Stroke presentation and outcome in developing countries: a prospective study in the Gambia.

BACKGROUND AND PURPOSE: Despite increasing burden of stroke in Africa, prospective descriptive data are rare. Our objective was to describe, in The Gambia, the clinical outcome of stroke patients admitted to the Royal Victoria Teaching Hospital in the capital Banjul, to assess mortality and morbidity, and propose preventive and therapeutic measures. METHODS: Prospective data were collected on consecutive patients older than 15 years old admitted between February 2000 and February 2001 with the diagnosis of nonsubarachnoid stroke. Risk factors, clinical characteristics, and social consequences were assessed using a modified National Institutes of Health Stroke Scale (mNIHSS), the Barthel Activity in Daily Living scale, the Siriraj score for subtypes, and the Bamford criteria for location/extension. Patients were followed-up at home up to 1 year after discharge. RESULTS: Ninety-one percent (148/162) of eligible patients were enrolled and followed-up. Hypertension and smoking were the most prevalent risk factors. Severity was high at admission, especially in women, and was strongly correlated to the outcome. mNIHSS and consciousness level on admission were strong predictors of the mortality risk. Swallowing difficulties at admission, fever, lung infection, and no aspirin treatment were, independently, risk factors for a lethal outcome susceptible to being addressed by treatment. Mortality was 41% in-hospital and 62% after 1 year. In survivors, autonomy levels improved over time. Drug compliance was poor. At home, family members provided care. Long-term socioeconomic and cultural activities were affected in most patients. CONCLUSIONS: Case-fatality was high compared with Western cohorts. Preventive measures can be developed. Rational treatment, in the absence of head imaging for initial assessment, requires adapted protocols. Providers should be trained, both at hospital and community levels.

Variants of the CD40 ligand gene are not associated with increased susceptibility to tuberculosis in West Africa.

Evidence for linkage between tuberculosis and human chromosomal region Xq26 has previously been described. The costimulatory molecule CD40 ligand, encoded by TNFSF5 and located at Xq26.3, is a promising positional candidate. Interactions between CD40 ligand and CD40 are involved in the development of humoral- and cell-mediated immunity, as well as the activation of macrophages, which are the primary host and effector cells for Mycobacterium tuberculosis. We hypothesised that common variation within TNFSF5 might affect susceptibility to tuberculosis disease and, thus, might be responsible for the observed linkage to Xq26. Sequencing 32 chromosomes from a Gambian population identified nine common polymorphisms within the coding, 3' and 5' regulatory sequences of the gene. Six single nucleotide polymorphisms (SNPs) and a 3' microsatellite were genotyped in 121 tuberculosis patients and their available parents. No association with tuberculosis was detected for these variants using a transmission disequilibrium test, although one SNP at -726 showed some evidence of association in males. This finding, however, did not replicate in a separate case control study of over 1,200 West African individuals. We conclude that common genetic variation in TNFSF5 is not likely to affect tuberculosis susceptibility in West Africa and the linkage observed in this region is not due to variation in TNFSF5.

Mature CD8(+) T lymphocyte response to viral infection during fetal life.

Immunization of newborns against viral infections may be hampered by ineffective CD8(+) T cell responses. To characterize the function of CD8(+) T lymphocytes in early life, we studied newborns with congenital human cytomegalovirus (HCMV) infection. We demonstrate that HCMV infection in utero leads to the expansion and the differentiation of mature HCMV-specific CD8(+) T cells, which have similar characteristics to those detected in adults. High frequencies of HCMV-specific CD8(+) T cells were detected by ex vivo tetramer staining as early as after 28 weeks of gestation. During the acute phase of infection, these cells had an early differentiation phenotype (CD28(-)CD27(+)CD45RO(+), perforin(low)), and they acquired a late differentiation phenotype (CD28(-)CD27(-)CD45RA(+), perforin(high)) during the course of the infection. The differentiated cells showed potent perforin-dependent cytolytic activity and produced antiviral cytokines. The finding of a mature and functional CD8(+) T cell response to HCMV suggests that the machinery required to prime such responses is in place during fetal life and could be used to immunize newborns against viral pathogens.

Association of a polymorphism in the P2X7 gene with tuberculosis in a Gambian population.

Adenosine triphosphate (ATP) ligation of P2X(7) receptors expressed on human macrophages that are infected with mycobacteria induces cell death and subsequent loss of intracellular bacterial viability. Marked heterogeneity observed in cell donor ATP responsiveness suggests that this antimycobacterial mechanism may be genetically regulated. Five single-nucleotide polymorphisms (SNPs) previously identified in a putative 1.8-kb promoter region upstream of P2RX7 exon 1 were screened for associations with clinical tuberculosis. The frequencies of these promoter SNPs and a polymorphism in P2RX7 exon 13 at position 1513 were compared among >300 Gambian patients with tuberculosis and >160 ethnically matched control subjects by sequence-specific oligonucleotide hybridization and ligation detection reaction analysis. A significant protective association against tuberculosis was found for 1 promoter SNP, at nucleotide position -762 (odds ratio [OR] for variant C allele, 0.70; 95% confidence interval [CI], 0.54-0.89; P=.003; OR for CC genotype, 0.545; 95% CI, 0.318-0.934; P=.027). This association supports a role for ATP/P2X(7)-mediated host regulation of Mycobacterium tuberculosis infection.

Fine mapping of a putative tuberculosis-susceptibility locus on chromosome 15q11-13 in African families.

Host genetics plays an important role in individual susceptibility and resistance to infectious diseases, but no genes have yet been identified using genome-wide screens. Twin studies have indicated that tuberculosis susceptibility has a significant host genetic component, and several genes appear to be involved. Recently, a genome-wide linkage analysis of 136 African families identified chromosome 15q11-13 as a region with suggestive evidence of linkage, with a LOD score of 2.0. We tested 10 microsatellite markers and 5 positional candidate genes in this chromosomal region for deviation from random transmission from parents to affected offspring. The polymorphisms, lying in a region of 14 cM, were initially typed in the same 79 Gambian families used in the genome screen. A borderline significant association with a 7 bp deletion in UBE3A (P = 0.01) was found. This polymorphism was then evaluated further in a larger series of families with tuberculosis, including 44 Guinean families and 57 families from South Africa. Testing for association between the deletion and tuberculosis across all the families using the exact symmetry test further supported the association (overall P = 0.002). These fine-mapping data suggest that UBE3A or a closely flanking gene may be a tuberculosis-susceptibility locus.

HLA-B*35-restricted CD8(+)-T-cell epitope in Mycobacterium tuberculosis Rv2903c.

Few human CD8(+) T-cell epitopes in mycobacterial antigens have been described to date. Here we have identified a novel HLA-B*35-restricted CD8(+) T-cell epitope in Mycobacterium tuberculosis Rv2903c based on a reverse immunogenetics approach. Peptide-specific CD8 T cells were able to kill M. tuberculosis-infected macrophages and produce gamma interferon and tumor necrosis factor alpha.