Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration

Microglia are the resident innate immune cells in the brain with a major role in orchestrating immune responses. They also provide a frontline of host defense in the central nervous system (CNS) through their active phagocytic capability. Being a professional phagocyte, microglia participate in phagocytic and autophagic clearance of cellular waste and debris as well as toxic protein aggregates, which relies on optimal lysosomal acidification and function. Defective microglial lysosomal acidification leads to impaired phagocytic and autophagic functions which result in the perpetuation of neuroinflammation and progression of neurodegeneration. Reacidification of impaired lysosomes in microglia has been shown to reverse neurodegenerative pathology in Alzheimer's disease. In this review, we summarize key factors and mechanisms contributing to lysosomal acidification impairment and the associated phagocytic and autophagic dysfunction in microglia, and how these defects contribute to neuroinflammation and neurodegeneration. We further discuss techniques to monitor lysosomal pH and therapeutic agents that can reacidify impaired lysosomes in microglia under disease conditions. Finally, we propose future directions to investigate the role of microglial lysosomal acidification in lysosome-mitochondria crosstalk and in neuron-glia interaction for more comprehensive understanding of its broader CNS physiological and pathological implications

Deficient supplies of drugs for life threatening diseases in an African community

<p>Abstract</p> <p>Background</p> <p>In Malawi essential drugs are provided free of charge to patients at all public health facilities in order to ensure equitable access to health care. The country thereby spends about 30% of the national health budget on drugs. In order to investigate the level of drug shortages and eventually find the reasons for the drugs shortages in Malawi, we studied the management of the drug supplies for common and life threatening diseases such as pneumonia and malaria in a random selection of health centres.</p> <p>Methods</p> <p>In July and August 2005 we visited eight out of a total of 37 health centres chosen at random in the Lilongwe District, Malawi. We recorded the logistics of eight essential and widely used drugs which according to the treatment guidelines should be available at all health centres. Five drugs are used regularly to treat pneumonia and three others to treat acute malaria. Out-of-stock situations in the course of one year were recorded retrospectively. We compared the quantity of each drug recorded on the Stock Cards with the actual stock of the drug on the shelves at the time of audit. We reviewed 8,968 Patient Records containing information on type and amount of drugs prescribed during one month.</p> <p>Results</p> <p>On average, drugs for treating pneumonia were out of stock for six months during one year of observation (median value 167 days); anti-malarial drugs were lacking for periods ranging from 42 to138 days. The cross-sectional audit was even more negative, but here too the situation was more positive for anti-malarial drugs. The main reason for the shortage of drugs was insufficient deliveries from the Regional Medical Store. Benzyl penicillin was in shortest supply (4% received). The median value for non-availability was 240 days in the course of a year. The supply was better for anti-malarial drugs, except for quinine injections (9 %). Only 66 % of Stock Card records of quantities received were reflected in Patient Records showing quantities dispensed.</p> <p>Conclusion</p> <p>We conclude that for the eight index drugs the levels of supply are unacceptable. The main reason for the observed shortage of drugs at the health centres was insufficient deliveries from the Regional Medical Store. A difference between the information recorded on the Stock Cards at the health centres and that recorded in the Patient Records may have contributed to the overall poor drug supply situation. In order to ensure equitable access to life saving drugs, logistics in general should be put in order before specific disease management programmes are initiated.</p

A comparative analysis of the Libyan national essential medicines list and the WHO model list of essential medicines

