Biomedical subjects

Peter G Kremsner

Publications and source records attributed to Peter G Kremsner.

At least 91 records · Page 5Linked to original sources

PubMed2003

Angiogenic proteins in brains of patients who died with cerebral malaria.

In cerebral malaria (CM), microvascular activation accompanies blood-brain barrier dysfunction which in turn represents the pathophysiological basis of neurological impairments in affected patients. To dissect the molecular basis of this process, we analyzed localization of proangiogenic vascular endothelial growth factor (VEGF), its receptor vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1), of downstream VEGF effectors matrix-metalloproteinase-1 (MMP-1) and connective tissue growth factor (CTGF), and of VEGF-interacting antiangiogenic thrombospondin-1 and -independent angiostatin in brains of patients who died with CM and controls by immunohistochemistry and Western blotting experiments. Most prominently, we detected more VEGF(+) astrocytes in CM patients and deposition of Flt-1 in Dürck's granulomas. MMP-1 and thrombospondin-1 accumulated in macrophages/microglial cells in Dürck's granulomas. In one CM patient, massive amounts of CTGF were detected as perivascular paracellular deposits. Angiostatin was observed in the serum of 2/7 control but in no CM patients. These data demonstrate the activation of the proangiogenic VEGF signaling cascade in patients with CM, probably reflecting compensatory mechanisms of general and focal brain hypoxia observed in these patients.

Angiogenic Proteins↗

PubMed2003

Serum cytokine profiles associated with clinical presentation in Vietnamese infected with hepatitis B virus.

BACKGROUND/OBJECTIVES: An ineffective cytokine response is thought to be one of the reasons for the failure to suppress hepatitis B virus (HBV) replication and to eliminate the virus. We investigated the serum levels of interleukin (IL)-6, IL-10, IL-12, and interferon (IFN)-gamma in HBV-infected Vietnamese patients to determine whether they were related to the outcome of HBV infection. STUDY DESIGN: Samples from a total of 154 HBV-infected patients with well-characterised clinical profiles and 56 healthy controls were assessed. RESULTS: Serum IL-6 levels, which were inversely correlated with transaminase levels, were highest in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) and lowest in those with either asymptomatic (ASYM), acute or chronic HBV, and thus, represented the best marker of HBV-related clinical progression. Compared with the healthy control group, serum IL-12 was uniformly elevated in all HBV-infected patients apart from those with ASYM infections, implying no impairment of production of this cytokine in HBV-infected individuals. Serum IL-10 and IFN-gamma levels, however, were uniformly low and showed no association with clinical presentation. Cytokine profiles were not influenced by the presence of hepatitis B e antigen (HbeAg). CONCLUSIONS: Serum IL-6 and IL-12 but not IL-10 and IFN-gamma are associated with the clinical presentation in HBV-infected Vietnamese patients.

Adult↗

PubMed2003

Short-course artesunate treatment of uncomplicated Plasmodium falciparum malaria in Gabon.

Artesunate is one of the most important antimalarial agents available, since it is effective against parasites that have developed resistance to conventional antimalarials in sub-Saharan Africa. Antimalarial combination chemotherapies with artesunate (4 mg/kg of body weight once daily for 3 days) as one partner have been proposed. However, the efficacy of a 3-day course of artesunate alone has never been evaluated in individuals in Africa (which has 90% of the worldwide malaria burden) living in regions of hyperendemicity, where a considerable degree of immunity might substantially enhance the efficacy of short courses of artesunate compared to those in regions where the levels of endemicity are low. This lack of information does not permit a systematic assessment of the value of artesunate-based combination chemotherapies in Africa. Therefore, we studied the efficacy and safety of a 3-day course of artesunate (4 mg/kg of body weight, orally, once daily) for the treatment of uncomplicated Plasmodium falciparum malaria in Gabonese patients aged 4 to 15 years (n = 50). Artesunate was well tolerated, and no severe adverse event was reported. Parasite elimination was rapid and was achieved in all patients within < or =72 h (geometric mean time to elimination, 34 h). The PCR-corrected cure rate by day 14 was 92% (46 of 50 patients), but it dropped to 72% (36 of 50 patients) by day 28. We conclude that a 3-day course of artesunate fails to achieve sufficiently high cure rates for uncomplicated falciparum malaria in Gabonese children.

