Targeting circulating labile heme as a defense strategy against malaria.

Severe presentations of malaria emerge as Plasmodium (P.) spp. parasites invade and lyse red blood cells (RBC), producing extracellular hemoglobin (HB), from which labile heme is released. Here, we tested whether scavenging of extracellular HB and/or labile heme, by haptoglobin (HP) and/or hemopexin (HPX), respectively, counter the pathogenesis of severe presentations of malaria. We found that circulating labile heme is an independent risk factor for cerebral and non-cerebral presentations of severe P. falciparum malaria in children. Labile heme was negatively correlated with circulating HP and HPX, which were, however, not risk factors for severe P. falciparum malaria. Genetic Hp and/or Hpx deletion in mice led to labile heme accumulation in plasma and kidneys, upon Plasmodium infection This was associated with higher incidence of mortality and acute kidney injury (AKI) in ageing but not adult Plasmodium-infected mice, and was corroborated by an inverse correlation between heme and HPX with serological markers of AKI in P. falciparum malaria. In conclusion, HP and HPX act in an age-dependent manner to prevent the pathogenesis of severe presentation of malaria in mice and presumably in humans.

Quantitative trait locus analysis of parasite density reveals that HbS gene carriage protects severe malaria patients against Plasmodium falciparum hyperparasitaemia.

BACKGROUND: Haemoglobin S (HbS) is the gene known to confer the strongest advantage against malaria morbidity and mortality. Multiple HbS effects have been described resulting in protection against parasitaemia and reduction of severe malaria risk. This study aimed to explore HbS protection against severe malaria and Plasmodium falciparum parasitaemia in Angolan children exhibiting different severe malaria syndromes. METHODS: A case-control study was designed with 430 malaria cases (n = 288 severe malaria and n = 142 uncomplicated malaria) and 319 uninfected controls, attending a central paediatric hospital in Luanda. Severe malaria syndromes were cerebral malaria (n = 130), severe malaria anaemia (n = 30) and hyperparasitaemia (n = 128). Quantitative trait locus analysis was carried out to study HbS association to parasite densities. RESULTS: Previously reported HbS protection against severe malaria was confirmed in case-control analysis (P = 2 × 10(-13)) and corroborated by transmission disequilibrium test (P = 4 × 10(-3)). High parasite density protection conferred by HbS was detectable within severe malaria patients (P = 0.04). Stratifying severe malaria patients according parasite densities, it was found that HbS was highly associated to hyperparasitaemia protection (P = 1.9 × 10(-9)) but did not protect non-hyperparasitaemic children against severe malaria complications, namely cerebral malaria and severe malaria anaemia. Many studies have shown that HbS protects from severe malaria and controls parasite densities but the analysis further suggests that HbS protection against severe malaria syndromes was at a large extent correlated with control of parasitaemia levels. CONCLUSIONS: This study supports the hypothesis that HbS confers resistance to hyperparasitaemia in patients exhibiting severe malaria syndromes and highlights that parasitaemia should be taken into account when evaluating HbS protection in severe malaria.

Autoevaluación de la facultad de medicina, Universidad Katyavala Bwila: experiencia piloto, procedimiento operacional y resultados preliminares / Self-evaluation of the faculty of Medicine, University Katyavala Bwila: pilot experience, operational procedure and preliminary results

Introducción. La evaluación institucional de las Facultades de medicina constituye una herramienta esencial para asegurar los estándares indispensables de calidad académica y científica, tanto para la planificación y el establecimiento de políticas estratégicas, como para la gestión, permite a la institución rendir cuentas a la sociedad sobre el cumplimiento de su objetivo principal : mejorar la salud de la población. Objetivos. Presentar la estructura del proceso de evaluación institucional y los resultados preliminares del estudio piloto llevado a cabo durante el curso académico 2012. Método. Se realizó una investigación documental que se complementa con encuestas a estudiantes y profesores que utilizó como herramienta de evaluación a los Estándares Globales de Educación Médica Básica de la Federación Mundial de Educación Médica. Resultados y Discusión. Se presenta un algoritmo del proceso de autoevaluación con cuatro etapas: 1- propósitos y capacitación; 2- programa de actividades; 3- Plan de acción y 4- aplicación del plan de acción. Con la aplicación de este algoritmo se destacan aspectos importantes relacionados con los recursos materiales y humanos y cómo estos recursos se organizan para garantizar el funcionamiento de la institución, se revelan los problemas en la concepción y metodologías de diseño e implementación del plan de estudios, entre otros problemas. El producto de la aplicación del algoritmo propuesto es una primera aproximación al análisis de la institución, en términos de su capacidad de enseñanza, de producción de conocimientos científicos y de sus relaciones con la sociedad (AU)

