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Biomedical subjects

W Metzger

Publications and source records attributed to W Metzger.

At least 19 recordsLinked to original sources
PubMed1999

Reduction in the mean number of Plasmodium falciparum genotypes in Gambian children immunized with the malaria vaccine SPf66.

SPf66, a synthetic peptide Plasmodium falciparum vaccine, did not protect young Gambian children against clinical attacks of malaria. Nevertheless, Gambian children who had been vaccinated with SPf66 and who were parasitaemic at the end of the first malaria transmission season after vaccination had significantly fewer detectable P. falciparum genotypes than control children, as determined by polymerase chain reaction analysis of 3 polymorphic loci--the msp1 block 2 repeat region, the msp2 repeat region, and the R11 region of the glutamate-rich protein gene (glurp). Geometric mean numbers of genotypes were 1.66 vs. 1.87, 1.95 vs. 2.43, and 1.21 vs. 1.50 for msp1, msp2 and glurp, respectively (P = 0.31, P = 0.04 and P < 0.01). Differences between groups became a little more marked for msp1 and msp2 when children with symptomatic malaria were excluded. No significant difference was found between parasites obtained from SPf66-vaccinated or control children in the prevalences of amino acid alleles at positions 44 and 47 in the 11 amino acid sequence of the merozoite surface protein 1 molecule, which is present in SPf66. The reduction in the number of genotypes observed could not be explained by a difference in parasite densities between SPf66-vaccinated and control children, as geometric mean parasite densities were almost identical in the 2 groups. These observations suggest that SPf66 vaccine may have induced an immune response which reduced the incidence of new infections in immunized children or accelerated the rate of clearance of parasites of individual genotypes. However, no reduction in the prevalence or density of parasitaemia was recorded in SPf66-vaccinated children, suggesting the existence of some kind of density-dependent mechanism for controlling low levels of malaria parasitaemia.

Animals↗
PubMed1997

Follow-up of Gambian children recruited to a pilot safety and immunogenicity study of the malaria vaccine SPf66.

A pilot safety and immunogenicity trial of the malaria vaccine SPf66 was undertaken in The Gambia in 1993. One hundred and fifty infants aged 6-11 months were immunized with either 0.5 mg or 1.0 mg of SPf66 produced either in Colombia or in the USA or with a control vaccine. Children who received SPf66 experienced more clinical attacks of malaria than did children in the control group during the first period of surveillance and the difference in incidence between children who had received high dose Colombian vaccine and the control children was statistically significant at the 5% level. During the 1995 malaria transmission season, 127 children from the original cohort of 150 were observed. During 18 weeks of intensive surveillance, the incidence of clinical malaria was again higher among children who had received SPf66 than among children who had received inactivated polio vaccine (6.23 vs 4.89 clinical attacks per 1000 days at risk), the effect being most marked among children who were in the high dose groups, but differences between groups were now no longer statistically significant.

Child↗
PubMed1996

Antischistosome IgG4 and IgE responses are affected differentially by chemotherapy in children versus adults.

Specific IgG4 and IgE responses and polyclonal cytokine profiles were studied in 110 Schistosoma haematobium-infected persons before and 5 weeks after chemotherapy. Pretreatment IgG4 responses to soluble egg antigen (SEA) correlated with intensity of infection. After chemotherapy, a significant decrease in egg output and circulating anodic antigen was associated with a substantial drop in the IgG4 response to SEA (IgG4-SEA) in adults and children, suggesting that egg laying is a major stimulus for IgG4-SEA. After chemotherapy, IgG4 and IgE to adult worm antigen and IgE to SEA increased in children but remained unchanged in adults. This indicates that the immunoregulatory mechanisms operative in S. haematobium-infected adults differ from those in infected children. The effect of treatment on cytokine profiles was determined following stimulation of whole blood with anti-CD3 antibodies. A significant decrease in interleukin-4 production after treatment indicated that reduction in helminth load may lead to a reduced number of Th2-type cells.

Adolescent↗
PubMed1995

Sulfadoxine/pyrimethamine or chloroquine/clindamycin treatment of Gabonese school children infected with chloroquine resistant malaria.

