Expulsion of amplified MYCN from neuroblastoma tumor cells.
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Biomedical subjects
Publications and source records attributed to S O'Neill.
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In the UK, prospective taxi-drivers with diabetes are licensed locally according to variable criteria. In order to determine the criteria used for licensing, questionnaires were sent to all 422 local licensing authorities. Responses were obtained from 372 authorities (88% response rate). Only 201 (54%) currently issue licences to drivers on insulin treatment, and 260 (70%) to those on diet and/or oral hypoglycaemic agents. Most local authorities would prefer taxi-licensing to operate centrally rather than locally. It is apparent that the current UK system for licensing diabetic taxi drivers is variable and not evidence-based. A nationally organized system with clearly defined criteria and the capacity for individual consideration, would be more fair and consistent, and would be unlikely to compromise road safety.
Resolving inflammation is a vital step in preventing the persistence of inflammatory disorders. Neutrophils play a major role in tissue damage associated with an inflammatory response. Their death by apoptosis is central to the final resolution of this response. Thiol depletion with diethylmaleate (DEM) or diamide represent important triggers for neutrophil apoptosis. The mechanism by which this process occurs remains unknown. The apoptotic cascade is associated with a number of cellular changes, including caspase activation and mitochondrial permeability. The aims of this study were to determine the role of mitochondrial permeability and the caspase cascade in thiol depletion-induced neutrophil apoptosis. Total cellular glutathione was reduced by DEM and diamide. This reduction was associated with neutrophil apoptosis and an increase in caspase 3 activity. The effects of DEM were blocked by the caspase 3 inhibitor, Z-DEVD-FMK. Mitochondrial permeability that occurred was also increased during this induction of apoptosis. Bongkrekic acid, a mitochondrial membrane stabilizer, inhibited DEM-induced apoptosis. The inhibitors' effects of LPS or GM-CSF on spontaneous neutrophil apoptosis was reversed by DEM, which was mediated by an increase in caspase 3 activity and independent of mitochondrial disruption. Caspase activation is an important step in glutathione depletion-induced apoptosis in resting and inflammatory neutrophils. Regulation of caspase activity may represent a possible target to trigger apoptosis and resolve inflammatory disorders.
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Acute pancreatitis (AP) may lead to the development of multiple organ dysfunction syndrome (MODS), especially in severe cases. Resolution of such inflammatory responses is dependent on neutrophil apoptosis. Delays in this apoptotic response are associated with persistent inflammation and subsequent tissue damage. The aim of this study is to determine the effects of AP on neutrophil apoptosis and to investigate the underlying mechanisms involved. Neutrophils and serum were isolated from control (n=10) and from patients with AP (mild, n=35, and severe, n=5). Neutrophil apoptosis was assessed by propidium iodide DNA staining using flow cytometry. Caspase, glutathione-S-transferase (GST), and Mcl-1 protein expression were assessed by SDS-PAGE western blotting. Serum interleukin (IL)-1beta and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were measured by ELISA. Neutrophils isolated from patients with AP show a significant delay in spontaneous neutrophil apoptosis. Serum factors contributed to this delay with increases in IL-1beta and GM-CSF. Isolated neutrophils were resistant to Fas antibody-induced apoptosis. Caspases represent a central mechanism for spontaneous and Fas antibody-induced neutrophil apoptosis. Procaspase 3 expression was decreased in mild and severe cases, but this effect was independent of serum factors. Increases in GST expression may also contribute to the antiapoptotic effect. Altered caspase expression may represent an additional factor contributing to delayed neutrophil apoptosis. This may contribute to the development of AP and its related complications.
BACKGROUND: Several years ago, Osteoporosis Australia published Guidelines for the management of osteoporosis. Since then significant advances in our understanding of the treatment of osteoporosis have been published. The importance of this is heightened as early diagnosis is now possible with precise methods of bone density measurement. OBJECTIVE: This article presents updated guidelines developed on behalf of Osteoporosis Australia for the treatment of postmenopausal osteoporosis to help general practitioners identify those women at risk and to review current treatment strategies. DISCUSSION: Osteoporosis and its associated problems are major health concerns in Australia, especially with an ageing population. While important principles of management are still considered to be maximising peak bone mass and prevention of postmenopausal bone loss by oestrogen therapy, new clinical trial data about drugs such as raloxifene and the bisphosphonates have recently become available and the relative role of various agents is gradually becoming clearer.
This article from the NHS Clinical Governance Support Team (NCGST) outlines the development of quality concerns since the NHS was founded in 1948. It traces the development of clinical governance as a means of achieving continuous quality improvement and describes what the implementation of clinical governance means for patients and professionals. It analyses features of the cultural shift necessary to underpin quality improvement initiatives and describes with practical examples the constituents of the culture necessary for successful clinical governance. Future articles in this series will address other issues around clinical governance and will explain the model being followed by delegates to the NCGST's Clinical Governance Development Programme as they implement clinical governance "on the ground".
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Research carried out on repeat prescribing indicates the low quality of repeat medication management. This paper reports on the project methodology, some initial results and ongoing work on the UK NHS Repeat Prescribing Project currently under way in the North East of England aimed at developing an intervention to improve the quality of repeat prescribing.
