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Biomedical subjects

B Lell

Publications and source records attributed to B Lell.

At least 37 records · Page 2Linked to original sources

Antibody responses to Plasmodium falciparum: evolution according to the severity of a prior clinical episode and association with subsequent reinfection.

We measured sporozoite- and total parasite antigen-specific IgG and IgM antibodies before and after treatment in matched groups of Gabonese children who presented with either mild or severe Plasmodium falciparum malaria. We investigated the influence of various parameters on these antibody responses, including clinical presentation, age, and post-treatment reinfection profiles. IgG but not IgM responses were strongly influenced by both clinical and parasitological status. IgG responses to the repeat region of the circumsporozoite protein, which were low at admission, particularly so in those with severe anemia, increased after treatment but showed no association with either age or reinfection profiles. Total parasite antigen-specific IgG responses were strongly influenced by parasitological status, and also differed significantly when segregated according to clinical status at admission, age, and reinfection histories. Most notably, anti-parasite IgG responses measured when children were parasite-free were higher and a good indicator of recent reinfections in those who presented with mild rather than with severe malaria. The profile of responses in the latter group suggests some immune system dysfunction, which may reflect the induction of tolerance to parasite antigens.

Animals↗

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↗

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↗

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↗

The role of red blood cell polymorphisms in resistance and susceptibility to malaria.

In regions highly endemic for Plasmodium falciparum malaria, red cell polymorphisms that confer resistance to severe disease are widespread. Sickle cell trait, alpha-thalassemia, glucose-6-phosphate dehydrogenase deficiency, and blood groups were determined in 100 children from Gabon with severe malaria who were matched with 100 children with mild malaria and followed up for evaluation of reinfections. The sickle cell trait was significantly associated with mild malaria and blood group A with severe malaria. During follow-up, the original severe cases had significantly higher rates of reinfection than the original mild cases, with higher parasitemia and lower hematocrit values. Incidence rates did not differ in the context of erythrocyte polymorphisms, but patients with sickle cell trait presented with markedly lower levels of parasitemia than those without. Thus, the severity of malaria is partly determined by the presence of blood group A and the sickle cell trait. The different presentation of reinfections in severe versus mild cases probably reflects different susceptibility to malaria.

ABO Blood-Group System↗

Low-dose treatment with sulfadoxine-pyrimethamine combinations selects for drug-resistant Plasmodium falciparum strains.

A total of 252 children were enrolled in a drug trial to assess the effect of minimal doses of sulfadoxine (Sdx) and pyrimethamine (Pyr). Parasite samples isolated from these patients were analyzed before and after treatment to investigate the level of drug-resistant strains. The parasite genes encoding dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) were assayed for point mutations that are associated with resistance against drugs. Before treatment, Pyr(r) genotypes of the DHFR gene were found in 42% of all samples, 8% of the patients harbored a mixed parasite population and 50% had a sensitive DHFR genotype. In terms of the DHPS gene, we found mutations in 45% of the parasites. Twenty-four percent had a Ser(436) mutation, and 26% had a Gly(437) mutation. Recrudescent parasites were highly enriched for both Pyr(r) and Sdx(r) strains after treatment (P < 0.001 and P = 0.029, respectively).

Africa↗

Association of the ICAM-1Kilifi mutation with protection against severe malaria in Lambaréné, Gabon.

The intercellular adhesion molecule-1 (ICAM-1) is thought to be a receptor that mediates binding of Plasmodium falciparum-infected erythrocytes. Especially in vital organs, the binding of parasitized cells to the endothelium via ICAM-1 may lead to severe disease and death. Recently, a mutation in the coding region of ICAM-1, termed ICAM-1Kilifi, was described, causing a change from Lys to Met in the loop that interacts with rhinoviruses, lymphocytes, and parasitized red blood cells. Surprisingly, this mutation was shown to increase susceptibility of Kenyan children to severe malaria in one study. When we compared the distribution of ICAM-1Kilifi in two groups of Gabonese children enrolled in a case-control, matched-pair study who presented with either mild or severe malaria, we found that 55% of the patients with mild malaria were carriers whereas only 39% of those with severe malaria were carriers. The difference in the distribution of ICAM-1Kilifi homozygous pairs between the groups, as well as the distribution of ICAM-1Kilifi carriers, was statistically highly significant (P = 0.027 and P = 0.012, by the McNemar test). In a group of healthy school children from the same region, a distribution of 52% ICAM-1Kilifi carriers to 48% wild-type individuals was found. In a survey for the ICAM-1Kilifi in other malaria-endemic regions, this allele was also found in Nigeria and Papua New Guinea, but not in Thailand.