Introduction: The institutional evaluation of the faculties of medicine constitutes an essential tool to ensure the indispensable standards of academic and scientific quality, not only for the planning and the establishment of strategic politics, but also for the management, which allows the institution to give explanations to the society about the fulfillment of its main objective: to improve the health of the population. Objectives: To present the structure of the process of institutional evaluation and the preliminary results of the pilot study carried out during the academic course 2012. Method: There was carried out a documentary investigation that complements itself with surveys to students and teachers which used as an evaluation tool the Global Standards of Basic Medical Education of the World Federation of Medical Education. Results and Discussion: It is presented an algorithm of the process of self-evaluation with four stages: 1 intentions and training; 2 activities program; 3 Action plan and 4 application of the action plan. With the implementation of this algorithm it stands out important aspects related to human and material resources and how these resources are organized to guarantee the functioning of the institution, it reveals the conceiving problems and methodologies of design and implementation of the curriculum, among other problems. The result of the application of the proposed algorithm is the first approach to the analysis of the institution, in terms of its teaching capacity, its production of scientific knowledge and its relationship with the society (AU)

IFNAR1 controls progression to cerebral malaria in children and CD8+ T cell brain pathology in Plasmodium berghei-infected mice.

Development of cerebral malaria (CM), a severe and fatal form of clinical Plasmodium falciparum infection, results from a damaging cascade of vascular, inflammatory, and immunological host responses that leads to brain injury. Progression to CM can be modified by host genetic factors. Our case-control study in Angolan children aimed at highlighting the role of IFN (α, ß) receptor 1 (IFNAR1) in progression to CM. We report a robust association between IFNAR1 and CM protection, as well as detailed studies showing analogous protection from experimental CM in Ifnar1(-/-) mice infected with P. berghei ANKA. We developed a novel cell-transfer protocol that enables spleen cell priming in the absence of disease. This led to the discovery that IFNAR1 expression in CD8(+) T cells is crucial and can abrogate resistance to experimental CM in Ifnar1(-/-) mice. Splenic CD8(+) T cells from Ifnar1(-/-) mice are functionally activated upon infection, yet are unable to mediate experimental CM development within the brain tissue. Our findings prove that IFNAR1 signaling unleashes CD8(+) T cell effector capacity, which is vital for CM, and raises the hypothesis that the cohesive role of IFNAR1 in both human and mouse CM operates through CD8(+) T cell triggering.

Transforming growth factor beta 2 and heme oxygenase 1 genes are risk factors for the cerebral malaria syndrome in Angolan children.

BACKGROUND: Cerebral malaria (CM) represents a severe outcome of the Plasmodium falciparum infection. Recent genetic studies have correlated human genes with severe malaria susceptibility, but there is little data on genetic variants that increase the risk of developing specific malaria clinical complications. Nevertheless, susceptibility to experimental CM in the mouse has been linked to host genes including Transforming Growth Factor Beta 2 (TGFB2) and Heme oxygenase-1 (HMOX1). Here, we tested whether those genes were governing the risk of progressing to CM in patients with severe malaria syndromes. METHODOLOGY/PRINCIPAL FINDINGS: We report that the clinical outcome of P. falciparum infection in a cohort of Angolan children (n = 430) correlated with nine TGFB2 SNPs that modify the risk of progression to CM as compared to other severe forms of malaria. This genetic effect was explained by two haplotypes harboring the CM-associated SNPs (Pcorrec. = 0.035 and 0.036). In addition, one HMOX1 haplotype composed of five CM-associated SNPs increased the risk of developing the CM syndrome (Pcorrec. = 0.002) and was under-transmitted to children with uncomplicated malaria (P = 0.036). Notably, the HMOX1-associated haplotype conferred increased HMOX1 mRNA expression in peripheral blood cells of CM patients (P = 0.012). CONCLUSIONS/SIGNIFICANCE: These results represent the first report on CM genetic risk factors in Angolan children and suggest the novel hypothesis that genetic variants of the TGFB2 and HMOX1 genes may contribute to confer a specific risk of developing the CM syndrome in patients with severe P. falciparum malaria. This work may provide motivation for future studies aiming to replicate our findings in larger populations and to confirm a role for these genes in determining the clinical course of malaria.