Biomedical subjects

T Smith

Publications and source records attributed to T Smith.

At least 433 records · Page 24Linked to original sources

PubMed1995

Randomised trial of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania.

Malaria, especially that due to Plasmodium falciparum, is one of the most important parasitic disease in man. It causes more than 400 million cases per year and between 1 to 3 million deaths, mainly among young children and pregnant women in sub-Saharan Africa. The current malaria control strategies using rapid diagnosis and treatment as well as methods to reduce the man-vector contact have had limited success. In Kilombero district (Southern Tanzania), malaria transmission is perennial (parasite prevalence > or = 80% all year) and intense (approximatively 300 infectious bites per year). At the household level, each under-5 child suffers on average 3 clinical fever episodes per year. Minimum estimated community rates for serious malaria (cerebral malaria or malaria and anaemia) affect approximatively 5% of all children. Under conditions of a field experiment, the annual incidence of a febrile illness (axillary temperature > or = 37.5 degrees C) reported to the curative primary health services in each child was 0.86 of which 0,35 can be attributed to Plasmodium falciparum malaria. The best estimate of the SPf66 vaccine protective efficacy in the Kilombero was 31% (95% CI : 0.52).

Child, Preschool↗

PubMed1995

Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer.

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.

Adult↗

PubMed1994

Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. AIDS Clinical Trials Group Protocol 157 Study Team.

OBJECTIVE: To determine the antimicrobial activity and tolerability of clarithromycin for treating bacteremic Mycobacterium avium complex disease in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: A randomized, double-blind, dose-ranging study. SETTING: Outpatient clinics. PATIENTS: 154 patients with human immunodeficiency virus (HIV) infection and blood cultures positive for M. avium complex who had symptomatic disease. INTERVENTIONS: Random assignment to clarithromycin at dosages of 500 mg, 1000 mg, or 2000 mg twice daily for 12 weeks. MAIN OUTCOME MEASURE: Median number of colony-forming units of M. avium complex per milliliter of blood. RESULTS: Clarithromycin decreased mycobacterial CFUs from 2.7 to 2.8 log 10/mL of blood at baseline to less than 0 log 10/mL during follow-up (P < 0.0001). After 2 weeks, patients receiving 500 mg twice daily were less likely to be culture negative than were patients receiving 1000 or 2000 mg twice daily (11% compared with 33% or 29%; P = 0.08). At 6 weeks, the median number of CFUs of M. avium complex/mL of blood was 0 or 1 for all three groups. Clarithromycin-resistant isolates of M. avium complex developed in 46% of patients at a median of 16 weeks. Median survival was longer in patients assigned to 500 mg twice daily (median, 249 days) than in patients assigned to 1000 mg or 2000 mg. Death in the first 12 weeks was lowest in the 500-mg group (P = 0.007). CONCLUSIONS: Clarithromycin therapy acutely decreased M. avium complex bacteremia in patients with HIV infection by more than 99%. Clarithromycin, 500 mg twice daily, was well tolerated and associated with better survival. Emergence of clarithromycin-resistant organisms was an important problem.

AIDS-Related Opportunistic Infections↗

PubMed1994

A comparison of two techniques for ankle jerk assessment in elderly subjects.

The reported prevalence of absent ankle jerks in elderly people varies greatly. This variation may be due to differences in the method of testing. Eight physicians examined 12 patients for the presence of ankle jerks using two techniques: plantar strike and tendon strike. Both intra-observer agreement (kappa 0.47 vs 0.20; p = 0.01) and inter-observer agreement (0.57 vs 0.21; p < 0.001) were greater with plantar strike. Reliability of ankle jerk assessment was greater for more experienced examiners. Differences in technique may explain some of the discrepancy between studies examining the prevalence of absent ankle jerks in elderly people.

Aged↗

PubMed1994

Attributable fraction estimates and case definitions for malaria in endemic areas.

