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Biomedical subjects

P G Kremsner

Publications and source records attributed to P G Kremsner.

At least 19 recordsLinked to original sources
PubMed1999

High recombination rate in natural populations of Plasmodium falciparum.

Malaria parasites are sexually reproducing protozoa, although the extent of effective meiotic recombination in natural populations has been debated. If meiotic recombination occurs frequently, compared with point mutation and mitotic rearrangement, linkage disequilibrium between polymorphic sites is expected to decline with increasing distance along a chromosome. The rate of this decline should be proportional to the effective meiotic recombination rate in the population. Multiple polymorphic sites covering a 5-kb region of chromosome 9 (the msp1 gene) have been typed in 547 isolates from six populations in Africa to test for such a decline and estimate its rate in populations of Plasmodium falciparum. The magnitude of two-site linkage disequilibrium declines markedly with increasing molecular map distance between the sites, reaching nonsignificant levels within a map range of 0.3-1.0 kb in five of the populations and over a larger map distance in the population with lowest malaria endemicity. The rate of decline in linkage disequilibrium over molecular map distance is at least as rapid as that observed in most chromosomal regions of other sexually reproducing eukaryotes, such as humans and Drosophila. These results are consistent with the effective recombination rate expected in natural populations of P. falciparum, predicted on the basis of the underlying molecular rate of meiotic crossover and the coefficient of inbreeding caused by self-fertilization events. This is conclusive evidence to reject any hypothesis of clonality or low rate of meiotic recombination in P. falciparum populations. Moreover, the data have major implications for the design and interpretation of population genetic studies of selection on P. falciparum genes.

Africa↗
PubMed1999

Plasmodium falciparum: molecular background to strain-specific rosette disruption by glycosaminoglycans and sulfated glycoconjugates.

Rosetting, the adhesion of Plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, is a virulent parasite phenotype associated with the occurrence of severe malaria, e.g., cerebral malaria. Compounds with specific anti-rosetting activity are potential therapeutic agents. Glycosaminoglycans and sulfated glycoconjugates were found to disrupt rosettes in a strain- and isolate-specific manner. Rosette disruption was strongly connected to the presence of N-sulfate groups in heparin/heparan sulfate as demonstrated by modified heparin preparations. This finding was corroborated by the disruption of rosettes with mono- and disaccharides derived from heparin/heparan sulfate that contained N-sulfated glucosamine. Furthermore, heparinase III treatment of erythrocyte cultures infected by FCR3S1 (and to some extent TM 284) P. falciparum strains abolished rosetting. Heparinase III treatment of the uninfected erythrocytes prior to mixing with the infected culture impeded formation of rosettes, indicating that the rosetting receptors at least partially are of glycosaminoglycan nature.

Animals↗
PubMed1999

Frequency of cytokine-producing T cells in patients of different age groups with Plasmodium falciparum malaria.

The frequency of cytokine-producing T cells was assessed in patients of different age groups (29 infants, aged 1-5 years; 30 schoolchildren, aged 6-14 years; 26 adults, aged >15 years) with acute Plasmodium falciparum malaria from Gabon. By using flow cytometry for the intracellular detection of cytokines, a striking expansion was seen, in adults compared with children, of CD4+ and CD8+ T cells with the following profiles of type 1 cytokine production: interleukin (IL)-2-/interferon (IFN)-gamma+, IL-2+/IFN-gamma+, and IL-2+/IFN-gamma-. Patients with hyperparasitemia had a significantly lower frequency of IL-2-/IFN-gamma+ CD4+ cells. Type 2 cytokine expression (IL-4+/IFN-gamma-, IL-13+/IFN-gamma-) and type 0 cytokine expression (IL-4+/IFN-gamma+, IL-13+/IFN-gamma+) were also increased in adults within the CD4+ subset. Frequencies of IL-5+/IL-4+, IL-10+/IFN-gamma-, and IL-10+/IFN-gamma+ cells were similar in all groups. The increased frequency of both type 1 and type 2 cytokine-producing T cells in adults is likely to be of significance in the protection against P. falciparum malaria.

Acute Disease↗
PubMed1999

HLA class II factors associated with Plasmodium falciparum merozoite surface antigen allele families.

In Plasmodium falciparum malaria, certain human leukocyte antigens (HLA) and the parasite's merozoite surface antigens 1 and 2 (MSA-1, MSA-2) have been shown to influence the course of the infection. This report is on associations of distinct HLA factors with the occurrence of particular MSA families in a group of patients with either severe or mild P. falciparum malaria in Gabon. Different distributions of HLA-DPB1 alleles were found in the 2 groups. DR *04 alleles were observed more frequently among patients with severe malaria. Several alleles of different loci were associated with distinct MSA allele families. In addition, carriers of the amino acid methionine at position 11 of the DPA1 allele were more often infected by MSA-1 K1 parasites and less frequently by MSA-1 RO33 parasites. Furthermore, associations of HLA factors with polyclonal infections were found.

