Preconditioning and augmented preconditioning via manipulation of metabolic and signalling pathways in the rat heart

Bibliographical references.Cardiac ischaemic preconditioning (IPC) describes a biological phenomenon whereby a short ischaemic stimulus confers protection to the heart against subsequent prolonged ischaemia and reperfusion injury. Understanding this survival programme will enable us to augment tissue tolerance against cell death. Ischaemic preconditioning is poorly understood, however, certain metabolic events and activation intracellular signalling events are known to trigger this cardioprotection. The purpose of this study was to investigate the metabolic and intracellular signalling events which occur during ischaemic preconditioning and their effects on improvement of contractile recovery following an ischaemia/reperfusion insult

Molecular regulation of the cardiac-enriched acetyl-CoA carboxylase isoform (ACCβ) : a novel target for therapeutic interventions in cardiovascular disease

Includes bibliographical references (leaves 130-173).Metabolic remodeling is thought to be an important contributor towards the development of various cardiac pathophysiologic conditions. Therefore, studies attempting to delineate undenying mechanisms driving cardiac metabolic remodeling represent an important initiative toward the development of novel therapeutic interventions. To further investigate the role of metabolic substrate switches in the heart, we focused on a pivotal, rate-limiting step of cardiac fatty acid metabolism i.e. an upstream modulator of long-chain fatty acid importation into the mitochondrion. In the heart, long-chain fatty acids are transported into the mitochondrion by the rate-limiting enzyme, carnitine palmitoyl transferase 1 (CPT1). CPT1 is potently inhibited by malonyl-CoA, the product of the acetylCoA carboxylation reaction that is catalyzed by acetyl-CoA carboxylase (ACC). Recent studies have demonstrated that metabolic fuels such as fatty acids and glucose can function as signaling ligands, directing transcriptional regulation of numerous metabolic genes. However, transcriptional mechanisms directing the gene expression of the cardiac isoform of acetyl-CoA carboxylase (ACCβ) are less well understood. Previously, four E-box (CANNTG) sequence motifs were identified on the human ACCβ promoter. Since E-boxes act as binding sites for upstream stimulatory factors (US F), putative glucose-responsive transcriptional modulators, we hypothesized that ACCβ is induced by USF1 in a glucosedependent manner. To investigate this, we began by acutely fasting and subsequently refeeding Balb/C mice with a carbohydrate-enriched diet. Here, high carbohydrate feeding resulted in elevated systemic glucose levels associated with increased cardiac ACCβ gene and protein expression. To further explore these interesting findings, we tranSiently cotransfected neonatal card iom yocytes , H9C2 myoblasts, CV-1 fibroblasts and HepG2 hepatocytes with the full-length and deletion constructs of the human ACC[3 gene promoter together with a putative activator and repressor expression vector, respectively: a) USF1 (glucose-responsive transcription factor) - the rationale that it should elevate ACCβ gene promoter activity in accordance with the glucose-fatty acid cycle, and b) nuclear respiratory factor 1(NRF1) - the hypothesis being that this mitochondrial biogenesis and β-oxidation enhancing modulator would be expected to attenuate ACCβ promoter activity in order to increase fatty acid oxidation capacity

Primary health care in rural Malawi - a qualitative assessment exploring the relevance of the community-directed interventions approach

BACKGROUND: Primary Health Care (PHC) is a strategy endorsed for attaining equitable access to basic health care including treatment and prevention of endemic diseases. Thirty four years later, its implementation remains sub-optimal in most Sub-Saharan African countries that access to health interventions is still a major challenge for a large proportion of the rural population. Community-directed treatment with ivermectin (CDTi) and community-directed interventions (CDI) are participatory approaches to strengthen health care at community level. Both approaches are based on values and principles associated with PHC. The CDI approach has successfully been used to improve the delivery of interventions in areas that have previously used CDTi. However, little is known about the added value of community participation in areas without prior experience with CDTi. This study aimed at assessing PHC in two rural Malawian districts without CDTi experience with a view to explore the relevance of the CDI approach. We examined health service providers’ and beneficiaries’ perceptions on existing PHC practices, and their perspectives on official priorities and strategies to strengthen PHC. METHODS: We conducted 27 key informant interviews with health officials and partners at national, district and health centre levels; 32 focus group discussions with community members and in-depth interviews with 32 community members and 32 community leaders. Additionally, official PHC related documents were reviewed. RESULTS: The findings show that there is a functional PHC system in place in the two study districts, though its implementation is faced with various challenges related to accessibility of services and shortage of resources. Health service providers and consumers shared perceptions on the importance of intensifying community participation to strengthen PHC, particularly within the areas of provision of insecticide treated bed nets, home case management for malaria, management of diarrhoeal diseases, treatment of schistosomiasis and provision of food supplements against malnutrition. CONCLUSION: Our study indicates that intensified community participation based on the CDI approach can be considered as a realistic means to increase accessibility of certain vital interventions at community level

