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Biomedical subjects

G Pasvol

Publications and source records attributed to G Pasvol.

At least 55 records · Page 3Linked to original sources
PubMed1994

Th1/Th2 profiles in tuberculosis, based on the proliferation and cytokine response of blood lymphocytes to mycobacterial antigens.

Proliferation and cytokine production profiles by blood mononuclear cells in response to in vitro stimulation with mycobacterial antigens were compared in patients with active tuberculosis and in sensitized healthy controls. Interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) were detected at single-cell level using the ELISPOT assay. Patients showed significantly (P < 0.01) increased numbers of IL-4-secreting cells and decreased thymidine incorporation, but no significant difference in IFN-gamma-producing cells in response to the 38,000 MW or 19,000 MW antigens and their immunodominant peptide epitopes. Pronounced individual variations were found in both patient and control groups, when comparing the responsiveness to the mycobacterial extract, two protein antigens and five synthetic peptides. None of the antigens or peptides tested showed preferential stimulation of either IL-4- or IFN-gamma-secreting T cells, and proliferation was not correlated with either IL-4 or IFN-gamma production. In particular, cytokine responsiveness was of similar frequency in subjects who did or did not show positive proliferation, indicating that the latter test was not fully representative of the active T-cell repertoire. It is concluded that the demonstrated Th2 type of profile in response to two prominent mycobacterial antigens may play a role in the mechanisms of defective host resistance in tuberculosis.

Adolescent↗
PubMed1993

Genetically permissive recognition of adjacent epitopes from the 19-kDa antigen of Mycobacterium tuberculosis by human and murine T cells.

The specificity of the T cell-immune repertoire at the level of individual antigenic determinants could play a fundamental role in the immunopathogenesis of tuberculous infections. Therefore, we analyzed the immunogenicity, genetic restriction, and epitope core structure of two adjacent, yet distinct, immunodominant T cell determinants from the 19-kDa Ag of Mycobacterium tuberculosis. After immunization with two peptides comprising residues 45 to 64 and 61 to 80, vigorous in vitro proliferative responses to the homologous peptide were elicited in five different strains of C57BL/10 mice (H-2b,k,d,s,f), indicating that both epitopes were recognized in a genetically permissive manner. When immunized with intact 19-kDa protein, lymph node cells from the same mouse strains responded to both peptides, with the exception of H-2b mice, which did not respond to p45-64. Delayed-type hypersensitivity responses in C57BL/10 (H-2b) mice were elicited by p61-80 only, whereas in H-2d mice both peptides were delayed-type hypersensitivity negative, despite eliciting pronounced proliferative responses. Analysis of the proliferative responses of human PBMC in purified protein derivative-positive healthy subjects and tuberculosis patients revealed significant differences in the antigenicity to the two peptides. All purified protein derivative-positive healthy and diseased individuals manifested strong responses to p45-64, indicating HLA permissive recognition. In contrast, pronounced responses to p61-80 were detected only in patients with lymphatic tuberculosis. Epitope core structures, composed of 6 or 7 residues within each peptide, have been mapped with peptides of overlapping sequence. Significantly, for both epitopes, the core sequences recognized by both human and murine T cells were almost identical. We conclude that despite many similarities between murine and human T cell epitope recognition, distinct differences in the responsiveness of the infected host could play a role in pathogenesis. Furthermore, the genetically permissive nature of the identified epitopes is a potentially important attribute for the development of peptide-based diagnostic reagents and vaccines.

Adult↗
PubMed1993

Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria.

The speed and stage specificity of antimalarial drug action on the metabolic activities of cultured Plasmodium falciparum were studied for chloroquine (CQ), quinine (QN), artemisinin (AR), and sodium artelinate (SA). CQ had the most rapid onset of action on [3H]hypoxanthine and [3H]isoleucine uptake, reaching 50% of its maximum effect in 1.8 hr compared with 3.5-7.4 hr for the other three drugs. In contrast there was a lag time of 1-4 hr before AR and SA had a measurable inhibitory effect, although after this delay antimalarial action was very rapid. Parasite glycolysis was relatively drug resistant; the inhibition of lactate production was < 60% of that for [3H]hypoxanthine and [3H]isoleucine uptake. The susceptibility of P. falciparum changed markedly as the parasite matured. Maximum drug effects occurred at the late ring and early trophozoite stage, which corresponds to the time at which the most rapid increases in synthetic and glycolytic activities occur. Mature schizonts and young rings were relatively unaffected by the antimalarial drugs. Young rings were particularly resistant to QN. Schizonts multiplied successfully in the presence of relatively high concentrations of all four drugs. The two artemisinin compounds had the broadest time window of action and may be particularly suitable for the treatment of severe malaria.

