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Biomedical subjects

Peter G Kremsner

Publications and source records attributed to Peter G Kremsner.

At least 19 recordsLinked to original sources
PubMed2004

Shared breastfeeding in central Africa.

In this study, shared breastfeeding is described asa novel risk factor for vertical HIV transmission. This cross-sectional survey conducted in the central African country Gabon found that 40% of lactating mothers also breastfed other children than their own, and as many children were additionally breastfed by other women. Shared breastfeeding is increasing the exposure to potentially infectious individuals and has therefore to be considered in breastfeeding recommendations.

Breast Feeding↗
PubMed2004

Plasmodium induces swelling-activated ClC-2 anion channels in the host erythrocyte.

Intraerythrocytic growth of the human malaria parasite Plasmodium falciparum depends on delivery of nutrients. Moreover, infection challenges cell volume constancy of the host erythrocyte requiring enhanced activity of cell volume regulatory mechanisms. Patch clamp recording demonstrated inwardly and outwardly rectifying anion channels in infected but not in control erythrocytes. The molecular identity of those channels remained elusive. We show here for one channel type that voltage dependence, cell volume sensitivity, and activation by oxidation are identical to ClC-2. Moreover, Western blots and FACS analysis showed protein and functional ClC-2 expression in human erythrocytes and erythrocytes from wild type (Clcn2(+/+)) but not from Clcn2(-/-) mice. Finally, patch clamp recording revealed activation of volume-sensitive inwardly rectifying channels in Plasmodium berghei-infected Clcn2(+/+) but not Clcn2(-/-) erythrocytes. Erythrocytes from infected mice of both genotypes differed in cell volume and inhibition of ClC-2 by ZnCl(2) (1 mm) induced an increase of cell volume only in parasitized Clcn2(+/+) erythrocytes. Lack of ClC-2 did not inhibit P. berghei development in vivo nor substantially affect the mortality of infected mice. In conclusion, activation of host ClC-2 channels participates in the altered permeability of Plasmodium-infected erythrocytes but is not required for intraerythrocytic parasite survival.

Animals↗
PubMed2004

Analysis of IgG with specificity for variant surface antigens expressed by placental Plasmodium falciparum isolates.

BACKGROUND: Pregnancy-associated malaria (PAM) is caused by Plasmodium falciparum-infected erythrocytes that can sequester in placental intervillous space by expressing particular variant surface antigens (VSA) that can mediate adhesion to chondroitin sulfate A (CSA) in vitro. IgG antibodies with specificity for the VSA expressed by these parasites (VSAPAM) are associated with protection from maternal anaemia, prematurity and low birth weight, which is the greatest risk factor for death in the first month of life. METHODS: In this study, the development of anti-VSAPAM antibodies in a group of 151 women who presented to the maternity ward of Albert Schweitzer Hospital in Lambaréné, Gabon for delivery was analysed using flow cytometry assays. Plasma samples from placenta infected primiparous women were also investigated for their capacity to inhibit parasite binding to CSA in vitro. RESULTS: In the study cohort, primiparous as well as secundiparous women had the greatest risk of infection at delivery as well as during pregnancy. Primiparous women with infected placentas at delivery showed higher levels of VSAPAM-specific IgG compared to women who had no malaria infections at delivery. Placental isolates of Gabonese and Senegalese origin tested on plasma samples from Gabon showed parity dependency and gender specificity patterns. There was a significant correlation of plasma reactivity as measured by flow cytometry between different placental isolates. In the plasma of infected primiparous women, VSAPAM-specific IgG measured by flow cytometry could be correlated with anti-adhesion antibodies measured by the inhibition of CSA binding. CONCLUSION: Recognition of placental parasites shows a parity- and sex- dependent pattern, like that previously observed in laboratory strains selected to bind to CSA. Placental infections at delivery in primiparous women appear to be sufficient to induce functional antibodies which can both recognize the surface of the infected erythrocytes as well as block their binding to CSA. The correlation between serum reactivities of placental field isolates from different geographic locations and collected at different times is indicative of the conserved nature of the antigen(s) mediating PAM.

