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Biomedical subjects

K Clarke

Publications and source records attributed to K Clarke.

At least 73 records · Page 4Linked to original sources
PubMed1998

Effect of gap length and position on results of treatment of cancer of the larynx in Scotland by radiotherapy: a linear quadratic analysis.

PURPOSE: This paper reports on the analysis of the effect of the length and position of unplanned gaps in radiotherapy treatment schedules. MATERIALS AND METHODS: Data from an audit of the treatment of carcinoma of the larynx are used. They represent all newly diagnosed cases of glottic node-negative carcinoma of the larynx between 1986 and 1990, inclusive, in Scotland that were referred to one of the five Scottish Oncology Centres for primary radical radiotherapy treatment. The end-points are local control of cancer of the larynx in 5 years and the length of the disease-free period. The local control rates at > or =5 years, Pc were analyzed by log linear models and Cox proportional hazard models were used to model the disease-free period. RESULTS: Unplanned gaps in treatment are associated with poorer local control rates and an increased hazard of a local recurrence through their effect on extending the treatment time. A gap of 1 day is potentially damaging but the greatest effect is at treatment extensions of 3 or more days, where the hazard of a failure of local control is increased by a factor of 1.75 (95% confidence interval 1.20-2.55) compared to no gap. The time factor for the actual time was imprecisely estimated at 2.7 Gy/day with a standard error of 13.2 Gy/day. Among those cases who had exactly one gap resulting in a treatment extension of 1 day, there is no evidence that gap position influences local control (P = 0.17). The treatment extension as a result of the gap is more important than the position of the gap in the schedule. CONCLUSIONS: Gaps in the treatment schedule have a detrimental effect on the disease-free period. A gap has a slightly greater effect than an increase in the prescribed treatment time. Any gap in treatment is potentially damaging. The position of the gap in the schedule was shown to be not important.

Appointments and Schedules↗
PubMed1998

Age-specific patterns of factors related to fatal motor vehicle traffic crashes: focus on young and elderly drivers.

This population-based study examines patterns of fatal motor vehicle traffic crashes (MVTCs) by age group (16-24, 25-64, 65+) among Canadian drivers. The Canadian Traffic Accident Information Databank (TRAID) provided information about fata MVTCs between 1984 and 1993. Distribution of risk factors was compared by age group. Crude odds ratios and 95% CIs were calculated for both young and elderly drivers compared with middle-aged drivers. The middle-age group was selected as reference population since it demonstrates the lowest risk of fatality. Compared to the middle-aged group, young drivers demonstrated excess risk for (1) risk-taking behaviours and conditions, specifically alcohol and illicit drug use, speeding, non use of seat belts, fatigue and falling asleep, and inexperience; (2) crashes during the summer, during weekends and at night; and (3) single-vehicle collisions and on performing overtaking manoeuvres. Excess risk among elderly drivers was noted for (1) medical and physical conditions, inattention and inexperience; (2) driver actions, for example, improper turning, failure to yield right-to-way; (3) occurrence on weekdays and during the day; and (4) collisions at intersection and vehicle--vehicle sideswipes. The results show notable differences in risk factors by age group and confirm the need for preventive efforts that incorporate age-specific strategies.

Accidents, Traffic↗
PubMed1998

Phase I and pharmacokinetic study of KRN8602 alone and with filgrastim in patients with advanced cancer.

