Killer-cell immunoglobulin-like receptors and malaria caused by Plasmodium falciparum in The Gambia.

The relevance of innate immune responses to Plasmodium falciparum infection, in particular the central role of natural killer (NK) cell-derived interferon gamma (IFN-γ), is becoming increasingly recognised. Recently, it has been shown that IFN-γ production in response to P. falciparum antigens is in part regulated by killer-cell immunoglobulin-like receptor (KIR) genes, and a study from malaria-exposed Melanesians suggested an association between KIR genotypes and susceptibility to infection. This prompted us to determine and compare the frequencies of 15 KIR genes in Gambian children presenting with either severe malaria (n = 133) or uncomplicated malaria (n = 188) and in cord-blood population control samples (n = 314) collected from the same area. While no significant differences were observed between severe and uncomplicated cases, proportions of individuals with KIR2DS2+C1 and KIR2DL2+C1 were significantly higher among malaria cases overall than in population control samples. In an exploratory analysis, activating KIR genes KIR2DS2, KIR3DS1 and KIR2DS5 were slightly higher in children in disease subgroups associated with the highest mortality. In addition, our data suggest that homozygosity for KIR genotype A might be associated with different malaria outcomes including protection from infection and higher blood parasitaemia levels in those that do get infected. These findings are consistent with a probable role of KIR genes in determining susceptibility to malaria, and further studies are warranted in different populations.

Oxygen for treatment of severe pneumonia in The Gambia, West Africa: a situational analysis.

SETTING: Health facilities in The Gambia, West Africa. OBJECTIVES: Oxygen treatment is vital in pneumonia, the leading cause of death in children globally. There are shortages of oxygen in developing countries, but little information is available on the extent of the problem. We assessed national oxygen availability and use in The Gambia, a sub-Saharan African country. METHODS: A government-led team visited 12 health facilities in The Gambia. A modified World Health Organization assessment tool was used to determine oxygen requirements, current provision and capacity to support effective oxygen use. RESULTS: Eleven of the 12 facilities managed severe pneumonia. Oxygen was reliable in three facilities. Requirement and supply were often mismatched. Both oxygen concentrators and oxygen cylinders were used. Suboptimal electricity and maintenance made using concentrators difficult, while logistical problems and cost hampered cylinder use. Children were usually triaged by trained nurses who reported lack of training in oxygen use. Oxygen was given typically by nasal prongs; pulse oximetry was available in two facilities. CONCLUSIONS: National data showed that oxygen availability did not meet needs in most Gambian health facilities. Remedial options must be carefully assessed for real costs, reliability and site-by-site usability. Training is needed to support oxygen use and equipment maintenance.

Variation in the ICAM1 gene is not associated with severe malaria phenotypes.

Evidence from autopsy and in vitro binding studies suggests that adhesion of erythrocytes infected with Plasmodium falciparum to the human host intercellular adhesion molecule (ICAM)-1 receptor is important in the pathogenesis of severe malaria. Previous association studies between polymorphisms in the ICAM1 gene and susceptibility to severe malarial phenotypes have been inconclusive and often contradictory. We performed genetic association studies with 15 single nucleotide polymorphisms (SNPs) around the ICAM1 locus. All SNPs were screened in a family study of 1071 trios from The Gambia, Malawi and Kenya. Two key non-synonymous SNPs with previously reported associations, rs5491 (K56M or 'ICAM-1(Kilifi)') and rs5498 (K469E), were tested in an additional 708 Gambian trios and a case-control study of 4058 individuals. None of the polymorphisms were associated with severe malaria phenotypes. Pooled results across our studies for ICAM-1(Kilifi) were, in severe malaria, odds ratio (OR) 1.02, 95% confidence interval (CI) 0.96-1.09, P=0.54, and cerebral malaria OR 1.07, CI 0.97-1.17, P=0.17. We assess the available epidemiological, population genetic and functional evidence that links ICAM-1(Kilifi) to severe malaria susceptibility.

