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Biomedical subjects

Michael Murphy

Publications and source records attributed to Michael Murphy.

At least 19 recordsLinked to original sources
PubMed2006

XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice.

Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the XRCC4 in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4/p53-deficient MBs have high-level N-myc gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which N-myc resides, or extrachromosomally within double minutes. In addition, most XRCC4/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the patched gene (Ptc), which lies on chromosome 13, was deleted in all tested XRCC4/p53-deficient MBs in the context of translocations or interstitial deletions. In addition, Cyclin D2, a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of Myc-family or Cyclin D2 genes and deletion of Ptc also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations.

Alleles↗
PubMed2006

Management of glioma in Victoria (1998-2000): retrospective cohort study.

OBJECTIVE: To describe the management of and outcomes in a population-based cohort of patients with newly diagnosed glioma. DESIGN, SETTING AND PATIENTS: Retrospective cohort study of patients with glioma newly diagnosed over the period 1998-2000 in Victoria. Patients were identified from the population-based Victorian Cancer Registry (VCR). Doctors involved in managing the patients were surveyed by a questionnaire sent out in 2003. The cohort was followed until the end of 2004 to obtain at least 4 years' follow-up data on all patients. MAIN OUTCOME MEASURES: Reported treatment, referral patterns and survival rates. RESULTS: Over the study period, 992 cases of glioma were identified; 828 completed surveys on eligible patients were obtained (response rate, 93%); 473 patients (57%) had glioblastoma multiforme (GBM); 105 patients (13%) diagnosed with "glioma" had had no histological confirmation. Complete macroscopic resection was performed in 209 patients (25%); 612 patients (74%) were referred for radiotherapy and 326 (54%) for chemotherapy; 39 (5%) were enrolled on a clinical trial. Median survival was 9.2 months for all patients and 7.4 months for patients with GBM. CONCLUSIONS: This is the largest reported glioma management survey in the world to date. Much of the patient demographics and approach to treatment were as expected and represent a reasonable "standard of care". However, there are some areas for improvement, including the absence of histological diagnosis in some patients, lack of multidisciplinary care, low clinical trial enrollment and poor use of ancillary services.

Adolescent↗
PubMed2006

Characterization of a clonal isolate of an oxaliplatin resistant ovarian carcinoma cell line A2780/C10.

A single cell clonal sub-line A2780/C10B that is 18-fold resistant to oxaliplatin and approximately threefold cross-resistant to cisplatin and exhibiting a metastasis associated cellular phenotype was characterized for mechanisms of resistance. The cell line exhibited a 50% reduction in the accumulation of both oxaliplatin and cisplatin relative to the parent line, while extensive decline in Pt-DNA adduct levels occurred only following oxaliplatin treatment. The basal GSH levels were fivefold higher in A2780/C10B compared to A2780 and had a fivefold elevation in gamma-GT suggesting this may be the mechanism involved in GSH elevation. The basal levels of ERCC-1, XPA and MRP-2 mRNA levels in A2780/C10B were not higher than those in A2780. The highly reduced Pt-DNA adduct formation only for oxaliplatin, but not cisplatin may be a reflection of the fact that at equimolar concentrations oxaliplatin makes fewer Pt-DNA adducts than cisplatin. The data indicate that multiple lesions occur in a single cell to produce the resistant phenotype.

Antineoplastic Agents↗
PubMed2006

Reactivity of ambulatory blood pressure to physical activity varies with time of day.

Blood pressure (BP) fluctuates over a 24-hour period, but it is unclear to what extent this variation is governed completely by changes in physical activity. Our aim was to use a BP "reactivity index" to investigate whether the BP response to a given level of physical activity changes during a normal sleep-wake cycle. Hypertensive patients (n=440) underwent simultaneous 24-hour ambulatory BP, heart rate (HR), and activity monitoring. BP and HR were measured every 20 minutes. Actigraphy data were averaged over the 15 minutes that preceded a BP measurement. Individual BP and HR reactivity indices were calculated using least-squares regression for twelve 2-hour periods. These indices were then analyzed for time-of-day differences using a general linear model. Systolic BP and HR were generally more reactive to physical activity than diastolic BP. The highest reactivity of systolic BP (mean+/-SE=4+/-1 mm Hg per logged unit change in activity) was observed between 8:00 AM and 10:00 AM (P=0.014). Between 10:00 AM and 12:00 PM, BP reactivity then decreased (P=0.048) and showed a secondary rise in the early afternoon. These 24-hour changes in BP reactivity did not differ significantly between groups formed on the basis of early and late wake times (P=0.485), medication use, age, and sex (P>0.350). In conclusion, under conditions of normal living, the reactivity of BP and HR to a given unit change in activity is highest in the morning and shows a secondary rise in the afternoon.