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of KRN8602 (MX2-hydrochloride), a novel morpholino anthracycline with potent cytotoxicity against anthracycline-sensitive and resistant experimental tumors in vitro and in vivo. PATIENTS AND METHODS: KRN8602 was administered alone in increasing doses to patients with advanced cancer or high-grade gliomas until dose-limiting toxicity (DLT) was observed in three or more of five patients treated in a dose level. Because neutropenia was dose limiting, further escalation was investigated with filgrastim support. RESULTS: Fifty-six assessable patients completed at least one cycle of chemotherapy. The recommended dose of KRN8602 alone was 40 mg/m2. Dose escalation was limited by neutropenia. The recommended dose of KRN8602 with filgrastim was 70 mg/m2, and limiting toxicities were neutropenia, diarrhea, and vomiting. The most commonly experienced nonhematologic toxicity was nausea and vomiting. Alopecia and mucositis were infrequent and mild. Pharmacokinetic parameters showed substantial variation, although the area under the plasma concentration-time curve (AUC) and maximum concentration both increased with dose. There was no relationship between pharmacokinetic parameters and toxicity. CONCLUSION: KRN8602 at doses of 40 mg/m2 when administered alone and 70 mg/m2 when administered with filgrastim appeared to be manageable. The major DLTs were neutropenia and, at higher doses, diarrhea and vomiting. The efficacy of this drug is currently being tested in phase II studies.

Adult↗
PubMed1998

Workshop report. National initiative to improve cancer survival information.

This workshop (held June 19 20, 1997, in Ottawa, Ontario) brought together major stakeholders to establish a Canadian initiative to develop systematic collection of population-based information on cancer survival. The broad goals of the workshop were to delineate the current needs regarding such data and to recommend practical mechanisms to systematically generate this information. Three key areas for discussion were identified: collection of staging data, collection of treatment data and standardized approaches to analysis. Presentations (summarized in report), designed to establish common ground for workshop discussions, provided background information on population-based collection mechanisms, data and methodology requirements for conducting meaningful cancer survival surveillance, and practical examples of using cancer survival information.

Canada↗
PubMed1997

Characterisation and properties of an intracellular lipid-binding protein from the tapeworm Moniezia expansa.

The tapeworm Moniezia expansa contains an extremely abundant cytoplasmic lipid-binding protein (LBP). It is a small protein consisting of 66 amino acids with a molecular mass of 7943 +/- 1.5 Da. The amino acid sequence has been established by Edman degradation and confirmed by PCR analysis. The Moniezia LBP shows no sequence similarity with any previously described binding protein, but does show similarity with antigen B from Echinococcus glanulosus and Echinococcus multilocularis and with Taenia crassiceps antigen. The predicted structure for Moniezia LBP shows four helices and a putative tyrosine kinase site on the loop between helix 1 and 2. Each of the four helices has a well defined hydrophobic face. Studies with fluorescent probes suggest a single hydrophobic binding site. Results indicate that the single tryptophan residue in the molecule (Trp41) is involved in ligand binding, and calculation of the Stern-Volmer quenching constant shows that Trp41 is in a relatively hydrophobic environment.

Amino Acid Sequence↗
PubMed1997

Deletion of PTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease.

We report on an 18-month-old boy with an interstitial deletion at 10q23.2-q24.1. This region includes the PTEN gene, mutations of which have been reported to cause Cowden disease. Our patient presented with manifestations of Bannayan-Riley-Ruvalcaba (BRR) syndrome. The BRR syndrome is a rare disorder which presents most commonly in childhood. Cowden disease is a disease of adulthood and is inadequately described in children. Because of the considerable phenotypic overlap between the two disorders, and the cytogenetic and molecular findings in our patient, we suggest that BRR syndrome and Cowden disease are allelic.

Adult↗
PubMed1997

Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer.

