Sandeep P. Kishore

Comparative Performance of Private and Public Healthcare Systems in Low- and Middle-Income Countries: A Systematic Review

A systematic review conducted by Sanjay Basu and colleagues reevaluates the evidence relating to comparative performance of public versus private sector healthcare delivery in low- and middle-income countries.

Recruitment of PfSET2 by RNA polymerase II to variant antigen encoding loci contributes to antigenic variation in P. falciparum.

Histone modifications are important regulators of gene expression in all eukaryotes. In Plasmodium falciparum, these epigenetic marks regulate expression of genes involved in several aspects of host-parasite interactions, including antigenic variation. While the identities and genomic positions of many histone modifications have now been cataloged, how they are targeted to defined genomic regions remains poorly understood. For example, how variant antigen encoding loci (var) are targeted for deposition of unique histone marks is a mystery that continues to perplex the field. Here we describe the recruitment of an ortholog of the histone modifier SET2 to var genes through direct interactions with the C-terminal domain (CTD) of RNA polymerase II. In higher eukaryotes, SET2 is a histone methyltransferase recruited by RNA pol II during mRNA transcription; however, the ortholog in P. falciparum (PfSET2) has an atypical architecture and its role in regulating transcription is unknown. Here we show that PfSET2 binds to the unphosphorylated form of the CTD, a property inconsistent with its recruitment during mRNA synthesis. Further, we show that H3K36me3, the epigenetic mark deposited by PfSET2, is enriched at both active and silent var gene loci, providing additional evidence that its recruitment is not associated with mRNA production. Over-expression of a dominant negative form of PfSET2 designed to disrupt binding to RNA pol II induced rapid var gene expression switching, confirming both the importance of PfSET2 in var gene regulation and a role for RNA pol II in its recruitment. RNA pol II is known to transcribe non-coding RNAs from both active and silent var genes, providing a possible mechanism by which it could recruit PfSET2 to var loci. This work unifies previous reports of histone modifications, the production of ncRNAs, and the promoter activity of var introns into a mechanism that contributes to antigenic variation by malaria parasites.

Promoting Global Cardiovascular Health: Ensuring Access to Essential Cardiovascular Medicines in Low- and Middle-Income Countries

On May 13, 2010, a resolution passed at the United Nations for a high-level meeting with heads of state on noncommunicable chronic diseases (NCDs), catapulting NCDs atop the political and health agendas. This meeting on NCDs, slated for September 2011, provides the rare political moment to commit to scaling up international, regional, and national efforts to prevent and treat NCDs, giving the issue the priority it deserves. An analogous high-profile meeting transpired in 2001 on human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), effectively serving as the nucleating event for a vigorous global and political movement towards universal prevention and treatment. As was the case at the HIV/AIDS meeting, a key priority area in the new NCD movement remains ensuring universal access to reliable, affordable essential medicines to prevent and treat NCDs. The upcoming meeting, therefore, provides the perfect opportunity to capitalize on the increased political and social awareness of NCDs and to apply the lessons learned from the HIV/antiretroviral experience in order to improve access to essential medicines for NCDs. Social mobilization and political advocacy, used in tandem with technical solutions, is an important lesson from the HIV experience, and will likely be important to ensure access to essential medicines for NCDs, including cardiovascular disease. Here, we use cardiovascular disease as a specific case study to examine the issue, outlining early solutions while drawing parallels and analogies to the HIV experience.

An unusual recent expansion of the C-terminal domain of RNA polymerase II in primate malaria parasites features a motif otherwise found only in mammalian polymerases.

The tail of the enzyme RNA polymerase II is responsible for integrating the diverse events of gene expression in eukaryotes and is indispensable for life in yeast, fruit flies, and mice. The tail features a C-terminal domain (CTD), which is comprised of tandemly repeated Y1-S2-P3-T4-S5-P6-S7 amino acid heptads that are highly conserved across evolutionary lineages, with all mammalian polymerases featuring 52 identical heptad repeats. However, the composition and function of protozoan CTDs remain less well understood. We find that malaria parasites (genus Plasmodium) display an unprecedented plasticity within the length and composition of their CTDs. The CTD in malaria parasites which infect human and nonhuman primates has expanded compared to closely related species that infect rodents or birds. In addition, this variability extends to different isolates within a single species, such as isolates of the human malaria parasite, Plasmodium falciparum. Our results indicate that expanded CTD heptads in malaria parasites correlates with parasitism of primates and provide the first demonstration of polymorphism of the RNA polymerase II CTD within a single species. The expanded set of CTD heptads feature lysine in the seventh position (Y1-S2-P3-T4-S5-P6-K7), a sequence only seen otherwise in the distal portion of mammalian polymerases. These observations raise new questions for the radiation of malaria parasites into diverse hosts and for the molecular evolution of RNA polymerase II.

