Search PubMed⌕ Search

Biomedical subjects

T Doherty

Publications and source records attributed to T Doherty.

At least 19 recordsLinked to original sources
PubMed2004

Cellular immunity induced by the recombinant Plasmodium falciparum malaria vaccine, RTS,S/AS02, in semi-immune adults in The Gambia.

Vaccination of malaria-naive humans with recombinant RTS,S/AS02, which includes the C-terminus of the circumsporozoite protein (CS), has been shown to induce strong T cell responses to both the whole protein antigen and to peptides from CS. Here we show that strong T cell responses were also observed in a semi-immune population in The Gambia, West Africa. In a Phase I study, 20 adult male volunteers, lifelong residents in a malaria-endemic region, were given three doses of RTS,S/AS02 at 0, 1 and 6 months. Responses to RTS,S, hepatitis B surface antigen and peptides from CS were tested using lymphocyte proliferation, interferon (IFN)-gamma production in microcultures, and IFN-gamma ex vivo and cultured ELISPOT, before and after vaccination. Cytotoxic responses were tested only after vaccination and none were detected. Before vaccination, the majority of the volunteers (15/20) had detectable responses in at least one of the tests. After vaccination, responses increased in all assays except cytotoxicity. The increase was most marked for proliferation; all donors responded to RTS,S after the third dose and all except one donor responded to at least one peptide after the second or third dose. There was a lack of close association of peptide responses detected by the different assays, although in microcultures IFN-gamma responses were found only when proliferative responses were high, and responses by cultured ELISPOT and proliferation were found together more frequently after vaccination. We have therefore identified several peptide-specific T cell responses induced by RTS,S/AS02 which provides a mechanism to investigate potentially protective immune responses in the field.

Adolescent↗
PubMed2002

CD40L association with protection from severe malaria.

CD40 ligand (CD40L), a glycoprotein involved in B cell proliferation, antigen presenting cell activation, and Ig class switching, is important in the immune response to infection. Rare coding mutations in CD40L can lead to life-threatening immunodeficiency but the potential for common variants to alter disease susceptibility remains to be explored. To identify polymorphisms in CD40L, we sequenced 2.3 kb of the 5' flanking region and the first exon of the gene in DNA samples from 36 Gambian females and one chimpanzee. Diversity was lower than the average reported for other areas of the X chromosome, and only two polymorphisms were identified. The polymorphisms were genotyped in DNA samples from 957 Gambian individuals, cases and controls from a study of severe malaria. A significant reduction in risk for severe malaria (OR = 0.52, P = 0.002) was associated with males hemizygous for the CD40L-726C. Analysis by transmission disequilibrium test of 371 cases, for whom DNA from both parents was also available, confirmed the result was not due to stratification (P = 0.04). A similar but non-significant trend was found in females. This preliminary association of a common variant in CD40L with a malaria resistance phenotype encourages further genetic characterization of the role of CD40L in infectious disease.

Alleles↗
PubMed2001

Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial.

BACKGROUND: RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a new adjuvant (AS02). We did a randomised trial of the efficacy of RTS,S/AS02 against natural P. falciparum infection in semi-immune adult men in The Gambia. METHODS: 306 men aged 18-45 years were randomly assigned three doses of either RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxine/pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P. falciparum. Analysis was per protocol. FINDINGS: 250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/AS02 was safe and well tolerated. P. falciparum infections occurred significantly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's test p=0.018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8.0-53, p=0.014). Protection seemed to wane: estimated efficacy during the first 9 weeks of follow-up was 71% (46-85), but decreased to 0% (-52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circumsporozoite protein and strong T-cell responses. Protection was not limited to the NF54 parasite genotype from which the vaccine was derived. 158 men received a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4-71, p=0.037). INTERPRETATION: RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P. falciparum infection.

Adult↗
PubMed2001

Unique T cell effector functions elicited by Plasmodium falciparum epitopes in malaria-exposed Africans tested by three T cell assays.

