopic Western populations. Geometric mean total serum IgE concentration was significantly higher among atopic subjects (570 IU/mL, IQR 91-833) than non-atopic subjects (259 IU/mL, IQR 274-1303) (P < 0.001). IgE concentration was not associated with the presence of helminth infection. CONCLUSION: Further studies are needed to clarify why asthma is still relatively uncommon in spite of the prevalence of atopy in Gambian adults. Our data are also compatible with the idea that atopy might protect against helminth infection.

Adolescent↗
PubMed2001

Asthma, smoking and chronic cough in rural and urban adult communities in The Gambia.

BACKGROUND: Asthma is reported to be rare in traditional rural communities, but is thought to be increasing as lifestyles become more urbanized or 'western'. OBJECTIVES: A community-based survey of non-communicable diseases was conducted from October 1996 to June 1997, and included comparison of the prevalence of asthma, smoking and chronic cough in rural and urban Gambia. METHODS: A cluster sample survey was conducted in a random sample of rural and urban adults (> or = 15 years of age). Subjects were asked about respiratory symptoms using a locally adapted version based on the IULTD questionnaire. Spirometry (basal, methacholine provocation and reversibility with a bronchodilator) and skin prick tests were performed on a randomly selected subsample of all subjects and those who, when interviewed, said they wheezed or had been diagnosed as asthmatic by a doctor. RESULTS: Out of 2166 participants in the urban population, 4.1% reported having had wheezing or whistling in the chest in the previous 12 months, 3.6% reported doctor-diagnosed asthma, and 0.6% chronic cough. In the rural population with 3223 participants these figures were 3.3%, 0.7% and 1.2%, respectively. Wheeze was more common in women, cough for 3 months of the year was more common in the age-groups 45+. Those who reported that they currently smoked accounted for 34% in urban and 42% in rural men. Figures were much lower for women (1.5% and 6.0%). Seven out of 574 randomly selected subjects (1.4%) exhibited bronchial hyper-responsiveness to methacholine challenge. Four of 133 (3.0%) people with self-reported wheeze and 3/69 (4.3%) participants with doctor-diagnosed asthma reacted positively on bronchial provocation with methacholine. There was a remarkably high prevalence of positive skin prick tests to aeroallergens: 38% in participants with a history of wheeze and 27% in those without. CONCLUSION: The prevalence of wheeze (particularly in association with bronchial hyper-responsiveness) was low in both rural and urban Gambia. This is in contrast to the relatively high prevalence of positive skin prick tests to aeroallergens (in both wheezers and non-wheezers), questioning the mechanisms of interaction between allergy and asthma and the presence of protective factors against asthma in this West African population. The high smoking rates justify international concern about tobacco marketing in developing societies.

Adolescent↗
PubMed2001

A template for improved prevention and control of cardiovascular disease in sub-Saharan Africa.

Cardiovascular disease (CVD) is rapidly becoming an important public health problem in sub-Saharan Africa, yet the response so far is often minimal and inadequate. While there is, undoubtedly, a 'double burden of disease' (persisting infectious diseases co-existing with emerging non-communicable disease), this is hardly reflected in current health planning, possibly due to a limited appreciation of the changing pattern of CVD and CVD risk factor exposure. In a situation where there are also considerable budget constraints and well-established infectious disease priorities, it is difficult to implement effective interventions for prevention or treatment of CVD. Yet such planning is urgently needed and a template for a comprehensive programme, adaptable to local situations, is presented here. The first step is to raise awareness and create evidence-based commitment among policy-makers, which could lead to the establishment of a multi-sectoral CVD unit at national level. Programmes need to focus on prevention of modifiable risk factors at population level, involving a wide range of institutions and individuals. Recommended strategies include decentralizing the design and implementation of programmes, with appropriate standardized surveillance of major risk factors, all complemented by operational, epidemiological and basic research.

Africa South of the Sahara↗
PubMed2001

Tuberculosis contacts but not patients have higher gamma interferon responses to ESAT-6 than do community controls in The Gambia.

The Mycobacterium tuberculosis antigen ESAT-6 has been proposed for tuberculosis immunodiagnosis. In The Gambia, 30% of community controls produced gamma interferon (IFN-gamma) in response to ESAT-6. Increased proportions of responders and intensities of responses were found in household contacts. Responses that were initially low in tuberculosis patients increased after treatment. An ESAT-6 IFN-gamma assay will be of limited use in the diagnosis of tuberculosis in countries where tuberculosis is endemic. Its role in contact tracing should be evaluated further.

