High Plasma Levels of Soluble Intercellular Adhesion Molecule (ICAM)-1 Are Associated with Cerebral Malaria

Background

Cerebral malaria (CM) is responsible for most of the malaria-related deaths in children in sub-Saharan Africa. Although, not well understood, the pathogenesis of CM involves parasite and host factors which contribute to parasite sequestration through cytoadherence to the vascular endothelium. Cytoadherence to brain microvasculature is believed to involve host endothelial receptor, CD54 or intercellular adhesion molecule (ICAM)-1, while other receptors such as CD36 are generally involved in cytoadherence of parasites in other organs. We therefore investigated the contributions of host ICAM-1 expression and levels of antibodies against ICAM-1 binding variant surface antigen (VSA) on parasites to the development of CM.

Methodology/Principal Findings

Paediatric malaria patients, 0.5 to 13 years were recruited and grouped into CM and uncomplicated malaria (UM) patients, based on well defined criteria. Standardized ELISA protocol was used to measure soluble ICAM-1 (sICAM-1) levels from acute plasma samples. Levels of IgG to CD36- or ICAM-1-binding VSA were measured by flow cytometry during acute and convalescent states. Wilcoxon sign rank-test analysis to compare groups revealed association between sICAM-1 levels and CM (p<0.0037). Median levels of antibodies to CD36-binding VSA were comparable in the two groups at the time of admission and 7 days after treatment was initiated (p>0.05). Median levels of antibodies to CD36-binding VSAs were also comparable between acute and convalescent samples within any patient group. Median levels of antibodies to ICAM-1-binding VSAs were however significantly lower at admission time than during recovery in both groups.

Conclusions/Significance

High levels of sICAM-1 were associated with CM, and the sICAM-1 levels may reflect expression levels of the membrane bound form. Anti-VSA antibody levels to ICAM-binding parasites was more strongly associated with both UM and CM than antibodies to CD36 binding parasites. Thus, increasing host sICAM-1 levels were associated with CM whilst antibodies to parasite expressing non-ICAM-1-binding VSAs were not.     

Co-evolution of Human Leukocyte Antigen (HLA) Class I Ligands with Killer-Cell Immunoglobulin-Like Receptors (KIR) in a Genetically Diverse Population of Sub-Saharan Africans

Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) control natural killer cell (NK) functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1–14 functional ligand-receptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and previous associations of cerebral malaria with HLA-B*53:01 and KIR, Plasmodium falciparum is a candidate pathogen.     

Hybridization and divergence in multi‐species oak (Quercus) communities

Oaks (Quercus: Fagaceae) commonly interbreed yet retain their morphological, genetic and ecological distinctiveness. Post‐zygotic isolation mechanisms, such as ecologically dependent selection on adaptive loci, may therefore limit introgression. To test this hypothesis, we quantified hybridization and genetic divergence across the contact zone of four red oaks (Quercus section Lobatae) in the Great Lakes region of North America using a suite of 259 amplified fragment length polymorphisms and 27 genic and genomic microsatellite markers. First, we identified hybrids using genetic structure analysis and confirmed the reliability of our assignments via simulations. Then, we identified candidate loci for species maintenance with three complementary tests for selection and obtained partial gene sequences linked to an outlier locus and three other loci. We detected evidence of recent hybridization among all species and considerable gene flow between Q. ellipsoidalis and Q. velutina. Overall, c. 20% of Q. velutina had recent ancestry from Q. ellipsoidalis, whereas nearly 30% of Q. ellipsoidalis had a Q. velutina ancestor. Most loci were negligibly to weakly differentiated among species, but two gene‐linked microsatellites deviated significantly from neutral expectations in multiple, complementary outlier tests. Both outlier loci were located in the same 15‐cM bin on an existing Q. robur linkage map, a region under divergent selection in other oak species. Adaptive loci in this highly differentiated genomic region may contribute to ecological divergence among species and limit introgression.     