Aim and Objectives: To examine the concordance of the Libyan Pharmaceutical List of Essential Medicines (LPLEM) with the World Health Organization Model List of Essential Medicines 2009 (WMLEM 2009). Methods: The concordance between generic medicines listed in the WMLEM 2009 (standard reference list) and the LPLEM 2006 (comparator list) was evaluated. Results: The total number of Basic Essential Medicines (BEMs) listed on the WMLEM 2009 was 347. The total number of generic medicines listed on the LPLEM was 584. Although the LPLEM has more listed medicines, only 270 (77.6%) of BEMs from the WMLEM were listed as available. However, 25 of the 77 missing medicines were deemed to have appropriate alternatives. A total of 52 medicines from the WMLEM 2009 were therefore missing from the LPLEM. Discrepancies compared to the WMLEM 2009 were identified in 15 out of 29 therapeutic sections. The highest discrepancy rate from the WMLEM 2009 was in the anti-infective section (35 missing medicines). Missing BEMs were noted in many subclassifications of the anti-infective medicines section, but omissions were particularly prevalent in the antibacterial medicines subsection (11 missing medicines). Antituberculosis medications had the highest discrepancy rate for antibacterial BEMs with one-third of the single medicines recommended by the WHO in the WMLEM 2009 not listed on the LPLEM. Of the 314 additional medicines on the LPLEM, 18 were deemed to be irrational non-essential medicines. Conclusion: The LPLEM does not include several essential medicines recommended by the WHO in the WMLEM 2009. These discrepancies may have serious public health implications for management of some infectious diseases, particularly, tuberculosis and HIV

A need for the standardization of the pharmaceutical sector in Libya

Medicines are health technologies that can translate into tangible benefits for numerous acute as well as chronic health conditions. A nation's pharmaceutical sector needs to be appropriately structured and managed in order to ensure a safe, effective and quality supply of medicines to society. The process of medicines management involves the sequential management of five critical activity areas; namely; registration, selection, procurement, distribution and use. Formalized and standardized management of all five critical activity areas positively influences the availability, quality and affordability of medicines and ultimately increases the reliability and quality of the national healthcare system

Rapid Implementation of an Integrated Large-Scale HIV Counseling and Testing, Malaria, and Diarrhea Prevention Campaign in Rural Kenya

BACKGROUND: Integrated disease prevention in low resource settings can increase coverage, equity and efficiency in controlling high burden infectious diseases. A public-private partnership with the Ministry of Health, CDC, Vestergaard Frandsen and CHF International implemented a one-week integrated multi-disease prevention campaign. METHOD: Residents of Lurambi, Western Kenya were eligible for participation. The aim was to offer services to at least 80% of those aged 15-49. 31 temporary sites in strategically dispersed locations offered: HIV counseling and testing, 60 male condoms, an insecticide-treated bednet, a household water filter for women or an individual filter for men, and for those testing positive, a 3-month supply of cotrimoxazole and referral for follow-up care and treatment. FINDINGS: Over 7 days, 47,311 people attended the campaign with a 96% uptake of the multi-disease preventive package. Of these, 99.7% were tested for HIV (87% in the target 15-49 age group); 80% had previously never tested. 4% of those tested were positive, 61% were women (5% of women and 3% of men), 6% had median CD4 counts of 541 cell/µL (IQR; 356, 754). 386 certified counselors attended to an average 17 participants per day, consistent with recommended national figures for mass campaigns. Among women, HIV infection varied by age, and was more likely with an ended marriage (e.g. widowed vs. never married, OR.3.91; 95% CI. 2.87-5.34), and lack of occupation. In men, quantitatively stronger relationships were found (e.g. widowed vs. never married, OR.7.0; 95% CI. 3.5-13.9). Always using condoms with a non-steady partner was more common among HIV-infected women participants who knew their status compared to those who did not (OR.5.4 95% CI. 2.3-12.8). CONCLUSION: Through integrated campaigns it is feasible to efficiently cover large proportions of eligible adults in rural underserved communities with multiple disease preventive services simultaneously achieving various national and international health development goals

Monitoring of National Drug Policy (NDP) and its standardized indicators; conformity to decisions of the national drug selecting committee in Iran