Animals↗
PubMed1993

DNA fingerprints of Mycobacterium tuberculosis do not change during the development of rifampicin resistance.

Drug-resistant tuberculosis has become a major public health problem. Resistance to rifampicin probably arises through mutations in the mycobacterial RNA polymerase. Patients may acquire rifampicin resistant tuberculosis by three mechanisms: (1) infection with a resistant organism, (2) selection of a sub-population of resistant organisms that remain contained whilst the more virulent wild type is present, (3) mutations within the population of bacilli causing the original infection. Sequential isolates of Mycobacterium tuberculosis were collected from 2 patients who developed rifampicin resistance whilst on treatment. One patient was immunosuppressed with HIV-infection; in the other patient the original isolate was also resistant to isoniazid. DNA fingerprinting techniques were used to type the isolates. No differences were found between the fingerprints of isolates from before and after the development of resistance. These data suggest that the third of the mechanisms listed above was responsible for the acquisition of rifampicin resistance in these 2 patients.

Adult↗
PubMed1993

The red cell membrane and invasion by malarial parasites.

The red cell membrane with its bilipid layer, integral membrane proteins (especially the GPs and band 3), and the red cell skeleton pose a formidable barrier for the malarial parasite to overcome during invasion. Invasion is an ordered and sequential process, indicating a highly complex and specific process involving numerous molecular interactions. For P. vivax and P. knowlesi infections the Duffy glycoprotein seems to be a specific requirement in invasion. For P. falciparum the GPs, and especially the N-acetyl neuraminic acid linked in an alpha 2-3 configuration on them, appear to act as specific ligands although some strains of P. falciparum may use alternate ligands for invasion. The parasite enters the red cells within an invagination continuous with the red cell bilipid layer, the parasitophorous vacuole membrane, and recent evidence would indicate that this membrane is largely of parasite origin. The numerous occasions in which the red cell needs to deform during invasion indicates that membrane deformability could be an important factor in determining invasion, but the dissociation of invasion and deformability as induced by a number of reagents would not support this contention. Instead it is suggested that reagents which modify invasion may be acting via alterations in red cell or parasite protein phosphorylation or dephosphorylation.

Amino Acid Sequence↗
PubMed1992

Follow up of patients presenting with fatigue to an infectious diseases clinic.

OBJECTIVES: To determine the symptomatic and functional status during follow up of patients referred to hospital with unexplained fatigue and to identify patient variables associated with persistent functional impairment. DESIGN: Follow up by postal questionnaire six weeks to four years (median 1 year) after initial clinical assessment of patients referred to hospital during 1984-8. SETTING: Infectious diseases outpatient clinic in a teaching hospital. PATIENTS: 200 consecutive patients with fatigue of uncertain cause for at least six weeks; 177 fulfilled the inclusion criteria. MAIN OUTCOME MEASURES: Findings at initial assessment; current symptoms, beliefs about the cause of illness, coping behaviours emotional disorder, social variables including membership of self help organizations, and degrees of recovery and functional impairment from questionnaire responses. RESULTS: 144 (81%) patients returned completed questionnaires. Initial assessment did not indicate the cause of fatigue, other than preceding infection. The proportion of patients with functional impairment was significantly smaller with longer follow up (33% (11/33) at two to four years, 73% (29/40) at six weeks to six months; chi 2 for trend = 12.5, df = 1; p less than 0.05). Functional impairment was significantly associated with belief in a viral cause of the illness (odds ratio = 3.9; 95% confidence interval 1.5 to 9.9), limiting exercise (3.2; 1.5 to 6.6), avoiding alcohol (4.5; 1.8 to 11.3), changing or leaving employment (3.1; 1.4 to 6.9), belonging to a self help organization (7.8; 2.5 to 23.9), and current emotional disorder (4.4; 2.0 to 9.3). CONCLUSIONS: Short term prognosis for recovery of function was poor but improved with time. Most patients had made a functional recovery by two years after initial clinic attendance. Impaired functioning was more likely with certain patient characteristics. Prospective studies are required to clarify whether these associations are the consequences of a more disabling illness or indicate factors contributing to impaired function.