Animals↗
PubMed2004

No change in parasite genotype during single episodes of Plasmodium falciparum malaria in Gabonese children.

Patients living in endemic areas can carry a mixture of Plasmodium falciparum genotypes. To investigate the genetic composition of parasite genotypes in malaria patients during the acute phase of the infection, we performed close follow-ups of 17 Gabonese pediatric patients aged 2-7 years. Capillary blood samples were taken on admission and every 4-6 h after the start of quinine therapy. Merozoite surface protein 2 (MSP2) genotypes were used to assess the parasites' genetic characteristics in each sample. We found that each patient carried parasites with the same genotypic pattern throughout the infection.

Animals↗
PubMed2004

Impact of increasing consultation fees on malaria in Africa.

To evaluate the impact of the increase in consultation fees on malaria incidence in children presenting in the outpatient clinic of a privately funded hospital, we measured the impact of two fee increases on the number of pediatric outpatients. A 74% reduction in outpatients and a 78% reduction in malaria cases occurred in a course of four years. No differences were observed in an adjacent public hospital that does not charge consultation fees. This surprisingly strong effect may be the basis for increase in malaria morbidity and mortality, since in the time course of 4 years, an estimated 3000 children did not receive adequate malaria treatment in this region. Furthermore, it may drive parasite resistance, due to inadequate auto-medication.

Child↗
PubMed2004

DNA phasing by TA dinucleotide microsatellite length determines in vitro and in vivo expression of the gp91phox subunit of NADPH oxidase and mediates protection against severe malaria.

Reactive oxygen intermediates (ROIs) play a major role in the nonspecific innate immune response to invading microorganisms, such as Plasmodium falciparum. In a search for genetic markers that determine differences in production of ROI, we detected a highly polymorphic region of dinucleotide TA repeats approximately 550 bp upstream of the NADPH oxidase gp91(phox) subunit promoter. We genotyped 183 matched Gabonese children with severe or mild malaria. Repeat lengths TA(11) and TA(16) differed significantly in frequency between mild and severe infection, which suggests protection against severe malaria. Both repeat lengths showed lower levels of NADPH oxidase and promoter activities, which can be explained by a cyclic trend in TA repeat length with a period of approximately 5, which indicates the necessity of correct DNA phasing between 2 possible control regions in the promoter. We provide a molecular model of how DNA phasing generated by TA dinucleotide polymorphisms may influence the expression level and protect against severe malaria.

Animals↗
PubMed2004

Responses to Toll-like receptor ligands in children living in areas where schistosome infections are endemic.

To study the effect of repeated challenge of the innate immune system with pathogen-associated molecular patterns, cytokine responses to schistosomal lipids and bacterial lipopolysaccharide (LPS) were analyzed in schoolchildren living in an area in Gabon where schistosomiasis, a helminth infection that is chronic in nature, is endemic. A schistosomal phosphatidylserine (PS) fraction containing the Toll-like receptor (TLR)-2 ligand lyso-PS stimulated the production of interleukin (IL)-8, IL-10, IL-6, and tumor necrosis factor (TNF)-alpha in children without Schistosoma haematobium infection. However, in infected children, the responses to this stimulus were lower, in particular for production of IL-8 and TNF-alpha. Responses to the TLR4 ligand, LPS, followed a similar pattern. In contrast, schistosomal adult worm glycolipids that did not stimulate any of the TLRs tested induced IL-8 and IL-6 responses that were significantly higher in schistosome-infected children than in schistosome-uninfected children. These results indicate that relentless exposure to pathogens can lead to altered responses to TLR ligands.

Adolescent↗
PubMed2004

Long-term treatment of intestinal helminths increases mite skin-test reactivity in Gabonese schoolchildren.