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BACKGROUND: Gain of genetic material from chromosome arm 17q (gain of segment 17q21-qter) is the most frequent cytogenetic abnormality of neuroblastoma cells. This gain has been associated with advanced disease, patients who are > or =1 year old, deletion of chromosome arm 1p, and amplification of the N-myc oncogene, all of which predict an adverse outcome. We investigated these associations and evaluated the prognostic importance of the status of chromosome 17. METHODS: We compiled molecular cytogenetic analyses of chromosome 17 in primary neuroblastomas in 313 patients at six European centers. Clinical and survival information were collected, along with data on 1p, N-myc, and ploidy. RESULTS: Unbalanced gain of segment 17q21-qter was found in 53.7 percent of the tumors, whereas the chromosome was normal in 46.3 percent. The gain of 17q was characteristic of advanced tumors and of tumors in children > or =1 year of age and was strongly associated with the deletion of 1p and amplification of N-myc. No tumor showed amplification of N-myc in the absence of either deletion of 1p or gain of 17q. Gain of 17q was a significant predictive factor for adverse outcome in univariate analysis. Among the patients with this abnormality, overall survival at five years was 30.6 percent (95 percent confidence interval, 21 to 40 percent), as compared with 86.0 percent (95 percent confidence interval, 78 to 91 percent) among those with normal 17q status. in multivariate analysis, gain of 17q was the most powerful prognostic factor, followed by the presence of stage 4 disease and deletion of 1p (hazard ratios, 3.4, 2.3, and 1.9, respectively). CONCLUSIONS: Gain of chromosome segment 17q21-qter is an important prognostic factor in children with neuroblastoma.
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BACKGROUND: The mortality rate associated with acute mesenteric ischaemia (AMI) remains high. Diagnosis is frequently confounded by the non-specific history and physical signs, in conjunction with the absence of a reliable biological assay. Glutathione S-transferase (GST) is an enzyme with a crucial role in cellular homoeostasis, the alpha isoenzyme of which is highly specific to small bowel and liver. This study assessed alphaGST as a marker for AMI. METHODS: Twenty-six patients with acute abdominal pain were enrolled. Each patient manifested a diagnostic dilemma, with a potential diagnosis of AMI. Plasma was reserved for alphaGST assay during routine blood testing and stored at -20 degrees C for analysis. A final diagnosis was made by autopsy, laparotomy, a definitive other investigation or a return to full health. RESULTS: Twelve patients had AMI. Plasma alphaGST was significantly increased in patients with AMI (P < 0.0001). Although pH differed and other biochemical changes occurred, only alphaGST accurately predicted AMI. CONCLUSION: A threshold of 4 ng/ml for alphaGST was 100 per cent sensitive and 86 per cent specific for AMI. If these observations can be confirmed, evaluation of alphaGST may reliably predict the presence or absence of AMI.
The mission of the United States Department of Energy sites has recently changed from nuclear weapons production to site remediation. Considering the mass of radiological and chemical contaminants at these sites, ensuring the health and safety of workers is a major challenge. This study used the findings from a written survey to describe occupational health services at 10 Department of Energy sites. The study aims were to describe and compare: (1) the primary hazards associated with the site activities; (2) the occupational safety and health structure, including service providers; and (3) the occupational health and safety functions, including surveillance, training, and service provision. Although explosions and radiological agents were identified as the hazards with the greatest associated risks, workers at these sites were most likely to be exposed to physical hazards, ergonomic hazards, and/or chemicals, including asbestos. Physicians accounted for 2.4% of service providers, nurses for 5.5%, industrial hygienists for 12.2%, safety personnel for 11.8%, and health physicists for 64.9%. It was concluded that there is an imbalance between the most important hazards and the types of health and safety personnel at these sites.
BACKGROUND: Inflammatory cytokine concentrations correlate with severity of sepsis. We hypothesised that patients with community acquired pneumonia (CAP) associated with systemic inflammatory response syndrome (SIRS) would have greater interleukin 6 (IL-6) production due to activation of the inflammatory cytokine cascade, matched by a significant anti-inflammatory cytokine response. Interleukin 10 (IL-10) was evaluated as a potential surrogate marker of severity of sepsis in CAP and age related impairment of the cytokine response was studied in elderly patients with CAP. METHODS: Circulating immunoreactive IL-6 and IL-10 levels were measured in 38 patients with CAP subdivided into a group fulfilling the criteria for SIRS (n = 28) and a non-SIRS group (n = 10) in a variety of age groups and correlated with APACHE II scores. RESULTS: 80% had circulating IL-6 levels (median 46.7 pg/ml, range 4.6-27,000) and 60% had circulating IL-10 levels (median 15.5 pg/ml, range 2.5-765). Concentrations of both were significantly increased in patients with SIRS compared with non-SIRS patients. Those with activation of the inflammatory cytokine cascade (IL-6 positive) produced more IL-10 than IL-6 negative patients. Older patients had a similar cytokine response. Both cytokines correlated positively with APACHE II scores. CONCLUSIONS: This is the first demonstration of circulating IL-10 in CAP. A greater counter-inflammatory response in patients with SIRS and in IL-6 positive patients suggests a potential immunomodulatory role for IL-10 in controlling the inflammatory cytokine response in CAP. IL-10 concentrations correlate with severity of illness in CAP and may be of prognostic importance. There is no age related impairment in the cytokine response.