Thrombocytopenia caused by chemotherapy is an important cause of morbidity and mortality in the treatment of malignant disease. Recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a potent stimulator of megakaryocytopoiesis and prevents chemotherapy-induced thrombocytopenia in preclinical studies. We administered PEG-rHuMGDF with filgrastim after dose-intensive chemotherapy to 41 patients with advanced cancers to determine its safety and effects on hematologic recovery. Carboplatin 600 mg/m2 and cyclophosphamide 1,200 mg/m2 were administered to patients with advanced cancer. Patients were randomly assigned to receive blinded study drug, either PEG-rHuMGDF or placebo (3-to-1 ratio), commencing the day after chemotherapy. PEG-rHuMGDF was given at doses of 0.03, 0.1, 0.3, 1.0, 3.0, and 5.0 microg per kilogram body weight by daily subcutaneous injection for between 7 and 20 days. All patients received concurrent filgrastim 5 microg per kilogram body weight per day until neutrophil recovery. Fifteen patients had received PEG-rHuMGDF alone in a previous phase I study. Platelet function and peripheral blood progenitor cells (PBPC) were assessed. PEG-rHuMGDF enhanced platelet recovery in a dose-related manner when compared with placebo. The platelet nadir occurred earlier in patients given PEG-rHuMGDF (P = .002) but there was no difference in the depth of the nadir. Recovery to baseline platelet count was achieved significantly earlier following PEG-rHuMGDF administration compared with placebo (median, 17 days for PEG-rHuMGDF 0.3 to 5.0 microg/kg versus 22 days for placebo, P = .014). In addition, platelet recovery was faster in patients who had previously received PEG-rHuMGDF, suggesting that pretreatment might be beneficial. Platelet function did not change during or after administration of PEG-rHuMGDF. Levels of PBPC on day 15 after chemotherapy were significantly greater in patients administered PEG-rHuMGDF 0.3 to 5.0 microg/kg and filgrastim compared with those given placebo plus filgrastim. PEG-rHuMGDF was well tolerated at all doses. Two patients given PEG-rHuMGDF had a thrombotic episode. PEG-rHuMGDF accelerates platelet recovery after moderately dose-intensive carboplatin and cyclophosphamide, and is likely to be clinically useful in treatment of chemotherapy-induced thrombocytopenia. Because it enhances mobilization of PBPC by filgrastim, PEG-rHuMGDF might also allow more efficient collection of stem cells for autologous or allogeneic transplantation.

Adult↗
PubMed1997

Modeling of internal pH, ion concentration, and bioenergetic changes during myocardial ischemia.

Arrhythmias are caused by the interdependent processes of change in energy metabolism and alterations in sarcolemmal ion gradients that occur during ischemia. Depletion of energy metabolites and increased proton concentrations in ischemic heart may underlie the observed phenomena of reduced contractile force and also of malignant ventricular arrhythmias that can lead to tachycardia and ventricular fibrillation. Recent advances in measuring changes in ion concentrations and metabolites during cardiac ischemia have provided a wealth of detail on the processes involved. Some of the experimental data have been used to construct a computer model that integrates cardiac energetics with electrophysiological changes. This is a novel approach to studying myocardial ischemia, and the resulting model would aid in the prediction of the effects of therapeutic interventions.

Adenine Nucleotides↗
PubMed1997

Pharmacokinetics and pharmacodynamics of MX2 hydrochloride in patients with advanced malignant disease.

The purpose of the present study was to investigate the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. A total of 27 patients with advanced cancer participated in a dose-escalation study in the first cycle of treatment with drug given i.v. at doses of 10-50 mg/m2 (total dose 16.8-107.5 mg). The mean total systemic plasma clearance (CL) of MX2 was 2.98 +/- 1.68 l/min, the mean volume of distribution at steady state was 1460 +/- 749 l and mean elimination half-life was 10.8 +/- 5.1 h. The area under the plasma concentration-time curve (AUC) of MX2 was linearly related to the dose per kilogram and the dose per body surface area (r2 = 0.43, P < 0.01 and r2 = 0.44, P < 0.01, respectively). CL did not correlate with total body weight, lean body mass or body surface area. The mean elimination half-lives of the metabolites M1, M2, M3 and M4 were 11.8 +/- 5.0, 21.9 +/- 11.8, 19.0 +/- 11.3 and 12.3 +/- 6.3 h, respectively. The fractional Emax model produced a much better fit to the relative nadir neutrophil count versus dose data (r2 = 0.42) than to the relative nadir neutrophil count versus AUC or peak concentration (Cmax) data (r2 = 0.15 and 0.09, respectively). There seemed to be a threshold dose of about 65 mg of MX2 at or above which a large proportion of patients had a nadir neutrophil count of less than 0.5 x 10(9)/l. This study shows that the pharmacokinetics of MX2 are similar to those of other anthracyclines. With other anthracyclines the degree of myelosuppression seems to depend more on the AUC and Cmax than on the delivered dose; however, with MX2 the degree of myelosuppression depends more on the dose given than on drug exposure expressed as the AUC or Cmax.