Alleles↗
PubMed1999

Interferon-gamma responses are associated with resistance to reinfection with Plasmodium falciparum in young African children.

The contribution of T cell-mediated responses was studied with regard to resistance to reinfection in groups of Gabonese children participating in a prospective study of severe and mild malaria due to infection with Plasmodium falciparum. In those admitted with mild malaria, but not in those with severe malaria, production of IFN-gamma by peripheral blood mononuclear cells (PBMC) in response to either liver-stage or merozoite antigen peptides was associated with significantly delayed first reinfections and with significantly lower rates of reinfection. Proliferative or tumor necrosis factor responses to the same peptides showed no such associations. Production of interferon-gamma by PBMC in response to sporozoite and merozoite antigen peptides was observed in a higher proportion of those presenting with mild malaria. Differences in the Th1/Th2 cytokine balance may be linked to the ability to control parasite multiplication in these young children, helping to explain the marked differences observed in both susceptibility to infection as well as in clinical presentation.

Amino Acid Sequence↗
PubMed1999

High oxygen radical production is associated with fast parasite clearance in children with Plasmodium falciparum malaria.

It has been hypothesized that reactive oxygen intermediates (ROI) released by leukocytes play a major role in the immune response to many infectious agents. In the present study, the parasitologic and clinical courses of 75 Gabonese children with Plasmodium falciparum malaria were compared with the ability of their granulocytes to produce oxygen radicals. The luminol-dependent chemiluminescence in granulocyte suspensions for the children was measured without stimulation and after stimulation with phorbol-12-myristate-13-acetate, N-formyl-methionyl-leucyl-phenylalanine, or tumor necrosis factor. A significant association was found between fast parasite clearance time and high oxygen radical generation in both the unstimulated and stimulated granulocyte preparations. No correlation was found between fever clearance time and ROI generation. These findings suggest that ROI play a pivotal role in the immune response as a first line of defense against P. falciparum malaria.

Child↗
PubMed1998

[Malaria therapy in the era of chloroquine resistance].

Despite few efforts to develop new antimalarial compounds by the major pharmaceutical companies, some promising new therapeutics have been developed and tested clinically by small groups and companies throughout the world. Really new substances are scarce but combinations of known medicarnents have been shown to be a rational and effective approach to overcome problems with single compounds. Additionally, combination regimens are more easily authorized and accepted for treatment than completely new substances. Some examples in this respect are combinations of either atovaquone, doxycycline or clindamycin with a 'classical' antimalarial. Artemisinin, benflumetol and pyronaridine were originally developed in China and disperse currently to the rest of the world. First independent and international clinical trials gave promising results and one should bear in mind those substances for future applications. Especially artemisinin and its derivatives are of great interest because they represent, besides quinine, the only other therapeutic option for the treatment of multidrug-resistant severe malaria.

Antimalarials↗
PubMed1998

Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children.

BACKGROUND: The combination of atovaquone and proguanil is highly effective and safe for the treatment of Plasmodium falciparum malaria. We aimed in this randomised, double-blind, placebo-controlled study to assess the efficacy and safety of this combination for malaria prophylaxis. METHODS: 320 children who lived in a hyperendemic area for P falciparum malaria were stratified by weight and randomly assigned atovaquone plus proguanil or placebo once daily for 12 weeks. All children received initial curative treatment with atovaquone and proguanil before the start of chemosuppression. We recorded adverse events daily and collected thick blood smears once a week. The primary endpoint was a positive blood smear. FINDINGS: 25 of 140 children in the placebo group and none of the 125 children in the atovaquone plus proguanil group had positive smears during chemosuppression (p<0.001). Adverse events during the chemosuppression phase did not differ between the groups. INTERPRETATION: The combination of atovaquone plus proguanil is a highly effective and well-tolerated chemosuppressive antimalarial in children. This drug combination could replace current regimens.

Adolescent↗
PubMed1998

Widespread expression of MRP8 and MRP14 in human cerebral malaria by microglial cells.

Human cerebral malaria (CM) is an often fatal infection. The cascades of signaling events resulting in tissue trauma and coma are only slowly becoming unraveled. Here we report that microglial cells--sensitive cellular sensors of threats to the central nervous system--in CM express the myeloid-related proteins MRP8 (S100A8) and MRP14 (S100A9), Ca2+-binding sensor proteins of activated monocytes. Surprisingly, microglial activation was widespread throughout the brain in white and gray matter and not limited to areas of petechial bleedings or sequestration of infected erythrocytes. Further, apoptosis/necrosis is prominent in CM; not only leukocytes appeared apoptotic, neurons also appeared damaged and DNA fragmentation was revealed by in situ nick translation. Thus, a prominent feature of human CM is activation of microglia, and analysis of these reactive microglia might further promote our understanding of CM pathology and guide development of future therapeutic intervention of the local reactive processes.