Natural immunity to malaria is characterized by low level CD4 T cell reactivity detected by either lymphoproliferation or IFN-gamma secretion. Here we show a doubling in the detection rate of responders to the carboxyl terminus of circumsporozoite protein (CS) of Plasmodium falciparum by employing three T cell assays simultaneously: rapid IFN-gamma secretion (ex vivo ELISPOT), IFN-gamma secretion after reactivation of memory T cells and expansion in vitro (cultured ELISPOT), and lymphoproliferation. Remarkably, for no individual peptide did a positive response for one T cell effector function correlate with any other. Thus these CS epitopes elicited unique T cell response patterns in malaria-exposed donors. Novel or important epitope responses may therefore be missed if only one T cell assay is employed. A borderline correlation was found between anti-CS Ab levels and proliferative responses, but no correlation was found with ex vivo or cultured IFN-gamma responses. This suggested that the proliferating population, but not the IFN-gamma-secreting cells, contained cells that provide help for Ab production. The data suggest that natural immunity to malaria is a complex function of T cell subgroups with different effector functions and has important implications for future studies of natural T cell immunity.

Adult↗
PubMed2001

Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae.

Combination therapy that includes artemisinin derivatives cures most falciparum malaria infections. Lowering transmission by reducing gametocyte infectivity would be an additional benefit. To examine the effect of such therapy on transmission, Gambian children with Plasmodium falciparum malaria were treated with standard regimens of chloroquine or pyrimethamine-sulfadoxine alone or in combination with 1 or 3 doses of artesunate. The infectivity to mosquitoes of gametocytes in peripheral blood was determined 4 or 7 days after treatment. Infection of mosquitoes was observed in all treatment groups and was positively associated with gametocyte density. The probability of transmission was lowest in those who received pyrimethamine-sulfadoxine and 3 doses of artesunate, and it was 8-fold higher in the group that received pyrimethamine-sulfadoxine alone. Artesunate reduced posttreatment infectivity dramatically but did not abolish it completely. The study raises questions about any policy to use pyrimethamine-sulfadoxine alone as the first-line treatment for malaria.

Adolescent↗
PubMed2001

Hypokalemia, metabolic alkalosis, and hypertension: Cushing's syndrome in a patient with metastatic prostate adenocarcinoma.

Ectopic adrenocorticotropic hormone (ACTH) and/or corticotropin-releasing hormone (CRH) are associated with a growing list of tumors. We report a 69-year-old white man with a history of high-grade prostate carcinoma and widely metastatic adenocarcinoma who presented with metabolic alkalosis, hypokalemia, and hypertension secondary to ectopic ACTH and CRH secretion. Laboratory values were consistent with hypokalemia and metabolic alkalosis. Markedly elevated serum cortisol (135 microg/dL), ACTH (1,387 pg/dL), CRH (69 pg/dL), and urine free cortisol (16,276 microg/24 h) levels were found. Chest computed tomographic (CT) scan showed small noncalcified parenchymal densities; however, bronchoscopy and bronchoalveolar lavage washings were unremarkable for a neoplastic process. Abdominal CT scan and magnetic resonance imaging showed multiple small liver lesions and multiple thoracic and lumbar intensities consistent with diffuse metastatic disease. Histological analysis of a biopsy specimen from the thoracic spine showed an undifferentiated adenocarcinoma consistent with a prostate primary tumor. The severe metabolic alkalosis secondary to glucocorticoid-induced excessive mineralocorticoid activity was treated with potassium supplements, spironolactone, and ketoconazole. In this case report, we describe an unusual tumor associated with ectopic ACTH and CRH production and the pharmacodynamic relationship of plasma cortisol levels and urinary cortisol excretion with ketoconazole treatment.

ACTH Syndrome, Ectopic↗
PubMed2001

Parasitaemia and gametocytaemia after treatment with chloroquine, pyrimethamine/sulfadoxine, and pyrimethamine/sulfadoxine combined with artesunate in young Gambians with uncomplicated malaria.

