1,721,207 research outputs found
Iron Deficiency and Iron Supplementation Conspire to Mediate Susceptibility to Erythrocytic Stage Plasmodium falciparum Infection
Full text linkMalaria and iron deficiency are interconnected public health concerns, which disproportionally affect children and pregnant women. Malaria causes an estimated 250 million infections and 1 million deaths per year. Plasmodium falciparum is the most virulent species of the malaria parasite that infects humans. Anemia, predominantly iron deficiency anemia, is the most common nutritional deficiency worldwide, and affects up to 50% of populations in the developing world. The World Health Organization recommends universal iron supplementation in regions where malnutrition is common. This recommendation has been complicated by clinical evidence that iron deficiency protects against malaria infection, and that iron supplementation increases susceptibility to malaria infection. The mechanisms underlying the interaction between malaria, host iron, and iron supplementation remain unclear. Here, I've employed the in vitro system for cultivating erythrocytic stage P. falciparum to assess first, the impact of extracellular iron on parasite growth as well as the bioavailable iron content of parasitized erythrocytes. I have found that extracellular iron is incorporated into parasitized erythrocytes but does not have affect parasite growth. Second, I assessed the capacity of erythrocytes from iron deficient and iron supplemented donors to support erythrocytic stage P. falciparum growth. In these studies I observed that P. falciparum propagation is reduced in iron deficient erythrocytes and that reduced parasite propagation is a result of decreased parasite invasion into iron deficient erythrocytes as well as decreased production of infectious daughter merozoites within iron deficient erythrocytes. I additionally observe that P. falciparum propagation is recovered in erythrocytes donated by iron supplemented iron deficient donors. Furthermore, I attribute the recovery of P. falciparum erythrocyte propagation to the replacement of iron deficient erythrocytes with young iron-replete erythrocytes that are produced in response to iron supplementation. These results are consistent with clinical observations that iron deficiency is protective against malaria infection and iron supplementation increases the risk of malaria infection. Moreover, my results suggest that iron mediated alterations to erythrocyte physiology and intra-host erythrocyte population dynamics as well as potentially altered serum iron levels contribute to the underlying mechanisms governing the relationship between the malaria parasite, iron deficiency, and iron supplementation.Doctor of Philosoph
Malaria and pregnancy outcomes in an area of high HIV and glucose-6-phosphate dehydrogenase deficiency prevalence
Full text linkHIV and G6PD deficiency are part of a milieu of population-level biological factors in which pregnancies occur in malaria-endemic areas. In this research we examine the effect of HIV infection and malaria parasitemia on pregnancy outcomes, the relationship between HIV infection and risk, frequency, and severity of maternal parasitemia, and the effect of G6PD deficiency on parasitemia risk and pregnancy outcomes. Between 2005 and 2006, we followed pregnant women attending two antenatal care clinics in southern Malawi from the second trimester of gestation until delivery. HIV was associated with increased risk of LBW (adjusted prevalence ratio, PRadj=3.08, 95% confidence interval, CI, = 1.40, 6.79). Placental parasitemia was associated with an elevated risk of LBW (PRadj=1.79, 95% CI = 0.83, 3.84), as was having [greater than or equal to]3 episodes of peripheral parasitemia during follow-up (PRadj=2.68, 95% CI = 1.06, 6.79). HIV was not associated with increased risk of parasitemia among primigravidae over follow-up (RR=1.0, 95% CI: 0.4, 2.8). Among multigravidae, the risk of parasitemia over follow-up among HIV-infected women was 2.2 times (95% CI: 1.5, 3.2) that of HIV-uninfected women. Further, the odds of having [greater