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Biomedical subjects

Mike Murphy

Publications and source records attributed to Mike Murphy.

14 recordsLinked to original sources
PubMed2007

Risk of breast cancer in female survivors of childhood Hodgkin's disease in Britain: a population-based study.

There is now widespread evidence that female survivors of Hodgkin's disease who have been treated with supradiaphragmatic radiotherapy are at an increased risk of breast cancer. Mantle irradiation, which includes irradiation of the mediastinum, conveys a particularly high risk. Previously published studies have found a wide variation in risk. To provide British estimates of risk to inform surveillance programmes, we carried out the first British population-based cohort study of breast cancer in female survivors of childhood Hodgkin's disease. From the underlying cohort of the British Childhood Cancer Survivor Study, a cohort of 18,123 British 5-year survivors of childhood cancer diagnosed between 1940 and 1991, there were in total 383 female 5-year survivors of childhood Hodgkin's disease. Sixteen of these 383 survivors went on to develop invasive breast cancer subsequent to 5-year survival (standardised incidence ratio, 11.5; 95% confidence interval (95% CI), 6.6-18.6) and all of these 16 survivors had been treated with supradiaphragmatic irradiation as treatment for childhood Hodgkin's disease. The cumulative risk of breast cancer by 25 years of follow up was 9.9% (95% CI, 3.3-16.6) for all patients and 12.2% (95% CI, 4.3-20.1) for those treated with supradiaphragmatic radiotherapy. The cumulative risk of breast cancer in female survivors of childhood Hodgkin's disease in Britain is at the lower end of previous estimates. We hope that our data may provide a basis for future surveillance and for counselling survivors as to their likely risk of breast cancer.

Adolescent↗
PubMed2006

Determinants of the rate of nicotine metabolism and effects on smoking behavior.

BACKGROUND: Studies on cytochrome P450 (CYP) 2A6 suggest that genotype affects the rate of nicotine metabolism and, consequently, cigarette consumption. However, known alleles of CYP2A6 associated with fast or slow metabolism are relatively uncommon, and there remains considerable variation in metabolic activity among those with presumed wild-type CYP2A6 alleles, suggesting that other genetic or environmental factors also influence the rate of nicotine metabolism. METHODS: We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism. RESULTS: The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and *12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P = .02), plasma nicotine concentration (P < .0001), and age (P = .02) but was not associated with dependence score (P > .20). The ratio also predicted the number of cigarettes smoked at will per day, although the association was weak (F(1, 492) = 4.05, P = .04). CONCLUSION: In this cohort the rate of nicotine metabolism is related to age, sex, CYP2A6 genotype, and CYP2B6 genotype and may affect the level of tobacco consumption.

Adult↗
PubMed2006

A descriptive analysis of international transfusion practice and bleeding outcomes in patients with acute leukemia.

BACKGROUND: Recently, bleeding has been used in platelet (PLT) trials rather than surrogate outcomes. The purpose of this study was to provide a descriptive summary of data from PLT studies conducted in four countries and exploratory analyses to determine the relationship between bleeding and PLT count. STUDY DESIGN AND METHODS: A descriptive analysis was performed on original data from the Italian trigger study, the US TRAP study, the Canadian febrile reaction study, and a clinical chart review from one hospital site in the United Kingdom. The relationship between bleeding and PLT count was explored with the Italian data. RESULTS: A total of 897 patients with acute leukemia received 10,506 PLT transfusions. Grade 3 or Grade 4 WHO bleeding frequency was 28.1 percent (252/897) but varied by country: Italy, 10.8 percent (27/250); United States, 36.4 percent (217/598); Canada, 18.9 percent (7/37); and the United Kingdom, 8.3 percent (1/12). Grade 1 or Grade 2 bleeding was reported only in the Italian study (46.4%[116/250] and 11.6%[29/250], respectively). The relative rates of WHO Grade 2, 3, or 4 bleeding for PLT counts in the ranges of 0 to 4, 5 to 9, 10 to 14, and 15 to 19 (x10(9)/L) were 8.8, 1.9, 1.8, and 1.2, respectively, compared to those counts within the range of 20 to 29 (x10(9)/L). CONCLUSION: The study provides descriptive data on PLT use and frequency of bleeding. When PLT counts were 0x10(9) to 4x10(9) per L there was an eightfold increase in bleeding and a twofold risk increase when counts were 5x10(9) to 14x10(9) per L compared to the 20x10(9) to 29x10(9) per L reference range. The increased rate of bleeding at low counts occurred despite PLT therapy.

Acute Disease↗
PubMed2005

Transjugular intrahepatic portosystemic stent shunt: 11 years' experience at a regional referral centre.