BACKGROUND: Several studies have shown an inverse association between helminth infections and atopy, but none have clearly established that the pathogens themselves, rather than other associated factors, cause the suppression of atopy. To show a direct link, prospective intervention studies are required. METHODS: A randomized, controlled trial was performed to study whether repeated anthelminthic treatment results in increased allergic sensitivity to house dust mites (HDMs) in chronically infected children. The trial population consisted of 317 Gabonese schoolchildren with a high prevalence of intestinal helminths. Intervention consisted of treatment every 3 months with praziquantel and mebendazole and with placebo in the control group. Follow-up lasted 30 months: at 6-month intervals, skin-test sensitivity to mites, helminth infection status, and levels of total IgE were determined. RESULTS: Treatment resulted in a significant increase in the rate of developing skin sensitivity to HDMs (hazard ratio, 2.51; 95% confidence interval, 1.85-3.41), which was mediated, in part, by reductions in Ascaris and/or Trichuris infections. Levels of total IgE were reduced, but this did not mediate the effect of treatment on skin-test reactivity. CONCLUSIONS: Anthelminthic treatment of chronically infected children results in increased atopic reactivity, which indicates that helminths directly suppress allergic reactions.

Adolescent↗
PubMed2004

Fosmidomycin-clindamycin for Plasmodium falciparum Infections in African children.

BACKGROUND: Fosmidomycin is a new antimalarial drug with a novel mechanism of action. Studies in Africa that have evaluated fosmidomycin as monotherapeutic agent demonstrated its excellent tolerance, but 3-times-daily treatment regimens of >or=4 days were required to achieve radical cure, prompting further research to identify and validate a suitable combination partner to enhance its efficacy. METHODS: We conducted a randomized, controlled, open-label study to evaluate the efficacy and safety of fosmidomycin combined with clindamycin (n=12; 30 and 5 mg/kg body weight every 12 h for 5 days, respectively), compared with fosmidomycin alone (n=12; 30 mg/kg body weight every 12 h for 5 days) and clindamycin alone (n=12; 5 mg/kg body weight every 12 h for 5 days) for the clearance of asymptomatic Plasmodium falciparum infections in schoolchildren in Gabon aged 7-14 years. RESULTS: Asexual parasites were rapidly cleared in children treated with fosmidomycin-clindamycin (median time, 18 h) and fosmidomycin alone (25 h) but slowly in children treated with clindamycin alone (71 h; P=.004). However, only treatment with fosmidomycin-clindamycin or clindamycin alone led to the radical elimination of asexual parasites as measured by day 14 and 28 cure rates of 100%. Asexual parasites reappeared by day 28 in 7 children who received fosmidomycin (day 14 cure rate, 92% [11/12; day 28 cure rate, 42% [5/12]). All regimens were well tolerated, and no serious adverse events occurred. CONCLUSION: The combination of fosmidomycin and clindamycin is well tolerated and superior to either agent on its own with respect to the rapid and radical clearance of P. falciparum infections in African children.

Antimalarials↗
PubMed2004

Depressed natural killer cell cytotoxicity against Plasmodium falciparum-infected erythrocytes during first pregnancies.

We measured natural killer (NK) cell cytotoxicity and cortisol and prolactin concentrations in peripheral venous blood samples obtained from pregnant Gabonese women at the time of delivery. The NK cell-mediated cytotoxicity against Plasmodium falciparum-infected erythrocytes in vitro was lower in samples obtained from primiparous women than in samples obtained from multiparous women; cortisol concentrations were significantly higher in primiparous women than in multiparous women, and prolactin concentrations were significantly lower. The highest cortisol concentrations were found in the plasma of P. falciparum-infected primiparous women. A positive correlation was found between cortisol concentration and parasite load; an inverse correlation was found between the magnitude of the NK cell cytolytic effect and cortisol production. A positive correlation was found between this effect and prolactin production. Thus, depressed NK cell cytotoxicity against P. falciparum-infected erythrocytes is correlated with high cortisol concentrations and may contribute to increased susceptibility to malaria during pregnancy.