In a randomized trial, a high dosage chloroquine monotherapy (45 mg/kg over 3 days) was compared with combination regimens of sulfadoxine/pyrimethamine and chloroquine/clindamycin for treating Gabonese school children with Plasmodium falciparum malaria. In chloroquine treated patients only 32% were ultimately cured. In contrast, more than 90% of patients were cured after treatment with either combination regimen.

Adolescent↗
PubMed1995

High efficacy of short-term quinine-antibiotic combinations for treating adult malaria patients in an area in which malaria is hyperendemic.

In a randomized trial, a three-dose quinine monotherapy was compared with short-term combination regimens of quinine-clindamycin and quinine-doxycycline for treating adult Gabonese patients with Plasmodium falciparum malaria. In quinine-treated patients, only 38% were ultimately cured. In contrast, more than 90% of patients were cured after treatment with either combination regimen.

Adolescent↗
PubMed1995

Quinine plus clindamycin improves chemotherapy of severe malaria in children.

In a randomized trial, a 4-day quinine-clindamycin regimen was compared with the standard 7-day quinine regimen for 100 Gabonese children (50 children in each group) with severe Plasmodium falciparum malaria. In each group, only one patient died. Parasite clearance and fever clearance times were significantly shorter in the quinine-clindamycin group (P = 0.03 and P = 0.01, respectively) than in the quinine group, and significantly more recurring fever episodes occurred in the quinine group than in the quinine-clindamycin group shortly after initial fever clearance and parasite clearance (P < 0.001).

Child, Preschool↗
PubMed1995

Upregulation of ICAM-1, IL-1 and reactive oxygen intermediates (ROI) by exogenous antigens from Plasmodium falciparum parasites in vitro, and of sICAM-1 in the acute phase of malaria.

After 4 hours of stimulation of human mononuclear leukocytes in the presence of 300 ng/ml exogenous Plasmodium falciparum antigens, the ICAM-1 expression increased variably from 15% to 375%. Simultaneously, an increase of IL-1 mRNA production could be observed in Northern blot hybridizations with a specific cDNA gene probe for human IL-1 alpha labelled with digoxigenin. Furthermore, the reactive oxygen intermediates (ROI) production was also found to be enhanced in similar conditions. Additionally, when the levels of soluble ICAM-1 (sICAM-1) in plasma of 122 patients with P. falciparum or Plasmodium vivax malaria were analyzed in an enzyme immunoassay (EIA), significant sICAM-1 increases were found, more pronounced in patients with P. falciparum malaria, in comparison with healthy controls and with the same patients 4 weeks after chemotherapy. The presented results indicate that the expression of ICAM-1 may also be upregulated by exogenous Plasmodium antigens besides cytokines like IL-1 during the acute phase of malaria, with subsequently elevated sICAM-1 concentrations in blood.

Acute Disease↗
PubMed1993

Nucleation of RNA chain formation by Escherichia coli DNA-dependent RNA polymerase.

We have studied the early steps in RNA synthesis. The kinetic behaviour of the nascent RNA, having chain lengths between 3 and 11 bases, and the transcription fidelity were analysed using the bacteriophage T7 A1 promoter. By moving the stop-inducing base at position +12 in the wild-type template in single base steps upstream, a set of closely related templates was constructed which allowed stalling of the complexes in the registers 11, 10, 9 and 8. Using this set of templates sigma-factor release was determined. It occurs when RNA synthesis has proceeded to base position +9. Analysis of the RNA synthesis both with and without heparin yielded the following results: there are three kinds of complexes, (a) the well-known abortively transcribing complex, which is present until the RNA has reached a length of 5 bases, (b) an intermediate complex having RNA chain lengths between 6 and 8 bases, which is stably bound but has high forward as well as back reaction rates, (c) complexes with RNA chains consisting of more than 8 bases, which are stably bound and do not contain the sigma-factor. In general, the likelihood of chain elongation and the stability of the complexes increases with increasing RNA chain length in the early stages of RNA synthesis. Also the transcription fidelity increases correspondingly. Lack of fidelity leads to additional RNA products during the abortive state of transcription. "Read through" of RNA polymerase at stall positions of +8 to +11 also result from misincorporation.

