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Biomedical subjects

E Petersen

Publications and source records attributed to E Petersen.

At least 127 records · Page 7Linked to original sources
PubMed1990

Consecutive determinations of seroreactivities to Pf 155/RESA antigen and to its different repetitive sequences in adult men from a holoendemic area of Liberia.

Sera from 32 adult men residing in a malaria holoendemic area of Liberia were investigated for seroreactivities to different asexual blood-stage malaria antigens on five consecutive occasions from 1984 to 1986. The seroreactivities to crude parasitic antigens and to Pf 155/RESA (EMIF) were determined by immunofluorescence and to repetitive sequences of Pf 155/RESA by enzyme-linked immunosorbent assay (ELISA). All sera were highly reactive against the crude parasitic antigens with reciprocal titres varying from 5000 to 100,000. The EMIF titres showed a wider variation from negative (less than 10) to 25,000, and when the same individuals were re-examined on subsequent surveys similar EMIF titres were found. The ELISA seroreactivities to three different repetitive sequences of Pf 155/RESA also showed different individual profiles which were rather consistent on consecutive surveys. High EMIF titres appeared to be correlated mainly to one of the peptide sequences, namely (EENV)2. The consistent individual profiles of the seroreactivities to Pf 155 and its repetitive sequences suggest genetic restriction of the humoral immune response. Although no significant correlation was found between EMIF titres and parasitic densities in the adult hyperimmune men the specific peptides, however, offer new possibilities of further investigating protective capacities of different immune responses to specific epitopes of the malaria parasite.

Adolescent↗
PubMed1989

Dissection of the human antibody response to the malaria antigen Pf155/RESA into epitope specific components.

The development of vaccines is presently receiving major attention in malaria research. As it is not possible to base malaria vaccines on the use of killed or attenuated organisms, the vaccines which are being developed are subunit vaccines in which the immunogens consist of defined parasite antigens or antigenic fragments. Since protective immunity to malaria involves both antibody-dependent and antibody-independent mechanisms, the immunogens in a subunit vaccine must have the capacity to induce relevant B- and T-cell responses in the majority of vaccinees. In turn, this requires good knowledge of these responses in humans who have acquired immunity through natural infection. In this paper we have summarized our recent work on the dissection into epitope-specific components of the human antibody response to the Plasmodium falciparum antigen Pf155/RESA, a recognized candidate for a vaccine against the asexual blood stages of this parasite. Epitope mapping of the antigen by means of short synthetic peptides led to the identification in several molecular regions of short amino acid sequences constituting linear and probably immunodominant B-cell epitopes. The antigenically most active region was located in the C-terminus of the molecule. This region, which consists of approximately 40 related, 4- or 8-amino acid long repeats, induced higher antibody concentrations in a larger number of malaria-immune donors than any of the other regions. A large fraction of these antibodies bound to short synthetic peptides representing the major repeat motifs of Pf155/RESA. Although these repeats are made up of closely related amino acid sequences, the antibody response to them was highly polyclonal, indicating the presence of several linear and probably also conformational epitopes which gave rise to a variety of cross-reacting as well as monospecific antibodies. Further analysis revealed that the levels of antibodies differing in specificity and/or avidity for different peptides varied independently of each other in individual donors. In an area (Liberia) where malaria transmission is holoendemic and perennial, these antibody profiles remained constant when individual donors were followed over several years. Since the C-terminal repeat region of Pf155/RESA is conserved in different P. falciparum strains, the results reflect differences in the genetic regulation of epitope-specific host responses rather than antigenic differences between infecting parasites. In donors living in an area with high but seasonal malaria transmission, antibody levels usually drop to lower levels when there is no transmission.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1989

Prophylactic one-dose treatment with clindamycin and gentamicin in transurethral prostatic resection. A double-blind placebo controlled study.