Distribution,degree of damage and risk of spread of Trioza erytreae (Hemiptera: Triozidae) in Kenya

The African citrus triozid (ACT), Trioza erytreae Del Guercio, is a destructive pest particularly on citrus, and vectors, “Candidatus” Liberibacter africanus (CLaf), which is the causal agent of the African citrus greening disease. Our study seeks to establish the distribution and host‐plant relationship of ACT across citrus production areas in Kenya. We also modelled the risk of spread using the maximum entropy modelling algorithm with known occurrence data. Our results infer that ACT is widely distributed and causes severe damage to four alternative host plants belonging to the family Rutaceae. The adults, immature stages (eggs and nymphs), galls and the percentage of infested leaves were significantly higher in shaded than unshaded trees. However, adult ACTs preferred Kenyan highlands to Victoria Lake and coastal regions. The average area under the curve of the model predictions was 0.97, indicating an optimal model performance. The environmental variables that most influenced the prediction were the precipitation of wettest quarter, precipitation of wettest month, mean diurnal range, temperature seasonality and mean temperature of the coldest quarter. The current prediction of ACT exceeded its existing range, especially in the Western, Nyanza, Central, Rift valley and Eastern regions of Kenya. The model predicted a contraction of suitable habitats for a potential spread in 2040 with an inland shift to higher altitudes in the cooler regions. The potential for further expansion to climatically suitable areas was more pronounced for the 2080 forecast. These findings provide relevant information to improve monitoring/surveillance and designing IPM strategies to limit its spread and damage.     

Body Anthropometry and the Risk of Hip and Wrist Fractures in Men: Results from a Prospective Study

Available epidemiological information on the associations between body anthropometry and the incidence of fractures in men is limited. We therefore prospectively investigated the association between body anthropometry and the incidence of hip and wrist fractures from low and moderate trauma among 43,053 men who were 40 years to 75 years of age in 1986 when they first enrolled in the Health Professionals Follow-Up Study. After 8 years of follow-up, 201 wrist fracture cases and 56 hip fracture cases were reported. Greater height was associated with significant elevations in both hip and wrist fractures, whereas nonsignificant inverse associations were observed with weight and body mass index. Men in the highest quintile of waist circumference had a relative risk (RR) of 2.57 (95% confidence interval [CI] 0.64 to 10.3) for hip fracture and 2.05 (95% CI 1.06 to 3.96) for wrist fracture when compared with men in the lowest quintile. Waist-to-hip ratio was also positively related to fracture incidence; comparing highest with lowest quintile, the RRs were 3.92 (95% CI 1.07 to 14.3) for hip fracture and 1.50 (95% CI 0.85 to 2.66) for wrist fracture. These anthropometric indicators, in particular waist-to-hip ratio, may be useful for the prediction of hip fracture in adult men.     

Hepatic Enzyme Alterations in HIV Patients on Antiretroviral Therapy: A Case-Control Study in a Hospital Setting in Ghana

Background

Diagnosing hepatic injury in HIV infection can be a herculean task for clinicians as several factors may be involved. In this study, we sought to determine the effects of antiretroviral therapy (ART) and disease progression on hepatic enzymes in HIV patients.

Methods

A case-control study conducted from January to May 2014 at the Akwatia Government Hospital, Eastern region, Ghana, The study included 209 HIV patients on ART (designated HIV-ART) and 132 ART-naive HIV patients (designated HIV-Controls). Data gathered included demography, clinical history and results of blood tests for hepatic enzymes. We employed the Fisher’s, Chi-square, unpaired t-test and Pearson’s correlation in analysis, using GraphPad Prism and SPSS. A P value < 0.05 was considered significant.

Results

Median CD4 lymphocyte count of HIV-ART participants (604.00 cells/mm³) was higher than that of HIV-Controls (491.50 cells/mm3; P = 0.0005). Mean values of ALP, ALT, AST and GGT did not differ between the two groups compared (P > 0.05). There was a significant positive correlation between hepatic enzymes (ALP, ALT, AST and GGT) for both groups (p < 0.01 each). Duration of ART correlated positively with ALT (p < 0.05). The effect size of disease progression on hepatic enzymes for both groups was small.