Childhood pneumonia and crowding, bed-sharing and nutrition: a case-control study from The Gambia.

SETTING: Greater Banjul and Upper River Regions, The Gambia. OBJECTIVE: To investigate tractable social, environmental and nutritional risk factors for childhood pneumonia. DESIGN: A case-control study examining the association of crowding, household air pollution (HAP) and nutritional factors with pneumonia was undertaken in children aged 2-59 months: 458 children with severe pneumonia, defined according to the modified WHO criteria, were compared with 322 children with non-severe pneumonia, and these groups were compared to 801 neighbourhood controls. Controls were matched by age, sex, area and season. RESULTS: Strong evidence was found of an association between bed-sharing with someone with a cough and severe pneumonia (adjusted OR [aOR] 5.1, 95%CI 3.2-8.2, P < 0.001) and non-severe pneumonia (aOR 7.3, 95%CI 4.1-13.1, P < 0.001), with 18% of severe cases estimated to be attributable to this risk factor. Malnutrition and pneumonia had clear evidence of association, which was strongest between severe malnutrition and severe pneumonia (aOR 8.7, 95%CI 4.2-17.8, P < 0.001). No association was found between pneumonia and individual carbon monoxide exposure as a measure of HAP. CONCLUSION: Bed-sharing with someone with a cough is an important risk factor for severe pneumonia, and potentially tractable to intervention, while malnutrition remains an important tractable determinant.

Elevated hepcidin at HIV diagnosis is associated with incident tuberculosis in a retrospective cohort study.

Hepcidin inhibits ferroportin-mediated iron efflux, leading to intracellular macrophage iron retention, possibly favoring Mycobacterium tuberculosis iron acquisition and tuberculosis (TB) pathogenesis. Plasma hepcidin was measured at human immunodeficiency virus (HIV) diagnosis in a retrospective HIV-prevalent, antiretroviral-naïve African cohort to investigate the association with incident pulmonary and/or extra-pulmonary TB. One hundred ninety-six participants were followed between 5 August 1992 and 1 June 2002, with 32 incident TB cases identified. Greater hepcidin was associated with significantly increased likelihood of TB after a median time to TB of 6 months. Elucidation of iron-related causal mechanisms and time-sensitive biomarkers that identify individual changes in TB risk are needed.

A hallmark of balancing selection is present at the promoter region of interleukin 10.

As an anti-inflammatory mediator IL10 is beneficial in certain contexts and deleterious in others. As increased production of IL10 favours protection against inflammatory disease, whereas low production promotes elimination of foreign pathogens by the host, we investigated the possible influence of balancing selection at this locus. We began by resequencing 48 European and 48 African chromosomes across 2.2 kb of the IL10 promoter region, and compared this with four neighbouring gene regions: MK2, IL19, IL20 and IL24. Analysis of nucleotide diversity showed a positive Tajima's D-test for IL10 in Europeans, of borderline statistical significance (1.89, P=0.05). Analysis of F(st) values showed significant population divergence at MK2, IL19, IL20 and IL24 (P<0.01) but not at IL10. Taken together, these findings are consistent with the hypothesis that balancing selection has played a role in the evolution of polymorphisms in the IL10 promoter region.

A comparison of case-control and family-based association methods: the example of sickle-cell and malaria.

There has been much debate about the relative merits of population- and family-based strategies for testing genetic association, yet there is little empirical data that directly compare the two approaches. Here we compare case-control and transmission/disequilibrium test (TDT) study designs using a well-established genetic association, the protective effect of the sickle-cell trait against severe malaria. We find that the two methods give similar estimates of the level of protection (case-control odds ratio = 0.10, 95% confidence interval 0.03-0.23; family-based estimate of the odds ratio = 0.11, 95% confidence interval 0.04-0.25) and similar statistical significance of the result (case-control: chi2= 41.26, p= 10(-10), TDT: chi2= 39.06, p= 10(-10)) when 315 TDT cases are compared to 583 controls. We propose a family plus population control study design, which allows both case-control and TDT analysis of the cases. This combination is robust against the respective weaknesses of the case-control and TDT study designs, namely population structure and segregation distortion. The combined study design is especially cost-effective when cases are difficult to ascertain and, when the case-control and TDT results agree, offers greater confidence in the result.