Adolescent↗
PubMed2001

Polarization of PPD-specific T-cell response of patients with tuberculosis from Th0 to Th1 profile after successful antimycobacterial therapy or in vitro conditioning with interferon-alpha or interleukin-12.

The T helper (Th) 1/Th2 balance in the T-lymphocyte response to purified protein derivative (PPD) was evaluated at the clonal level in six Italian and five Gambian patients with pulmonary tuberculosis (TB) before and after antimycobacterial therapy, as well as in five Gambian and four Italian healthy immune control subjects. In untreated patients, most PPD-specific clones derived from either peripheral blood or pleural effusions showed a Th0 cytokine profile (production of both interferon [IFN]-gamma and interleukin [IL]-4/IL-5). After 6 mo of therapy and clinical healing, most PPD-specific clones showed a polarized Th1 profile (production of IFN-gamma but not IL-4/IL-5) in both Italian and Gambian patients. The Th1 polarization was less marked in Gambian than in Italian patients and failed to occur in another group of four Italian patients who experienced treatment failure. The cytokine profile observed after successful therapy in patients with TB was similar to that found in healthy control subjects. T-cell clones of undefined specificity generated from PPD-stimulated cultures showed a similar Th0/Th2 bias in Gambian individuals and Italian patients with treatment failure. The Th0/Th2-biased responses in Gambian patients before therapy could be modulated in vitro by IFN-alpha or IL-12, which induced a Th1 polarization of both PPD-specific and bystander T cells. Our data show that active TB associates with a predominant Th0 response to mycobacterial antigens that could play a role in the pathogenesis of the disease. Adjunctive immunotherapy using Th1-polarizing cytokines could increase host defense against mycobacteria and accelerate healing.

Adult↗
PubMed2001

Obesity and undernutrition and cardiovascular risk factors in rural and urban Gambian communities.

OBJECTIVES: This study documented the prevalence of and cardiovascular risk factors associated with obesity and undernutrition in the Gambia. METHODS: Adults (> or =15 years; N = 5373) from rural and urban areas completed a questionnaire; their height, weight, and waist and hip circumferences were measured, and their cardiovascular risk factors were assessed. RESULTS: Prevalence of undernutrition (body mass index < 18 kg/m(2)) was 18.0%; all strata of society were affected. Prevalence of obesity (body mass index > or =30 kg/m(2)) was 4.0% but was higher (32.6%) among urban women 35 years or older. Cardiovascular risk factors were more prevalent among obese participants. CONCLUSIONS: Undernutrition coexists with obesity, demonstrating a "double burden of disease." Differential interventions should focus on high-risk groups; prevention needs a multisectorial approach.

Adolescent↗
PubMed2001

Changing causes of death in the West African town of Banjul, 1942-97.

OBJECTIVE: To determine trends in the causes of death in a West African town. Mortality caused by infectious diseases is reported to be declining while degenerative and man-made mortality factors are increasingly significant. Most mortality analyses for sub-Saharan Africa have involved extrapolation and have not been derived from community-based data. METHODS: Historical data on causes of death coded by physicians were analysed for the urban population of Banjul for the period 1942-97. As the calculation of rates is not possible in the absence of a reliable population denominator, age-standardized proportional mortality ratios (PMRs) for men and women by major groups of causes of death were calculated, using the 1942-49 data for reference purposes. FINDINGS: Most deaths were attributable to communicable diseases. There was a shift in proportional mortality over the study period: the contribution of communicable diseases declined and that of noncommunicable diseases and injuries increased. These trends were more marked among men than women. CONCLUSION: The data illustrate that while noncommunicable diseases and injuries are emerging as important contributors to mortality in sub-Saharan Africa, communicable diseases remain significant causes of mortality and should not be neglected.

Adult↗
PubMed2001

Factors affecting time delay to treatment in a tuberculosis control programme in a sub-Saharan African country: the experience of The Gambia.

SETTING: Rural and urban health centres in The Gambia, West Africa. OBJECTIVES: To estimate the time delay between onset of symptoms and initiation of treatment and identify the risk factors influencing the delay in patients with tuberculosis (TB). DESIGN: Structured interviews with newly diagnosed TB patients aged over 15 years presenting to TB control staff in four health centres. RESULTS: A total of 152 TB patients were interviewed. The median delay from onset of symptoms to commencement of treatment was 8.6 weeks (range 5-17). Delay to treatment was independent of sex, but was shorter in young TB patients. The median delay was longer in rural than in urban areas (12 weeks [range 8.5-17] vs. 8 [4-12], P < 0.01) and in those who did not attend school, but this effect disappeared after adjusting for age and area of residence. Patients who reported haemoptysis as one of their initial symptoms had shorter delays to treatment. There was no relation between duration of delay to treatment and cure rate, but longer delay did increase the risk of death. CONCLUSION: Starting TB patients on treatment as early as possible plays a major role in reducing disease transmission in the community. Key to this is increasing awareness of the signs and symptoms of TB and ensuring easy access to diagnostic facilities and treatment.