Adult↗
PubMed1997

Evaluation of an expert system on lymph node pathology.

BACKGROUND: Pathfinder is an Expert System that assists pathologists in making accurate diagnoses in the domain of lymph-node pathology. Pathfinder provides a differential diagnosis based on the initial histological feature(s) observed by the pathologist, and suggests to the user additional histological features for observation that are likely to narrow the differential diagnosis. PURPOSE: To evaluate the diagnostic accuracy of pathologists with and without the Pathfinder. METHODS: Thirty H&E stained slides from 30 lymph node biopsy specimens on which a Consensus diagnosis was made by two experts were reviewed by 19 pathologists to evaluate Pathfinder. After a period of training, 10 pathologists using Pathfinder (Interactive Computer Method) and 9 pathologists using the Routine Method (diagnosis without computer) determined a differential diagnosis for 15 slides (Test 1). Pathologists were then crossed over, trained, and evaluated the remaining 15 slides (Test 2). For each test, the proportion of "correct" diagnoses was compared between methods. In addition, the information integration attributes (making logical diagnosis given a set of specific histologic features) of Pathfinder and pathologists were compared. Finally, feature identification and quantification skills of pathologists were determined and correlated with the percent correct diagnosis. RESULTS: The diagnostic accuracy using Pathfinder was greater than that using the Routine Method (40% v 32%, P = .02). Diagnostic accuracy for the group of pathologists who made diagnosis using the Routine Method in Test 1 increased when they made diagnosis using Pathfinder in Test 2 (27% to 44%, P < .0001). The proportion of correct diagnosis for the group of pathologists who used Pathfinder in Test 1 remained virtually unchanged when they gave up Pathfinder in Test 2 (35% to 37%). The percentage of incompatible feature identification ("atypical proliferation" diagnosis) was significantly lower after using Pathfinder (P < .0001). In addition, information integration attributes of Pathfinder were significantly superior than that of the pathologists (P < .0001). CONCLUSIONS: Pathfinder is a valuable tool that assists pathologists in making accurate diagnosis because it has superior attributes than pathologists to integrate information and to screen for observations incompatible with any specific disease.

Biopsy↗
PubMed1997

Multilineage mobilization of peripheral blood progenitor cells in humans following administration of PEG-rHuMGDF.

The most important physiological regulator of megakaryocytopoiesis is the ligand for the c-mpl receptor (thrombopoietin/megakaryocyte growth and development factor, MGDF). We examined the effect of pegylated-recombinant human MGDF (PEG-rHuMGDF): patients received PEG-rHuMGDF at doses of 0.03, 0.1, 0.3 or 1.0 microg/kg/d or placebo for 10d maximum in a double-blinded randomized study. There was a dose-dependent elevation in circulating platelet counts but no alteration in erythrocyte or total leucocyte counts. The number of bone marrow megakaryocytes was increased approximately 2-fold. The frequency of bone marrow progenitor cells was not altered. In contrast, both to the bone marrow results and to published pre-clinical data, there was a dose-dependent mobilization into the blood of progenitor cells of multiple cell lineages. Increased levels of Meg-CFC (maximum increase 30-fold), day 7 and day 14 GM-CFC and BFU-E were demonstrated at doses of 0.3 and 1.0 microg/kg/d PEG-rHuMGDF. At 0.1 microg/kg/d, mobilization of Meg-CFC alone occurred in two-thirds of patients. Maximum blood levels of progenitor cells occurred at day 12. Thus, administration of PEG-rHuMGDF to humans resulted in mobilization of progenitor cells of multiple lineages despite its 'lineage-specific' activity on mature cell development.