Adult↗
PubMed2006

Recurrent intramedullary sarcoidosis.

We present a 47-year-old man with recurrent intramedullary sarcoidosis. This condition, without any other manifestations of the disease, is rare, with less than 20 reports in the literature. Further, to our knowledge our presentation is the only reported case of intramedullary sarcoidosis recurring in a separate, distant region of the cord after a period of treatment with steroids, to which the patient had initially responded.

Humans↗
PubMed2006

Are type II endoleaks after endovascular aneurysm repair endograft dependent?

PURPOSE: Most clinical end points after endovascular aneurysm repair (EVAR) are endograft-specific, but type II endoleaks have been assumed to be an unavoidable consequence of the repair method and independent of the type of endograft used. Some recent data have suggested that the rate of type II endoleaks may also be graft-dependent. We reviewed a large clinical experience with six endografts to determine the behavior of type II endoleaks and whether they are graft-specific. METHODS: All elective EVAR cases from five university institutions from 1996 to 2003 were retrospectively analyzed. Endografts used in <50 patients were excluded. Endoleaks were diagnosed and classified from contrast-enhanced computed tomography (CT) scans by the treating surgeons. Results of angiography and interventions for endoleaks were tracked. The rate of type II endoleaks was compared among endografts at 1, 6, and 12 months, and yearly thereafter. Statistical significance was defined as P < .05. RESULTS: During the study period, 1909 patients underwent elective EVAR and had an adequate imaging follow-up at one of the specified time points. At 1 month, the overall rate of type II endoleak was 14.0% (range, 9.8% to 25.2%.) The Excluder had a significantly higher incidence of type II endoleaks at 1 month but was similar to most other grafts during longer follow-up. At 6 months, the overall rate of type II endoleak was 16.3% (range, 8.3% to 16.8%). The Talent and Lifepath had an apparent lower initial rate of type II leaks, but this was only significant for the Talent at 6 months compared with Excluder, Zenith, and Ancure, and at 1 year compared with Excluder and Zenith. No graft had a long-term statistically significant difference in the rate of type II endoleak formation. Intervention rates varied by institution and graft type but in general were quite low. Of 25 successful interventions (Ancure, 12; AneuRx, 8; Excluder, 2; Lifepath, 2; Zenith, 1; Talent, 0), 21 were performed during the first year. Interim spontaneous resolution, defined as a negative CT scan after a CT positive for endoleak, was high, especially in the first year. Resolution of type II endoleaks occurred in 54 (33%) of 164 between 1 and 6 months, in 37 (33%) of 112 between 6 and 12 months, in 20 (35%) of 57 from 12 to 24 months, and in 5 (20%) of 25 between 24 and 36 months. The various grafts had a nearly identical pattern, but the rates were highest for the Talent. Late appearing endoleaks, defined as a positive CT after a negative CT, were frequent. At 6 months, 44 (30%) of 147 type II endoleaks were newly diagnosed. The rates were 37 (35%) of 107 at 12 months, 15 (27%) of 56 at 2 years and 5 (25%) of 20 at 3 years. No conversions to open repair for type II endoleaks were noted in the first 4 years. The thrombus burden could not be determined in this analysis. CONCLUSIONS: Type II endoleaks occur in nearly 15% of patients treated by EVAR. The early incidence varies only slightly with graft type. The long-term prevalence and clinical significance are masked by different treatment patterns, spontaneous resolution, newly evident endoleaks, and aneurysm size at initial treatment.

Adult↗
PubMed2005

Alcohol consumption and increased mortality in Russian men and women: a cohort study based on the mortality of relatives.

