Arsenic-induced developmental changes in the liver and adult cardiovascular disease.

Chronic arsenic exposure is associated with increased cardiovascular disease (CVD). Prenatal arsenic exposure at 49 ppm arsenic accelerates atherosclerosis underlying CVD in ApoE-/- mice, but the mechanism is unknown. This dissertation examines the mechanisms by which prenatal arsenic exposure accelerates atherosclerosis. Arsenic is a hepatotoxicant, and liver disease increases atherosclerosis risk. I hypothesized that prenatal arsenic exposure alters liver development and primes the liver for susceptibility to other environmental insults, predisposing to liver disease and accelerated atherosclerosis in ApoE-/- mice. I showed that prenatal arsenic exposure caused subtle but significant liver damage in 10 and 24 week old ApoE-/- mice, thus increasing the risk of atherosclerosis. This arsenic-induced liver injury was characterized by increased basal levels of plasma ALT and AST (circulating markers of liver damage), and IL-6 (pro-inflammatory cytokine). Determination of the effects of prenatal arsenic exposure on Hsp70 and Hsc70 expression during pre- and postnatal development (GD18, and 3, 10 and 24 weeks) showed that Hsp70 was induced at age 3 and 10 weeks, but returned to unexposed levels by 24 weeks, thus indicating a temporal state of stress. However Hsc70 expression was not altered at any of these ages. Determination of Hsp70 and Hsc70 expression in isolated liver cell types showed that Hsp70 is expressed only in the liver hepatocytes, while Hsc70 is expressed in all liver cell types. It is likely that stressed hepatocytes can release excess Hsp70 into the circulation, thus contributing to increased atherosclerosis as reported in the literature. Hsp70 induction was also associated with increased CpG site methylation at +503 to +856 bp, thus indicating epigenetic change. Lastly, I showed that prenatal and whole-life arsenic exposures at lower exposures (4.9 and 1 ppm arsenic) increased atherosclerotic lesion formation in aortic aches, which was associated with altered plasma triglyceride and cholesterol. However, there was no difference in lesion formation between prenatal and whole-life exposures. Both exposure types also increased plasma cytokine/chemokine expression, thus indicating inflammation which is proatherogenic. Thus, infants are at high risk of developing atherosclerosis even at very low exposure levels

Participation of African social scientists in malaria control: identifying enabling and constraining factors

OBJECTIVE: To examine the enabling and constraining factors that influence African social scientists involvement in malaria control. METHODS: Convenience and snowball sampling was used to identify participants. Data collection was conducted in two phases: a mailed survey was followed by in-depth phone interviews with selected individuals chosen from the survey. FINDINGS: Most participants did not necessarily seek malaria as a career path. Having a mentor who provided research and training opportunities, and developing strong technical skills in malaria control and grant or proposal writing facilitated career opportunities in malaria. A paucity of jobs and funding and inadequate technical skills in malaria limited the type and number of opportunities available to social scientists in malaria control. CONCLUSION: Understanding the factors that influence job satisfaction, recruitment and retention in malaria control is necessary for better integration of social scientists into malaria control. However, given the wide array of skills that social scientists have and the variety of deadly diseases competing for attention in Sub Saharan Africa, it might be more cost effective to employ social scientists to work broadly on issues common to communicable diseases in general rather than solely on malaria

Role of information and communication networks in malaria survival

<p>Abstract</p> <p>Background</p> <p>Quite often symptoms of malaria go unrecognized or untreated. According to the Multilateral Initiative on Malaria, 70% of the malaria cases that are treated at home are mismanaged. Up to 82% of all malaria episodes in sub-Saharan Africa are treated outside the formal health sector. Fast and appropriate diagnosis and treatment of malaria is extremely important in reducing morbidity and mortality.</p> <p>Method</p> <p>Data from 70 different countries is pooled together to construct a panel dataset of health and socio-economic variables for a time span of (1960–2004). The generalized two-stage least squares and panel data models are used to investigate the impact of information and communication network (ICN) variables on malaria death probability. The intensity of ICN is represented by the number of telephone main lines per 1,000 people and the number of television sets per 1,000 people.</p> <p>Results</p> <p>The major finding is that the intensity of ICN is associated with reduced probability of deaths of people that are clinically identified as malaria infected. The results are robust for both indicators i.e. interpersonal and mass communication networks and for all model specifications examined.</p> <p>Conclusion</p> <p>The results suggest that information and communication networks can substantially scale up the effectiveness of the existing resources for malaria prevention. Resources spent in preventing malaria are far less than needed. Expanded information and communication networks will widen the avenues for community based "participatory development", that encourages the use of local information, knowledge and decision making. Timely information, immediate care and collective knowledge based treatment can be extremely important in reducing child mortality and achieving the millennium development goal.</p

Prenatal Arsenic Exposure Alters Gene Expression in the Adult Liver to a Proinflammatory State Contributing to Accelerated Atherosclerosis

The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE−/−) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE−/− mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans

Efficient Wind Power Generation Using Control Technology

Undergraduat

Vaccination with T cell-defined antigens

Tumour immunology encompasses a broad array of biological phenomena including interactions between neoplastic cells and the innate and adaptive immune response. Among immune cells, T cells have taken the centre stage because they can be easily demonstrated to specifically recognise autologous cancer cells. As most tumour-associated antigens are intracellular proteins, T cells appear to be the most suitable tool for cancer-specific attack, as antibodies do not cross the cell membrane and the innate immune response lacks the same level of specificity. Finally, the relative ease in which T cells can be educated through antigen-specific immunisation to recognise cancer cells has elevated them to an even higher stature. In this review, it will be argued that T cells represent a unique anticancer agent, characterised by absolute specificity. Although other therapeutic modalities (antibody-based) have been effectively implemented, a comparison of T cell-based approaches with other modalities goes beyond the purposes of this review and will not be included in the discussion. However, it is obvious that the role of the T cell is limited and other components of the immune response (effector mononuclear phagocytes, natural killer cells, cytokines, chemokines, soluble factors), genetic background and tumour heterogeneity are likely to be necessary for the completion of cancer rejection