One hundred and sixty-eight patients scheduled for transurethral prostatic resection were randomly assigned to treatment either with a combination of clindamycin and gentamycin or with placebo, administered preoperatively as a single bolus infusion. The patients were stratified into a group of 35 with preoperative bacteriuria, and a group of 133 with preoperative sterile urine. Postoperatively the frequency of bacteriuria and bacteriaemia, the maximum body temperature measured, the number of patients with antibiotic therapy instituted, and the duration of hospitalization were significantly lower in the treated than in the placebo group. This applied both to the group with preoperative sterile urine and to the group with preoperative bacteriuria.

Aged↗
PubMed1989

An epidemiological study of humoral and cell-mediated immune response to the Plasmodium falciparum antigen PF155/RESA in adult Liberians.

We investigated the seroreactivity and T cell reactivity against the Plasmodium falciparum antigen Pf155/RESA, different oligopeptides from the 3' and 5' repeat regions of the Pf155/RESA antigen, and crude Plasmodium falciparum antigens in 164 adult Liberians. We compared 2 long-term residential groups with high and low exposure to malaria. The seropositive rate to the peptides was significantly higher with increased exposure. There was no significant difference in response rates to the Pf155/RESA. This may indicate the level of persistent T cell memory in previously primed donors. The seropositive rates to 3 Pf155/RESA peptides and the rates measured by either 3H-thymidine incorporation or IFN-gamma release after stimulation with Pf155/RESA and the peptides were all lower in parasite positive individuals. Even low grade, asymptomatic parasitemia can impair the T cell response in vitro. The lower antibody response in parasite positive subjects may be explained by either antibody consumption or lower protection against malaria parasitemia in subjects with low concentrations of antibodies against the Pf155/RESA antigen.

Adult↗
PubMed1988

T cell reactivity of defined peptides from a major Plasmodium falciparum vaccine candidate: the Pf155/RESA antigen.

Several immunodominant B-cell epitopes of the P. falciparum antigen blood stage Pf155/RESA, a major vaccine candidate antigen, are located in the molecular regions containing amino acid repeats. We started to map Pf155/RESA for T cell reactive epitopes. For this purpose, short synthetic peptides corresponding to the 3'- and 5' repeat regions of the molecule as well as to non-repeated sequences outside these regions were prepared. T cells from P. falciparum primed donors from two highly endemic areas of Africa were tested for their responsiveness to the peptides by thymidine incorporation and/or interferon gamma (IFN-gamma) release. There was a considerable variation in the response to the different peptides. However, the strongest and most frequent responses were seen with a few peptides from the 3'- and 5'-repeat regions. Thus, the immunodominant B cell epitope regions of Pf155/RESA, contain several T cell epitopes. Since the repeat regions are known to be conserved in different P. falciparum strains, the T cell epitopes reported here may be suitable constituents of a P. falciparum subunit vaccine.

Animals↗
PubMed1988

T-cell epitopes in Pf155/RESA, a major candidate for a Plasmodium falciparum malaria vaccine.

Immunogens included in a subunit vaccine should contain both B- and T-cell-activating sites to ensure anamnestic responses following reinfection after vaccination as well as antibody-independent cellular immunity. The Plasmodium falciparum antigen Pf155/RESA, a major candidate for a vaccine against the asexual blood stages of this malaria parasite, was investigated for T-cell epitopes in its C-terminal amino acid repeat region, a region known to be conserved in different P. falciparum strains. It was found to contain several related sequences that activated T cells from humans primed to P. falciparum by natural exposure, to proliferation, and/or interferon-gamma release in vitro. T cells from approximately half of the donor group investigated responded to the intact protein, and 65% of these responders also responded to short synthetic peptides, probably representing a small number of partly overlapping T-cell epitopes. Thus, sequences from the C terminus of Pf155 may be suitable constituents of a P. falciparum subunit vaccine and also provide a basis for epitope-specific epidemiological studies relating cellular immune responses in vitro to clinical immunity and P. falciparum endemicity.

Amino Acid Sequence↗
PubMed1987

In vitro susceptibility of Plasmodium falciparum malaria to pyrimethamine, sulfadoxine, trimethoprim and sulfamethoxazole, singly and in combination.