than or equal to]3 episodes of parasitemia among HIV-infected multigravidae were 4.8 (95% CI: 2.1, 10.9) times that of HIV-uninfected multigravidae. Among both primigravidae and multigravidae, placental parasite density among HIV-infected women was on average 3.6 (95% CI: 1.8, 7.2) times as high as among HIV-uninfected women. G6PD A- primigravidae were as likely to have placental parasitemia as G6PD-normal primigravidae (PR=1.0, 95% confidence interval (CI): 0.7, 1.3). Among multigravid G6PD A- carriers, the prevalence of placental parasitemia was 0.9 (95% CI: 0.8, 1.0) times that of G6PD-normal women. Further, their placental parasite density was on average 0.22 times that of G6PD-normal multigravidae. Among primigravidae, G6PD A- carriers had 1.7 (95% CI: 1.0, 2.9) times the average risk of maternal anemia over follow-up when compared to G6PD-normal women. Across gravidities, G6PD deficiency was associated with an increased risk of low birth weight (PR=2.5, 95% CI: 1.2, 5.2). Understanding the contribution of these different coexistent factors should aid in the design of effective interventions to improve maternal and infant health in malaria-endemic areas
Reducing Malaria Transmission: The Epidemiology and Treatment of Plasmodium falciparum Gametocytemia
Full text linkGametocytes are the sexual stage of the Plasmodia life cycle which render malaria cases infectious to mosquitoes. The proportion of P. falciparum malaria cases with gametocytemia and the duration of gametocytemia are varied. Interventions for detecting and treating gametocytemia also differ from those used against asexual parasitemia. In areas of low transmission, such as most of India, the size of the infectious reservoir drives transmission. The purpose of this dissertation was to 1) determine the epidemiology and risk factors for gametocytemia in order to better target interventions, and 2) estimate the effect of primaquine in addition to artesunate+sulphadoxine-pyrimethamine (AS+SP) to guide policy for reducing post-treatment malaria transmission. Using data from therapeutic efficacy studies conducted through the National Antimalarial Drug Resistance Monitoring System from 2009 to 2010, we measured the prevalence of gametocytemia in relation to various clinical and demographic factors. We found that all age groups, including adults, contribute substantially to the reservoir for potential transmission. We identified four risk factors - younger age group, previous antimalarial drug intake, sex, and region - from which we created a clinical algorithm for predicting gametocytemia. The predictive power of the model was low, suggesting the need for a universal approach for anti-gametocyte interventions. We compared trial sites which used primaquine to sites which did not to estimate the additional effect of primaquine. AS+SP with primaquine increased the rate of gametocyte clearance, prevented the development of new gametocytemia, and reduced the area under the gametocyte density over time curve over the study follow-up compared to AS+SP alone. Primaquine was well tolerated and no serious adverse events were reported. Adding primaquine to AS+SP for the treatment of P. falciparum infection in India would decrease the potential for post-treatment malaria transmission.Doctor of Philosoph
Molecular markers of drug resistance and clinical outcome in falciparum malaria in Cambodia and the Democratic Republic of Congo
Full text linkBackground. Drug resistance is a major obstacle to the control of Plasmodium falciparum malaria. Monitoring the efficacy of antimalarials is a critical component to malaria control. One possible surveillance method is to use molecular markers. However, their relationship with clinical resistance needs to be established before they can be used. Methods. Clinical samples from an in vivo efficacy study of sulfadoxine-pyrimethamine (SP) based therapy in Rutshuru, Democratic Republic of Congo were used to estimate the effect of mutations in dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) on treatment failure. In addition, clinical samples from an in vivo efficacy study of