Antibodies, Monoclonal↗
PubMed1998

Overexpression of endothelium-derived nitric oxide synthase isoform 3 in the vasculature of human pancreatic tumor biopsies.

Cellular nitric oxide (NO) synthesis determines whether NO has cytoprotective or cytotoxic effects at anatomic sites; thus it is important to identify potential NO synthase isoforms in tumor tissue and tumor cell lines which might be involved in tumor development or destruction. Incubation of human pancreatic adenocarcinoma cell lines (AsPc-1, BxPc-3, CaPan-2) with cytokines resulted in increased NO formation, indicating the existence of the NOS2 isoform. This was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analysis. Furthermore, we identified the presence of the endothelium-derived NOS isoform 3 by RT-PCR analysis and immunohistochemistry in normal and pancreatic tumor biopsies. NOS3 was markedly overexpressed in the vasculature of the tumor tissue. RT-PCR analysis of tumor biopsies identified NOS isoform 2 mRNA in 60% of cases, but western blot analysis or immunohistochemistry scored negative for this isoform. It is noteworthy that the NOS enzyme activity in pancreatic tumor cell lines and tumor biopsies was inhibited by EGTA by approximately 30% and 65%, respectively. Our results suggest that increased endothelium-derived NOS isoform 3 expression in pancreatic adenocarcinomas regulates blood flow and is therefore involved in the vascularization and neovascularization of human pancreatic tumors.

Adenocarcinoma↗
PubMed1998

Protection of mice previously infected with Plasmodium vinckei against subsequent Salmonella enteritidis infection is associated with nitric oxide production capacity.

When mice previously cured of a Plasmodium vinckei infection were subsequently infected with Salmonella enteritidis the course of bacterial infection was significantly retarded, showing increased survival duration as compared with control infections in naive mice. Moreover, on stimulation with lipopolysaccharide and/or interferon-gamma, spleen cells from malaria-cured mice showed an increased capacity to produce tumor necrosis factor, interleukin 6, and reactive nitrogen intermediates as compared with spleen cells from naive mice. However, no significant variation in the capacity of spleen cells to release reactive oxygen intermediates was observed between previously malarious and naive mice. The most significant increases were observed in the capacity for reactive nitrogen intermediate production after P. vinckei malaria. These results suggest that the observed protection of mice against salmonellosis in the convalescent phase after malaria may be mediated by nitric oxides.

Animals↗
PubMed1998

Plasmodium falciparum: in vitro chloroquine susceptibility and allele-specific PCR detection of Pfmdr1 Asn86Tyr polymorphism in Lambarene, Gabon.

Plasmodium falciparum resistance to chloroquine has been described in many parts of the world particularly in Africa where malaria is endemic. High levels of chloroquine resistance in our study area, Lambarene-Gabon, has led to the use of an alternative regimen for treatment and prevention of P. falciparum infection. In this study, we examined the in vitro chloroquine sensitivity of 15 isolates from this area and assessed the prevalence of a putative chloroquine resistance associated Pfmdr1 polymorphism (Asn86Tyr) using a novel allele-specific polymerase chain reaction (PCR). Only 4 of the isolates examined were chloroquine sensitive. The allele-specific PCR shows that all 15 isolates carried the variant (86Tyr) codon. Eleven of these were resistant to chloroquine suggesting a 73% agreement between chloroquine resistance phenotype and the point mutation. This molecular marker was examined in a further 73 Gabonese isolates, where 58 (79.5%) showed 86Tyr and 15 (20.5%) showed 86Asn. In all, 4 (4.5%) of the 88 isolates assessed carry both mutant and wild-type codons, suggesting mixed parasite populations. The incomplete agreement found between chloroquine resistance phenotype and Pfmdr1 (86Tyr) polymorphism would support the view that other genetic factors as well as Pfmdr1 may be involved in chloroquine resistance. While our results suggest a high prevalence of 86Tyr polymorphism in Lambarene, the Asp1246Tyr polymorphism (a point mutation which to date has only been associated with South American P. falciparum) seems to be absent in our study area.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

The effect of anti-IL-10 on proliferation and cytokine production in human schistosomiasis: fresh versus cryopreserved cells.

