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Biomedical subjects

M Pinder

Publications and source records attributed to M Pinder.

At least 55 records · Page 3Linked to original sources
PubMed1999

A phase I safety and immunogenicity trial with the candidate malaria vaccine RTS,S/SBAS2 in semi-immune adults in The Gambia.

RTS,S is a novel pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein (CSP) of Plasmodium falciparum linked to hepatitis B surface antigen (HBs) and combined with a novel adjuvant system (SBAS2). We have conducted a Phase I trial with three doses of this vaccine given at 0, 1, and 6 months to 20 semi-immune, adult, male volunteers in The Gambia to assess its safety and immunogenicity. Eighteen of the 20 volunteers completed the study. There were no clinically significant local or systemic adverse events following each vaccination. Hematologic and biochemical indices before and two weeks after each vaccination showed no evidence of toxicity. Antibody titers to both CSP and HBs showed a significant increase after vaccination; these were the largest after the third dose. We conclude that the RTS,S/SBAS2 vaccine induces no significant toxicity in this semi-immune population and produces significant increases in antibody titers to CSP.

Adolescent↗
PubMed1998

Critical care research and pre-emptive informed consent: a practical approach used in Chris Hani Baragwanath ICU.

OBJECTIVES: 1) To establish a protocol within international and local ethical guidelines to obtain informed consent for critical care research, overcoming constraints previously described and 2) To evaluate eventual recruitment using this protocol. DESIGN: Prospective descriptive study. SETTING: Multidisciplinary ICU in a community-based university teaching hospital. PATIENTS AND PARTICIPANTS: Following approval by the University Ethics Committee and Hospital Review Board, patients admitted between January and May 1996 were assessed on weekdays for potential enrollment into existing clinical trials. Discussion with potential candidates and/or next-of-kin occurred at the earliest opportunity and informed consent was obtained preemptively. Next-of-kin was notified if enrollment subsequently occurred. We evaluated the number of patients screened, the number of potential study candidates, the number for whom consent was obtained or refused and the number subsequently enrolled. INTERVENTIONS: None RESULTS: Of 249 patients screened, 149 (60%) did not meet the inclusion criteria. Of 100 potential study candidates (40% of all patients screened), we failed to make contact with the next-of-kin in 29 cases (12% of all patients screened). Thus 71 patients or next-of-kin were counselled (28% of all patients screened). In all, 30 patients (12% of all patients screened) were subsequently enrolled into a study. CONCLUSIONS: A policy of pre-emptive informed consent enabled us to overcome some of the problems previously experienced in our unit with regards to patient enrollment in critical care research. Although overall recruitment remained low, predictions for future enrollment can be made from this study.

Algorithms↗
PubMed1998

Comparison of bednets treated with alphacypermethrin, permethrin or lambdacyhalothrin against Anopheles gambiae in the Gambia.

In the Gambian village of Saruja, where malaria is transmitted mainly by mosquitoes of the Anopheles gambiae complex, a trial was undertaken of the acceptability and efficacy of bednets treated with one of three pyrethroid insecticides--alphacypermethrin 40 mg/m2, permethrin 500 mg/m2 and lambdacyhalothrin 10 mg/ m2. Fewer mosquitoes were found alive under nets treated with insecticide than under control nets. Significantly more dead mosquitoes were found under nets treated with alphacypermethrin than under nets treated with permethrin or lambdacyhalothrin. Side-effects were reported by a proportion of the users of nets treated with each of the insecticides, but none were severe and their prevalence was similar between treatment groups. Unwashed nets treated with alphacypermethrin were more effective at killing anopheline mosquitoes in bioassays than nets treated with permethrin or lambdacyhalothrin. Killing activity was reduced when nets were washed, irrespective of which insecticide was used. Bednets treated with alphacypermethrin are well accepted, effectively killed anopheline mosquitoes and should therefore be evaluated for personal protection against malaria transmission.

Animals↗
PubMed1998

A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children.

We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1-5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections. Three days after the start of treatment, 133 (100%) of the CGP56697-treated children compared with 128 (93.4%) of children treated with P/S had cleared their parasites (P = 0.003). The day 15 cure rate was 93.3% for CGP56697 and 97.7% for P/S (P = 0.13). Within the third and fourth week after initiation of therapy, 20 children treated with CGP56697 and one of the P/S-treated children returned with second malaria episodes (P < 0.0001). Genotyping suggested that the majority (19 of 23 [82.6%]) of these second episodes were due to new infections, supporting the World Health Organization recommendation that longer follow-up is not relevant for the assessment of drug efficacy. At the two-week follow-up, 28.9% of the P/S treated children but none of the CGP56697-treated children carried gametocytes (P < 0.0001). This study showed that CGP56697 is safe in African children with acute uncomplicated falciparum malaria, clears parasites more rapidly than P/S, and results in fewer gametocyte carriers. More frequent new infections within the third and fourth week following treatment with CGP56697 than treatment with P/S are likely to be due to the short prophylactic effect of CGP56697.