Animals↗

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↗

Malaria chemotherapy trial at a minimal effective dose of mefloquine/sulfadoxine/pyrimethamine compared with equivalent doses of sulfadoxine/pyrimethamine or mefloquine alone.

In murine malaria the addition of mefloquine to sulfadoxine/pyrimethamine has been shown to exert an additive effect and to significantly slow the emergence of resistance to the individual components. In a pilot study carried out in Gabon, a reduced dosage of the triple combination with a mean of 1 mg/kg of mefloquine/2 mg/kg of sulfadoxine/0.1 mg/kg of pyrimethamine (Fansimef; Roche, Basel, Switzerland) had previously been shown to achieve high cure rates in Plasmodium falciparum malaria. To evaluate the additive effect, a randomized, double-blind trial in school children with mild P. falciparum malaria was performed in Gabon. Two hundred thirty-one patients evaluated received a single dose of either the triple combination with a mean of 1.07 mg/kg of mefloquine/2.14 mg/kg of sulfadoxine/0.11 mg/kg of pyrimethamine (group MSP), or 1.07 mg/kg of mefloquine alone (group M), or 2.14 mg/kg of sulfadoxine/0.11 mg/kg of pyrimethamine alone (group SP). In the MSP group and the SP group, 67% and 69% of the patients were parasitologically cured, respectively, compared with only 13% in the M group (P < 0.001). A significantly higher parasitemia was found in the M group compared with the MSP group or the SP group on days 2 and 3 after the start of treatment. The high efficacy of the low dose sulfadoxine/pyrimethamine regimen was the most surprising finding of this study.

Adolescent↗

Parasite antigen-specific interleukin-10 and antibody reponses predict accelerated parasite clearance in Plasmodium falciparum malaria.

Using strict inclusion criteria, we conducted a hospital-based, case-control study in which 100 Gabonese children with severe Plasmodium falciparum malaria were matched for age, gender and provenance with 100 children presenting with mild malaria. Parasite antigen-specific cellular and humoral immunological responses were measured and compared with post-treatment parasite clearance times in each group. Significantly faster parasite clearance times were associated with in vitro production of IL-10 by acute-phase peripheral blood mononuclear cells (PBMC) in response to both liver and asexual stage parasite antigens, but not with proliferative, IFN-gamma, or TNF responses to the same antigens. In addition, in those children with mild malaria, higher levels of acute-phase antibody responses to liver stage antigen-1 (LSA-1) were associated with faster parasite clearance times, and were correlated with the presence of IL-10 responses to the same antigen. No such associations were found for IL-10 or antibody responses to a range of asexual blood stage antigens. Those with severe malaria had significantly lower levels of anti-LSA-1 antibodies compared to their counterparts with mild malaria. In conclusion, the results of this study suggest that parasite antigen-specific IL-10-mediated antibody responses may play a role in the control of asexual stage parasite multiplication in P. falciparum malaria.

Amino Acid Sequence↗

Basal and stimulated plasma levels of pancreatic amylin indicate its co-secretion with insulin in humans.

Amylin is a 37-amino acid pancreatic polypeptide, probably involved in the pathophysiology of Type 2 (non-insulin-dependent) diabetes mellitus. We have determined amylin in human plasma by extraction-based radioimmunoassay (Sep-Pak C18). Of 23 healthy control subjects plasma amylin was determined as 11.9 +/- 3.5 ng/l. Of 27 patients with Type 2 diabetes receiving insulin the amylin levels were lower, and in 16 patients with Type 2 diabetes on oral medication they were higher than in the control subjects; 8.2 +/- 4.4 ng/l (p less than 0.01) vs 18.8 +/- 9.9 ng/l (p less than 0.05). In 14 Type 1 (insulin-dependent) diabetic patients we found extremely low mean amounts of amylin: 2.9 +/- 1.9 ng/l (p less than 0.002). Thus, basal amylin appears to be associated with the capacity to release insulin. An oral glucose load stimulated the release of amylin, this was more pronounced in patients with Type 2 diabetes than in healthy subjects. An excellent correlation of mean amylin with mean insulin concentrations was obtained (r = 0.949). In patients with Type 2 diabetes amylin was reduced congruent to decreases in C-peptide during a hyperinsulinaemic, euglycaemic glucose clamp experiment (r = 0.971 for linear correlation between C-peptide levels and amylin). We conclude, that amylin and insulin are co-secreted in humans, and that the amylin release is under feedback-control by insulin.