Adolescent↗

PubMed2003

Antibodies to Plasmodium falciparum rifin proteins are associated with rapid parasite clearance and asymptomatic infections.

Plasmodium falciparum rifin proteins, belonging to the largest known family of variable infected-erythrocyte surface-expressed proteins encoded by rif genes, were recently shown to be capable of inducing a strong immune response in P. falciparum-infected adults living in an area in Gabon where malaria is endemic. In the present study, the levels of antirifin antibodies were analyzed in serum obtained from 60 children from the same area who were admitted to hospital and diagnosed with severe malaria. High antirifin antibody concentrations in these individuals correlated significantly with their capacity to rapidly clear their parasites from the circulation after the start of chemotherapy. A doubling of antirifin antibody concentrations reduced the clearance time by 5 h (95% confidence interval, 4.1 to 6.9 h). In the same group of children, who were followed up for 2 years, antirifin antibody levels did not correlate with a reduced rate of reinfection or with a delay in the time to the first reinfection. However, the initial antirifin antibody levels were sustained over the study period. The likelihood that these antibodies could confer a certain degree of protection against malaria is supported by our findings of statistically higher levels of antirifin antibodies to all four rifin proteins in a group of 42 asymptomatic parasitemic children.

Age Factors↗

PubMed2003

Normal riboflavin status in malaria patients in Gabon.

Previous publications reported commonly the occurrence of riboflavin deficiency and a positive correlation between riboflavin status and parasitemia in patients with Plasmodium falciparum malaria. In these studies, riboflavin status was determined by erythrocyte glutathione reductase activation coefficients (EGRACs). Inherited low erythrocyte glutathione reductase activity is highly prevalent in malarial regions, however. To rule out falsely diagnosed riboflavin deficiency in affected patients, we conducted an investigation using a high-performance liquid chromatography method (HPLC) instead of the EGRAC method. In 29 infants (age range, 1-5 years), 22 schoolchildren (age range, 6-12 years), and 33 adolescents and adults (age range, 13-74 years) from Lambaréné, Gabon, with acute P. falciparum malaria, plasma concentrations of riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) were measured by HPLC. Results were correlated with parasite densities. Profiles of plasma concentrations of all 3 flavin compounds were within the normal range in all patients. Concentrations of free riboflavin were not different between the 3 age groups. In adolescents and adults, FMN and FAD concentrations were higher than in infants (P = 0.002 and P = 0.001) and schoolchildren (P = 0.003 and P = 0.002). Comparing children with hyperparasitemic and uncomplicated malaria, no difference in the concentrations of either flavin compound was found. Neither the concentrations of free riboflavin nor the concentrations of one of the flavin nucleotides correlated with parasitemia within subgroups of age or of children with uncomplicated and hyperparasitemic malaria. Our data indicate that nutritional riboflavin deficiency might have been overestimated in previous malaria studies and do not support a relationship between flavin concentrations and parasitemia in P. falciparum malaria.

Adolescent↗

PubMed2003

Frequency and virulence properties of diarrheagenic Escherichia coli in children with diarrhea in Gabon.

To investigate the presence of diarrheagenic Escherichia coli in Lambaréné, Gabon, 150 children with diarrhea were screened for enteroaggregative E. coli (EAEC), enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC), and enteroinvasive E. coli (EIEC) using polymerase chain reaction and an HEp-2 cell culture techniques. Isolates of EAEC were detected in 57 children, two thirds of them between six months and two years of age, and isolates of ETEC were detected in seven patients. Isolates of EPEC, EHEC, and EIEC were not present in this population. Among the EAEC, the pCVD432 plasmid, a heat stable (ST)-like (ST-like) enterotoxin (EAST), and a plasmid-encoded heat-labile toxin (PET) were detected in 19, 34, and 42 cases, respectively. Detection of pCVD432, EAST, and PET were significantly associated with EAEC identified by the HEp-2 cell assay. Although detected only in 16 patients, the presence of the fimbriae AAF I (aagA) and AAF II (aafA) were more likely to occur in EAEC than in non-EAEC (odds ratio [OR] = 4.1, 95% confidence interval [CI] = 0.5-38.6, and OR = 2.3, 95% CI = 1.0-5.3, respectively). The EAEC isolates exhibited decreased susceptibility for ampicillin, tetracycline, and trimethoprim.

