Interactions between Global Health Initiatives and Country Health Systems: The Case of a Neglected Tropical Diseases Control Program in Mali

Prevention of neglected tropical diseases was recently significantly scaled up in sub-Saharan Africa, protecting entire populations with mass distribution of drugs: five different diseases are now addressed simultaneously with a package of four drugs. Some argue however that, similarly to other major control programs dealing with specific diseases, this NTD campaign fails to strengthen health systems and might even negatively affect regular care provision. In 2007, we conducted an exploratory field study in Mali, observing how the program was implemented in two rural areas and how it affected the health system. At the local level, we found that the campaign effects of care delivery differed across health services. In robust and well staffed health centres, the personnel successfully facilitated mass drug distribution while running routine consultations, and overall service functioning benefitted from programme resources. In more fragile health centres however, additional program workload severely disturbed access to regular care, and we observed operational problems affecting the quality of mass drug distribution. Strong health services appeared to be profitable to the NTD control program as well as to general care

The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline

Hypoxia-Inducible Factor 2 Regulates Hepatic Lipid Metabolism▿ †

In mammals, the liver integrates nutrient uptake and delivery of carbohydrates and lipids to peripheral tissues to control overall energy balance. Hepatocytes maintain metabolic homeostasis by coordinating gene expression programs in response to dietary and systemic signals. Hepatic tissue oxygenation is an important systemic signal that contributes to normal hepatocyte function as well as disease. Hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2, respectively) are oxygen-sensitive heterodimeric transcription factors, which act as key mediators of cellular adaptation to low oxygen. Previously, we have shown that HIF-2 plays an important role in both physiologic and pathophysiologic processes in the liver. HIF-2 is essential for normal fetal EPO production and erythropoiesis, while constitutive HIF-2 activity in the adult results in polycythemia and vascular tumorigenesis. Here we report a novel role for HIF-2 in regulating hepatic lipid metabolism. We found that constitutive activation of HIF-2 in the adult results in the development of severe hepatic steatosis associated with impaired fatty acid β-oxidation, decreased lipogenic gene expression, and increased lipid storage capacity. These findings demonstrate that HIF-2 functions as an important regulator of hepatic lipid metabolism and identify HIF-2 as a potential target for the treatment of fatty liver disease

Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies*S⃞

The disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) was identified recently as the TDP-43 (TAR DNA-binding protein 43), thereby providing a molecular link between these two disorders. In FTLD-U and ALS, TDP-43 is redistributed from its normal nuclear localization to form cytoplasmic insoluble aggregates. Moreover, pathological TDP-43 is abnormally ubiquitinated, hyperphosphorylated, and N-terminally cleaved to generate C-terminal fragments (CTFs). However, the specific cleavage site(s) and the biochemical properties as well as the functional consequences of pathological TDP-43 CTFs remained unknown. Here we have identified the specific cleavage site, Arg208, of a pathological TDP-43 CTF purified from FTLD-U brains and show that the expression of this and other TDP-43 CTFs in cultured cells recapitulates key features of TDP-43 proteinopathy. These include the formation of cytoplasmic aggregates that are ubiquitinated and abnormally phosphorylated at sites found in FTLD-U and ALS brain and spinal cord samples. Furthermore, we observed splicing abnormalities in a cell culture system expressing TDP-43 CTFs, and this is significant because the regulation of exon splicing is a known function of TDP-43. Thus, our results show that TDP-43 CTF expression recapitulates key biochemical features of pathological TDP-43 and support the hypothesis that the generation of TDP-43 CTFs is an important step in the pathogenesis of FTLD-U and ALS

Accountable priority setting for trust in health systems : the need for research into a new approach for strengthening sustainable health action in developing countries

Despite multiple efforts to strengthen health systems in low and middle income countries, intended sustainable improvements in health outcomes have not been shown. To date most priority setting initiatives in health systems have mainly focused on technical approaches involving information derived from burden of disease statistics, cost effectiveness analysis, and published clinical trials. However, priority setting involves value-laden choices and these technical approaches do not equip decision-makers to address a broader range of relevant values - such as trust, equity, accountability and fairness - that are of concern to other partners and, not least, the populations concerned. A new focus for priority setting is needed. Accountability for Reasonableness (AFR) is an explicit ethical framework for legitimate and fair priority setting that provides guidance for decision-makers who must identify and consider the full range of relevant values. AFR consists of four conditions: i) relevance to the local setting, decided by agreed criteria; ii) publicizing priority-setting decisions and the reasons behind them; iii) the establishment of revisions/appeal mechanisms for challenging and revising decisions; iv) the provision of leadership to ensure that the first three conditions are met. REACT - "REsponse to ACcountable priority setting for Trust in health systems" is an EU-funded five-year intervention study started in 2006, which is testing the application and effects of the AFR approach in one district each in Kenya, Tanzania and Zambia. The objectives of REACT are to describe and evaluate district-level priority setting, to develop and implement improvement strategies guided by AFR and to measure their effect on quality, equity and trust indicators. Effects are monitored within selected disease and programme interventions and services and within human resources and health systems management. Qualitative and quantitative methods are being applied in an action research framework to examine the potential of AFR to support sustainable improvements to health systems performance. This paper reports on the project design and progress and argues that there is a high need for research into legitimate and fair priority setting to improve the knowledge base for achieving sustainable improvements in health outcomes