mefloquineartesunate in Pailin, Cambodia were used to estimate the effect of changes in the P. falciparum multidrug resistance-1 (pfmdr1) gene on recrudescence. Lastly, a cross-sectional survey of Cambodia was conducted to determine the geographic distribution of the genetic changes in pfmdr1. Results. In Rutshuru, the effect of mutations at dhps-437 and dhps-540 on SP treatment failure differed by level of parasitemia: for children with low parasitemia, the presence of both mutations was associated with a 17% (95%CI: -3%, 36%) greater absolute risk of treatment failure compared to having neither mutation (baseline risk: 21%). For children with high parasitemia, the risk difference was 50% (95%CI: 35%, 64%; baseline risk: 8%). In Pailin, pfmdr1 copy number was strongly related to time to recrudescence after mefloquine-artesunate treatment (adjusted HR = 7.91, 95%CI: 2.38, 26.29). In the cross-sectional study of Cambodia, increased pfmdr1 copy number was found not only in Pailin, where mefloquine resistance has been well documented, but also in Chumkiri, an area not previously known for drug resistance. Conclusion. These studies demonstrated dhps mutations are associated with SP treatment failure in the DRC and pfmdr1 copy number is associated with recrudescence after mefloquine-artesunate treatment in Cambodia. The cross-sectional study demonstrates how the use of a molecular marker can be operationalized to detect resistant areas outside of current sentinel surveillance sites. Detecting dhps mutations in DRC and pfmdr1 copy number in Cambodia are potentially cost-effective methods to complement the current in vivo efficacy monitoring of drug resistance in these countries
Malaria in pregnancy and drug therapies in Malawi
Full text linkIn this dissertation, I investigated the effect of timing and frequency of Plasmodium falciparum infection during pregnancy on the risk of low birth weight and maternal anemia. I also investigated the efficacy of sulfadoxine-pyrimethamine combined with azithromycin or artesunate compared with sulfadoxine-pyrimethamine monotherapy as treatment for uncomplicated Plasmodium falciparum infection in pregnant women. We conducted a prospective observational study recruiting 2,462 pregnant women in Malawi. Malaria was assessed during follow-up and delivery. Birth weight and hemoglobin concentration were measured at delivery. The prevalence of low birth weight increased with the number of malaria episodes: [1 episode (prevalence ratio [PR] =2.17; 95% C.I. 1.22-3.86), and 2 episodes (PR=3.68; 95% C.I. 1.81-7.47)]. The prevalence of anemia increased with the number of episodes of malaria: [1 episode (PR= 1.16; 95% C.I. 0.77-1.77) and 2 episodes (PR= 1.82 95% C.I. 1.04-3.19)]. The prevalence of low birth weight was higher with infection in the second trimester (PR=2.97; 95% CI 1.60-5.53) than in the third trimester (PR=1.42; 95% CI 0.63-3.22). The prevalence of maternal anemia was higher with infection in the third trimester (PR=1.44; 95% CI 0.90-2.29) than in the second trimester (PR=0.94; 95% CI 0.51-1.71). Timing and frequency of infection affect the risk of maternal anemia and low birth weight. We conducted a randomized open-label clinical trial, recruiting 141 pregnant women. They were randomly allocated to 3 treatment groups: sulfadoxine-pyrimethamine (SP; 3 tablets, 500mg sulfadoxine and 25mg pyrimethamine per tablet); SP plus azithromycin (1g/day x 2 days); or SP plus artesunate (400mg/day x 3 days). All treatment regimens were well tolerated. Two women vomited soon after ingesting azithromycin. Recrudescent episodes of malaria were less frequent with SP-azithromycin [Hazard Ratio 0.14 (95% confidence interval 0.02 to 0.78)] and SP-artesunate [Hazard Ratio 0.13 (95% confidence interval 0.03 to 0.53)] compared with SP monotherapy. There were more abortions in the SP-azithromycin group, and more stillbirths in the SP-artesunate groups, but they were probably unrelated to treatment. A larger study is needed to determine its safety and efficacy in preventing poor birth outcomes
Falciparum malaria: Gene expression in the parasite and host.