Anti-Infective Agents↗

PubMed2002

Functional analysis of a promoter variant of the gene encoding the interferon-gamma receptor chain I.

We analyzed a single nucleotide polymorphism (SNP) at position -56 (T-->C) in the promoter region of the gene encoding the human interferon-gamma receptor ligand-binding chain I (IFN-gammaR1). The mutation was present at similar frequencies in Gabonese children with either mild or severe malaria. Functional investigations of the promoter in a transfected human B-cell line showed lower levels of luciferase reporter gene expression in the presence of the mutation, indicating the importance of this position for promoter activity, and suggesting that this SNP might negatively influence the expression level of IFN-gammaR1 at the cell surface. Further examinations of the DNA sequence at this polymorphic site showed a perfectly matched binding site for the transcription factor activator protein 4 (AP-4) on both strands. Binding sites for other important transcription factors involved in gene expression and regulation of the immune response against infections, including Ikaros 2 (Ik-2), nuclear factor kappaB (NFkappaB), and CETS1p54, are also situated in this region.

Binding Sites↗

PubMed2002

Fosmidomycin for malaria.

Safe and effective antimalarial drugs with new methods of action are urgently needed. Fosmidomycin inhibits the synthesis of isoprenoid by Plasmodium falciparum, and suppresses the growth of multidrug-resistant strains in vitro. Our aim was to assess the efficacy and tolerability of fosmidomycin in adults with malaria in Gabon. We administered the drug for 5, 4, or 3 days (1.2 g every 8 h), in nine, eight, and ten evaluable patients, respectively. All treatment regimens were well tolerated. Cure rates by day 14 were 89% (eight of nine), 88% (seven of eight), and 60% (six of ten), for treatment durations of 5, 4, and 3 days, respectively. These data suggest that fosmidomycin is a safe and effective treatment for uncomplicated malaria if given for 4 days or more.

Adult↗

PubMed2002

Transport processes in Plasmodium falciparum-infected erythrocytes: potential as new drug targets.

Plasmodium falciparum infection induces alterations in the transport properties of infected erythrocytes that have recently been defined using electrophysiological techniques. Mechanisms responsible for transport of substrates into intraerythrocytic parasites have also been clarified by studies of three substrate-specific (hexose, nucleoside and aquaglyceroporin) parasite plasma membrane transporters. These have been characterised functionally using the Xenopus laevis oocyte heterologous expression system. The same expression system is currently being used to define the function of parasite 'P' type ATPases responsible for intraparasitic [Ca(2+)] homeostasis. We review studies on these transport processes and examine their potential as novel drug targets.

Adenosine Triphosphatases↗

PubMed2002

Efficacy of atovaquone/proguanil for malaria prophylaxis in children and its effect on the immunogenicity of live oral typhoid and cholera vaccines.

A double-blind, placebo-controlled study was conducted to measure the impact of malaria prophylaxis with atovaquone/proguanil (A-P) on the immunogenicity of vaccines against typhoid fever and cholera, Salmonella serotype Typhi Ty21a and Vibrio cholerae CVD103-HgR, respectively. A total of 330 Gabonese schoolchildren were assigned to receive either A-P or placebo for 12 weeks. Vaccination occurred 3 weeks after the start of prophylaxis, and immunogenicity was assessed 4 weeks after vaccination. The protective efficacy of A-P against Plasmodium falciparum malaria was of 97% (95% confidence interval, 79%-100%). The 2 treatment groups did not differ significantly with regard to changes in antibody titers after vaccination (P=.96 for anti-S. Typhi IgG antibodies, P=.07 for anti-S. Typhi IgA antibodies, and P=.64 for vibriocidal antibodies). The A-P combination was highly effective for malaria prophylaxis, without interfering with the in vivo immunogenicity of CVD103-HgR and Ty21a vaccines, and it could therefore be simultaneously administered with these vaccines.

Administration, Oral↗

PubMed2002

Restricted polymorphisms of the mannose-binding lectin gene in a population of Papua New Guinea.

