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Biomedical subjects

S R Meshnick

Publications and source records attributed to S R Meshnick.

At least 19 recordsLinked to original sources
PubMed2004

Prevalence of dihydropteroate synthase mutants in HIV-infected South African children with Pneumocystis jiroveci pneumonia.

BACKGROUND: Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP) is a major cause of mortality in human immunodeficiency virus (HIV)-infected infants in Africa, but the prevalence of mutations in the gene encoding dihydropteroate synthase (DHPS) in isolates from Africa has not been reported. METHODS: This study investigated the prevalence of DHPS mutations in P. jiroveci isolates from South African HIV-infected children with PCP by amplifying DNA using 2 different polymerase chain reactions. RESULTS: P. jiroveci DNA from 30 respiratory specimens was amplified; 26 specimens (86.7%) contained wild-type DHPS alleles. Of the 4 samples (13.3%) with DHPS mutations, 2 contained a homogenous population with single DHPS mutations, 1 contained a homogenous population with 2 DHPS mutations, and the fourth contained a heterogenous population of organisms with both wild-type and single-mutant DHPS genotypes. Only 1 child was receiving trimethoprim-sulphamethoxazole (TMP-SMZ) prophylaxis; this patient was infected with wild-type P. jiroveci. The mortality rate (overall, 20 [66.7%] of 30 children) was not significantly different between children infected with wild-type P. jiroveci (17 [65.4%] of 26) and those infected with mutant strains (3 [75%] of 4; P=.8). CONCLUSIONS: DHPS mutations are uncommon in P. jiroveci isolates from South Africa. However, increasing use of TMP-SMZ prophylaxis may result in widespread development of mutations.

AIDS-Related Opportunistic Infections↗
PubMed2002

TNF-alpha promoter single nucleotide polymorphisms are markers of human ancestry.

We present a map of single nucleotide polymorphisms (SNPs) in the human tumor necrosis factor (TNF)-alpha promoter based upon exploratory sequencing of 333 human TNF-alpha gene promoters from individuals of distinct ancestral backgrounds. We detect 10 TNF-alpha promoter SNPs that occur with distinct frequencies in populations of different ancestry. Consistent with these findings, we show that two TNF-alpha SNPs, the -243 SNP and the -856 SNP, are the first SNP markers of a sub-Saharan African-derived extended haplotype and an Amerindian HLA haplotype, respectively. Comparisons of TNF-alpha promoter SNP allele frequencies can thus help elucidate variation of HLA haplotypes and their distribution among existing ethnic groups and shed light into the history of human populations.

Evolution, Molecular↗
PubMed2001

Immune mimicry in malaria: Plasmodium falciparum secretes a functional histamine-releasing factor homolog in vitro and in vivo.

The Plasmodium falciparum translationally controlled tumor protein (TCTP) is a homolog of the mammalian histamine-releasing factor (HRF), which causes histamine release from human basophils and IL-8 secretion from eosinophils. Histamine, IL-8, and eosinophils have been reported to be elevated in patients with malaria. This study was undertaken to determine whether malarial TCTP is found in the plasma of malaria-infected patients and to determine whether it has HRF biologic activity. Malarial TCTP was found in lightly infected human volunteers and in heavily infected Malawian children, but not in uninfected patients. Recombinant malarial TCTP, like HRF, stimulated histamine release from basophils and IL-8 secretion from eosinophils in vitro. Whereas malarial TCTP was less active than HRF, the concentrations that were effective in vitro could be achievable in vivo. These data suggest that malarial TCTP, present in human plasma during a malarial illness, may affect host immune responses in vivo.

Adult↗
PubMed2001

Malaria enhances expression of CC chemokine receptor 5 on placental macrophages.

Malaria and human immunodeficiency virus (HIV) coinfections are common in pregnant women in sub-Saharan Africa. The current study shows that placentas of malaria-infected women contain 3 times as much CC chemokine receptor 5 (CCR5) RNA as placentas of women without malaria. By immunohistochemistry, CCR5(+) maternal macrophages were seen in placentas from malaria-infected women but not in placentas from malaria-uninfected women. In addition, CCR5 also was found on fetal Hofbauer cells in placentas from both groups. Thus, malaria infections increase the potential reservoir for HIV in the placenta by increasing the number of HIV target cells.

CD4 Antigens↗
PubMed2001

Pneumocystis carinii cytochrome b mutations are associated with atovaquone exposure in patients with AIDS.