Two isolates of Plasmodium falciparum (F 32 and K 1) were tested against sulfadoxine (SDX), sulfamethoxazole (SMZ), pyrimethamine (PYR) and trimethoprim (TMP), using a 48 h microtest, with RPMI-1640 low in PABA and folic acid. The IC50 for F 32 was: PYR 6.1 X 10(-9) M (mol/litre), TMP 1.3 X 10(-7) M, Fansidar (SDX/PYR 80:1) less than 10(-8) to 1.3 X 10(-10) M and cotrimoxazole (SMZ/TMP 20:1) 2.6 X 10(-7) to 1.3 X 10(-8) M. The IC50 for K 1 was: PYR greater than 10(-6) M, TMP 8.2 X 10(-7) M, Fansidar 4.1 X 10(-7) to 1.1 X 10(-9) M and cotrimoxazole 1.8 X 10(-6) to 9.0 X 10(-8) M. The difference in IC50 between F 32 and K 1 against TMP and cotrimoxazole is much less than the difference between the IC50 values against PYR and Fansidar, indicating that cross-resistance between PYR and TMP exists, but is not complete. A method for calculating the IC50 by linear regression analysis is described.

Animals↗
PubMed1987

Modulation of anxiety by beta-carbolines and other benzodiazepine receptor ligands: relationship of pharmacological to biochemical measures of efficacy.

Several beta-carbolines and other benzodiazepines (BZ) receptor ligands have been investigated for anxiolytic or anxiogenic action in 4 unrelated animal models of anxiety using rats. The substances could be grouped into essentially 2 groups. The first, anxiolytics, exhibited antipunishment activity in a lick-suppression test, antagonised the discriminative stimulus provided by pentylenetetrazol, resembled chlordiazepoxide (CDP) in a drug discrimination test, and reduced the rise in plasma corticosterone levels following swim stress. Such substances included several benzodiazepines, the beta-carboline ZK 93 423, and the triazolapyridazine CL 218 872. A subgroup of anxiolytics were active in only some of these tests. They included two beta-carbolines, ZK 91 296 and ZK 95 962, and the pyrazoloquinoline CGS 9896, and these 3 substances were also distinguishable in not producing rate-decreasing effects in any of the 3 operant tests. The second group were anxiogenic in that they produced a discriminative stimulus resembling that of PTZ, they antagonised the CDP cue, exhibited propunishment effects in the lick-suppression test, and themselves caused increases in plasma corticosterone in otherwise unstressed animals. Such substances included the beta-carbolines DMCM, FG 7142 and ZK 90 886, and the pyrazoloquinoline CGS 8216. Two substances, Ro 15-1788 and ZK 93 426 had little or only weak activity in any test. The classification of these substances into anxiolytics or anxiogenics could be predicted qualitatively both by their ability to enhance (anxiolytics) or decrease the binding of 35S-TBPS to rat brain membranes and by whether their own binding was increased (anxiolytics) by adding the GABA agonist muscimol to the in vitro incubation medium. For the limited number of substances for which full data was available, there was also a quantitative relationship between the degree of enhancement of 35S-TBPS binding by a substance and its potency in the CDP cue test when such potency was expressed as numbers of BZ receptors occupied at the ED50 value in the pharmacological test. Furthermore, for the anxiolytics, activity in the CDP cue correlated significantly with potency in 2 other tests. Otherwise, surprisingly weak correlations existed between potencies in the different tests. In particular, the beta-carboline ZK 95 962 was highly potent in antagonising the PTZ cue but inactive in both a conflict test and in protecting against stress. These results are discussed in terms of differences in the neuropharmacologies of the 4 tests and in selectivity of the BZ receptor ligands for subtypes of BZ receptor.

Animals↗
PubMed1987

Bidirectional effects of beta-carbolines in rats with spontaneous petit mal-like seizures.