Conclusion

Antiretroviral therapy amongst this population has minimal effects on hepatic enzymes and does not suggest modifications in therapy. Hepatic injury may occur in HIV, even in the absence of ART and other traditional factors. Monitoring of hepatic enzymes is still important in HIV patients.     

Two-year evaluation of Intermittent Preventive Treatment for Children (IPTc) combined with timely home treatment for malaria control in Ghana

Background

Intermittent preventive treatment (IPT) has recently been accepted as an important component of the malaria control strategy. Intermittent preventive treatment for children (IPTc) combined with timely treatment of malaria related febrile illness at home to reduce parasite prevalence and malaria morbidity in children aged between six and 60 months in a coastal community in Ghana. This paper reports persistence of reduced parasitaemia two years into the intervention. The baseline and year-one-evaluation findings were published earlier.

Objective

The main objective in the second year was to demonstrate whether the two interventions would further reduce parasite prevalence and malaria-related febrile illness in the study population.

Methods

This was an intervention study designed to compare baseline and evaluation findings without a control group. The study combined home-based delivery of intermittent preventive treatment for children (IPTc) aged 6 - 60 months and home treatment of suspected febrile malaria-related illness within 24 hours. All children aged 6 - 60 months received home-based delivery of intermittent preventive treatment using amodiaquine + artesunate, delivered at home by community assistants every four months (6 times in 24 months). Malaria parasite prevalence surveys were conducted before the first and after the third and sixth IPTc to the children. The evaluation surveys were done four months after the third and sixth IPTc was given.

Results

Parasite prevalence which reduced from 25% to 3.0% at year-one evaluation had reduced further from 3% to 1% at year-two-evaluation. At baseline, 13.8% of the children were febrile (axilary temperature of ≥37.5°C) compared to 2.2% at year-one-evaluation while 2.1% were febrile at year-two-evaluation.

Conclusion

The year-two-evaluation result indicates that IPTc given three times in a year (every four months) combined with timely treatment of febrile malaria illness, is effective to reduce malaria parasite prevalence in children aged 6 to 60 months in the study community. This must give hope to malaria control programme managers in sub-Saharan Africa where the burden of the disease is most debilitating.

     

T cell responses to the RTS,S/AS01(E) and RTS,S/AS02(D) malaria candidate vaccines administered according to different schedules to Ghanaian children

Background

The Plasmodium falciparum pre-erythrocytic stage candidate vaccine RTS,S is being developed for protection of young children against malaria in sub-Saharan Africa. RTS,S formulated with the liposome based adjuvant AS01_E or the oil-in-water based adjuvant AS02_D induces P. falciparum circumsporozoite (CSP) antigen-specific antibody and T cell responses which have been associated with protection in the experimental malaria challenge model in adults.

Methods

This study was designed to evaluate the safety and immunogenicity induced over a 19 month period by three vaccination schedules (0,1-, 0,1,2- and 0,1,7-month) of RTS,S/AS01_E and RTS,S/AS02_D in children aged 5–17 months in two research centers in Ghana. Control Rabies vaccine using the 0,1,2-month schedule was used in one of two study sites.

Results

Whole blood antigen stimulation followed by intra-cellular cytokine staining showed RTS,S/AS01_E induced CSP specific CD4 T cells producing IL-2, TNF-α, and IFN-γ. Higher T cell responses were induced by a 0,1,7-month immunization schedule as compared with a 0,1- or 0,1,2-month schedule. RTS,S/AS01_E induced higher CD4 T cell responses as compared to RTS,S/AS02_D when given on a 0,1,7-month schedule.

Conclusions

These findings support further Phase III evaluation of RTS,S/AS01_E. The role of immune effectors and immunization schedules on vaccine protection are currently under evaluation.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00360230","term_id":"NCT00360230"}}NCT00360230