Adaptation, Psychological↗
PubMed1992

T cell repertoire in tuberculosis: selective anergy to an immunodominant epitope of the 38-kDa antigen in patients with active disease.

It is generally accepted that both host protection and pathogenic reactions in tuberculosis are mediated by T lymphocytes. However, little is known about the structures and discreet functions of epitopes stimulating the immune response. In this study, proliferative responses of blood T lymphocytes to synthetic peptides derived from the sequence of the 38-kDa antigen from Mycobacterium tuberculosis have been investigated in 41 healthy individuals and in 36 patients with active tuberculosis. Of the healthy purified protein derivative (PPD)-positive donors, 90% responded to a permissively recognized peptide, 38.G (residues 350-359), located at the carboxy terminus of the molecule. Four other permissively recognized epitopes of this molecule (38.A, 38.I, 38.E, 38.K) were stimulatory for more than 50% of healthy PPD-positive individuals. Patients with lymphatic tuberculosis responded to these peptides in a similar manner. In contrast, we observed a selective anergy to stimulation with peptide 38.G in the majority of patients with pulmonary (11% responders) and nonlymphatic extrapulmonary tuberculosis (25% responders). The lack of responsiveness to 38.G was epitope specific since the degree of responsiveness to the other four permissively recognized peptide epitopes was similar for patients and PPD-positive controls. Using the PEPSCAN technology and truncated peptides, the core epitope of 38.G was localized to a peptide 10 amino acids long (HFQPLPPAVV). This minimal structure was capable of inducing a proliferative response in all healthy 38.G responders tested. The mechanisms influencing this epitope-specific anergy in patients could give new insights into the immunopathogenesis of tuberculosis.

Amino Acid Sequence↗
PubMed1992

Malaria and the red cell membrane.

Malarial parasites are primarily parasites of red cells and during infection ingest most of the haemoglobin within these cells, leaving the membrane as the only vestige of the original host cell. The red cell membrane thus plays a key role at all stages of infection with malarial parasites, and is modified in many ways during parasitisation, so that at least functionally it has little resemblance to the membrane from which it was originally derived. The highly specific and ordered process of parasite invasion of red cells is regulated at least in part by the uninfected red cell membrane. The red cell sialoglycoproteins or glycophorins of this membrane have been shown to play an important role in invasion by Plasmodium falciparum, the species of most importance to man because of it's high morbidity and mortality. Structurally, dynamic changes occur within the membrane during parasitisation, and a number of parasite proteins have been found to be associated within it, but changes on the surface of the infected cell have been more difficult to demonstrate. The membrane of the infected cell is important in the many metabolic processes of the parasite, as well as the critical cell-cell interactions that occur when cells containing mature parasites bind to endothelial cells (cytoadherence), bind to uninfected cells (rosetting), or interact with macrophages and other leucocytes. The recognition molecules on the red cell membrane involved in invasion, cytoadherence and rosetting appear to be quite distinct. Structural and functional changes have also been shown to occur in the membranes of uninfected red cells, both in infected patients, and in the presence of parasites in vitro. Interactions of the parasite P. falciparum with the red cell membrane hold the key to our understanding of the pathogenesis of severe falciparum infection in man.

Animals↗
PubMed1992

Anaemia of Plasmodium falciparum malaria.

The pathophysiology of the anaemia of falciparum malaria is both complex and multifactorial, and results in a condition which is a major cause of mortality and morbidity in patients, especially children and pregnant women, living in malarial endemic areas. The importance of anaemia as a cause of death in malaria may well be underestimated because of difficulty in diagnosis, especially where parasitaemia may be low and the clinical picture may be confused with other causes of anaemia. Two clinical presentations predominate: severe acute malaria in which anaemia supervenes, and severe anaemia in patients in whom there have been repeated attacks of malaria. The major mechanisms are those of red cell destruction and decreased red cell production. Potential causes of haemolysis include loss of infected cells by rupture or phagocytosis, removal of uninfected cells due to antibody sensitization or other physicochemical membrane changes, and increased reticuloendothelial activity, particularly in organs such as the spleen. Decreased production results from marrow hypoplasia seen in acute infections, and dyserythropoiesis, a morphological appearance, which in functional terms results in ineffective erythropoiesis. The role of parvovirus B19 as a possible cause of bone marrow aplasia in a few cases is postulated. Finally, there is now evidence which points to genetic factors, HLA associated, which may protect against the development of malarial anaemia and which has become common in areas endemic for malaria.

