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J Deadman

Publications and source records attributed to J Deadman.

13 recordsLinked to original sources
PubMed2004

General considerations for proteolytic cascades.

Proteases are involved in the regulation of a wide variety of essential physiological processes, often by participating in a highly orchestrated sequence of events termed a 'proteolytic cascade'. Four major proteolytic cascades with disease relevance are candidates for therapeutic intervention, namely caspase-mediated apoptosis, blood coagulation, the matrix metalloproteinase cascade and the complement cascade. Understanding the various steps involved in the functioning of a cascade is key to deciding possible points of intervention for the design of potential drug molecules. This brief review illustrates some of the common features of proteolytic cascades using the blood coagulation pathway as an example.

Blood Coagulation↗
PubMed2001

The determinants of Canadian children's personal exposures to magnetic fields.

Study of the health effects of magnetic fields often depends on identifying determinants and hence indicators of personal exposure. This study identified determinants of children's exposure to magnetic fields and constructed a prediction model for them. For 632 children participating in a case-control study of childhood leukemia, we made direct measures of exposure over 48 h using a portable device, together with observations on candidate determinants. A child's age and sex, the proportion of time spent in the home, and their parents' education or income were very weak predictors of (logged) mean 48 h magnetic field (R(2) < 1%). More important were province (R(2) = 8.0%) and type of residence (R(2) = 11.3%). Low temperatures at the time of measurement were associated with high fields (about 20% increase for each 10 degrees C below 14, R(2) = 4.9%). Several visible attributes of wiring around residences predicted exposure, mostly captured in the Wertheimer-Leeper wire code (R(2) = 13.5%). Stationary 24 h measurement in the bedroom (R(2) = 63.3%) and spot measurements outside the house (R(2) = 40.7%) predicted personal exposures best. Adding other minor predictors increased only slightly variance explained by 24 h stationary (R(2) = 66.2%) and spot (R(2) = 46.8%) measurements. Without spot or stationary measurements, the best model was much less powerful (R(2) = 29.0%). We conclude that spot measurements outside the residence provide a moderately effective basis for estimating exposure for children living there, but do not perform as well as 24 h stationary measurements in the child's bedroom. Although several other easily-observed variables were associated with personal exposure, they were weak determinants, either individually or in combination.

Adolescent↗
PubMed2000

Proteinase inhibitors and activators strategic targets for therapeutic intervention.

The contributions in this meeting represent the state of the art in study of proteinases and their biological and therapeutic regulation. The near future of proteinase research will be fashioned by the new horizons of proteomics research [61], adding substance to the genomic data. Even new approaches in drug discovery, such as combinatorial chemistry, impact upon the understanding of the proteinase function, as with the discovery of a novel allosteric exosite in FVIIa by probing with libraries of ligands [62]. What is without question is that proteinases will remain at the forefront of understanding and intervention in human biochemistry and human disease pathology.

Animals↗
PubMed1996

A case cohort study of suicide in relation to exposure to electric and magnetic fields among electrical utility workers.

OBJECTIVES: This case cohort study examines whether there is an association between exposure to electric and magnetic fields and suicide in a population of 21,744 male electrical utility workers from the Canadian Province of Québec. METHODS: 49 deaths from suicide were identified between 1970 and 1988 and a subcohort was selected comprising a 1% random sample from this cohort as a basis for risk estimation. Cumulative and current exposures to electric fields, magnetic fields, and pulsed electromagnetic fields (as recorded by the POSITRON meter) were estimated for the subcohort and cases through a job exposure matrix. Two versions of each of these six indices were calculated, one based on the arithmetic mean (AM), and one on the geometric mean (GM) of field strengths. RESULTS: For cumulative exposure, rate ratios (RR) for all three fields showed mostly small non-significant increases in the medium and high exposure groups. The most increased risk was found in the medium exposure group for the GM of the electric field (RR = 2.76, 95% CI 1.15-6.62). The results did not differ after adjustment for socioeconomic state, alcohol use, marital state, and mental disorders. There was a little evidence for an association of risk with exposure immediately before the suicide. CONCLUSION: Some evidence for an association between suicide and cumulative exposure to the GM of the electric fields was found. This specific index was not initially identified as the most relevant index, but rather emerged afterwards as showing the most positive association with suicide among the 10 indices studied. Thus the evidence from this study for a causal association between exposure to electric fields and suicide is weak. Small sample size (deaths from suicide) and inability to control for all potential confounding factors were the main limitations of this study.