Horizontal gene transfer of epigenetic machinery and evolution of parasitism in the malaria parasite Plasmodium falciparum and other apicomplexans

BackgroundThe acquisition of complex transcriptional regulatory abilities and epigenetic machinery facilitated the transition of the ancestor of apicomplexans from a free-living organism to an obligate parasite. The ability to control sophisticated gene expression patterns enabled these ancient organisms to evolve several differentiated forms, invade multiple hosts and evade host immunity. How these abilities were acquired remains an outstanding question in protistan biology.ResultsIn this work, we study SET domain bearing genes that are implicated in mediating immune evasion, invasion and cytoadhesion pathways of modern apicomplexans, including malaria parasites. We provide the first conclusive evidence of a horizontal gene transfer of a Histone H4 Lysine 20 (H4K20) modifier, Set8, from an animal host to the ancestor of apicomplexans. Set8 is known to contribute to the coordinated expression of genes involved in immune evasion in modern apicomplexans. We also show the likely transfer of a H3K36 methyltransferase (Ashr3 from plants), possibly derived from algal endosymbionts. These transfers appear to date to the transition from free-living organisms to parasitism and coincide with the proposed horizontal acquisition of cytoadhesion domains, the O-glycosyltransferase that modifies these domains, and the primary family of transcription factors found in apicomplexan parasites. Notably, phylogenetic support for these conclusions is robust and the genes clearly are dissimilar to SET sequences found in the closely related parasite Perkinsus marinus, and in ciliates, the nearest free-living organisms with complete genome sequences available.ConclusionsAnimal and plant sources of epigenetic machinery provide new insights into the evolution of parasitism in apicomplexans. Along with the horizontal transfer of cytoadhesive domains, O-linked glycosylation and key transcription factors, the acquisition of SET domain methyltransferases marks a key transitional event in the evolution to parasitism in this important protozoan lineage.

Enabling access to new WHO essential medicines: the case for nicotine replacement therapies

Nicotine replacement therapies (NRT) are powerful tools for the successful treatment of nicotine addiction and tobacco use. The medicines are clinically effective, supported by the Framework Convention on Tobacco Control, and are now World Health Organization-approved essential medicines. Enabling global access to NRT remains a challenge given ongoing confusion and misperceptions about their efficacy, cost-effectiveness, and availability with respect to other tobacco control and public health opportunities. In this commentary, we review existing evidence and guidelines to make the case for global access to NRT highlighting the smokers right to access treatment to sensibly address nicotine addiction.

A Unified Code of Ethics for Health Professionals Insights From an IOM Workshop

A social contract is an agreement among members of a society to cooperate for social benefits. The most prominent example, around which Rousseau first described the social contract in 1762,1 is democratic governance, in which free citizens exchange some individual freedom for shared state protections. In democracies, a number of different structures and documents, such as laws and regulations, make the social contract tangible—and keep it open to debate and evolution.

The global health crisis and our nation's research universities.

On September 14th, 2009, the presidents of five United States universities—Boston University, Brown, Duke, Johns Hopkins, and the University of Washington—and representatives of over 50 North American institutions convened for the first meeting of the Consortium of Universities for Global Health (http://www.cugh.org). The meeting was in response to the demonstrated passion and interest of students in the field of global health and the responses needed from universities to cope with increasing student interest in this field. Of 37 institutions surveyed that feature global heath programs, the number of undergraduate and masters level students studying in the field has doubled since 2006. In this arena, growing student movements have helped lead the way. Organizations such as Clinton Global Initiative Universities have also successfully tapped into university student interest in global public health outreach and research. To be sure, universities are well poised to lead such a movement for global health: They are independent organizations, boast central missions to promote public welfare, and possess copious resources and knowledge to share with partner institutions globally [1]. All the while, what remains overlooked in this rapidly expanding global health movement is real innovation for prevention and treatment of the diseases of poverty; existing drugs, some more than 50 years old, accrue microbial resistance and, on the whole, exist only in unadjusted dosages for pediatric patients [2]. Whats more, some drugs (e.g., the arsenicals and pentamadine) exhibit toxicities that we would consider unacceptable if they were widely used in the developed world. The innovation gap for the diseases of poverty is growing at a frightening pace. For instance, some estimates indicate that the total research and development funding for diabetes is more than 15 times that of malaria, and more than 100 times that of other parasitic infections such as hookworm, elephantiasis, and schistosomiasis. Because these diseases almost exclusively afflict the worlds poorest people we must look to universities to provide some of the leadership on this issue. Other funding bodies—including the US National Institutes of Health (NIH)—are providing fresh capital for basic science research, but more funds are needed to cope with the global burden of neglected diseases [3]. Certainly, Dr. Francis Collins, the new NIH Director, has affirmed a strong commitment to global health in his strategic vision. but while we feel that he has made almost heroic efforts to ensure prioritization of a global health research agenda, the harsh reality is that the NIH budget has been essentially flat since 2003 [4]. The American Recovery and Reinvestment Act committed to

Overcoming Obstacles To Enable Access To Medicines For Noncommunicable Diseases In Poor Countries

10 billion of stimulus funds to the NIH, US

Noncommunicable Diseases In East Africa: Assessing The Gaps In Care And Identifying Opportunities For Improvement

8.2 billion of which is to be directed to scientific research priorities [5]. Treating the full range of diseases prominent in the global health arena is important. While we advocate an increase in the overall investment in global health disease research, we specifically call for a new and prominent focus on research for neglected tropical diseases (NTDs), a group of infections that together rival the disease burdens of more widely known global health epidemics, yet receive especially limited research and development [6]. The most recent global estimate of funding on all neglected diseases is at US