Anemia↗
PubMed1992

Prophylactic phenobarbitone in young children with severe falciparum malaria: pharmacokinetics and clinical effects.

1. A method is described for the measurement of phenobarbitone (PB) by reversed phase high performance liquid chromatography (h.p.l.c.) from small samples of whole blood dried onto filter paper strips. 2. The disposition of PB given prophylactically to young children with severe malaria on parenteral quinine is contrasted with that in aparasitaemic Kenyan children on no antimalarial drugs. There were no differences in the disposition of PB between the two groups. 3. Peak blood PB concentrations were equal to or greater than 15 mg l-1 in 27% of the patients on quinine and 23% of those not on quinine; a concentration of 10 mg l-1 was achieved or exceeded by 100% and 92% of each group, respectively, and was maintained for 39 +/- 24 h (mean +/- s.d.), and 33 +/- 21 h, respectively. 4. In an open, dose-finding study, the progress of young children with cerebral malaria given prophylactic PB (10 mg kg-1), was contrasted with that of controls given no seizure prophylaxis. 5. The drug had no apparent effect on depth or duration of coma, but neither was the incidence of seizures reduced. 6. A controlled trial of prophylactic PB in young children with cerebral malaria is needed, but a larger dose than 10 mg kg-1 should be studied.

Child↗
PubMed1992

Fulminant community acquired infections admitted to an intensive care unit.

Disease progression, support required, prognostic indicators and survival in hospital and after discharge were studied in 53 patients with community acquired infections who required admission to the intensive care unit from the Department of Infectious Diseases between January, 1985 and August, 1991. The median age was 37 years and over two-thirds of patients were previously fully fit; 38 per cent of patients required intensive care within 6 hours of admission with rapidly progressive disease. Both APACHE II scores and number of organ systems failed were good indicators of prognosis: mortality was 85 per cent in those with three or more organ failures and 86 per cent in those with APACHE II scores of > or = 25. No deaths were observed in those with scores of < 10. Some organ failures (cardiovascular, renal and respiratory) occurred more frequently in those who died. Mechanical ventilation was required by 60 per cent of patients, inotropic drugs by 42 per cent and renal dialysis by 17 per cent. Mortality in hospital was 25 per cent with no further deaths at 6 months to 2 years. As a group these patients were young and previously fit. Deterioration was rapid, necessitating admission to the intensive care unit at short notice. Our results highlight the importance of having intensive care facilities in close proximity to infectious disease units. In contrast to many other groups of patients admitted to the intensive care unit, the overall outlook for patients with community acquired life-threatening infections is good, and long-term monitoring suggests that these patients remain well once recovery has occurred.

Adolescent↗
PubMed1991

Surface antigen expression on Plasmodium falciparum-infected erythrocytes is modified in alpha- and beta-thalassemia.

In an attempt to determine the mechanism whereby thalassemia in its milder forms may protect against malaria, we have examined the expression of neoantigen at the surface of Plasmodium falciparum-parasitized thalassemic red cells. Neoantigen expression was estimated by measurement of antibody bound after incubation in serum from adults living in a malaria-endemic area, using a quantitative radiometric antiglobulin assay. We found that P. falciparum-parasitized alpha- and beta-thalassemic red cells bind greater levels of antibody from endemic serum than controls: mean binding ratios (+/- SE), respectively, for alpha- and beta-thalassemia compared with controls were 1.69 +/- 0.12 and 1.23 +/- 0.06 on a cell for cell basis, and 1.97 +/- 0.11 and 1.47 +/- 0.08 after a correction for surface area differences. Binding of antibody increased exponentially during parasite maturation. In addition, we found a small but significant degree of binding of naturally occurring antibody to parasitized red cells, the extent of which was also greater in thalassemia. The apparent protective effect of thalassemia against malaria may be related to enhanced immune recognition and hence clearance of parasitized erythrocytes.

Animals↗
PubMed1991

Intracranial pressure in African children with cerebral malaria.