BACKGROUND: Pharmaceuticals have made an important contribution to global reductions in morbidity and mortality. To help save lives and improve health, it is important to be sure about equity to access to drugs, drug efficacy, quality and safety, and rational use of drugs, which are standardized National Drug Policy (NDP) objectives. NDP's indicators are useful to evaluate the pharmaceutical system performance in a country. Iran has adapted a National Drug List (NDL). Since management of drug supply in Iran takes place only for drugs that have been selected in NDL and this list is selected by the member of Iran Drug Selecting Committee (IDSC), thus evaluation of IDSC's decision making during last 5 years is an appropriate way to evaluate the implementation of drug supply system in the country. METHODS: To identify strengths and weaknesses of pharmaceutical policy formation and implementation in Iran, four standard questionnaires of the World Health Organization (WHO) were used. To assess the agreement between decisions of IDSC and standardized NDP indicators in the last 5 years (1998–2002), a weighted questionnaire by nominal group technique based on the questions that should be answered during discussion about one drug in IDSC was designed and used. RESULTS: There is a totally generics based NDP with 95% local production, that provides affordable access to drugs. The system, structures, and mechanisms were in place; however, they did not function properly in some topics. Assessment of 59 dossiers of approved drugs for adding to NDL during last 5 years showed that IDSC's members pay more attention to efficacy, safety, and rationality in use rather than accessibility and affordability. CONCLUSION: Revision of drug system in term of implementation of the processes to achieve NDP's objectives is necessary to save public health. Clarification of NDP's objectives and their impact for IDSC's members will result in improvement of the equity in access to pharmaceuticals

Factors influencing the utilization of research findings by health policy-makers in a developing country: the selection of Mali's essential medicines

BACKGROUND: Research findings are increasingly being recognized as an important input in the formation of health policy. There is concern that research findings are not being utilized by health policy-makers to the extent that they could be. The factors influencing the utilization of various types of research by health policy-makers are beginning to emerge in the literature, however there is still little known about these factors in developing countries. The object of this study was to explore these factors by examining the policy-making process for a pharmaceutical policy common in developing countries; an essential medicines list. METHODS: A study of the selection and updating of Mali's national essential medicines list was undertaken using qualitative methods. In-depth semi-structured interviews and a natural group discussion were held with national policy-makers, most specifically members of the national commission that selects and updates the country's list. The resulting text was analyzed using a phenomenological approach. A document analysis was also performed. RESULTS: Several factors emerged from the textual data that appear to be influencing the utilization of health research findings for these policy-makers. These factors include: access to information, relevance of the research, use of research perceived as a time consuming process, trust in the research, authority of those who presented their view, competency in research methods, priority of research in the policy process, and accountability. CONCLUSION: Improving the transfer of research to policy will require effort on the part of researchers, policy-makers, and third parties. This will include: collaboration between researchers and policy-makers, increased production and dissemination of relevant and useful research, and continued and improved technical support from networks and multi-national organizations. Policy-makers from developing countries will then be better equipped to make informed decisions concerning their health policy issues

Is music enriching for group-housed captive chimpanzees (Pan troglodytes)?

Many facilities that house captive primates play music for animal enrichment or for caregiver enjoyment. However, the impact on primates is unknown as previous studies have been inconclusive. We conducted three studies with zoo-housed chimpanzees (Pan troglodytes) and one with group-housed chimpanzees at the National Centre for Chimpanzee Care to investigate the effects of classical and pop/rock music on various variables that may be indicative of increased welfare. Study one compared the behaviour and use of space of 18 animals when silence, classical or pop/rock music was played into one of several indoor areas. Overall, chimpanzees did not actively avoid the area when music was playing but were more likely to exit the area when songs with higher beats per minute were broadcast. Chimpanzees showed significantly fewer active social behaviours when music, rather than silence, was playing. They also tended to be more active and engage in less abnormal behaviour during the music but there was no change to either self-grooming or aggression between music and silent conditions. The genre of music had no differential effects on the chimpanzees’ use of space and behaviour. In the second study, continuous focal observations were carried out on three individuals with relatively high levels of abnormal behaviour. No differences in behaviour between music and silence periods were found in any of the individuals. The final two studies used devices that allowed chimpanzees to choose if they wanted to listen to music of various types or silence. Both studies showed that there were no persistent preferences for any type of music or silence. When taken together, our results do not suggest music is enriching for group-housed captive chimpanzees, but they also do not suggest that music has a negative effect on welfare