OBJECTIVE: To examine the relations between frequency of alcohol consumption and of binge drinking and adult mortality in Russian men and women. METHODS: Using modified indirect demographic techniques, a convenience cohort was constructed based on survey respondents' information about their close relatives. A random sample general population of the Russian Federation of 7172 respondents (response rate 61%) provided information on 10 475 male and 3129 female relatives, including age, vital status, and frequency of alcohol consumption and binge drinking. These relatives formed the cohort analysed in this report. The outcome measure was all-cause mortality after the age of 30 years. FINDINGS: There was a strong linear relation between frequency of drinking and of binge drinking and all-cause mortality in men; after controlling for smoking and calendar period of birth, the relative risk of death in daily drinkers compared to occasional drinkers was 1.52 (95% confidence interval (CI) 1.33-1.75). Male binge drinkers had higher mortality than drinkers who did not binge, which persisted after adjustment for drinking frequency (adjusted relative risk 1.09, 95% CI 1.00-1.19). In women, the increased mortality was confined to a small group of those who binged at least once a month (adjusted relative risk 2.68, 95% CI 1.54-4.66). CONCLUSION: The results suggest a positive association between alcohol and mortality in the Russian Federation. There was no evidence for the protective effect of drinking seen in western populations. Alcohol appears to have contributed to the high long-term mortality rates in Russian men, but it is unlikely to be a major cause of female mortality.

Adult↗
PubMed2005

Socio-economic influences on self-rated health in Russian men and women--a life course approach.

Socio-economic differentials in health in Russia are not well understood and the life course approach has been relatively neglected. This paper examines the influence of socio-economic risk factors over the life course on the self-rated health of older Russian men and women. A random sample (response rate 61%) of the general population of the Russian Federation in 2002 included 1004 men and 1930 women aged 50 years and over in a cross-sectional study. They provided information concerning their childhood circumstances, including going to bed hungry; education; current social conditions, including per capita household income; health behaviours and self-rated health. There was considerable tracking of adverse social conditions across the life course with men and women who reported hunger in childhood having lower educational achievements, and current household income was strongly influenced by educational attainment. The effect of these socio-economic risk factors on health accumulated with an odds ratio of poor health of 1.87 [1.07-3.28] for men with one risk factor, 3.64 [2.13-6.22] for two risk factors and 4.51 [2.57-7.91] for all three compared to men with no risk factors. For women, the odds ratios were 1.44 [1.05-2.01], 2.88 [2.10-3.93] and 4.27 [3.03-6.00] for one, two and three risk factors, respectively. Current income was the strongest individual predictor for men, and education for women. Adjustment for health behaviours reduced the odds ratios only marginally. The results suggest that self-rated health in older Russians reflects social exposures accumulated over the life course, with the differentials observed only partially explained by current social conditions. Health behaviours were not involved in mediating social differences in self-rated health. Our results indicate that a life course approach may contribute to the understanding of health in Russia.

Adolescent↗
PubMed2005

Standards for education and training for interagency working in child protection in the UK: implications for nurses, midwives and health visitors.

This article presents a discussion of key issues for the education of nurses, midwives and health visitors following the completion of a Department of Health funded project, managed by the General Social Care Council and conducted jointly by two research centres; Salford Centre for Social Work Research and Salford Centre for Nursing, Midwifery and Collaborative Research. The work was initiated in response to Lord Laming's report on the circumstances leading to the death of Victoria Climbié. The project was conducted in relation to specified professions and occupational groups: doctors; health visitors; midwives; nurses; police; teachers, and social workers. It was undertaken in two stages. The first stage mapped existing material about standards in relation to education and training for interagency working. The second stage engaged in an extensive consultation exercise through which a model and a set of proposed standards for interagency education and training for interagency work were developed. The former is detailed fully in this report, while nine examples of standards are presented. The project final report was presented seven months after commencement.

Child↗
PubMed2005

Characterization of the low-energy electronic excited states of benzoyl-substituted ruthenocenes.

Electronic absorption and resonance Raman spectral studies of benzoylruthenocene (BRc) and 1,1'-dibenzoylruthenocene (DRc) indicate that the low-energy electronic excited states of these 4d(6) metallocenes possess metal-to-ligand charge transfer (MLCT) character. While this MLCT contribution should weaken the metal-ring bonding in the excited state, neither compound is photosensitive in nonhalogenated solvents such as methanol, acetonitrile, and cyclohexane. In contrast, irradiating BRc and DRc in the good electron-accepting solvent, carbon tetrachloride, results in ring loss via a pathway that appears to originate from a charge-transfer-to-solvent excited state. Both metallocenes function as photoinitiators for the anionic polymerization of ethyl 2-cyanoacrylate, and the kinetics and mechanism of this process have been investigated. Comparing the present results on BRc and DRc with those reported earlier for the corresponding benzoyl-substituted ferrocene compounds reveals some interesting commonalities and differences between the excited-state properties of these 3d and 4d metallocenes.