Investigation of malaria susceptibility determinants in the IFNG/IL26/IL22 genomic region.

Interferon-gamma, encoded by IFNG, is a key immunological mediator that is believed to play both a protective and a pathological role in malaria. Here, we investigate the relationship between IFNG variation and susceptibility to malaria. We began by analysing West African and European haplotype structure and patterns of linkage disequilibrium across a 100 kb genomic region encompassing IFNG and its immediate neighbours IL22 and IL26. A large case-control study of severe malaria in a West Africa population identified several weak associations with individual single-nucleotide polymorphisms in the IFNG and IL22 genes, and defined two IL22 haplotypes that are, respectively, associated with resistance and susceptibility. These data provide a starting point for functional and genetic analysis of the IFNG genomic region in malaria and other infectious and inflammatory conditions affecting African populations.

Analysis of IL10 haplotypic associations with severe malaria.

We investigated the association between severe malaria and genetic variation of IL10 in Gambian children, as several lines of evidence indicate that IL10 is protective against severe malaria and that IL10 production is genetically determined. We began by identifying five informative SNPs in the Gambian population that were genotyped in a combined case-control and intrafamilial study including 654 cases of severe malaria, 579 sets of parents and 459 ethnically matched controls. No significant associations were identified with individual SNPs. One haplotype of frequency 0.11 was strongly associated with protection against severe malaria in the case-control analysis (odds ratio 0.52, P=0.00002), but the transmission disequilibrium test in families showed no significant effect. These findings raise the question of whether IL10 associations with severe malaria might be confounded by foetal survival rates or other sources of transmission bias.

Population-specific patterns of linkage disequilibrium in the human 5q31 region.

Linkage disequilibrium across the human genome is generally lower in West Africans than Europeans. However in the 5q31 region, which is rich in immune genes, we find significantly more examples of apparent nonrecombination between distant marker pairs in West Africans. Much of this effect is due to SNPs that are absent in Europeans, possibly reflecting recent positive selection in the West African population.

Essential drugs in the Gambia.

PIP: The Gambia is a small West African country with a population of approximately 900,000. With more than half of the 48 physicians registered in 1989 in the public sector working in the country's main hospital, nurses are responsible for most drug prescribing in the public health care system. At the primary care level, village health workers, most of whom are illiterate, are trained to prescribe a limited number of drugs. Numerous difficulties in this field prompted the Gambia to request assistance from the World Health Organization's Drug Action Program in reviewing the pharmaceutical sector and formulating a national drug policy. The Essential Drugs Program was introduced in 1984 with the main objectives of achieving regulatory control over drugs in the private sector and the availability of safe, effective, and affordable drugs in the public sector. Assessment of the impact and progress of the program indicate that the essential drugs concept in the country has helped resolve some serious problems. The Essential Drugs Program has substantially improved the efficacy and efficiency of pharmaceutical services in the Gambia. While the small size of the country can be an asset when implementing national programs, only very limited scope exists for training medical and other health workers. The national drug policy, the essential drugs list, the state supply system, the private sector, and the drug revolving funds project are discussed.^ieng

[Drugs in developing countries. Current status, problems and possible solutions]. / Legemidler i utviklingsland. Statusbeskrivelse, problemer og mulige løsninger.

