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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigates protein glycosylation in the asexual intraerythrocytic stage of the malaria parasite, Plasmodium falciparum, and the presence in the infected erythrocyte of the respective precursors. In in vitro cultures, P. falciparum can be metabolically labeled with radioactive sugars, and its multiplication can be affected by glycosylation inhibitors, suggesting the capability of the parasite to perform protein-glycosylation reactions. Gel-filtration analysis of sugar-labeled malarial proteins before and after specific cleavage of N-glycans or O-glycans, respectively, revealed the majority of the protein-bound sugar label to be incorporated into O-glycans, but only little (7-12% of the glucosamine label) or no N-glycans were found. Analysis of the nucleotide sugar and sugar-phosphate fraction showed that radioactive galactose, glucosamine, fucose and ethanolamine were converted to their activated derivatives required for incorporation into protein. Mannose was mainly recovered as a bisphosphate, whereas the level of radiolabeled GDP-mannose was below the detection limit. The analysis of organic-solvent extracts of sugar-labeled cultures showed no evidence for the formation by the parasite of dolichol cycle intermediates, the dedicated precursors in protein N-glycosylation. Consistently, the amount of UDP-N-acetylglucosamine formed did not seem to be affected by the presence of tunicamycin in the culture. Oligosaccharyl-transferase activity was not detectable in a lysate of P. falciparum, using exogenous glycosyl donors and acceptors. Our studies show that O-glycosylation is the major form of protein glycosylation in intraerythrocytic P. falciparum, whereas there is little or no protein N-glycosylation. A part of these studies has been published in abstract form [Dieckmann-Schuppert, A., Hensel, J. and Schwarz, R. T. (1991) Biol. Chem. Hoppe-Seyler 372, 645].
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PMID:Apparent lack of N-glycosylation in the asexual intraerythrocytic stage of Plasmodium falciparum. 137 32

Although malaria is widely recognized as a major public health problem in much of Africa, its impact on a specific national or regional economy has proved difficult to assess. This paper demonstrates the kind of analysis possible given available national aggregate statistics on epidemiology and economic indicators, the type of data most readily available. An economic model which applies the average cost of malaria per case to the known number of cases in Rwanda for 1989 estimated the total cost to be $ 2.88 per capita (in 1987 US dollars). Of this cost, $0.63 per capita represents the direct cost of treatment, including care of outpatients and hospitalized cases in both government and private facilities, as well as self-treatment. The other $ 2.25 per capita represents the indirect costs of productive time lost to malaria morbidity in adults and to care for sick children, and the cost of lifetime earnings lost through premature malaria mortality. The average output per day of the Rwandan economy was $0.83 in 1989. Thus, the per capita malaria cost equals 3.5 days of production or 1% of GDP. The average cost of each of the 1,722,271 reported malaria cases in 1989 was $11.82: $2.58 in direct and $9.24 in indirect cost. The direct cost per case is equal to 160% of the per capita budget of the Ministry of Health. Economic and epidemiological projections to 1995 yield an increase in malaria cases to over 4 million at a cost of $7.11 per capita. Direct costs are projected to rise over 200% due to increasing costs of drugs and supplies to treat increasingly drug-resistant cases. Indirect costs, which are tied to a declining economy, are projected to rise by just over 100%. By 1995, malaria is projected to cost 2.4% of the Rwandan GDP, exacerbating an already serious impact.
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PMID:Economic cost of malaria in Rwanda. 180 Nov 46

This is an historical survey of the reasons for the rapid increase in life expectancy and decline in infant mortality in Costa Rica in this century, with regression analysis of determinants of infant mortality. Costa Rica, although a small, relatively poor Central American country, has as of 1985 a life expectancy of 74 years and infant mortality rate of 19/1000. Some of the general social features contributing to its success are racial and cultural homogeneity, constitutional renunciation of an army, a social-democratic welfare-oriented government since the 1940's and a universal education. In recent decades institutional reorganization included formation of a Central Sanitary Office in the Ministry of Health, a Central Assistance Office, and a Social Security System providing medical and hospital care. In the 1970s all hospitals were placed under Social Security. Now 98.9% of hospitalizations are covered, and 7% of the GDP goes for health care. The epidemiological transition began gradually with sanitation and economic growth in the early 20th century and accelerated with the advent of antibiotics, vaccines, and DDT in the 1940s and 1950s. After a stagnant period in the 1960s due to volcano eruptions, the 1970s saw vast improvements in education, communication, and health infrastructure resulting in control of malaria, tuberculosis, helminthiases, tetanus, measles, diarrheal and respiratory infectious deaths. In the 1970s, primary health care, in the form of quarterly home visits to disadvantaged rural and urban areas, equalized health indices across the country. Immunization reached 95% an sanitation 96% of homes. Secondary health care (outpatient) was extended under Social Security. In this era, fertility fell by half, primarily due to birth spacing and limiting of higher order births. Regression analysis shows that primary health care accounted for 41%, secondary medical care for 32%, socioeconomic progress for 22%, and decline in fertility for 5% of the fall in infant mortality.
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PMID:Socioeconomic development, health interventions and mortality decline in Costa Rica. 180 67