No full textMalaria parasites infect 300 to 500 million people annually resulting in 1.5 to 2.7 million deaths. Expanding our knowledge concerning parasite biology and malaria pathophysiology will assist in identifying new antimalarial interventions. First we investigated the iron-chelating drug, deferoxamine's effect on transcript levels in Plasmodium falciparum. Using differential display analysis we identified a transcript homologous to large ribosomal subunit E encoded by the mitochondria that increased after deferoxamine treatment. However, northern results contradicted this finding suggesting that differential display may be unreliable when investigating A-T rich genomes. To further characterize deferoxamine's effect on mitochondrial and nuclear gene expression we used northerns to examine transcripts for proteins that both contain and lack iron or heme cofactors. Five nuclear encoded messages (ribosomal P2 phosphoprotein, beta-tubulin, hypoxanthine-guanine phosphoribosyltransferase, ribonucleotide reductase small subunit, and lactate dehydrogenase) showed small decreases after deferoxamine treatment. One other nuclear encoded message, glyceraldehyde 3-phosphate dehydrogenase, showed a 40% increase after deferoxamine treatment. In contrast, deferoxamine caused 40--60% reductions in the expression of mitochondrial genes encoding three heme-containing proteins (cytochrome c oxidase subunits I and III, cytochrome b) without affecting mitochondrial DNA levels. Decreased mitochondrial gene expression was associated with decreased mitochondrial function, as manifested by a 40% reduction in parasite dihydroorotate dehydrogenase activity. These results indicate that deferoxamine inhibits mitochondrial gene expression which may contribute to deferoxamine's antimalarial activity. Secondly, we examined malaria infections during pregnancy, which can lead to the delivery of low-birth weight infants. Using Ribonuclease Protection Assays, we measured placental cytokine expression from P. falciparum -infected and uninfected primigravids. Significantly increased expression of IL-1beta, IL-8 and TNF-alpha and decreased expression of IL-6 and TGF-beta1 were found in malaria-infected placenta compared to uninfected placenta. Elevated TNF-alpha expression was associated with hemozoin content in placental tissue. Immunohistochemistry revealed that both TNF-alpha and IL-8 were produced by maternally derived hemozoin-laden placental macrophages. Fetal vascular endothelial cells within the chorionic villi produced IL-8 in both the infected and uninfected placentas. Increases in either TNF-alpha or IL-8 expression in the placenta was associated with intrauterine growth retardation. Our results suggest that severe malaria infection induces potentially harmful proinflammatory cytokine expression in the placenta.PhDBiological SciencesHealth and Environmental SciencesImmunologyMolecular biologyPathologyPharmacologyPublic healthUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/131734/2/9929903.pd
Plasmodium falciparum malaria in pregnancy and fetal, newborn, and maternal outcomes among a cohort of pregnant women in coastal Kenya, 2006 - 2009
Full text linkPlasmodium falciparum malaria in pregnancy causes adverse pregnancy outcomes, most notably reduced birth weight and maternal anemia. Preventive treatment that is safe during pregnancy has been shown to effectively reduce rates of malaria in pregnancy, yet in malaria-endemic regions rates of adverse pregnancy outcomes remain high. We sought to explore the association of malaria in pregnancy and other risk factors with poor outcomes, among a cohort of pregnant women who received the recommended preventative treatment for malaria at antenatal care. The prevalence of malaria at the first antenatal care visit was 11%, and malaria infection was associated with lower measures of fetal growth, as measured by ultrasound. Among live, term births, the mean birth weight was not significantly different for malaria-positive vs. malaria-negative women. However, among women with under-nutrition, as measured by low body-mass-index, malaria exposure was associated with significantly decreased birth weight (mean difference -370 grams, 95% CI -728, -12 g). The rates of maternal anemia (hemoglobin <11.0 g/dL) and moderate/severe anemia (hemoglobin < 9.0 