Adult↗
PubMed1997

High serum D-lactate in patients on continuous ambulatory peritoneal dialysis.

BACKGROUND: As abnormally high serum D-lactate levels may cause neurological impairment, we determined whether patients undergoing continuous ambulatory peritoneal dialysis (CAPD) with lactate-containing fluids have increased serum D-lactate concentrations. METHODS: D- and L-lactate concentrations were determined in peritoneal dialysis fluids and in serum from control subjects (n = 10), haemodialysis patients (n = 10), and CAPD patients (n = 30) before and after 1 h of dialysis. RESULTS: We found the median D-lactate concentration in Dianeal CAPD fluid to be 26 mM (range 19-27), whereas it was less than 0.5 mM in DPCA2 fluid. Control, haemodialysis, and CAPD (DPCA2) patient median serum D-lactate concentrations were below 0.07 mM. However, CAPD (Dianeal) patient serum D-lactate concentrations were 4-fold higher than controls (P < 0.0001), at 0.28 mM, an hour after instillation of D-lactate-containing fluid. Three patients, whose serum D-lactate averaged 0.59 mM, were found to have D-lactate concentrations at 0.22 mM after overnight cessation of dialysis. CONCLUSION: We conclude that CAPD with D-lactate-containing fluids raises serum D-lactate to abnormal levels.

Adult↗
PubMed1997

Factors affecting the severity of motor vehicle traffic crashes involving young drivers in Ontario.

OBJECTIVES: To assess the factors affecting the severity of motor vehicles traffic crashes involving young drivers in Ontario. POPULATION: Ontario young drivers, aged 16 to 20, involved in traffic crashes resulting in injury, between 1 January 1988 and 31 December 1993, on public roads in Ontario. METHODS: Population based case-control study. Cases were fatal injury, major injury, and minor injury crashes involving young drivers. Controls were minimal injury crashes involving young drivers. Cases and controls were obtained retrospectively from the Canadian Traffic Accident Information Databank. Unconditional logistic regression was used for data analysis. RESULTS: Factors significantly increasing the risk of fatal injury crashes include: drinking and driving (odds ratio (OR) 2.3), impairment by alcohol (OR 4.8), exceeding speed limits (OR 2.8), not using seat belts (OR 4.7), full ejection from vehicle (OR 21.3), intersection without traffic control (OR 2.2), bridge or tunnel (OR 4.1), road with speed limit 70-90 km/hour (OR 5.6) or 100 km/hour (OR 5.4), bad weather (OR 1.6), head-on collision (OR 80.0), and overtaking (OR 1.9). Results of the same model applied to major and minor injury crashes demonstrated consistent but weaker associations with decreasing levels of crash severity. CONCLUSIONS: A casual relationship between crash severity and the risk factors listed above was proposed. Risk factors recommended for preventive intervention include: alcohol consumption, speeding, and use of seat belts. Head-on collisions are of primary concern.

Accidents, Traffic↗
PubMed1997

Heat stability of two candidate international reference preparations for recombinant human tissue factor.

Adequate heat stability of international reference preparations (IRP) for thromboplastin (tissue factor) is an essential requirement. Accelerated degradation testing was performed by three laboratories on two candidate IRP for recombinant human tissue factor. Heat treatment of these candidates resulted in slight shortening of the PT, contrasting with heat-induced prolongation of the PT observed with a conventional human brain derived IRP. Heat stability of these candidates was improved when compared with the stability of previous recombinant human tissue factor preparations. The PT-ratio did not change significantly when the candidates were stored for 28 days at 44 degrees C. It can therefore be concluded that both candidates are acceptable with regard to stability.

Coagulants↗