A first report of Pseudosuccinea columella (Say, 1817), an alien intermediate host for liver fluke, in Malawi

Starting in October 2021, quarterly malacological surveys have been undertaken in Malawi, with the sampling of 12 specified freshwater habitats throughout a calendar year. Each survey monitors the presence of aquatic intermediate snail hosts of medical and veterinary importance. In March 2023, the alien lymnaeid species Pseudosuccinea columella was encountered for the first time in the surveys, in Nsanje District. This species identity was later confirmed upon DNA analysis of mitochondrial ribosomal 16S sequences. In July 2023, P. columella was also noted at single sites within Mangochi and Chikwawa Districts, and again in Nsanje District, with an additional location observed. Of particular importance, our sampled location in Mangochi District was directly connected to Lake Malawi, which expands the species list of invasive molluscs in this lake. While P. columella is a well-known intermediate snail host for human and animal fascioliasis, screening collected snails for trematode cercariae, alongside molecular xenomonitoring, did not yield equivocal evidence of active fluke infection. However, the newly recognized presence of this alien intermediate snail host within Lake Malawi, and along the Shire River Valley, flags a new concern in altered local transmission potential for human and animal fascioliasis

Risk factors for oesophageal, lung, oral and laryngeal cancers in black South Africans

The authors used data collected from 1995 to 1999, from an on-going cancer case–control study in greater Johannesburg, to estimate the importance of tobacco and alcohol consumption and other suspected risk factors with respect to cancer of the oesophagus (267 men and 138 women), lung (105 men and 41 women), oral cavity (87 men and 37 women), and larynx (51 men). Cancers not associated with tobacco or alcohol consumption were used as controls (804 men and 1370 women). Tobacco smoking was found to be the major risk factor for all of these cancers with odds ratios ranging from 2.6 (95% CI 1.5–4.5) for oesophageal cancer in female ex-smokers to 50.9 (95% CI 12.6–204.6) for lung cancer in women, and 23.9 (95% CI 9.5–60.3) for lung cancer and 23.6 (95% CI 4.6–121.2) for laryngeal cancer in men who smoked 15 or more grams of tobacco a day. This is the first time an association between smoking and oral and laryngeal cancers has been shown in sub-Saharan Africa. Long-term residence in the Transkei region in the southeast of the country continues to be a risk factor for oesophageal cancer, especially in women (odds ratio=14.7, 95% CI 4.7–46.0), possibly due to nutritional factors. There was a slight increase in lung cancer (odds ratio=2.9, 95% CI 1.1–7.5) in men working in ‘potentially noxious’ industries. ‘Frequent’ alcohol consumption, on its own, caused a marginally elevated risk for oesophageal cancer (odds ratio=1.7, 95% CI 1.0–2.9, for women and odds ratio=1.8, 95% CI 1.2–2.8, for men). The risks for oesophageal cancer in relation to alcohol consumption increased significantly in male and female smokers (odds ratio=4.7, 95% CI=2.8–7.9 in males and odds ratio=4.8, 95% CI 3.2–6.1 in females). The above results are broadly in line with international findings

Primary health care in rural Malawi - a qualitative assessment exploring the relevance of the community-directed interventions approach

Abstract Background Primary Health Care (PHC) is a strategy endorsed for attaining equitable access to basic health care including treatment and prevention of endemic diseases. Thirty four years later, its implementation remains sub-optimal in most Sub-Saharan African countries that access to health interventions is still a major challenge for a large proportion of the rural population. Community-directed treatment with ivermectin (CDTi) and community-directed interventions (CDI) are participatory approaches to strengthen health care at community level. Both approaches are based on values and principles associated with PHC. The CDI approach has successfully been used to improve the delivery of interventions in areas that have previously used CDTi. However, little is known about the added value of community participation in areas without prior experience with CDTi. This study aimed at assessing PHC in two rural Malawian districts without CDTi experience with a view to explore the relevance of the CDI approach. We examined health service providers’ and beneficiaries’ perceptions on existing PHC practices, and their perspectives on official priorities and strategies to strengthen PHC. Methods We conducted 27 key informant interviews with health officials and partners at national, district and health centre levels; 32 focus group discussions with community members and in-depth interviews with 32 community members and 32 community leaders. Additionally, official PHC related documents were reviewed. Results The findings show that there is a functional PHC system in place in the two study districts, though its implementation is faced with various challenges related to accessibility of services and shortage of resources. Health service providers and consumers shared perceptions on the importance of intensifying community participation to strengthen PHC, particularly within the areas of provision of insecticide treated bed nets, home case management for malaria, management of diarrhoeal diseases, treatment of schistosomiasis and provision of food supplements against malnutrition. Conclusion Our study indicates that intensified community participation based on the CDI approach can be considered as a realistic means to increase accessibility of certain vital interventions at community level.</p