Base Sequence↗
PubMed1993

Hydroxyl radical footprint analysis of human immunodeficiency virus reverse transcriptase-template.primer complexes.

Human immunodeficiency virus type 1 reverse transcriptase protects sugar moieties of a model template.primer DNA in a region from positions +3 to -15 from hydroxyl radical attack. A protected region of equivalent size migrates in concert with the translocating enzyme, as shown by hydroxyl radical footprints of replication complexes after primer extension by 4, 10, and 19 nt. The pattern of these footprints suggests that the DNA template.primer is in the A conformation when complexed with reverse transcriptase. Enhanced accessibility of the DNA template strand around position -15 to hydroxyl radicals indicates a conformational change in the template induced by the C-terminal RNase H-containing domain of p66 reverse transcriptase.

Base Sequence↗
PubMed1990

Topography of intermediates in transcription initiation of E.coli.

Three characteristic footprinting patterns resulted from probing the Escherichia coli RNA polymerase T7 A1 promoter complex by hydroxyl radicals in the temperature range between 4 degrees C and 37 degrees C. These were attributed to the closed complex, the intermediate complex and the open complex. In the closed complex, the RNA polymerase protects the DNA only at one side over five helical turns. In the intermediate complex, the range of the protected area is extended further downstream by two helical turns. This region of the DNA helix is fully protected, indicating that the RNA polymerase wraps around the DNA between base positions -13 and +20. In the open complex, a stretch between base positions -7 and +2, which was fully protected in the intermediate complex, becomes accessible towards hydroxyl radicals but only in the codogenic strand, indicating that the DNA strands are unwound. Our data suggest that only the DNA downstream of the promoter is involved in this unwinding process.

DNA, Viral↗
PubMed1990

Hemocyanins in spiders, XXIII. Complete amino-acid sequence of subunit a of Eurypelma californicum hemocyanin.

The complete amino-acid sequence of subunit a of the hemocyanin of the tarantula Eurypelma californicum was determined by manual sequencing. By limited chymotrypsinolysis, subunit a is split into two fragments of 25 kDa and 40 kDa, respectively, only one single peptide bond being attacked. The whole chain contains 15 methionine residues, after cyanogen bromide cleavage, 15 peptides were identified indicating that one residue (Met85) was not split by the cyanogen bromide reaction. For subcleavages, trypsin, chymotrypsin, Staphylococcus aureus proteinase, and Astacus fluviatilis proteinase were employed. The total chain length comprises 627 amino-acid residues, carbohydrate side chains were not found.

Amino Acid Sequence↗
PubMed1989

A cinematographic view of Escherichia coli RNA polymerase translocation.

A series of RNA synthesizing transcription complexes, initiated at the T7 A1 promoter and halted at specific base positions ranging from +12 to +40, were analyzed by footprinting techniques; exonuclease III was used to determine the position of the bound RNA polymerase on the DNA and hydroxyl radicals were used to visualize the protein--DNA contact sites within the protected areas. In the binding (open) complex without RNA there are two DNA-domains, differing in their protection pattern. The first, extending from position +18 to -13, termed 'melting domain', is fully protected, whereas the second, extending from -14 to -55, termed 'recognition domain', shows only partial protection. At this domain, RNA polymerase is attached to one side of the DNA only, as indicated by the 10-bp periodicity of the protection pattern. Our data show that the formation of a mature RNA transcribing complex is characterized by dissociation of the RNA polymerase from the recognition domain, whereby the size of the melting domain remains constant. This process is accomplished if the nascent RNA has reached a length of 11 bases. As the RNA reaches a length of 20 bases, the size of the melting domain decreases from approximately 30 to 23 bp. Further RNA synthesis leaves the protection pattern essentially unchanged. These data demonstrate that the formation of a mature RNA transcribing complex can be described by at least two transitions.

Base Sequence↗