Antimalarials↗
PubMed1997

Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa.

BACKGROUND: Malaria remains a major cause of mortality and morbidity in Africa. Many approaches to malaria control involve reducing the chances of infection but little is known of the relations between parasite exposure and the development of effective clinical immunity so the long-term effect of such approaches to control on the pattern and frequency of malaria cannot be predicted. METHODS: We have prospectively recorded paediatric admissions with severe malaria over three to five years from five discrete communities in The Gambia and Kenya. Demographic analysis of the communities exposed to disease risk allowed the estimation of age-specific rates for severe malaria. Within each community the exposure to Plasmodium falciparum infection was determined through repeated parasitological and serological surveys among children and infants. We used acute respiratory-tract infections (ARI) as a comparison. FINDINGS: 3556 malaria admissions were recorded for the five sites. Marked differences were observed in age, clinical spectrum and rates of severe malaria between the five sites. Paradoxically, the risks of severe disease in childhood were lowest among populations with the highest transmission intensities, and the highest disease risks were observed among populations exposed to low-to-moderate intensities of transmission. For severe malaria, for example, admission rates (per 1000 per year) for children up to their 10th birthday were estimated as 3.9, 25.8, 25.9, 16.7, and 18.0 in the five communities; the forces of infection estimated for those communities (new infections per infant per month) were 0.001, 0.034, 0.050, 0.093, and 0.176, respectively. Similar trends were noted for cerebral malaria and for severe malaria anaemia but not for ARI. Mean age of disease decreased with increasing transmission intensity. INTERPRETATION: We propose that a critical determinant of life-time disease risk is the ability to develop clinical immunity early in life during a period when other protective mechanisms may operate. In highly endemic areas measures which reduce parasite transmission, and thus immunity, may lead to a change in both the clinical spectrum of severe disease and the overall burden of severe malaria morbidity.

Anemia↗
PubMed1997

Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697.

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.

Animals↗
PubMed1997

Characterization of human T- and B-cell epitopes in the C terminus of Plasmodium falciparum merozoite surface protein 1: evidence for poor T-cell recognition of polypeptides with numerous disulfide bonds.

We have investigated the relationship between cellular and humoral immune responses to defined epitopes of the C terminus of merozoite surface protein 1 (MSP-1) of the human malaria parasite, Plasmodium falciparum, in immune blood donors. Sera from almost all donors contained antibodies to the 33-kDa processing product of the MAD20 allele of MSP-1 (MSP-1(33)), but these antibodies did not cross-react with the equivalent sequence of the Wellcome allele. In contrast, T-cell responses to MSP-1(33) are directed towards epitopes that are conserved between the two allelic families. Only 50% of adult blood donors possessed antibodies which recognized the 19-kDa processing product of MSP-1 (MSP-1(19)). These antibodies predominantly recognized conserved epitopes involving both of the constituent epidermal growth factor-like domains of MSP-1(19). T-cell responses were found in only 26% (for recombinant proteins) or 44% (for synthetic peptides) of donors and were directed mainly at dimorphic sequences of the protein. There was no obvious association, at an individual level, between the presence of antibodies and the detection of T-cell proliferative or gamma interferon responses, suggesting that the T cells identified in this manner are not providing significant levels of help to B cells. T-cell responses to reduced recombinant proteins and linear peptides were more prevalent than responses to disulfide-bonded proteins, suggesting that the complex disulfide-bonded structure of native MSP-1(19) may inhibit antigen processing or presentation.

Amino Acid Sequence↗
PubMed1996

A randomized trial of chloroquine, amodiaquine and pyrimethamine-sulphadoxine in Gambian children with uncomplicated malaria.