Asymptomatic carriage of malaria parasites occurs frequently in endemic areas and the detection of parasites in a blood film from a febrile individual does not necessarily indicate clinical malaria. In areas of low and moderate endemicity the parasite prevalence in fever cases can be compared with that in community controls to estimate the fraction of cases which are attributable to malaria. In areas of very high transmission such estimates of the attributable fraction may be imprecise because very few individuals are without parasites. Furthermore, non-malarial fevers appear to suppress low levels of parasitaemia resulting in biased estimates of the attributable fraction. Alternative estimation techniques were therefore explored using data collected during 1989-1991 from a highly endemic area of Tanzania, where over 80 per cent of young children are parasitaemic. Logistic regression methods which model fever risk as a continuous function of parasite density give more precise estimates than simple analyses of parasite prevalence and overcome problems of bias caused by the effects of non-malarial fevers. Such models can be used to estimate the probability that any individual episode is malaria-attributable and can be extended to allow for covariates. A case definition for symptomatic malaria that is used widely in endemic areas requires fever together with a parasite density above a specific cutoff. The choice of a cutoff value can be assisted by using the probabilities derived from the logistic model to estimate the sensitivity and specificity of the case definition.

Animals↗

PubMed1994

Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania.

Effective, safe antimalarial vaccines have proved elusive. The synthetic polypeptide SPf66 vaccine is based on preerythrocytic and asexual blood-stage proteins of Plasmodium falciparum. We report here a randomised double-blind placebo-controlled trial of the efficacy of the SPf66 vaccine against clinical P falciparum malaria in idete, southern Tanzania, an area of intense perennial malaria transmission. 586 children aged 1-5 years received three doses of vaccine (n = 274) or placebo (n = 312). The incidence and density of parasitaemia were assessed through repeated cross-sectional surveys on subgroups of children. Morbidity was monitored over a 1 year period through passive case detection in all children plus active case detection in a subgroup of 191. An episode of clinical malaria was defined as measured fever (> or = 37.5 degrees C) and parasite density > 20,000/microL. No severe side-effects were seen and the frequency of mild side-effects after the third dose was less than 6%. The vaccine was highly immunogenic and after three doses all vaccine recipients had detectable anti-SPf66 antibodies: the geometric mean index of response was 8.3 in the vaccine group and 0.7 in the placebo group. The incidence of parasitaemia was similar in both groups. 123 children had at least one episode of clinical malaria during the follow-up period after the third dose and annual incidence rates were 0.25 in the vaccine group and 0.35 in the placebo group. Estimated vaccine efficacy was 31% (95% confidence interval 0-52%; p = 0.046). After the third dose there were 6 deaths among the study cohort (1 vaccine, 5 placebo). This study confirms that SPf66 is safe, immunogenic and reduces the risk of clinical malaria among children exposed to intense P falciparum transmission.

Child, Preschool↗

PubMed1994

Waiting times: monitoring the total postreferral wait.

OBJECTIVES: To determine whether the period spent on the true inpatient waiting list is a valid indication of the total time that patients have to wait for an operation; and to assess the feasibility of monitoring the total "postreferral waiting time" by using existing computerised information systems. SETTING: Three randomly selected Scottish hospitals. SUBJECTS: Waiting list patients admitted to hospital for operations during June to August 1993 in six major specialties, separate attention being focused on cataract operations and hip and knee replacements. MAIN OUTCOME MEASURE: The total time that patients have to wait for an operation after the initial general practitioner referral--the postreferral waiting time--compared with that spent at the final stage of the process on the true inpatient waiting list. RESULTS: In the specialties investigated roughly half (58 days; 53%) of the average postreferral wait of 110 days was spent on the true inpatient waiting list, one third (35 days; 32%) being spent on the outpatient waiting list and one sixth (17 days; 15%) waiting between waiting lists. Only a quarter of cataract patients (73/292) were treated within three months of general practitioner referral compared with over three quarters (228/292) within three months of being placed on the inpatient waiting list. Nevertheless, within a year over 99% of patients (290) had been treated whichever date was taken as the starting point. CONCLUSIONS: Monitoring postreferral waiting times would provide a much more accurate picture for purchasers and patients of waiting times for treatment than is obtained by focusing exclusively on the true inpatient waiting list and facilitate fairer comparisons between NHS trusts in national league tables. Stringent national and local monitoring is essential to ensure (a) that future reductions in the time waiting on true inpatient waiting lists are not gained at the expense of longer periods waiting to be placed on the lists, and (b) that no increases occur in the number of patients placed instead on deferred waiting lists or exempted from the normal maximum waiting time guarantees.