As part of a study to assess the infectivity of gametocytes after treatment with four antimalarial regimens, the efficacy of each treatment was also determined. From September to December 1998, 598 children with uncomplicated malaria were treated; 135 received chloroquine (CQ) alone, 276 received pyrimethamine/sulfadoxine (Fansidar, PSD) alone, 113 received PSD with a single dose of artesunate (PSD + 1ART) and 74 received PSD combined with three doses of artesunate (PSD + 3ART). On day 28 19/63 (30.2%; 95% C.I. 19.2% to 43.1%) of children treated with CQ alone, 5/134 (3.7%; 95% C.I. 1.2% to 8.5%) treated with PSD alone, 1/71 (1.4%, 95% C.I. 0.0% to 7.9%) treated with PSD + 1ART and 0/45 (0.0%; 95% C.I. 0.0% to 7.9%) treated with PSD + 3ART were parasitaemic. The proportion of children with gametocytes on day 7 after treatment with CQ alone was 16/89 (18.0%; 95% C.I. 10.6% to 27.6%), 98/174 (56.3%; 95% C.I. 48.6% to 63.8%) after treatment with PSD alone, 8/70 (11.4%; 95% C.I. 5.1% to 21.3%) after treatment with PSD + 1ART and 4/46 (8.7%; 95% C.I., 2.4% to 20.8%) after treatment with PSD + 3ART. CQ thus has a lower efficacy than PSD or either of the PSD and artesunate combinations. Use of PSD alone as an alternative first line treatment results in a very high post-treatment gametocyte prevalence that is likely to enhance transmission. There would be greater and more sustainable benefits from using PSD and artesunate combinations.

Animals↗
PubMed2000

High-throughput sequence typing of T-cell epitope polymorphisms in Plasmodium falciparum circumsporozoite protein.

We report a method for typing polymorphisms at the T-cell epitopes within the Th2R and Th3R regions of the Plasmodium falciparum circumsporozoite protein (CSP). This method combines the use of PCR and sequence specific oligonucleotide probes (PCR-SSOP), and allows the identification of single nucleotide polymorphisms in these epitope regions. PCR-SSOP is a robust and a high-throughput sequence typing technique which has the same specificity and fidelity as direct sequencing. This method has been developed specifically for the assessment of the protective efficacy of RTS,S/SBAS2 vaccine against the 3D7 strain of P. falciparum (RTS,S/SBAS2 vaccine contains a part of the 3D7 CSP protein) in a phase IIb trial in Gambia which has been completed recently. PCR-SSOP could be used to determine the allelic frequencies of other parasite antigens and their geographical distribution.

Alleles↗
PubMed2000

Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial.

BACKGROUND: Resistance to cheap effective antimalarial drugs, especially to pyrimethaminesulphadoxine (Fansidar), is likely to have a striking impact on childhood mortality in sub-Sharan Africa. The use of artesunate (artesunic acid) [corrected] in combination with pyrimethamine-sulphadoxine may delay or prevent resistance. We investigated the efficacy, safety, and tolerability of this combined treatment. METHODS: We did a double-blind, randomised, placebo-controlled trial in The Gambia. 600 children with acute uncomplicated Plasmodium falciparum malaria, aged 6 months to 10 years, at five health centres were randomly assigned pyrimethaminesulphadoxine (25 mg/500 mg) with placebo; pyrimethamine-sulphadoxine plus one dose of artesunate (4mg/kg bodyweight); or pyrimethamine-sulphadoxine plus one dose 4 mg/kg bodyweight artesunate daily for 3 days. Children were visited at home each day after the start of treatment until parasitaemia had cleared. FINDINGS: The combined treatment was well tolerated. No adverse reactions attributable to treatment were recorded. By day 1, only 178 (47%) of 381 children treated with artesunate were still parasitaemic, compared with 157 (81%) of 195 children in the pyrimethamine-sulphadoxine alone group (relative risk 1.7 [95% CI 1.5-2.0], p<0.001). Treatment-failure rates at day 14 were 3.1% in the pyrimethamine sulphadoxine alone group, and 3.7% in the one-dose artesunate group (risk difference -0.6% [-4.2 to 3.0]) and 1.6% in the three-dose group (1.5 [1.5-4.5], p=0.048). Symptoms resolved faster in children who received artesunate, but there was no additional benefit for three doses of artesunate over one dose. Children given artesunate were less likely to be gametocytaemic after treatment. INTERPRETATION: The combined treatment was safe, well tolerated, and effective. The addition of artesunate to malaria treatment regimens in Africa results in lower gametocyte rates and may lower transmission rates.