Cohort Studies↗
PubMed1996

A mortality study of electrical utility workers in Québec.

OBJECTIVES: The objective of this study was to investigate the mortality of electrical utility workers exposed to electric and magnetic fields. METHODS: A historical cohort mortality study was carried out on 21,744 workers who were employed in an electrical company in the province of Québec between 1970 and 1988. The last job held by each study subject was coded. A job exposure matrix (JEM) was used to estimate the exposure to 60 Hz electric and magnetic fields, and pulsed electromagnetic fields (as recorded by the PEMF (POSITRON) meter) in this job. Standardised mortality ratios (SMRs) were calculated relative to Québec men. Because the exposure was exclusively among blue collar workers, the remainder of the analyses by exposure were restricted to them. Rate ratios (RRs) in the exposed groups relative to the background groups were estimated with Poisson regression. There were 1582 deaths by the end of follow up. RESULTS: SMRs were almost all below one and never substantially increased, although there were a few increased rate ratios (RRs). There was a significant RR of 2.00 (95% confidence interval (95% CI) 1.37-2.93) for deaths caused by accidents and violence in workers exposed to magnetic fields, RR of 1.82 (95% CI 1.25-2.65) for electric fields, and RR of 1.62 (95% CI 1.13-2.32) for pulsed electromagnetic fields. Occupational accidents related to power lines explain some of the excess of deaths from accidents and violence. Some association was found between magnetic fields and leukaemia, brain cancer, and suicide, between electric fields and brain cancer and suicide, and between pulsed electromagnetic fields and lung cancer, but these were not significant. CONCLUSION: These results are broadly reassuring that major causes of death are not strongly associated with exposure to electric and magnetic fields, but small numbers and approximate exposure assessments preclude the denial of any risk, in particular if it were to affect a rare cause of death.

Accidents, Occupational↗
PubMed1995

Structure/function aspects of neutral P1 residue peptide inhibitors of thrombin.

Control of thrombin by its inhibition in indications such as myocardial infarction, unstable angina or stroke has been demonstrated to be therapeutically valuable. However restoration of hemostasis by targeting thrombin while avoiding its fellow serine proteinases, (e.g. plasmin, trypsin), remains a challenge of medicinal chemistry. Tripeptide-boronates and -phosphonates with neutral P1 side chains meet these criteria. Development of novel, high yielding chemical routes furnishes a wide range of un-natural P1 functionalities, demonstrating that this indeed is a class effect with selectivity conferred by the uncharged P1 residue. For example N-benzyloxycarbonyl-D-phenylalanylprolyl-1- (3-methoxypropyl) boroglycine ester (1) has a Ki value for thrombin of 7 nM and greater than two order of magnitude higher with all other serine proteinases tested. The ester group determines the kinetics of inhibition by tripeptide phosphonates, with diphenylphosphonates being slow tight binding inhibitors, showing 50% reversibility of inhibition. Therefore this design of inhibitors offers a facile strategic approach to development as thrombin specific pharmaceutical agents.

Amino Acid Sequence↗
PubMed1995

Thrombin receptor activating peptide (TRAP) stimulates mitogenesis, c-fos and PDGF-A gene expression in human vascular smooth muscle cells.