g/dL) at antenatal care were 70% and 27%, respectively. Moderate/severe maternal anemia at first antenatal care was associated with malaria as diagnosed by microscopy (aRR 2.06, 95% CI 1.24, 3.44) as was high-intensity hookworm infection in multivariate regression (aRR 2.37, 95% CI 1.44, 3.91). Our findings suggest the importance of good preventative treatment for malaria in pregnancy to minimize the impact of exposure to malaria on fetal and newborn growth. However, under-nutrition has an important role and research and programs to improve maternal nutritional health may be important to important to further improving birth outcomes in low-resource settings. Furthermore, given the high prevalence of anemia seen in our study, also associated with under-nutrition, as well as hookworm, and malaria, further research is needed to optimize interventions around pregnancy to improve maternal and newborn health in malaria-endemic regions.Doctor of Philosoph
Human genetic susceptibility to mother to child transmission of HIV: a study of mother-infant pairs in Malawi
Full text linkMother-To-Child Transmission of HIV (HIV MTCT) is a worldwide public health problem and particularly burdens mothers and children in Sub-Saharan Africa, where in 2006, over 500,000 infants were newly infected with HIV 1. To more clearly understand the mechanisms of transmission, we studied genetic exposures and HIV MTCT in consenting mother-infant pairs receiving antenatal care in Blantyre, Malawi. We first examined infant genetic susceptibility to maternal infection through a genome wide association (GWA) scan of 655,000 SNPs. Top associations with HIV MTCT were found for 20 SNPs within 7 genes (p<5 x 10-5, Bonferroni p=1), including rs8069770, located within the gene, HS3ST3A1, which facilitates the biosynthesis of a subtype of Heparan Sulfate that plays a role in viral infection. We then applied our GWA data to determine how genetic variation in our Malawi population compares to that of African ancestry (AFA) populations from the International HapMap Project. Allele frequency in the Malawian population was highly correlated to that of AFA populations (r2>0.90) but not with other ancestry populations (r2<0.51). Similar findings were observed for adjacent linkage disequilibrium (AFA r2>0.80, other ancestry r2<0.54). Frequencies of 4 SNPs in the lactase gene (LCT) varied greatly between the Malawi population and Maasai in Kenyawa, Kenya (Bonferroni p<1x10-33). The Malawi population was genetically homogenous but distinct from other populations. Finally, we examined the regulation of chemokine co-receptor 5 (CCR5) expression in human placenta by infant polymorphisms and maternal infection. The CCR5 promoter polymorphisms CCR5-2554T (rs2734648, β= -0.67, 95% CI= -1.23, - 0.11) and -2132T (β=-0.75, 95% CI=-0.131, -0.18) were significantly associated with reduced placental expression of CCR5. An incremental increase in CCR5 expression by expression of HS3ST3A1 (β=0.27, 95% CI=0.18, 0.35) and HS3ST3B1 (β=0.11, 95% CI=0.06, 0.18) was observed. CCR5 expression was up-regulated for higher maternal HIV viral load (β=0.76, 95% CI=0.12, 1.39; p=0.020) and malaria infection (β=0.37, 95% CI=-0.43, 1.18, p=0.362), with variable statistical significance. This cumulative body of work provides a fresh look at genetic factors involved in the risk of HIV MTCT as well as how such findings can be generalized to other populations in Africa
The effects of malaria in pregnancy on utero- and fetoplacental blood flow and fetal growth: a longitudinal Doppler ultrasound study from Kinshasa, Democratic Republic of Congo
Full text linkMalaria during pregnancy is thought to affect both uterine and umbilical artery blood flow, leading to decreased oxygen and nutrient exchange between the mother and fetus, and ultimately to intrauterine growth restriction. We examined the effect of concurrent malaria on changes in uterine artery and umbilical artery resistance indices over gestational age. We used data from 177 pregnant women enrolled in a longitudinal Doppler ultrasound study. Women with high uterine artery and umbilical artery resistance had neonates that weighed less and were smaller. Compared to multigravidae with no malaria, primigravidae with concurrent malaria had an 11-13% increase in uterine artery resistance. Compared to