The increasing occurrence of chloroquine-resistant Plasmodium falciparum in sub-Saharan Africa makes it essential to reconsider current recommendations for the treatment of uncomplicated P.falciparum malaria. In an open, randomized trial, we have compared chloroquine (CQ), amodiaquine (AQ), and pyrimethamine-sulphadoxine (PS) in rural Gambian children with uncomplicated P.falciparum malaria. Three hundred children were randomly assigned at the time of consultation (Do) to oral treatment with 25 mg/kg CQ, 25 mg/kg AQ (both given over 3 days), or 1.25/25 mg/kg PS. They were reviewed on day 7 (D7) and day 28 (D28) for symptoms, malaria parasitaemia, and packed cell volume (PCV). Significantly more children treated with PS compared to CQ (17 vs 7%, P = 0.03) or AQ (17 vs 3%, P = 0.001) returned with clinical complaints during the first 3 days after treatment. Five of these patients had a generalized convulsion (1 from the AQ group, 4 from the PS group), of whom 4 developed cerebral malaria. At D7, significantly more patients treated with CQ compared to AQ (25 vs 7%, P = 0.0009) or PS (25 vs 4%, P = 0.0001) were parasitaemic. By D28, the cumulative number of parasitological failures was significantly higher in the CQ group compared to the AQ group (65 vs 35%, P = 0.0001), and significantly higher in the AQ group compared to the PS group (35 vs 14%, P = 0.001). Overall, 91% of parasitological failures observed during the study period were symptomatic and were consequently treated with an alternative antimalarial drug. Over the 28-day study period the mean PCV increased significantly less in the CQ group than in the PS group (1.2 vs 3.8%, P = 0.016) and was lower in the CQ group than in the AQ group (1.2 vs 2.7%, P = 0.12, not significant). These results suggest that PS acts more slowly than 4-aminoquinolines in controlling the clinical features of malaria, and that AQ can be considered as an interim alternative to CQ in the first-line therapy of uncomplicated malaria in African areas of high CQ resistance.

Amodiaquine↗
PubMed1996

Acute stridor as a presentation of bilateral abductor vocal cord paralysis.

We report the case of a 48-year-old woman, referred to the Intensive Care Unit with community-acquired pneumonia, who was noted to have stridor of acute onset. Subsequent indirect laryngoscopy revealed bilateral abductor vocal cord paralysis, secondary to unsuspected carcinoma of the oesophagus, requiring immediate tracheostomy. We highlight the importance of visualisation of the vocal cords in cases of stridor of uncertain aetiology.

Carcinoma, Squamous Cell↗
PubMed1995

Systemic response to gram-positive and gram-negative infections--comparison and contrast.

The concept of the systemic inflammatory response (SIRS) has recently been defined with suggested new terminology and criteria for diagnosis, and this has gained acceptance in the international literature. The importance of Gram-positive organisms as a cause of the SIRS has become increasingly recognised in recent years. This report describes a case of severe staphylococcal infection with a clinical picture similar to 'classic' endotoxic shock associated with Gram-negative organisms. We use this report to discuss the management of severe sepsis with organ dysfunction, outline the clinical complications and specific therapy of staphylococcal infections, discuss the new terminology, and compare and contrast the features of SIRS associated with varying causes.

Adult↗
PubMed1994

Loa loa: immunological responses during experimental infections in mandrills (Mandrillus sphinx).

Six intact, adult mandrills (Mandrillus sphinx) were infected with human-derived, diurnal Loa loa infective larvae. Microfilaremia, hematological, and immunological parameters were followed for 2-4 years. A major aim was to investigate the relationship between specific humoral immunity to microfilariae and microfilaremia and also to assess whether infection led to generalized immune dysfunction. Microfilaremia was similar to previous studies for 4 mandrills, with a prepatent period of 153.5 +/- 10.1 days, a peak of 34-1,798 mf/ml around Day 200, followed by a decline to low, persistent microfilaremia. One mandrill (No. 20) had a longer prepatent period and very low, but persistent, levels of microfilaremia, and one (No. 19) had gradually increasing levels which remained > 10,000 mf/ml for 3 years. To assess generalized immune perturbations several parameters were studied. There was neither generalized leukocytosis nor relative or absolute eosinophila. Serum Ig concentrations were measured from 0-600 days postinfection by radial immunodiffusion using a rabbit anti-mandrill Ig serum, and these were remarkably stable. Proliferative responses of peripheral blood mononuclear cells from these infected mandrills and noninfected controls showed no significant differences in the magnitude of proliferation after stimulation with a range of doses of PHA, PWM, or Concanavalin A. Thus, no evidence of generalized immune dysfunction was found in the peripheral blood. Serum IgG levels to soluble mf antigens were estimated by an indirect ELISA and all animals had maximal levels around Week 22 postinfection, at the time of maximum microfilaremia, and these decreased over the next 2-3 years in all mandrills except No. 19, in which levels remained fairly constant. Serum IgG levels to adult worm antigens showed a similar pattern but were not, or were only slightly, diminished late in infection. Antibody to mf sheath antigens were detected by indirect immunofluorescence and agglutination of live mf. Antibody to sheath antigens were never detected in mandrill 19 but were present from Week 8 postinfection to 2-4 weeks before patency in all the others. Anti-sheath antibodies were not detected in serum at later time points, i.e., postpatency, in any mandrill, even at time points when microfilaremia was < 1 mf/ml. The anti-sheath antibody was IgM and no anti-sheath IgG was detected. Ig was detected on the surface of circulating mf in 1 mandrill (No. 20). The appearance of these antibodies prior to maturation of the adults indicates that certain L4 or immature adult antigens cross-react with the surface of mf.(ABSTRACT TRUNCATED AT 400 WORDS)

Agglutination Tests↗