Adult↗
PubMed2004

Variations in the serum concentrations of soluble Fas and soluble Fas ligand in Vietnamese patients infected with hepatitis B virus.

Earlier studies of both chronic hepatitis B and C virus (HBV and HCV) patients have shown a strong correlation between the soluble membrane Fas (sFas) and Fas protein expression on hepatocytes. The serum concentrations of sFas and soluble Fas ligand (sFasL) was examined in both healthy and HBV-infected Vietnamese patients to determine their relationship with the outcome of HBV infection. Patients with chronic rather than acute HBV had significantly higher amounts of sFas and sFasL, whilst the highest concentrations of both molecules were detected in those with malignant forms of HBV infection. sFas and sFasL concentrations tended to increase with a profile that paralleled the progression from asymptomatic to acute through chronic to malignant states, most markedly in the case of sFas. The sFas:sFasL ratio highlighted the relative predominance of sFas in those with acute and chronic HBV compared with asymptomatic or severe forms. In patients with hepatocellular carcinoma (HCC) a significant correlation was also observed between sFasL and alpha-feto protein (AFP) levels. The results indicate that sFas and to a lesser extent sFasL levels are to some degree associated with clinical progression in HBV infection.

Adult↗
PubMed2004

Submicroscopic Plasmodium falciparum infections and multiplicity of infection in matched peripheral, placental and umbilical cord blood samples from Gabonese women.

Summary In malaria-endemic regions, pregnant women are more susceptible to malarial infections than non-pregnant women. The main objective of this study, which was conducted in the malaria hyperendemic town of Lambaréné (Gabon, Central Africa), was to characterize Plasmodium falciparum infections in peripheral, placental and cord blood from women of different gravidities with submicroscopic infections. Using the P. falciparum merozoite surface protein 2 (MSP 2)* gene as a polymorphic marker in polymerase chain reactions, we analysed genetic diversity and multiplicity of infection in isolates from all three kinds of samples of 184 pregnant women at delivery. We detected infection in 44% of the women who were originally negative by microscopy. Equally important was the finding that the placenta had the highest prevalence of infection (P < 0.001). There was no correlation with gravidity status or age of the patients. The multiplicities of infection in the peripheral and placental blood samples did not differ and single infection was observed in cord blood, independently of the gravidity. The FC27/MSP 2 was the predominant allelic family. The major FC27 alleles detected in the peripheral, placental and cord blood were sequenced and found to be closely related to the published K1 form sequence. Below microscopy level, the placenta remains the most infected organ and this submicroscopic carriage of parasites may contribute to the development and maintenance of immunity to malaria during pregnancy.

Adolescent↗
PubMed2004

Immunoglobulin G isotype responses to variant surface antigens of Plasmodium falciparum in healthy Gabonese adults and children during and after successive malaria attacks.

We assessed immunoglobulin G (IgG) isotype responses with specificity for the variant surface antigens (VSA) of heterologous Plasmodium falciparum isolates by using flow cytometry and plasma from healthy Gabonese adults and from children during and after two consecutive malaria episodes. The individual isolate-specific antibody profiles differed markedly in terms of their isotype content but were similar for healthy adults and healthy uninfected children. In healthy adults, IgG3 and IgG2 responses were the highest, while in healthy children, IgG3 and IgG4 predominated. A transiently elevated IgG1 response was observed during the second of two successive malaria episodes in children, signaling P. falciparum infection-induced cross-reactive anti-VSA responses. Our findings highlight the prominence of IgG3 in the overall profile of these responses but also indicate a marked age-related increase in the prevalence of anti-VSA antibodies of the classically noncytophilic IgG2 isotype, possibly reflecting the high frequency of the histidine-131 variant of FcgammaRIIA in the Gabonese population.