This retrospective cohort study was conducted to determine whether Pneumocystis carinii cytochrome b gene mutations in patients with AIDS and P. carinii pneumonia (PCP) are associated with atovaquone exposure. Portions of the P. carinii cytochrome b genes that were obtained from 60 patients with AIDS and PCP from 6 medical centers between 1995 and 1999 were amplified and sequenced by using polymerase chain reaction. Fifteen patients with previous atovaquone prophylaxis or treatment exposure were matched with 45 patients with no atovaquone exposure. Cytochrome b coenzyme Q binding site mutations were observed in 33% of isolates from patients exposed to atovaquone, compared with 6% from those who were not (P=.018). There was no difference in survival 1 month after treatment between patients with or without cytochrome b mutations (P=.14). Thus, cytochrome b mutations are significantly more common in patients with AIDS and PCP with atovaquone exposure, but the clinical significance of these mutations remains unknown.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Activities and conformational fitting of 1,4-naphthoquinone derivatives and other cyclic 1,4-diones tested in vitro against Pneumocystis carinii.

Atovaquone is a chemotherapeutic agent used to treat pneumonia caused by Pneumocystis carinii in some immunocompromised patients. A set of cyclic 1,4-diones were tested in vitro for ability to inhibit growth of P. carinii, including 22 variously substituted 1,4-naphthoquinones, one bis-1,4-naphthoquinone, and three other quinones. For comparison, the antipneumocystic primaquine and its 5-hydroxy-6-desmethyl metabolite were also tested. At 1.0 microg/ml, seven compounds inhibited growth by at least 39%, with atovaquone at 92%; of these seven, five are 2-hydroxy-1,4-naphthoquinones, while one is a 2-chloro- and another is a 2-methyl-1,4-naphthoquinone. At 0.1 microg/ml, however, the most active compound tested was the primaquine metabolite, which inhibited growth by more than 42% at this concentration. To ascertain a structure-activity relationship, all 1,4-naphthoquinones were compared conformationally by means of computer-based molecular modeling (Spartan) incorporating the Sybyl force field. Without exception, for all 21 monomers tested, the substituent at position 3 of the 1,4-naphthoquinone favored activity most strongly when it simultaneously occupied (i) space centered at about 3 A from position 3, without projecting steric bulk from the area encompassed by atovaquone's cyclohexyl ring, and (ii) roughly planar space at about 7.3 A from position 3, without projecting steric bulk perpendicularly. This structure-activity relationship may prove useful in the rational design of better antipneumocystis agents.

Antifungal Agents↗
PubMed2001

Immunoprecipitation of [(3)H]dihydroartemisinin translationally controlled tumor protein (TCTP) adducts from Plasmodium falciparum-infected erythrocytes by using anti-TCTP antibodies.

Artemisinin and its derivatives are endoperoxide-containing antimalarial drugs that appear to form adducts in situ with the Plasmodium falciparum translationally controlled tumor protein (TCTP) homolog. Immunoprecipitation with antibody to recombinant TCTP suggests that adducts may form with both monomeric and dimeric TCTP.

Animals↗
PubMed2000

Pneumocystis carinii mutations are associated with duration of sulfa or sulfone prophylaxis exposure in AIDS patients.

This study was conducted to determine whether Pneumocystis carinii dyhydropteroate synthase (DHPS) gene mutations in AIDS patients with P. carinii pneumonia (PCP) are affected by duration of sulfa or sulfone prophylaxis and influence response to sulfa or sulfone therapy. The P. carinii DHPS genes from 97 AIDS patients with PCP between 1991 and 1999 from 4 medical centers were amplified, using polymerase chain reaction (PCR), and sequenced. Mutations were observed in 76% of isolates from patients exposed to sulfa or sulfone prophylaxis compared with 23% of isolates from patients not exposed (P=.001). Duration of prophylaxis increased the risk of mutations (relative risk [RR] for each exposure month, 1.06; P=.02). Twenty-eight percent of patients with mutations failed sulfa or sulfone treatment; mutations increased the risk of sulfa or sulfone treatment failure (RR, 2.1; P=0.01). Thus, an increased duration of sulfa or sulfone prophylaxis increases the chance of developing a P. carinii mutation. The majority of patients with mutations respond to sulfa or sulfone therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Placental haemozoin and malaria in pregnancy.

Malaria infections in pregnant women cause poor birth outcomes. Malaria pigment (haemozoin) accumulates in the placenta within macrophages and extracellularly, but its pathological significance is not understood. In order to study the potential role of haemozoin in malaria pathogenesis, we enrolled primigravid women at a Malawian government antenatal clinic and followed them through delivery. One hundred and thirteen women (71 per cent) out of 159 women followed through delivery were parasitaemic at least once. Mean placental haemozoin concentrations were significantly higher in women with delivery parasitaemias (223 ng/mg protein) than in women who never had a detectable parasitaemia (43 ng/mg protein; P<0.05), but were not significantly higher in women who were parasitaemic only during the antenatal period (67 ng/mg protein). Haemozoin was not associated with preterm delivery (PTD) or intrauterine growth retardation (IUGR) (P -values, 0.307-0.787). Thus, placental haemozoin is associated with malaria infection at the time of delivery and does not seem to be associated with poor birth outcome.