Cataract Extraction↗

PubMed1994

Pulmonary lung surfactant synthetic peptide concentration-dependent modulation of DPPC and POPG acyl chain order in a DPPC:POPG:palmitic acid lipid mixture.

Lung surfactant-associated protein interaction with lipid matrices and the effects on lipid thermotropic phase behavior are areas of active research. Many studies limit the lipids to a single or two-component system. The current investigation utilizes a three-lipid component matrix (DPPC:POPG:palmitic acid) to investigate the impact of a synthetic surfactant protein B fragment (SP-B 53-78 DiACM) on the dynamic surface activity of the lipid admixture as measured by a Wilhelmy surface balance. Also, the modulation of the individual lipid acyl chain order by the peptide within the lipid matrix is studied through the use of thermal perturbation FTIR spectroscopy. The data clearly demonstrate a concentration-dependent effect of the peptide on the surface activity with an improvement in the dynamic surface tension diagram characteristics (decreased surface tension and increased collapse plateau) especially at low, 0.36 M%, peptide concentrations. These effects are diminished upon further addition of the peptide. FTIR spectral data demonstrate that the peptide addition results in a significant increase in the acyl chain order of the DPPC and POPG components as measured by the position of the methylene stretching vibrational bands. DPPC is most sensitive to the peptide presence, while the palmitic acid is least affected. The transition temperatures of the individual lipids are also increased with the addition of the peptide. The presence of POPG in the matrix achieves the surface activity similarly seen with natural lung surfactant relative to a DPPC/palmitic acid lipid matrix alone. Its presence increases the sensitivity of the DPPC acyl chains to the presence of the peptide. These effects on the chain order are most probably related to the increased acyl chain fluidity which POPG imparts to the lipid matrix because of the presence of the cis double bond. The phosphatidylglycerol headgroup also adds a negative charge to the lipid matrix which enhances the peptide-lipid interaction. Although the palmitic acid is minimally affected by the peptide, its presence, as suggested by surface balance measurements, results in the establishment of a stable lipid film with DPPC, capable of achieving low surface tension values.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1994

Hsp47 and the translation-translocation machinery cooperate in the production of alpha 1(I) chains of type I procollagen.

Hsp47, an endoplasmic reticulum resident protein, has gelatin-binding and procollagen-binding properties and has been hypothesized to function as a molecular chaperone in regulating procollagen folding and/or assembly. In this report, we further investigate the interaction of Hsp47 with polysome-associated alpha 1(I) procollagen chains following antisense treatment of 3T6 cells. For these studies, we employed phosphorothioate oligodeoxynucleotides directed to the first five codons of Hsp47 that straddle the predicted translation initiation site of mouse Hsp47. Cells depleted of Hsp47 in this manner were observed to produce diminished amounts of fully elongated nascent alpha 1(I) procollagen while accumulating shorter procollagen peptides associated with peptidyl-tRNA. Pulse-labeling of cells with [35S]methionine followed by treatment with puromycin and immunoprecipitation with anti-Hsp47 and anti-procollagen antibodies revealed that Hsp47 is associated with alpha 1(I) procollagen at a very early point during translocation of the nascent procollagen chains. Although Hsp47 appears to possess properties similar to grp78/BiP, Hsp47 binding early during translocation favors a more specialized specific function relative to chain selection or completion of stable folding in type I procollagen.

Animals↗

PubMed1994

Limited value of myeloablative therapy for late multiple myeloma.