The role of mononuclear phagocytes in acquired immunity resulting in the intraerythrocytic destruction and elimination of malarial parasites was investigated in the murine model of infection with Plasmodium chabaudi AS. Mice were treated 1 day before or 6 days after infection with agents which either result in augmentation or activation of the non-specific, microbicidal effector function of mononuclear phagocytes or in depletion of cells of this lineage. To examine the effect of agents which activate mononuclear phagocytes. A/J mice, which are susceptible to P. chabaudi AS and exhibit fulminant parasitaemia and death within 10 days of intraperitoneal infection with 10(6) P-RBC, were treated intravenously with muramyl dipeptide (MDP) or liposome-encapsulated MDP-glycerol dipalmitate (MDP-GDP). Treatment administered 1 day before infection was ineffective. Treatment on day 6 post-infection with liposome-encapsulated MDP-GDP (1 microgram) resulted in a significant decrease in parasitaemia on day 8 and survival, while treatment with free MDP (100 micrograms) resulted only in a significant decrease in parasitaemia. To examine the effect of depletion of mononuclear phagocytes, C57BL/6 mice, which are resistant to P. chabaudi AS infection and eliminate the parasite by 4 weeks, were treated intravenously with 3 mg silica. Silica administered 1 day before or 6 days post-infection abrogated resistance resulting in a delay in elimination of the parasite and host mortality. Treatment on day 6 was more effective, with death by day 13 post-infection of 70% of the normally resistant C57BL/6 mice which exhibited fulminant parasitaemia levels. These results thus provide in-vivo evidence that mononuclear phagocytes play a critical role in the elimination of infection with the murine malaria species P. chabaudi AS. Furthermore, these results suggest that the time of administration of agents which alter mononuclear phagocyte function may be important in determining their effect on host antimalarial defences.
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PMID:Role of mononuclear phagocytes in elimination of Plasmodium chabaudi AS infection. 255 63

A proposed method is presented by which the cost-effectiveness of investing in the physical and human infrastructure of the health system can be evaluated. The role of health systems infrastructure in studies of cost-effectiveness analysis and health resource allocation is discussed, and previous health sector cost-effectiveness analyses are cited. Two substantial difficulties concerning the nature of health system costs and the policy choices are presented. First, the issue of health system infrastructure can be addressed by use of computer models such as the Health Resource Allocation Model (HRAM) developed at Harvard in the General Algebraic Modeling System (GAMS), which integrates cost-effectiveness and burden of disease data. It was found that a model which allows for expansion in health infrastructure yields nearly 40% more total disability-adjusted life years (DALYs) for a hypothetical Sub-Saharan African country with a population of 10 million and GDP per capita of $340, than a model which neglects infrastructure expansion. The most important interventions by expenditure are screening and treatment of acute respiratory infections, malaria, tuberculosis, measles as well as promotion of oral rehydration therapy, breast-feeding, tetanus, and hygiene. Widespread use of cost-effectiveness databases for resource allocations in the health sector will require that cost-effectiveness analyses shift from reporting costs to reporting production functions. Distinct policy questions can be addressed with cost-effectiveness analysis, each necessitating its own inputs and constraints: 1) allocations when given a fixed budget and health infrastructure, or 2) when given resources for marginal expansion, or 3) when given a politically constrained situation of expanding resources. The development of a consistent approach to using cost-effectiveness data for informing resource allocations precludes confusion concerning which question must be addressed. Finally, some implications for future cost-effectiveness studies are highlighted.
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PMID:Cost-effectiveness analysis and policy choices: investing in health systems. 792 45

The structures of glycosylphosphatidylinositols (GPIs) in Plasmodium have been described [Gerold, Schuppert and Schwarz (1994) J. Biol. Chem. 269, 2597-2606]. A detailed understanding of GPI synthesis in Plasmodium is a prerequisite for identifying differences present in biosynthetic pathways of parasites and host cells. A comparison of the biosynthetic pathway of GPIs has revealed differences between mammalian cells and parasitic protozoans. A cell-free incubation system prepared from asexual erythrocytic stages of Plasmodium falciparum, the causative agent of malaria in humans, is capable of synthesizing the same spectrum of GPIs as that found in metabolically labelled parasites. The formation of mannosylated GPIs in the cell-free system is shown to be inhibited by GTP and, unexpectedly, micromolar concentrations of GDP-Man. Lower concentrations of GDP-Man affect the spectrum of GPIs synthesized. The inositol ring of GPIs of P. falciparum is modified by an acyl group. The preferred donor of this fatty acid at the inositol ring is myristoyl-CoA. Inositol acylation has to precede the mannosylation of GPIs because, in the absence of acyl-CoA or CoA, mannosylated GPIs were not detected. Inositol myristoylation is a unique feature of plasmodial GPIs and thus might provide a potential target for drug therapy.
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PMID:Biosynthesis of glycosylphosphatidylinositols of Plasmodium falciparum in a cell-free incubation system: inositol acylation is needed for mannosylation of glycosylphosphatidylinositols. 1058 59