women with no concurrent malaria and a male fetus, concurrent malaria caused an acute 10-14% increase in umbilical artery resistance among women female fetus, while women with a male fetus and concurrent malaria had a 2-3% increase in umbilical artery resistance. We also examined the effect of early pregnancy malaria parasitemia ([less than or equal to] 20 weeks' gestation) on subsequent changes in uteroplacental blood flow and fetal growth among a subset of 128 women with early pregnancy malaria exposure data. Early pregnancy malaria infection affected placentation, reflected by changes in uterine artery blood flow. Among nourished women, early pregnancy malaria decreased uterine artery resistance (-0.036; 95% CI: -0.065, -0.0058), but among undernourished women, early pregnancy malaria increased uterine artery resistance (+0.022; 95% CI: -0.031, 0.074). Among primigravidae, early pregnancy malaria decreased umbilical artery resistance, reflecting adaptive villous angiogenesis with early pregnancy malaria. Primigravidae with early pregnancy malaria had 3.6 times the risk of subsequent IUGR (95% CI: 2.1, 6.2) compared to multigravidae with no early pregnancy malaria. Our findings point to both the acute effects of concurrent parasitemia and the effects of early pregnancy malaria on placental development. The acute effects of malaria on placental blood flow indicate the need for management and control strategies during pregnancy. Early pregnancy malaria infection leads to changes in placentation, villous angiogenesis, and intrauterine growth restriction. Our findings support the initiation of malaria prevention and control efforts earlier in pregnancy
Malaria and anemia in HIV-infected pregnant women in Malawi: associations with cotrimoxazole prophylaxis, submicroscopic malaria, iron supplementation and iron deficiency
Full text linkIn HIV-infected pregnant women, we examined the effectiveness of cotrimoxazole (CTX) with or without sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) compared to SP-IPTp at reducing malaria and anemia in aim 1. In aim 2, we investigated the predictors and effects of submicroscopic malaria on anemia. In aim 3 we assessed the associations of iron supplementation and iron deficiency with malaria. Between December 2005 and July 2009, 1,142 HIV-infected pregnant women attending Thyolo hospital antenatal clinic in Malawi were recruited in a cross-sectional study. Peripheral blood was tested for hemoglobin concentration (Hb) and malaria using microscopy and polymerase chain reaction (PCR). Iron biomarkers were measured in 455 women. Information on socio-demographics, obstetric and medical history, use of malaria control interventions was collected using a standardized questionnaire and antenatal records. For aim 1, women in SP-IPTp plus CTX and CTX groups were less likely to have microscopic (Adjusted OR, [95%CI]: 0.09, [0.01-0.66] and 0.43, [0.19-0.97] respectively) or PCR-detected malaria infections (AOR, [95%CI]: 0.24, [0.10-0.62] and 0.44, [0.25-0.78] respectively) compared to women in the SP-IPTp group. Anemia was lower in the SP-IPTp plus CTX and CTX groups than in the SP-IPTp group (Adjusted prevalence ratio (APR), [95%CI] 0.67, [0.54-0.83] and 0.72, [0.61-0.83] respectively). For aim 2, submicroscopic malaria was higher in primigravidae compared to multigravidae, during rainy season and in women not taking CTX. Mean Hb of women with submicroscopic malaria was lower than in women without malaria (Adjusted mean difference=-0.69; 95%CI -1.03,-0.35; p=<0.0001). Anemia was higher in women with submicroscopic malaria (APR =1.44; 95%CI 1.18-1.76) compared to women without malaria. For aim 3, the prevalence of microscopic and PCR-detected malaria was similar between women who took iron and those who did not (AOR, [95%CI): 2.50, [0.89-7.06] and 1.42, [0.61-3.33] respectively). Women with iron deficiency were less likely to have microscopic infection or PCR-detected malaria infection (AOR, [95%CI]: 0.22, [0.11-0.47] and 0.21, [0.12-0.39] respectively). Our findings support use of CTX instead of SP for IPTp and submicroscopic malaria infection has clinical significance in HIV-infected pregnant women. Iron supplementation should not be withheld from HIV-infected pregnant women in Malawi
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