Adult↗
PubMed2000

Mechanisms of artemisinin resistance in the rodent malaria pathogen Plasmodium yoelii.

Artemisinin and its derivatives are important new antimalarials which are now used widely in Southeast Asia. Clinically relevant artemisinin resistance has not yet been reported but is likely to occur. In order to understand how the malaria parasite might become resistant to this drug, we studied artemisinin resistance in the murine malaria parasite Plasmodium yoelii. The artemisinin-resistant strain (ART), which is approximately fourfold less sensitive to artemisinin than the sensitive NS strain, accumulated 43% less radiolabeled drug in vitro (P < 0.01). Within the parasite, the drug appeared to react with the same parasite proteins in both strains. The translationally controlled tumor protein, one of the artemisinin target proteins, did not differ between the strains. No DNA sequence difference was found, but the resistant strain was found to express 2.5-fold-more protein than the sensitive strain (P < 0.01). Thus, the phenotype of artemisinin resistance in P. yoelii appears to be multifactorial.

Amino Acid Sequence↗
PubMed2000

Effect of Plasmodium falciparum parasitemia density on hemoglobin concentrations among full-term, normal birth weight children in western Kenya, IV. The Asembo Bay Cohort Project.

The relative importance of acute high-density versus persistent low-density Plasmodium falciparum parasitemia in contributing to the public health problem of malarial anemia remains unclear. The Asembo Bay Cohort Project in western Kenya collected monthly hemoglobin (Hb) and parasitologic measurements and biweekly assessments of antimalarial drug use among 942 singleton live births between 1992 and 1996. A mixed-model analysis appropriate for repeated measures data was used to study how time-varying parasitemia and antimalarial drug exposures influenced mean Hb profiles. Incidence of World Health Organization-defined severe malarial anemia was 28.1 per 1,000 person-years. Among children aged less than 24 months, concurrent parasitemia was significantly associated with lower mean Hb, especially when compared to children with no concurrent parasitemia. Increased densities of the 90-day history of parasitemia preceding Hb measurement was more strongly associated with mean Hb levels than concurrent parasitemia density. While the highest quartile of 90-day parasitemia history was associated with lowest mean Hb levels, children in the lowest 90-day exposure quartile still experienced significantly lower Hb levels when compared to children who remained parasitemia-free for the same 90-day period. The results highlight the importance of collecting and analyzing longitudinal Hb and parasitologic data when studying the natural history of malarial anemia.

Anemia↗
PubMed1999

The Plasmodium falciparum translationally controlled tumor protein: subcellular localization and calcium binding.

Artemisinin derivatives are endoperoxide antimalarials widely used to treat falciparum malaria in areas where drug resistance is common. In Plasmodium falciparum-infected erythrocytes, radiolabeled artemisinin derivatives have been shown to react with malarial proteins, one of which is the Translationally Controlled Tumor Protein (TCTP). The P. falciparum TCTP was found by immunofluorescence to be located in both the cytoplasm and food vacuoles. Immunoelectron microscopy shows that it is present in the parasite cytoplasm as well as in its food vacuolar and limiting membranes. Like other TCTPs, the P. falciparum protein binds to calcium. Further studies on the physiological role of TCTP may aid in understanding the mechanism of action of endoperoxide antimalarials.

Animals↗
PubMed1999

Malaria infection during pregnancy: intrauterine growth retardation and preterm delivery in Malawi.

In sub-Saharan Africa, malaria infection in pregnancy contributes to low birth weight through intrauterine growth retardation (IUGR) and preterm delivery (PTD). It was hypothesized that malaria-associated PTD and IUGR have differing etiologies due to timing of infection. In a prospective cohort of primigravid women enrolled at the antenatal clinic of Mangochi District Hospital in Malawi, the associations were investigated between antenatal or delivery parasitemias and IUGR or PTD. Among 178 singleton deliveries, 35% of infants were preterm or had IUGR. Cord blood parasitemia (odds ratio [OR]=3.34; 95% confidence interval [CI], 1.3-8.8], placental parasitemia (OR=2.43; 95% CI, 1.2-5.1), and postdelivery maternal peripheral parasitemia (OR=2.78; 95% CI, 1.3-6.1) were associated with PTD. Parasitemia and/or clinically diagnosed malaria in the antenatal period was associated with IUGR (OR=5.13; 95% CI, 1.4-19.4). Delivery parasitemias had borderline associations with IUGR. The risk patterns observed suggest that the timing and severity of infection influences the occurrence of IUGR or PTD.

Female↗