The utility of myeloablative therapy supported by autologous bone marrow (BM) or blood progenitor cells was assessed in 49 patients with multiple myeloma who had received at least 1 year of prior chemotherapy. Outcomes were compared with those of similar patients who did not receive intensive treatment primarily for socioeconomic reasons. Among patients with disease in resistant relapse despite treatment with vincristine-doxorubicin by continuous infusion with pulse dexamethasone (VAD), a 61% response rate was associated with a median remission time of 5 months. After primary resistance for more than 1 year, 6 of 15 patients responded and the overall survival was similar to that of control patients. For patients with melphalan-resistant disease that responded to VAD, the remission time was similar to that of control patients. Current myeloablative treatments supported by autologous BM or blood stem cells were useful to very few patients with multiple myeloma after the first year of chemotherapy.

Adult↗

PubMed1994

Altitude, language, and class I HLA allele frequencies in Papua New Guinea.

Class I HLA gene frequencies show considerable variation over short geographical distances in Papua New Guinea. Hypothesis to account for this invoke natural selection, population structure, the pattern of population movement, or past demographic changes. To determine the role of the various factors in shaping this distribution, we have studied correlations between HLA-based genetic distances, geographical distances, altitude, and linguistic differences in Papua New Guinea. Linguistic differences at the family or stock level within the Trans-New Guinea Phylum generally correspond to genetic differences. However, on the basis of their HLA gene frequencies, speakers of Austronesian (AN) languages do not form a distinct group of populations. Linguistic variation and spatial autocorrelation do not fully account for the altitudinal cline differences noted in gene frequencies, particularly at the HLA-A locus. We propose that the distribution of HLA gene frequencies in Papua New Guinea is partially under the control of selection operating differentially along the altitude gradient.

Alleles↗

PubMed1994

Nonsteroidal antiinflammatory drug-induced small intestinal inflammation and blood loss. Effects of sulfasalazine and other disease-modifying antirheumatic drugs.

OBJECTIVE: To identify the source of intestinal blood loss in rheumatoid arthritis patients being treated with nonsteroidal antiinflammatory drugs (NSAIDs) and assess the response to sulfasalazine and other disease-modifying antirheumatic drugs (DMARDs). METHODS: Intestinal inflammation, blood loss, and gastroduodenal damage, and the response to treatment with DMARDs, were assessed in 46 patients taking NSAIDs. RESULTS: Intestinal inflammation and blood loss correlated significantly with one another (r = 0.43, P < 0.003), but not with the macroscopic or microscopic appearance of the gastroduodenal mucosa. Sulfasalazine reduced both intestinal inflammation and blood loss, whereas the other DMARDs did not. CONCLUSION: The small intestine is the main site of mild chronic blood loss in patients receiving NSAIDs, and this blood loss can be reduced with sulfasalazine treatment.

Aged↗

PubMed1994

Association of Hsp47, Grp78, and Grp94 with procollagen supports the successive or coupled action of molecular chaperones.

Hsp47, Grp78, and Grp94 have been implicated with procollagen maturation events. In particular, Hsp47 has been shown to nascent procollagen alpha 1(I) chains in the course of synthesis and/or translocation into the endoplasmic reticulum (ER). Although, Hsp47 binding to gelatin and collagen has previously been suggested to be independent of ATP. Grp78 and Grp94 are known to dissociate from its substrates by an ATP-dependent release mechanism. The early association of Hsp47 with procollagen and its relatively late release suggested that other chaperones, Grp78 and Grp94, interact successively or concurrently with Hsp47. Herein, we examined how these events occur in cells metabolically stressed by depletion of ATP. In cells depleted of ATP, the release of Hsp47, Grp78, and Grp94 from maturing procollagen is delayed. Thus, in cells experiencing metabolic stress, newly synthesized procollagen unable to properly fold became stably bound to a complex of molecular chaperones. In that Hsp47, Grp78, and Grp94 could be recovered with nascent procollagen and as oligomers in ATP depleted cells suggests that these chaperones function in a series of coupled or successive reactions.

2,2'-Dipyridyl↗

PubMed1994

Dosimetry of intravenously administered oxygen-15 labelled water in man: a model based on experimental human data from 21 subjects.