The synthetic peptide SFLLRNPNDKYEPF, identical in sequence to the new amino-terminus of the thrombin receptor generated following cleavage of thrombin, acts a thrombin receptor agonist/activating peptide (TRAP). In this study, Northern blot analysis showed that cultured human vascular smooth muscle cells (HVSMC) express a thrombin receptor transcript. TRAP, in contrast to thrombin was shown to be a weak mitogen for HVSMC. A combination of TRAP and enzymatically-inactivated thrombin (PPACK-thrombin) which provides receptor occupancy, did not potentiate TRAP-induced mitogenesis, indicating that TRAP and PPACK-thrombin do not reproduce the mitogenic effect of enzymatically-active thrombin. Both thrombin and TRAP, induced the expression of c-fos and the PDGF-A gene in a pertussis toxin (PTX)-insensitive manner. Examination of thrombin and TRAP-treated cells by immunofluorescence staining followed by computer assisted image analysis revealed that thrombin and to a lesser extent TRAP induced PDGF-AA protein expression. Antibodies to PDGF-AA partially inhibited thrombin but not TRAP-induced mitogenesis in HVSMC. This study indicates that in addition to the common signalling pathways utilised by thrombin and TRAP, enzymatically-active thrombin activates other signalling pathways and hence TRAP does not mimic fully the biological effect of thrombin on HVSMC.

Cells, Cultured↗
PubMed1994

Association between exposure to pulsed electromagnetic fields and cancer in electric utility workers in Quebec, Canada, and France.

The authors report the association between exposure to pulsed electromagnetic fields (PEMFs) and cancer in a nested case-control study of electric utility workers in Quebec, Canada (follow-up, 1970-1988), and France (follow-up, 1978-1989), among whom 2,679 cases of cancer were identified. Exposures were assessed through a job-exposure matrix based on about 1,000 person-weeks of measurements from exposure meters worn by workers. Exposures were considerably higher in Quebec than in France. No association was found between PEMFs and cancers previously suspected of association with magnetic fields (leukemia, other hematopoietic cancers, brain cancer, or melanoma). However, there was a clear association between cumulative exposure to PEMFs and lung cancer, with odds ratios rising to 3.11 (95% confidence interval (CI) 1.60-6.04) in the highest exposure group (84 cases). This association with largely confined to Quebec, where there was a monotonic exposure-response relation with an odds ratio of 6.67 (95% CI 2.68-16.57) in the highest exposure group (32 cases). The association is substantial and was not explained by smoking or other occupational exposures. However, several factors limit the strength of the evidence for a causal relation: lack of precision in what the meters measured; little previous evidence for this association; and no elevated risk for lung cancer in the utility workers overall in comparison with the general population.

Case-Control Studies↗
PubMed1994

Cancer risks associated with occupational exposure to magnetic fields among electric utility workers in Ontario and Quebec, Canada, and France: 1970-1989.

To determine whether occupational exposure to magnetic fields of 50-60 Hz was associated with cancer among electric utility workers, the authors used a case-control design nested within three cohorts of workers at electric utilities: Electricité de France--Gaz de France, 170,000 men; Ontario Hydro, 31,543 men; and Hydro-Québec, 21,749 men. During the observation period, 1970-1989, 4,151 new cases of cancer occurred. Each participant's cumulative exposure to magnetic fields was estimated based on measurements of current exposure of 2,066 workers performing tasks similar to those in the cohorts using personal dosimetry. Estimates were also made of past exposure based on knowledge of current loading, work practices, and usage. Workers who had more than the median cumulative exposure to magnetic fields (3.1 microtesla (microT)-years) had a higher risk for acute nonlymphoid leukemia (odds ratio (OR) = 2.41, 95% confidence interval (CI) 1.07-5.44). The same observation holds for acute myeloid leukemia (OR = 3.15, 95% CI 1.20-8.27). There was also an elevated risk for mean exposure above 0.2 microT (acute nonlymphoid leukemia, OR = 2.36, 95% CI 1.00-5.58; acute myeloid leukemia, OR = 2.25, 95% CI 0.79-6.46). However, there were no clear dose-response trends with increasing exposure and no consistency among the three utilities. Men whose cumulative exposure to magnetic fields was above the 90th percentile (15.7 microT-years) had an elevated risk for brain cancer (OR = 1.95, 95% CI 0.76-5.00) that was not statistically significant. No association with magnetic fields was observed for any of the other 29 types of cancer studied, including skin melanoma, male breast cancer, and prostate cancer. Controlling for potential confounding factors did not change the results.

Aged↗