OBJECTIVES: Transjugular intrahepatic portosystemic stent shunt (TIPSS) is now widely used in the treatment of uncontrolled and recurrent variceal haemorrhage. This study reports the outcome and long-term follow-up of 125 patients who were referred to a single centre for TIPSS. METHODS: One hundred and twenty-five patients were referred to undergo TIPSS. All but 10 had variceal haemorrhage. The 10 patients referred with refractory ascites were excluded from the analysis. Our follow-up protocol was to assess shunt patency only if bleeding recurred or there was a clinical indication. The mean age was 51.5 years (range 18-87 years) and 64 patients (56%) were male. The commonest aetiology for chronic liver disease was alcohol (80%). At referral, 19 patients (16%) were Child-Pugh class A, 26 patients (23%) were Child-Pugh class B and 70 patients (61%) were Child-Pugh class C. The mean follow-up period was 20.4 months (range 0-95 months). RESULTS: TIPSS was successfully placed in 108 of 115 patients (94%). The thirty-day mortality was 30%. One-year and 2-year overall cumulative survival was 52% (survival ratio, 0.525; 95% confidence interval, 0.432-0.619) and 43% (survival ratio, 0.436; 95% confidence interval, 0.340-0.532), respectively. CONCLUSION: TIPSS is effective in the treatment of uncontrolled or recurrent variceal bleeding. In comparison with previously published studies, our study suggests no value in regular or routine shunt surveillance to reduce rebleeding episodes or mortality, but this needs to be further assessed in prospective randomized studies.

Adolescent↗
PubMed2004

Can a simple measure of vigorous physical activity predict future mortality? Results from the OXCHECK study.

BACKGROUND: As epidemiological studies have become more complex, demands for short, easily administered measures of risk factors have increased. This study investigates whether such a measure of physical activity is associated with the risk of death from all causes and death from specific causes. METHODS: A prospective follow-up study of 11,090 men and women, aged 35-64 years, recruited from five UK general practices who responded to a postal questionnaire in 1989. Self-reported frequency of vigorous-intensity physical activity and data on confounding factors were collected at baseline survey. Death notifications up to 31 December 2001 were provided by the Office for National Statistics. The relative risk (and 95% confidence interval) of dying associated with each level of exposure to physical activity was estimated by the hazard ratio in a series of Cox regression models. RESULTS: After >10 years' follow-up there were 825 deaths among the 10 522 subjects with no previous history of angina or myocardial infarction. Participation in vigorous exercise was associated with a significantly lower risk of all-cause mortality. Similar associations were found for ischaemic heart disease and cancer mortality, although the relationships were not significant at the 5% level. CONCLUSIONS: Simple measures of self-reported vigorous physical activity are associated with the risk of future mortality, at least all-cause mortality in a somewhat selected group. Interpretation of the finding should be treated with caution due to the reliance on self-report and the possibility that residual confounding may underlie the associations. Because moderate-intensity physical activity is also beneficial to health, short physical activity questionnaires should include measures of such physical activity in the future.

Adult↗
PubMed2003

Redox regulation of cAMP-responsive element-binding protein and induction of manganous superoxide dismutase in nerve growth factor-dependent cell survival.

Reactive oxygen species (ROS) act as both signaling molecules and mediators of cell damage in the nervous system and are implicated in the pathogenesis of neurodegenerative diseases. Neurotrophic factors such as the nerve-derived growth factor (NGF) support neuronal survival during development and promote regeneration after neuronal injury through the activation of intracellular signals whose molecular effectors and downstream targets are still largely unknown. Here we present evidence that early oxidative signals initiated by NGF in PC12 cells, an NGF-responsive cell line, play a critical role in preventing apoptosis induced by serum deprivation. This redox-signaling cascade involves phosphatidylinositol 3-kinase, the small GTPase Rac-1, and the transcription factor cAMP-responsive element-binding protein (CREB), a molecule essential to promote NGF-dependent survival. We found that ROS are necessary for NGF-dependent phosphorylation of CREB, an event directly correlated with CREB activity, whereas hydrogen peroxide induces a robust CREB phosphorylation. Cells exposed to NGF show a late decrease in the intracellular content of ROS when compared with untreated cells and increased expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase, a general inhibitor of cell death. Accordingly, serum deprivation-induced apoptosis was selectively inhibited by low concentrations of the mitochondrially targeted antioxidant Mito Q (mitoquinol/mitoquinone). Taken together, these data demonstrate that the oxidant-dependent activation of CREB is a component of NGF survival signaling in PC12 cells and outline an intriguing circuitry by which a cytosolic redox cascade promotes cell survival at least in part by increasing mitochondrial resistance to oxidative stress.

Animals↗
PubMedDate not supplied

Zyban for smoking cessation in a general practice setting: the response to an invitation to make a quit attempt.

The objective of this study was to assess the feasibility and success of Zyban as part of a moderately supported smoking cessation programme within UK general practice. Treatment was offered to 479 moderately dependent smokers (smoking 15 or more cigarettes per day) who had never used Zyban, and who had taken part in a previous NRT trial (the PATCH study). Main outcome measures were point prevalence and continuous abstinence from smoking at 6 and at 12 months. Two hundred and forty were excluded because of medical reasons or prescribing contraindication. Of the remainder (n=239) only 54 (23%) made an active quit attempt. Thirty percent (16/54) were abstinent at six months, and 22% (12/54) at 12 months (biochemically validated point prevalence rates). Age, socio-economic status, nicotine dependence, and genetic profile appeared to have little impact on success rates, but male quit-attempters were significantly more successful than female (40% vs. 10% at 12 months, p<0.05). In conclusion, a real-world smoking cessation programme using Zyban with moderate support within a general practice setting may achieve satisfactory quit rates without widening existing disparities in cessation.

Adult↗