The human mannose-binding lectin (MBL) is an important protein of the innate immune system. MBL is able to eliminate potential pathogens by activating the complement cascade or by opsonisation. We investigated the gene and promoter region of MBL in a population from Papua New Guinea infected with Plasmodium falciparum parasites and measured the appropriate serum concentrations of these individuals. Their serum levels of MBL, detected by ELISA, showed a wide range with concentrations between 632 and 7325 microg/l MBL. A known polymorphism in exon 1 at codon 54 causing an amino acid exchange from Gly to Asp occurred with a low frequency of 3%. Additional to the previously reported polymorphisms in the gene and promoter region of MBL, two novel polymorphic sites were found in the promoter region. One site was in the untranslated region of the MBL gene at position +1 (G-->A, termed R/S), and the second was located upstream of the gene at position -4 (G-->A, termed T/U).

5' Untranslated Regions↗

PubMed2002

Age-dependent enhancement of IFN-gamma responses to Plasmodium falciparum liver stage antigen-1 T cell epitopes.

We assessed the cellular immunological responses to two Plasmodium falciparum liver-stage antigen (LSA)-1-derived T-cell epitopes in healthy Gabonese children and adults. The N-terminal peptide, designated T1, induced interferon (IFN)-gamma production in peripheral blood mononuclear cells (PBMC) from a significantly lower proportion of children compared to adults, but both interleukin (IL)-10 and IL-12 were produced by similar proportions of PBMC from the two groups. The LSA-1 junction region peptide (LSA-J) also induced IFN-gamma in a lower, but in this case statistically non-significant, proportion of PBMC from children compared to adults, whilst the proportions producing either IL-10 or IL-12 were again similar. Higher amounts of both IFN-gamma and IL-10 were induced by LSA-J compared to T1. CD8+ T-cells were shown to be primarily responsible for the production of peptide-driven IFN-gamma. The results suggest a significant age-related increase in the proportion of individuals capable of producing IFN-gamma to the N-terminal T1 epitope, with a shift from a predominantly IL-10-led response in children.

Adolescent↗

PubMed2002

The impact of malaria on common lipid parameters.

No data are available in the literature to indicate whether low-level Plasmodium falciparum infections induce lipid parameter changes. We hypothesized that low-level P. falciparum infections induce significant changes in common lipid parameters. We retrospectively selected samples from a malaria prophylaxis study to measure the impact of sustained parasite clearance on common lipid parameters [total cholesterol (TChol), high-density lipoprotein (HDL)-cholesterol (HDL-c), low-density lipoprotein (LDL)-cholesterol (LDL-c) and triglycerides (TG)] in 47 apparently healthy schoolchildren whose P. falciparum parasitemia was initially below 1000/ microl. After parasite clearance, mean values were significantly increased for Tchol ( P<0.001) and HDL-c ( P<0.001), unlike LDL-c ( P=0.93); and TG were significantly decreased from the baseline ( P=0.004). No significant change was found in a control group. This is the first study showing significant lipid changes related to low-level P. falciparum infections. Further studies are needed to explore the relevance of this finding at the population level in hyperendemic malaria areas.

Adolescent↗

PubMed2002

A model for estimating total parasite load in falciparum malaria patients.

We describe an age-structured mathematical model of the malaria parasite life cycle that uses clinical observations of peripheral parasitaemia to estimate population dynamics of sequestered parasites, which are hidden from the clinical investigator. First, the model was tested on parasite populations cultured in vitro, and was found to account for approximately 72% of the variation in that sub-population of parasites that would have been sequestered in vivo. Next, the model was applied to patients undergoing antimalarial therapy. Using individual data sets we found that although the model fitted the peripheral parasite curves very well, unique solutions for the fit could not be obtained; therefore, robust estimates of sequestered parasite dynamics remained unavailable. We conclude that even given detailed data on individual parasitaemia, estimates of sequestered numbers may be difficult to obtain. However, if data on individuals undergoing similar therapy are collected at equal time intervals, some of these problems may be overcome by estimating specific parameters over groups of patients. In this manner we estimated sequestered parasite density in a group of patients sampled at identical time points following antimalarial treatment. Using this approach we found significant relationships between changes in parasite density, age structure and temperature that were not apparent from the analysis of peripheral parasitaemia only.