Models based on uniform distribution of tracer in total body water underestimate the absorbed dose from H2(15)O because of the short half-life (2.04 min) of 15O, which leads to non-uniform distribution of absorbed dose and also complicates the direct measurement of organ retention curves. However, organ absorbed doses can be predicted by the present kinetic model based on the convolution technique. The measured time course of arterial H2(15)O concentration following intravenous administration represents the input function to organs. The impulse response of a given organ is its transit time function determined by blood flow and the partition of water between tissue and blood. Values of these two parameters were taken from the literature. Integrals of the arterial input function and organ transit time functions were used to derive integrals of organ retention functions (organ residence times). The latter were used with absorbed dose calculation software (MIRDOSE-2) to obtain estimates for 24 organs. From the mean values of organ absorbed doses, the effective dose equivalent (EDE) and effective dose (ED) were calculated. From measurements on 21 subjects, the average value for both EDE and ED was calculated to be 1.2 microSv.MBq-1 compared with a value of about 0.5 microSv.MBq-1 predicted by uniform water distribution models. Based on the human data, a method of approximating H2(15)O absorbed dose values from body surface area is described.

Adult↗

PubMed1994

Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for marrow transplantation: risk factors for early regimen-related toxicity.

One hundred twenty-seven adults with advanced hematologic malignancies received thiotepa 450-750 mg/m2, busulfan 10 or 12 mg/kg, and cyclophosphamide 120 or 150 mg/kg as a preparative regimen for autologous (86 patients) or allogeneic (41 patients) marrow transplantation. Early regimen-related toxicity (RRT) was scored according to the Seattle toxicity grading system. Grade 1-4 RRT occurred in 94% of the patients. Grade 3-4 RRT was noted in 19 patients (9% of the autologous and 27% of the allogeneic marrow recipients) and included 6% hepatic, 5% pulmonary, 3% renal, 2% mucosal, 2% bladder, 2% cardiac, and 1% CNS toxicity at the grade 3 or 4 level. No patient experienced life-threatening or fatal gastrointestinal or cutaneous toxicity. A stepwise logistic regression analysis suggested that the higher busulfan dose, Zubrod performance status of 2 or 3, and ten or more previous cycles of chemotherapy were factors predictive of grade 3-4 RRT. The regimen-related mortality for all patients was 8% (95% Cl 4-14%). The incidence and spectrum of RRT for this novel drug combination are similar to those reported for the standard preparative regimens. Heavily pretreated patients with poor performance status receiving the higher busulfan dose have a higher incidence of severe or fatal RRT.

Adult↗

PubMed1994

What is clinical malaria? Finding case definitions for field research in highly endemic areas.

In non-endemic areas, the diagnosis of clinical malaria may be made on the basis of fever and a positive blood film. However, in areas of high endemicity, asymptomatic parasitaemia is very common: to assume that a child who presents with fever and parasitaemia is ill from malaria will result in overdiagnosis. In this article, Jo Schellenberg, Tom Smith, Pedro Alonso and Richard Hayes discuss the relationship between fever and parasite density in such areas, and show how the proportion of fevers due to malaria (the attributable fraction) can be estimated and used to evaluate case definitions for use in field trials.

Journal Article↗

PubMed1994

PCR based fingerprinting of Enterobacter cloacae.

An outbreak of lower respiratory tract infection with Enterobacter cloacae occurred in an intensive care unit in a university teaching hospital. Random amplification of polymorphic DNA (RAPD) was used to assist in the investigation of the outbreak. The technique was readily applied to this organism and permitted differentiation between strains which had identical biochemical profiles and antibiograms. The versatility of this technique makes it attractive for use in hospitals where fingerprinting of any one of the many Gram-negative rods associated with nosocomial infection may be required from time to time.

Cross Infection↗

PubMed1994

A trial of the synthetic malaria vaccine SPf66 in Tanzania: rationale and design.

The development of a safe, affordable and effective malaria vaccine to form part of control schemes in malaria endemic countries is a priority for researchers and public health officials. SPf66 is the first malaria vaccine to have shown partial protection against natural challenge in a phase III trial carried out in a hypoendemic area of Colombia. This paper describes the rationale and design of the first field trial of SPf66 outside South America, and the first to be conducted in an area of high perennial transmission.

Adult↗