Based mainly on economic, administrative and drug logistics indicators, the article critically reviews the use of drugs in less developed countries in the context of the global drug scene. The lack of balance in less developed countries (LDCs) between indicators of need and determinants of political, economic, professional, educational and sociocultural nature, including product marketing efforts is highlighted. Special emphasis is given to the global WHO Action Programme on Essential Drugs, its background, strategies, implementation and tentative impacts. Country case examples from Sri Lanka, Bangladesh, Kenya, Zimbabwe and the Gambia are used for illustration. Varying progress is made in about half the 110 LDCs which have formally adopted the WHO concepts. Delayed implementation, setbacks and failures are prevalent. These reflect financial and other resource constraints, political ambiguity, qualitative and quantitative deficiencies related to manpower and insufficient back-up measures of an educational and informative character. An orientation towards operational research based on competence-building according to needs and strategies is highly desirable. Accordingly a plea is made for multidisciplinary collaboration in North-South networks at university level.

CD40L association with protection from severe malaria.

CD40 ligand (CD40L), a glycoprotein involved in B cell proliferation, antigen presenting cell activation, and Ig class switching, is important in the immune response to infection. Rare coding mutations in CD40L can lead to life-threatening immunodeficiency but the potential for common variants to alter disease susceptibility remains to be explored. To identify polymorphisms in CD40L, we sequenced 2.3 kb of the 5' flanking region and the first exon of the gene in DNA samples from 36 Gambian females and one chimpanzee. Diversity was lower than the average reported for other areas of the X chromosome, and only two polymorphisms were identified. The polymorphisms were genotyped in DNA samples from 957 Gambian individuals, cases and controls from a study of severe malaria. A significant reduction in risk for severe malaria (OR = 0.52, P = 0.002) was associated with males hemizygous for the CD40L-726C. Analysis by transmission disequilibrium test of 371 cases, for whom DNA from both parents was also available, confirmed the result was not due to stratification (P = 0.04). A similar but non-significant trend was found in females. This preliminary association of a common variant in CD40L with a malaria resistance phenotype encourages further genetic characterization of the role of CD40L in infectious disease.

Epidemic poliomyelitis in The Gambia following the control of poliomyelitis as an endemic disease. II. Clinical efficacy of trivalent oral polio vaccine.

An epidemic of poliomyelitis caused by poliovirus type 1 occurred in The Gambia from May to November 1986. Descriptive findings and vaccination coverage levels are reported in part I. This article (part II) describes a case-control study to estimate the clinical efficacy of three or more doses of trivalent oral polio vaccine compared with zero doses. "Cases" were 1- to 7-year-old children paralyzed during the epidemic who were diagnosed as having poliomyelitis by designated referral physicians. They were identified by reports from referral physicians during the epidemic and by a nationwide village-to-village search after the epidemic. Up to five controls were randomly selected for each case from among children of the same age and sex living in neighboring households. In a matched analysis of 195 cases and 839 controls, the efficacy of three or more doses of trivalent oral polio vaccine was 72% (95% confidence interval 57-82) when children without vaccination cards were considered unvaccinated. The efficacy of three or more doses in 1- to 2-year-old children, in whom the determination of vaccination status was considered to be more accurate than in older children, was 81% (95% confidence interval 66-90). Vaccine failure was not associated with short intervals between doses. Higher levels of vaccination coverage and efficacy than those achieved in The Gambia may be needed in African countries to prevent the return of poliomyelitis as an epidemic disease after it has been controlled as an endemic disease.

Complex haplotypic structure of the central MHC region flanking TNF in a West African population.

TNF polymorphisms have been associated with susceptibility to malaria and other infectious and inflammatory conditions. We investigated a sample of 150 West African chromosomes to determine linkage disequilibrium (LD) between 25 SNP markers located in an 80 kb segment of the MHC Class III region encompassing TNF and eight neighbouring genes. We observed 45 haplotypes, and 22 of them comprise 80% of the sample. The pattern of LD is remarkably patchy, such that many markers show no LD with adjacent markers but high LD with markers that are much further away. We introduce a method of examining the implications of LD data for disease association studies based on sample size considerations: this shows that certain TNF polymorphisms would be likely to yield positive associations if the true disease allele resided in LTA or BAT1. We conclude that detailed marker maps are needed to resolve the causal origin of disease associations observed at the TNF locus.