Adult↗

Decrease of stimulated amylin release precedes impairment of insulin secretion in type II diabetes.

Amylin, a 37-amino acid polypeptide, has been identified as the major protein component of pancreatic amyloid deposits in patients with non-insulin-dependent (type II) diabetes mellitus. Amylin is stored and released together with insulin and has been proposed to play a major role in the pathogenesis of type II diabetes. To compare amylin release and its proportion to insulin secretion under different metabolic conditions, oral and intravenous glucose tolerance tests (OGTT and IVGTT, respectively) were performed in healthy, lean control subjects, obese patients with normal and impaired glucose tolerance (NGT and IGT, respectively), and obese type II diabetic patients. Compared with control subjects, basal and stimulated amylin secretion during OGTT was significantly higher in obese patients with NGT and IGT but not in type II diabetic patients. The integrated amylin response was significantly higher in obese patients with NGT than lean control subjects and type II diabetic patients matched for degree of obesity. The amylin-insulin ratio decreased slightly in obese subjects with NGT and IGT and significantly in type II diabetic patients. Amylin secretion was significantly stimulated during IVGTT in control subjects and obese patients with NGT and IGT but not in type II diabetic patients. These findings suggest that amylin is physiologically released by pancreatic beta-cells in a constant ratio to insulin in nondiabetic subjects. Glucose-stimulated amylin secretion is increased in obese subjects with NGT and IGT. In type II diabetes mellitus, amylin secretion relative to that of insulin is decreased, and amylin is not stimulated by IVGTT.

Adult↗

Molecular analysis of recrudescent parasites in a Plasmodium falciparum drug efficacy trial in Gabon.

Recrudescent Plasmodium falciparum parasites were sampled from 108 children taking part in a drug efficacy trial in Gabon. A finger-prick blood sample was taken from each child before treatment, and a post-treatment sample taken of the recrudescent parasites. Sample deoxyribonucleic acid was amplified by the polymerase chain reaction using primers specific to the P. falciparum antigen genes MSP-1, MSP-2 and GLURP. Seventy-seven children had identical parasites in their pre- and post-treatment samples, indicating genuine recrudescences of resistant parasites. Fourteen children had completely different parasites in their pre- and post-treatment samples, indicating either a fresh infection from a mosquito or growth of a population of parasites not detected in the pre-treatment sample, perhaps due to sequestration. The remaining 17 children had a mixture of pre-treatment and new parasites in their post-treatment samples. This study demonstrated the use of polymorphic markers to confirm whether parasites in patients with clinical recrudescences after drug treatment are genuinely resistant.

Adolescent↗

No influence of socioeconomic factors on severe malarial anaemia, hyperparasitaemia or reinfection.

Malaria is responsible for nearly 500 million clinical cases per year, only a small proportion of whom will become severely ill. Socioeconomic risk factors may play a role in the development of severe malaria in African children and in their susceptibility to reinfection. In Gabon, 100 children suffering from severe malaria, defined as hyperparasitaemia and/or severe anaemia, were matched for sex, age and provenance to 100 children with mild malaria. Socioeconomic factors were assessed using a standard questionnaire and compared between the 2 groups. The children were followed-up and the time to first reinfection was recorded. No significant influence of socioeconomic factors could be detected on the severity of disease or the time to first reinfection. Socioeconomic factors are not major determinants of severe malarial anaemia and hyperparasitaemia in children in Gabon.

Adult↗

Merozoite surface antigen 1 and 2 genotypes and rosetting of Plasmodium falciparum in severe and mild malaria in Lambaréné, Gabon.

We present a case-control study to investigate the distribution of Plasmodium falciparum genotypes in patients with severe and mild malaria. We compared clinical and parasitological data with the parasites' genotype and rosetting. The study group consisted of 100 children suffering severe malaria, defined as severe anaemia and hyperparasitaemia. These children were matched by age, sex and provenance with 100 children with mild malaria. For characterization of the parasites we used the polymerase chain reaction to determine merozoite surface antigen (MSA) 1 and 2 genotypes and the phenomenon of rosette formation. We found a significant association between rosette formation and disease severity, and a significant association of severe anaemia with the presence of the MSA-1 allele K1. Infections with 2 genotypes in the severely affected group were significantly associated with severe anaemia and the presence of MSA-1 allele K1. Comparison with the findings of other groups led to the conclusion that the occurrence of P. falciparum genotypes seems to differ geographically.

Animals↗