Algorithms↗
PubMed2005

Staged open and endovascular repair of thoracoabdominal aneurysms using the common carotid artery.

The purpose of this study was to demonstrate the feasibility of staged open and endoluminal repair of complex thoracoabdominal aneurysms. We report the management of two patients with a staged, open abdominal and endoluminal thoracic repair of Crawford extent II aneurysms, where iliofemoral access was impossible and thoracic repair effected by endograft deployment via a common carotid artery. From this experience we conclude that staged open and endovascular repair for both ruptured and elective Crawford extent II thoracoabdominal aneurysms can be performed using the common carotid artery, when anatomy is favorable.

Aged↗
PubMed2005

Ovulation induction, assisted conception and childhood cancer.

Rapid advances have been made in the treatment of infertility over the last 30 years following the introduction of in vitro fertilisation and intracytoplasmic sperm injection. Whilst effects of assisted reproductive technology (ART) on birth outcomes are well documented little is known about effects on child health after the neonatal period. Childhood cancer is one area warranting further examination. The hypothesis that cancer in children may be initiated during early fetal development means that events leading up to and around conception may be important. Whilst the few large-scale epidemiological studies that have looked at childhood cancer incidence following ART have failed to find any significant increased risk, some case-control studies have reported an increased risk of specific cancers. However, it is important not to over interpret these findings as the reason for the infertility may be the predisposing factor, rather than the procedure itself. Recent recommendations by the UK's National Health Service to offer intra-uterine insemination and one free treatment cycle for infertile couples will result in increasing numbers of children born following ART. More detailed investigations that include larger numbers plus sufficient follow-up periods and information on the underlying causes of the infertility are needed since long term outcomes for these children, in particular the risk of developing cancer, remain largely unknown.

Adult↗
PubMed2004

Cytokine-modified Mycobacterium smegmatis as a novel anticancer immunotherapy.

Intravesical administration of live M. bovis BCG organisms for carcinoma in situ of the urinary bladder is the most successful immunotherapy for solid malignancy. Nevertheless BCG-therapy is associated with significant toxicity and is ineffective in 30-40% of cases. Recently it has been proposed that cytokine-modified mycobacteria may give greater efficacy. As any immunotherapy involving administration of live BCG organisms (wild-type or recombinant) is likely to have associated toxicity (notably in the immunocompromised), we examined the anti-tumour potential of the closely related nonpathogenic organism, Mycobacterium smegmatis, and a TNFalpha gene-modified recombinant M. smegmatis. When wild-type M. smegmatis were delivered to immunocompetent C57Bl/6 mice bearing the transplantable MB49 bladder tumour, efficacy comparable to live BCG was observed with 10-20% long-term survival. However, this effect was lost in both Nude and Beige mice, lacking functional T and NK cells, respectively. Recombinant M. smegmatis secreting TNFalpha, however, gave a 70% durable tumour-free survival. Lymphocytes from draining lymph-nodes and spleens of these mice exhibited pronounced IFNgamma production to mycobacterial-antigen and tumour-lysate, indicating a bias towards cell-mediated immunity. This was further supported by histopathological examination of the tumour site, which revealed significantly increased numbers of CD3+ lymphocytes in animals receiving the recombinant vaccine, but not in those receiving wild-type bacteria. Importantly, tumour rejection following M. smegmatis/TNFalpha was independent of T lymphocytes, as athymic Nude mice efficiently eradicated MB49 tumours. In contrast, the therapeutic efficacy of M. smegmatis/TNFalpha was reduced in animals deficient in NK cytolytic function, suggesting a role for NK-cells in initial tumour destruction. Furthermore the absence of NK-function in Beige mice did not prevent the establishment of tumour-protective memory. No toxicity was observed with wild-type or recombinant M. smegmatis in immunocompetent, T-deficient or NK-deficient models. We demonstrate for the first time that recombinant mycobacteria expressing mammalian cytokines have markedly increased anti-tumour properties. The lack of toxicity suggests that M. smegmatis is a "safe" vehicle for use in immunocompromised patients.

Animals↗