Animals↗
PubMed1999

Comparison of a parasite lactate dehydrogenase-based immunochromatographic antigen detection assay (OptiMAL) with microscopy for the detection of malaria parasites in human blood samples.

Microscopic examination of blood smears remains the gold standard for malaria diagnosis, but is labor-intensive and requires skilled operators. Rapid dipstick technology provides a potential alternative. A study was conducted in The Gambia to compare the performance of OptiMAL, an immunochromatographic antigen detection assay for the diagnosis of malaria using parasite lactate dehydrogenase, against standard microscopy in patients with suspected malaria. For initial diagnosis of Plasmodium falciparum, irrespective of stage, this assay had a sensitivity of 91.3%, a specificity of 92%, a positive predictive value of 87.2%, and a negative predictive value of 94.7%. The sensitivity of the test decreased markedly at parasitemias < 0.01%. This assay can be used for the diagnosis of malaria in areas where microscopy is not available and for urgent malaria diagnosis at night and at weekends, when routine laboratories are closed and when relatively inexperienced microscopists may be on duty.

Animals↗
PubMed1998

A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. Recombinant Outer-Surface Protein A Lyme Disease Vaccine Study Consortium.

BACKGROUND: Lyme disease is a multisystem inflammatory disease caused by infection with the tick-borne spirochete Borrelia burgdorferi and is the most common vector-borne infection in the United States. We assessed the efficacy of a recombinant vaccine consisting of outer-surface protein A (OspA) without adjuvant in subjects at risk for Lyme disease. METHODS: For this double-blind trial, 10,305 subjects 18 years of age or older were recruited at 14 sites in areas of the United States where Lyme disease was endemic; the subjects were randomly assigned to receive either placebo (5149 subjects) or 30 microg of OspA vaccine (5156 subjects). The first two injections were administered 1 month apart, and 7515 subjects also received a booster dose at 12 months. The subjects were observed for two seasons during which the risk of transmission of Lyme disease was high. The primary end point was the number of new clinically and serologically confirmed cases of Lyme disease. RESULTS: The efficacy of the vaccine was 68 percent in the first year of the study in the entire population and 92 percent in the second year among the 3745 subjects who received the third injection. The vaccine was well tolerated. There was a higher incidence of mild, self-limited local and systemic reactions in the vaccine group, but only during the seven days after vaccination. There was no significant increase in the frequency of arthritis or neurologic events in vaccine recipients. CONCLUSIONS: In this study, OspA vaccine was safe and effective in the prevention of Lyme disease.

Adolescent↗
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

Active serum vitamin D levels are inversely correlated with coronary calcification.

BACKGROUND: Arterial calcification is a common feature of atherosclerosis, occurring in >90% of angiographically significant lesions. Recent evidence from this and other studies suggests that development of atherosclerotic calcification is similar to osteogenesis; thus, we undertook the current investigation on the potential role of osteoregulatory factors in arterial calcification. METHODS AND RESULTS: We studied two human populations (173 subjects) at high and moderate risk for coronary heart disease and assessed them for associations between vascular calcification and serum levels of the osteoregulatory molecules osteocalcin, parathyroid hormone, and 1alpha,25-dihydroxyvitamin D3 (1,25-vitamin D). Our results revealed that 1,25-vitamin D levels are inversely correlated with the extent of vascular calcification in both groups. No correlations were found between extent of calcification and levels of osteocalcin or parathyroid hormone. CONCLUSIONS: These data suggest a possible role for vitamin D in the development of vascular calcification. Vitamin D is also known to be important in bone mineralization; thus, 1,25-vitamin D may be one factor to explain the long observed association between osteoporosis and vascular calcification.

Adult↗
PubMed1997

Electron beam computed tomographic coronary calcium as a predictor of coronary events: comparison of two protocols.