Rab proteins are small Ras-like GTPases which play important roles in regulating intracellular vesicle trafficking. The nucleotide-binding domain of Rab6 from the malaria parasite Plasmodium falciparum was crystallized with GDP bound to the active site. The MAD phasing technique was used to determine the crystal structure to 2.3 A resolution. Comparisons of the structure of GDP-bound PfRab6 with the recently determined structures of Rab3A in complex with either a GTP analog or with GTP and Rabphillin present structural evidence supporting the traditional model for the molecular GTP/GDP switch in Rab proteins. PfRab6 residues homologous to those distinguishing human Rab6 isoforms, which differ in binding to Rabkinesin-6 in human cells, are located next to the recognized complementarity-determining region (CDR) and constitute a conceptual broadening of that domain. Despite significant observable differences in Golgi ultrastructure, the Rab6 core structure and switch mechanism appear highly conserved when compared with murine Rab3a structures. A significant difference between the PfRab6 and higher eukaryotic Rabs may be the lack of CDR features that allow binding interactions with Rabkinesin-type effectors.
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PMID:Structure of the nucleotide-binding domain of Plasmodium falciparum rab6 in the GDP-bound form. 1094 29

In the absence of the de novo purine nucleotide biosynthetic pathway in parasitic protozoa, purine salvage is of primary importance for parasite survival. Enzymes of the salvage pathway are, therefore, good targets for anti-parasitic drugs. Adenylosuccinate synthetase (AdSS), catalysing the first committed step in the synthesis of AMP from IMP, is a potential target for anti-protozoal chemotherapy. We report here the crystal structure of adenylosuccinate synthetase from the malaria parasite, Plasmodium falciparum, complexed to 6-phosphoryl IMP, GDP, Mg2+ and the aspartate analogue, hadacidin at 2 A resolution. The overall architecture of P. falciparum AdSS (PfAdSS) is similar to the known structures from Escherichia coli, mouse and plants. Differences in substrate interactions seen in this structure provide a plausible explanation for the kinetic differences between PfAdSS and the enzyme from other species. Additional hydrogen bonding interactions of the protein with GDP may account for the ordered binding of substrates to the enzyme. The dimer interface of PfAdSS is also different, with a pronounced excess of positively charged residues. Differences highlighted here provide a basis for the design of species-specific inhibitors of the enzyme.
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PMID:Crystal structure of fully ligated adenylosuccinate synthetase from Plasmodium falciparum. 1472 41

High molecular weight ADP ribosylation factor GDP-GTP exchange factors (ARF-GEF) play an essential role in the formation of COP I coated transport vesicles and are characterized by a structurally and functionally conserved sec 7 domain. The genome of the malaria parasite Plasmodium falciparum encodes a single ARF-GEF that contains an unusual sec 7 domain. In comparison to the sec 7 domain of other eukaryotes, the plasmodial sec 7 domain is characterized by an insertion sequence of 146 amino acids that disrupt helices essential for the GDP-GTP exchange activity of the protein. In a previous study we have shown a correlation between a methionine to isoleucine exchange in helix H of the sec 7 domain and resistance to brefeldin A in a parasite line generated by drug selection. Here we have transfected brefeldin A sensitive parasites with plasmid constructs containing the sec 7 domain of the resistant line either with or without the insertion sequence. Transfection with sec 7 sequences including the insertion resulted in brefeldin A resistant parasites in which double cross-over recombination had replaced the endogenous sec 7 sequences with the transgenic sequences. Thus, the point mutation in helix H is sufficient to confer brefeldin A resistance in P. falciparum. Transfections using constructs lacking the insertion did not result in resistant parasites. Gene replacement by targeted double cross-over recombination is a rare event in P. falciparum. This approach has taken advantage of the fact that the successful integration of the transgene results in a drug selectable phenotype. We anticipate that the strategy described here will be useful for the identification of mutations within target genes that have the potential to confer increased drug resistance.
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PMID:Double cross-over gene replacement within the sec 7 domain of a GDP-GTP exchange factor from Plasmodium falciparum allows the generation of a transgenic brefeldin A-resistant parasite line. 1550 Sep 15

Malaria is the cause of more mortality and morbidity in Tanzania than any other disease, in large part due to growing resistance to anti-malarial drugs. This study estimates that over 1% of GDP is devoted to the disease, representing US$2.2 per capita, and 39% of total health expenditure nationally. Government facilities devote almost one-third of their resources to the disease. Private expenditure, primarily on drugs, coils, sprays and bed-nets, represents 71% of total expenditures. Given the dominance of malaria treatment outside Government facilities, strategies to control behaviour in the private sector are critical. Together with regulations on private providers, and other interventions such as promoting the use of bed-nets in rural areas, greater research into and use of information strategies is required. Public policies should be designed to influence behaviour, to encourage households to seek adequate diagnosis of fever and to complete appropriate treatment with the right drugs.
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PMID:The financial burden of malaria in Tanzania: implications for future government policy. 1579 58


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