Opening lumbar cerebrospinal fluid (CSF) pressure was measured with a paediatric spinal fluid manometer in 26 of 61 Kenyan children (mean age 39 months) with cerebral malaria. In all cases pressure was above normal (mean [SD]22.6 [7.4] cm CSF, range 10.5-36). Clinical features of our patients suggest that intracranial hypertension is important in the pathogenesis of cerebral malaria in children, especially as a cause of death. We suggest that raised intracranial pressure is secondary to increased cerebral blood volume. Lowering intracranial pressure may significantly reduce the mortality and morbidity of cerebral malaria. The potential risks and benefits of lumbar puncture should be considered carefully in patients with suspected cerebral malaria.

Animals↗
PubMed1991

Protection by alpha-thalassaemia against Plasmodium falciparum malaria: modified surface antigen expression rather than impaired growth or cytoadherence.

We have attempted to determine the cellular mechanism by which alpha-thalassaemia may protect against Plasmodium falciparum malaria. Invasion and development of P. falciparum in the microcytic red cells of two-gene deletion forms of alpha-thalassaemia when measured morphologically or by [3H]hypoxanthine incorporation were normal compared to controls. Normal invasion rates were also observed following schizogony in thalassaemic red cells. Neither the addition of the oxidant menadione, 30% oxygen, nor modified medium, produced differential damage to parasites within thalassaemic cells. Furthermore, there were no significant differences in the binding of P. falciparum-parasitized alpha-thalassaemic and normal cells to C32 melanoma cells in vitro. However, when neoantigen expression on the surface of infected thalassaemic cells was estimated using a quantitative radiometric antiglobulin assay, clear differences were observed. It was found that alpha-thalassaemic cells bound higher levels of antibody from serum obtained from individuals living in a malaria endemic area than control normal red cells. The binding ratio for thalassaemic compared with controls was 1.69 on a cell-for-cell basis, and 1.97 when related to surface area. The binding of antibody from immune serum increased exponentially during parasite maturation. We also found increased binding of naturally occurring antibody present in non-immune serum to parasitized thalassaemic red cells which also increased during parasite maturation. We conclude that the protection afforded by thalassaemia against malaria may not reside in the ability of parasites to enter, grow or cytoadhere to endothelium in such cells, but may be related to immune recognition and subsequent clearance of parasitized red cells.

Animals↗
PubMed1991

Quinine treatment of severe falciparum malaria in African children: a randomized comparison of three regimens.

The pharmacokinetics and effectiveness of three dosage regimens of quinine were studied in a group of 59 children with severe malaria. The children were randomized to receive high-dose intravenous or intramuscular quinine (20 mg salt/kg loading, then 10 mg salt/kg every 12 hr), or low-dose intravenous quinine (10 mg salt/kg loading, then 5 mg salt/kg every 12 hr). In the group receiving the high-dose intravenous regimen, mean high and low quinine concentrations were consistently greater than 10 and 6.5 mg/l, respectively. Peak concentrations as well as the time required to achieve them were similar in the intramuscular and high-dose intravenous groups. The low-dose intravenous quinine regimen resulted in mean peak concentrations greater than 6 mg/l and mean low concentrations greater than 3.5 mg/l. All blood concentrations exceeded the 99% in vitro inhibitory concentration (EC99) of 0.89 mg/l or less of quinine for 60 isolates of Plasmodium falciparum, which were taken from children with malaria during the same period. Judged by a number of clinical criteria, the response was better in patients receiving the high-dose than the low-dose intravenous regimen. The time taken to clear parasites with both the high-dose intravenous and intramuscular regimens were significantly shorter than those obtained in the low-dose group. We have also shown for the first time that the rate of parasite clearance can be directly related to the area under the quinine concentration versus time curve. This applied to all three quinine regimens (r = 0.4252, P less than 0.02; n less than or equal to 35). Five patients, two on the low-dose regimen, two on the intramuscular regimen, and one on the high-dose regimen, developed hypoglycemia after admission, but in these cases, insulin concentrations were correspondingly low. No significant quinine toxicity was observed in any of the cases. The high-dose intravenous quinine regimen described here may be optimal for treatment of severe falciparum malaria in areas of chloroquine resistance in Africa. Our data provide no justification for reducing the dose of quinine in the treatment of severe malaria in Africa. The intramuscular regimen could provide a satisfactory alternative in areas where intravenous administration might be delayed or is impossible.

Child↗