Adolescent↗
PubMed2004

Elevated nitric oxide production in children with malarial anemia: hemozoin-induced nitric oxide synthase type 2 transcripts and nitric oxide in blood mononuclear cells.

Experiments outlined here investigate the role of nitric oxide (NO) in the pathogenesis of Plasmodium falciparum-induced malarial anemia (MA). The results show that ex vivo and in vitro NO synthase (NOS) activity in peripheral blood mononuclear cells (PBMCs) is significantly elevated in children with MA and inversely associated with hemoglobin levels. Additional experiments using PBMCs from non-malaria-exposed donors demonstrate that physiologic amounts of P. falciparum-derived hemozoin augment NOS type 2 (NOS2) transcripts and NO production. Results of these experiments illustrate that elevated NO production in children with MA is associated with decreased hemoglobin concentrations and that hemozoin can induce NOS2-derived NO formation in cultured blood mononuclear cells.

Anemia↗
PubMed2004

Antibodies to rifin: a component of naturally acquired responses to Plasmodium falciparum variant surface antigens on infected erythrocytes.

We used a pool of recombinant rifin proteins to pre-adsorb antibodies to rifin in the plasma of semi-immune African (Gabonese) adults and showed that this results in a reduction in the level of IgG antibody reactivity to variant surface antigens (VSA) measured in a standardized flow cytometric assay with a panel of heterologous parasite isolates. The same methods demonstrated a similar but less-marked contribution of antibodies to the duffy binding-like 1alpha (DBL-1alpha ) domain to the overall anti-VSA response. Thus, we conclude that both antibodies to rifin and, to a lesser extent, antibodies directed to conserved regions of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) DBL-1alpha domain contribute to the overall antibody response to VSA. We also assessed the associations between these different antibody responses in a cohort of Gabonese children. We found marked differences related to the childrens' history of presentation with either mild or severe malaria, but no consistent pattern that would indicate a specific role or influence of antibody responses to rifin.

Adult↗
PubMed2003

Atovaquone and proguanil versus amodiaquine for the treatment of Plasmodium falciparum malaria in African infants and young children.

Malaria-related morbidity and mortality are greatest among young children in areas with high malaria transmission intensity. An open-label, randomized study was done to evaluate the efficacy and safety of the combination of atovaquone and proguanil formulated as pediatric-strength tablets (20 and 8 mg/kg of body weight, respectively, administered once daily for 3 days), compared with amodiaquine (10 mg/kg of body weight, once daily for 3 days), among children weighing > or =5 and <11 kg in Gabon. Two hundred patients aged 3-43 months were recruited. Use of atovaquone/proguanil resulted in a cure rate on day 28 of 95% (87 of 92 children), compared with 53% (41 of 78 children) for amodiaquine (difference, 42%; 95% CI, 30%-54%; P<.001). The incidence of adverse events was similar in both groups, and no serious adverse events were attributed to the use of atovaquone/proguanil. Atovaquone/proguanil was found to be highly effective and safe for the treatment of Plasmodium falciparum malaria in infants and young children weighing 5-10 kg in Africa.

Amodiaquine↗
PubMed2003

Commonly recognised Plasmodium falciparum parasites cause cerebral malaria.

Cerebral malaria (CM) is a devastating form of Plasmodium falciparum malaria, in which adherence and sequestration of infected red blood cells in cerebral blood vessels play a major role. In order to determine whether a distinct parasite phenotype favours the development of this severe complication, P. falciparum isolates from Gabonese children suffering from CM or uncomplicated malaria (UM) were analysed for their binding phenotypes and their recognition in flow cytometry. CM isolates exhibited the ability to form rosettes and to bind ICAM-1, in line with previous studies correlating these phenotypes with CM disease pathology. CM isolates were more reactive with plasma from our cohort than UM parasites. This observation, together with the finding that some CM isolates were highly correlated with each other in their immunoreactivities, confirms that common parasites bearing conserved epitopes, which are capable of inducing cross-reactive antibodies, can cause CM in children.

Animals↗