Seven benzodiazepine-receptor ligands of the beta-carbolines' group were administered IP in Wistar rats from (1) a strain displaying spontaneous petit mal-like seizures (PMLS) characterized by spike and wave discharges (SWD) and, (2) a strain where no seizure is ever observed (NS). Five different types of effects were observed. (1) Injection of a full agonist (ZK 93 423) suppressed SWD in PMLS rats, in a dose-dependent manner, and induced marked sedation with alteration of EEG background activity; (2) Injection of partial agonists (ZK 95 962, ZK 91 296) suppressed SWD in PMLS rats without sedation; (3) Injection of low doses of a full inverse agonist (DMCM) significantly increased the total duration of SWD in PMLS rats and induced SWD in NS rats. Higher doses of DMCM induced convulsions in both strains; (4) Injection of partial inverse agonists (FG 7142, ZK 90 886) aggravated SWD in PMLS and induced SWD in NS rats. FG 7142 induced convulsions only in PMLS animals, whereas no convulsions were ever observed with ZK 90 886; (5) Injection of an antagonist (ZK 93 426) did not significantly modify SWD in PMLS rats. However, this compound was able to reverse both antiepileptic effects of agonists and epileptogenic effects of inverse agonists. These results suggest the involvement of the benzodiazepine-GABA receptor complex in the control of petit mal-like seizures in rats.

Animals↗
PubMed1987

Comparison of different methods for determining pyrimethamine susceptibility in P. falciparum malaria.

Resistance against pyrimethamine was determined for Plasmodium falciparum adapted to continuous culture and for 'wild' isolates. The IC50 values were found by incubating for 48 hours or 48 + 24 hours (the last 24 hours without drug) and counting either the total parasites or the ring forms only. It was found that in continuous, asynchronous cultures the IC50 values were not significantly influenced by the choice of method. The IC50 value found when counting ring forms only were slightly lower than those obtained by counting the total number of parasites, but the confidence limits did overlap. The same was the case for the 48 hours and 48 + 24 hours tests. The isolates collected directly from patients with acute malaria were incubated for 48 hours. The percentage of ring forms in the control wells varied between 21% and 63% after 48 hours, indicating that the plasmodial cycle could be prolonged under test conditions. The IC50 values were estimated in two ways, by counting either the total parasitaemia or the ring forms only. On theoretical grounds, estimating the IC50 value from the number of ring forms is the most satisfactory method, as this number corresponds to the number of undamaged schizonts. The IC50 values found by 3H-hypoxanthine incorporation were lower than those found by any other method.

Animals↗
PubMed1987

Novel type of proliferating lymphoplasmacytoid cell with a characteristic spotted immunofluorescence pattern.

We examined bone marrow from myeloma patients for the presence of cells with the characteristics of the clonogenic cell in the myeloma stem cell assay. We identified a novel type of cell that contained cytoplasmic immunoglobulin of the relevant idiotype located in a cytoplasmic spot. This "spotted" Ig could be located in the rough endoplasmic reticulum. Spotted cells are highly proliferative, as evidenced by the nuclear staining with the antibody Ki67, and were found in the bone marrow from most of the myeloma patients studied. This type of cell was also present in patients with immunocytomas, in some cases of benign monoclonal gammopathy, and in patients in the state of polyclonal hypergammaglobulinemia. IgG subclass distribution of so-called spotted cells and plasma cells, found in a patient with pseudo biclonal gammopathy, indicates that spotted cells are intermediate between B cells and plasma cells. Spotted cells express the B cell-associated antigens HB4 and HB6 but do not express other B cluster of differentiation antigens or plasmacytoid antigens tested.

Adult↗
PubMed1986

Raised serum levels of tumour necrosis factor in parasitic infections.

In a study of serum levels of endogenous tumour necrosis factor (TNF) in healthy people and patients with neoplastic or infectious disease, only patients with kala-azar (visceral leishmaniasis) and malaria were found to have a strikingly increased frequency of raised TNF levels (66.6% and 70.0%, respectively). 7.9% of samples from both healthy subjects and patients with neoplastic disease contained measurable TNF. The discovery of elevated TNF levels in the sera of patients with parasitic diseases suggests that this cytokine may play a part in host defences against parasitic infections.

Adult↗