Animals↗

PubMed2002

Allergy, parasites, and the hygiene hypothesis.

The increase of allergic diseases in the industrialized world has often been explained by a decline in infections during childhood. The immunological explanation has been put into the context of the functional T cell subsets known as T helper 1 (TH1) and T helper 2 (TH2) that display polarized cytokine profiles. It has been argued that bacterial and viral infections during early life direct the maturing immune system toward TH1, which counterbalance proallergic responses of TH2 cells. Thus, a reduction in the overall microbial burden will result in weak TH1 imprinting and unrestrained TH2 responses that allow an increase in allergy. This notion is contradicted by observations that the prevalence of TH1-autoimmune diseases is also increasing and that TH2-skewed parasitic worm (helminth) infections are not associated with allergy. More recently, elevations of anti-inflammatory cytokines, such as interleukin-10, that occur during long-term helminth infections have been shown to be inversely correlated with allergy. The induction of a robust anti-inflammatory regulatory network by persistent immune challenge offers a unifying explanation for the observed inverse association of many infections with allergic disorders.

Antibody Specificity↗

PubMed2002

Plasmodium falciparum activates endogenous Cl(-) channels of human erythrocytes by membrane oxidation.

Intraerythrocytic survival of the malaria parasite Plasmodium falciparum requires that host cells supply nutrients and dispose of waste products. This solute transport is accomplished by infection-induced new permeability pathways (NPP) in the erythrocyte membrane. Here, whole-cell patch-clamp and hemolysis experiments were performed to define properties of the NPP. Parasitized but not control erythrocytes constitutively expressed two types of anion conductances, differing in voltage dependence and sensitivity to inhibitors. In addition, infected but not control cells hemolyzed in isosmotic sorbitol solution. Both conductances and hemolysis of infected cells were inhibited by reducing agents. Conversely, oxidation induced identical conductances and hemolysis in non-infected erythrocytes. In conclusion, P.falciparum activates endogenous erythrocyte channels by applying oxidative stress to the host cell membrane.

Animals↗

PubMed2002

Recognition of plasmodium falciparum proteins by mannan-binding lectin, a component of the human innate immune system.

The mannan-binding lectin (MBL) is a serum protein, which is involved in the immune defence against viruses, bacteria and parasites. Children who have mutations in the MBL gene that lead to a MBL deficiency are more susceptible to infectious diseases and are more likely to suffer from severe malaria. In this report we investigate the interaction between MBL and the proteins of red blood cells infected with the parasite Plasmodium falciparum. Protein extracts were separated on MBL-sepharose columns. After the elution of bound material, the proteins were detected either by Western blot with human antibodies, or radioactive labelling with 35S-methionine or 3H-glucosamine. MBL recognises proteins of P. falciparum-infected erythrocytes that are immunogenic in humans, parasite-derived and glycosylated. Whether the proteins identified in the different assays are identical remains to be explored. MBL added to in vitro cultures of P. falciparum, however, does not inhibit parasite growth. The positive effect of MBL in the blood of malaria patients could be caused by detoxification of parasite products.

Animals↗

PubMed2002

Accumulation of endostatin/collagenXVIII in brains of patients who died with cerebral malaria.

Endostatin is a 20 kDa C-terminal fragment of collagenXVIII that, when added exogenously, inhibits angiogenesis by inducing apoptosis of endothelial cells. In cerebral malaria (CM), blood-brain barrier dysfunction is a hallmark alteration in the formation of edema, inflammation, hemorrhage and Dürck's granulomas that are thought to represent the histopathological basis of neurological impairments observed in CM patients. We now analyzed endostatin/collagenXVIII expression in brains of seven patients who died with CM and in seven control patients by immunohistochemistry double-labeling experiments. Endostatin/collagenXVIII immunoreactive macrophages/microglial cells accumulated predominantly in Dürck's granulomas. Some immunoreactivity was observed in macrophages located in cerebral capillaries with deposition of malarial pigment and sequestration, but almost no immunoreactivity was detected in ring hemorrhages. Focal accumulation of endostatin/collagenXVIII in granulomas but not in ring hemorrhages of CM brains suggests a novel process that is involved in the destruction of endothelial cells at the time of Dürck's granuloma formation.

Brain↗