Adolescent↗
PubMed2001

Family history: an opportunity for early interventions and improved control of hypertension, obesity and diabetes.

OBJECTIVE: To examine whether a family history of high-risk groups for major noncommunicable diseases (NCDs) was a significant risk factor for these conditions among family members in a study population in the Gambia, where strong community and family coherence are important determinants that have to be taken into consideration in promoting lifestyle changes. METHODS: We questioned 5389 adults as to any first-degree family history of major noncommunicable diseases (hypertension, obesity, diabetes and stroke), and measured their blood pressure (BP) and body mass index (BMI). Total blood cholesterol, triglyceride, uric acid, and creatinine concentrations were measured in a stratified subsample, as well as blood glucose (2 hours after ingesting 75 g glucose) in persons aged > or = 35 years. FINDINGS: A significant number of subjects reported a family history of hypertension (8.0%), obesity (5.4%), diabetes (3.3%) and stroke (1.4%), with 14.6% of participants reporting any of these NCDs. Subjects with a family history of hypertension had a higher diastolic BP and BMI, higher cholesterol and uric acid concentrations, and an increased risk of obesity. Those with a family history of obesity had a higher BMI and were at increased risk of obesity. Individuals with a family history of diabetes had a higher BMI and higher concentrations of glucose, cholesterol, triglycerides and uric acid, and their risk of obesity and diabetes was increased. Subjects with a family history of stroke had a higher BMI, as well as higher cholesterol, triglyceride and uric acid concentrations. CONCLUSIONS: A family history of hypertension, obesity, diabetes, or stroke was a significant risk factor for obesity and hyperlipidaemia. With increase of age, more pathological manifestations can develop in this high-risk group. Health professionals should therefore utilize every opportunity to include direct family members in health education.

Adult↗
PubMed2000

Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.

Human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis. We have conducted a two-stage genome-wide linkage study to search for regions of the human genome containing tuberculosis-susceptibility genes. This approach uses sibpair families that contain two full siblings who have both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis-susceptibility gene, affected sibpairs inherit the same parental alleles more often than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sibpairs from The Gambia and South Africa. Seven chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis were identified. To identify whether any of these regions contained a potential tuberculosis-susceptibility gene, 22 markers from these regions were genotyped in a second set of 81 sibpairs from the same countries. Markers on chromosomes 15q and Xq showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. The potential identification of susceptibility loci on both chromosomes 15q and Xq was supported by an independent analysis designated common ancestry using microsatellite mapping. These results indicate that genome-wide linkage analysis can contribute to the mapping and identification of major genes for multifactorial infectious diseases of humans. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many different populations.

Adolescent↗
PubMed2000

Blood pressure patterns and cardiovascular risk factors in rural and urban gambian communities.

Hypertension is emerging as an important public health problem in sub-Saharan Africa. We studied blood pressure (BP) patterns, hypertension and other cardiovascular risk factors in a rural and an urban area of The Gambia. A total of 5389 adults (> or =15 years) were selected by cluster sampling in the capital Banjul and a rural area around Farafenni. A questionnaire was completed, BP, pulse rate, height and weight were recorded. Glucose was measured 2 h after a 75 g glucose load among participants > or =35 years (n = 2301); total cholesterol, triglycerides, creatinine and uric acid were measured among a stratified subsample (n = 1075). A total of 7.1% of the study participants had a BP > or =160/95 mm Hg; 18.4% of them had a BP > or =140/90 mm Hg. BP was significantly higher in the urban area. BP increased with age in both sexes in both areas. Increasing age was the major independent risk factor for hypertension. Related cardiovascular risk factors (obesity, diabetes and hyperlipidaemia) were significantly more prevalent in the urban area and among hypertensives; 17% of measured hypertensives were aware of this, 73% of people who reported to have been diagnosed as hypertensive before had discontinued treatment; 56% of those who reported being on treatment were normotensive. We conclude that hypertension is no longer rare in either urban or rural Gambians. In the urban site hypertension and related cardiovascular risk factors were more prevalent. Compliance with treatment was low. Interventions aimed at modifying risk factors at the population level, and at improving control of diagnosed hypertension are essential to prevent future increases of cardiovascular morbidity and mortality. In view of limited resources and feasibility of intervention in rural Gambia, these could initially be directed towards urbanised populations.

Adolescent↗