In this study we neutralized endogenous IL-10 in PBMC from individuals chronically infected with Schistosoma haematobium by using anti-IL-10 MoAbs, and examined the effect and adult worm antigen (AWA)-specific responses in both fresh or cryopreserved cells. Anti-IL-10 alone increased background proliferation of PBMC, but did not augment the AWA-specific responses in either fresh or frozen cells. In freshly isolated PBMC, IFN-gamma production in response to AWA was enhanced significantly in the presence of anti-IL-10. In cryopreserved cells, the augmentation of IFN-gamma in the presence of anti-IL-10 was four-fold less than in the freshly-isolated cells. Neutralization of IL-10 had no effect on IL-4 production. These data show that IL-10 plays a role in specifically down-regulating Th1-but not Th2-type responses and, in contrast to previous reports, anti-IL-10 does not augment proliferation to parasite antigen in chronic schistosomiasis.

Animals↗
PubMed1998

Hyperparasitemia and blood exchange transfusion for treatment of children with falciparum malaria.

A substantial number of reports of cases and small investigations support blood exchange transfusion as a therapy for hyperparasitemia in cases of Plasmodium falciparum malaria, although a prospective and randomized study has never been undertaken. We report on 113 prospectively enrolled children in Lambaréné, Gabon, who had more than 10% parasitized erythrocytes and were treated with chemotherapy alone. All 86 patients with hyperparasitemia as the sole complication recovered uneventfully. Among the 27 patients who had additional complications, parasitemia levels as high as 81% responded well to chemotherapy alone. Two patients with cerebral malaria, who also had other complications and hence a poor prognosis, died. Hyperparasitemia itself might be important for the development of a fatal event in malaria, but a recommendation to perform a dangerous, expensive, and labor-intensive procedure such as blood exchange transfusion for its treatment should be based on substantial clinical research, especially in areas where malaria is a major health problem.

Antimalarials↗
PubMed1998

Mannose-binding lectin plasma levels and gene polymorphisms in Plasmodium falciparum malaria.

The contribution of mannose-binding lectin (MBL) to protection from malaria was assessed by comparing plasma concentrations of MBL and the frequency of MBL gene polymorphisms in groups of Gabonese children participating in a prospective study of severe and mild malaria due to infection with Plasmodium falciparum. At admission, a higher proportion of patients with severe malaria had a low level of MBL compared with subjects with mild malaria (0.35 vs. 0.19, P = .02). Two mutations in codons 54 and 57 of the MBL gene were detected. They were present at higher frequency in those with severe malaria (0.45 vs. 0.31, P = .04). These results suggest that deficient innate immune responses, in the form of low MBL levels, may be a risk factor for severe malaria in some young children who lack well-developed, clinically protective acquired immune responses.

Carrier Proteins↗
PubMed1998

Antigen-specific proliferation and interferon-gamma and interleukin-5 production are down-regulated during Schistosoma haematobium infection.

Antigen-specific cellular immune responses were examined in persons previously infected with Schistosoma haematobium and who were, 2 years after chemotherapy, either free from infection (n = 17) or reinfected (n = 20). Proliferation to adult worm antigen (AWA) was significantly higher in uninfected than in reinfected subjects (P = .02), whereas responses to soluble egg antigen (SEA) remained low in both groups. Interleukin (IL)-5 production in uninfected persons in response to AWA and SEA was higher than in infected subjects (P = .05 and P < .001, respectively), while IL-4 and IL-13 release was similar in the 2 groups. Levels of interferon-gamma to AWA and to SEA were inversely correlated with egg output (P = .03 and P = .02, respectively). These data indicate that the presence of schistosome infection leads to T cell proliferative hyporesponsiveness and that both typical Th1 and Th2 cytokines can be down-regulated by active infection.

Adolescent↗
PubMed1998

Human IgE, IgG subclass, and IgM responses to worm and egg antigens in schistosomiasis haematobium: a 12-month study of reinfection in Cameroonian children.

Levels of IgE, IgM, and IgG subclasses against Schistosoma haematobium adult worm antigen (AWA) and soluble egg antigen (SEA) in a cohort of 148 S. haematobium-infected schoolchildren were determined before and up to 12 months after chemotherapy. Infection intensities were determined as concentrations of circulating anodic antigen (CAA) in serum. One month posttreatment, the antibody levels of all isotypes against AWA were increased, but 1 year after treatment they returned to pretreatment levels. CAA concentrations were positively associated with levels of IgG4 against AWA and SEA but not with levels of IgE. Age correlated negatively with CAA concentrations and positively with levels of IgE to AWA. The balance of anti-AWA IgG4 and IgE was significantly correlated to the CAA concentration, in particular in the older age group (11-13 years). This may suggest that protective immune mechanisms in S. haematobium infections become effective around the age of 12 years.

Adolescent↗