BACKGROUND: We assessed the accuracy of two electron beam computed tomography (EBCT) protocols for predicting coronary events. METHODS AND RESULTS: In 1994, 24 months after enrollment in a longitudinal study, 326 high-risk adults underwent both 3- and 6-mm image-slice thickness EBCT scanning and were followed up for 32.0+/-4.0 additional months. Events were defined as either coronary death, myocardial infarction, or revascularization. We monitored these subjects for the 32-month postscanning period with yearly phone calls and acquisition of records for all hospital admissions. At the time of scanning, 11 subjects (3%) had already suffered 12 events (5 infarctions and 7 revascularizations) during the 24-month prescanning period. During the postscanning period, 18 subjects (6%) suffered 23 events (5 coronary deaths, 6 infarctions, and 12 revascularizations). Thus, 28 subjects (9%) suffered 35 events. Calcium quantities calculated for both protocols, performed on the same subjects, were sorted in ascending order and divided into equal quartiles. When revascularizations were included, there was a significant trend toward higher frequencies of events with increasing calcium quantity (P<.01). However, coronary death and infarction were not significantly more frequent in higher quartiles. These relationships were preserved in the subjects without prior events at the time of scanning. CONCLUSIONS: Calcium quantities from the 3-mm and the more reproducible 6-mm scanning are equally accurate for predicting events. Coronary calcium amount appears to be a weak predictor of coronary death and infarction. Its predictive accuracy is superior for predicting revascularization.

Aged↗
PubMed1997

Controlled cord traction versus minimal intervention techniques in delivery of the placenta: a randomized controlled trial.

OBJECTIVES: Our purpose was to compare the controlled cord traction technique with the minimal intervention technique for delivery of the placenta. The primary outcome was the incidence of postpartum hemorrhage. Secondary outcomes included duration of third stage of labor, frequency of retained placenta, hemorrhagic shock, the need for blood transfusion, and the need for uterotonic agents to control postpartum hemorrhage. STUDY DESIGN: A total of 1648 women who were delivered vaginally were randomly allocated during labor to the controlled cord traction group (n = 827) or the minimal intervention group (n = 821). In the controlled cord traction group women received oxytocin, 10 units intramuscularly, with delivery of the baby's anterior shoulder, after which the placenta was delivered actively by controlled cord traction (Brandt-Andrews method). In the minimal intervention group the placenta was delivered by maternal pushing. Continuous intravenous oxytocin was given after delivery of the placenta. Odds ratios with 95% confidence intervals were calculated for each variable. RESULTS: The overall incidence of postpartum hemorrhage was significantly lower in the controlled cord traction group (5.8% vs 11%; odds ratio 0.50, 95% confidence interval 0.34 to 0.73). The incidence of retained placenta (> or = 30 minutes) was 1.6% in the controlled cord traction group and 4.5% in the minimal intervention group (odds ratio 0.31, 95% confidence interval 0.15 to 0.63). Significantly more patients in the minimal intervention group required additional uterotonic agents to control hemorrhage (5.1% vs 2.3%; odds ratio 0.44, 95% confidence interval 0.24 to 0.78). CONCLUSION: The controlled cord traction technique for delivery of the placenta results in a significantly lower incidence of postpartum hemorrhage and retained placenta, as well as less need for uterotonic agents, compared with the minimal intervention technique.

Delivery, Obstetric↗
PubMed1995

Methods for estimating the numbers of motor units in human muscles.

After the introduction by A. J. McComas of the original method for estimating the number of motor units based on manual incremental stimulation of a motor nerve, several new techniques have been developed, designed to correct for some of the errors inherent in the original technique. These methods incorporate algorithms to adjust for alternation and, to a greater or lesser extent, automate the methods, rendering the techniques less subject to operator bias and various physiological and technical errors. This review explores the advantages and drawbacks in the multiple-point stimulation (MPS), spike-triggered averaging (STA), and decomposition-enhanced STA techniques, illustrates some of the current applications of the techniques, and explores some tantalizing prospects for new studies of motor-unit physiology in the future.

Algorithms↗