402 research outputs found

    Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial

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    Background: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. Patients and methods: The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients agedā€‰ā‰„18ā€‰years with bulky stage I-IV DLBCL (nā€‰=ā€‰1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. Results: 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) nā€‰=ā€‰163, intravenous (IV) MTX nā€‰=ā€‰2, prophylaxis type unknown nā€‰=ā€‰11 and IT MTX and cytarabine nā€‰=ā€‰1). At a median follow-up of 6.5ā€‰years, 21 cases of CNS relapse (isolated nā€‰=ā€‰11, with systemic relapse nā€‰=ā€‰10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI,ā€‰>1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. Conclusion: Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. ClinicalTrials.gov: ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34

    Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

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    The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12ā€“18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults

    Understanding market failure in the developing country context.

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    Market failure makes it difficult to achieve the condition of economic efficiency by distorting price mechanisms and normal distribution of goods and services thereby, leading to welfare loss. They are entrenched in the socio-economic fabrics of most developing countries, underpinned by the lack of well-functioning market structures and economic systems ā€“ which are supposed to make the market economy resilient to such economic shortcomings

    Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment

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    Background Breast cancer survivors often encounter physiological and psychological problems related to their diagnosis and treatment that can influence long-term prognosis. The aim of this research is to investigate the effects of a lifestyle intervention on body weight and psychological well-being in women recovering from breast cancer treatment, and to determine the relationship between changes in these variables and biomarkers associated with disease recurrence and survival. Methods/design Following ethical approval, a total of 100 patients will be randomly assigned to a lifestyle intervention (incorporating dietary energy restriction in conjunction with aerobic exercise training) or normal care control group. Patients randomised to the dietary and exercise intervention will be given individualised healthy eating dietary advice and written information and attend moderate intensity aerobic exercise sessions on three to five days per week for a period of 24 weeks. The aim of this strategy is to induce a steady weight loss of up to 0.5 Kg each week. In addition, the overall quality of the diet will be examined with a view to (i) reducing the dietary intake of fat to ~25% of the total calories, (ii) eating at least 5 portions of fruit and vegetables a day, (iii) increasing the intake of fibre and reducing refined carbohydrates, and (iv) taking moderate amounts of alcohol. Outcome measures will include body weight and body composition, psychological health status (stress and depression), cardiorespiratory fitness and quality of life. In addition, biomarkers associated with disease recurrence, including stress hormones, estrogen status, inflammatory markers and indices of innate and adaptive immune function will be monitored. Discussion This research will provide valuable information on the effectiveness of a practical, easily implemented lifestyle intervention for evoking positive effects on body weight and psychological well-being, two important factors that can influence long-term prognosis in breast cancer survivors. However, the added value of the study is that it will also evaluate the effects of the lifestyle intervention on a range of biomarkers associated with disease recurrence and survival. Considered together, the results should improve our understanding of the potential role that lifestyle-modifiable factors could play in saving or prolonging lives

    Intracranial bleeding due to vitaminĀ K deficiency: advantages of using a pediatric intensive care registry

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    Item does not contain fulltextAIM: To determine the incidence of late intracranial vitamin K deficiency bleeding (VKDB) in The Netherlands using the Dutch Pediatric Intensive Care Evaluation (PICE) registry. METHODS: The PICE registry was used to identify all infants who were admitted to a Dutch pediatric intensive care unit (PICU) with intracranial bleeding between 1 January 2004 and 31 December 2007. Cases of confirmed late intracranial VKDB were used to calculate the incidence for each year. To estimate the completeness of ascertainment of the PICE registry, data from 2005 were compared with general surveillance data from that year. RESULTS: In the 4-year study period, 16/64 (25%) of the infants admitted with intracranial bleeding had late intracranial VKDB, resulting in an overall incidence of 2.1/100,000 live births (95% confidence interval 1.2-3.5). The single-year incidence varied markedly between 0.5 and 3.3 per 100,000 live births. All five ascertained cases in 2005 were identified using the PICE registry, while general surveillance identified only three. CONCLUSIONS: The PICE registry allows ongoing monitoring of the incidence of late intracranial VKDB and appears to be associated with a higher rate of completeness than general surveillance. We propose the use of pediatric intensive care registries to assess the efficacy of national vitamin K prophylactic regimens

    The stellar and sub-stellar IMF of simple and composite populations

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    The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

    mTOR Is Essential for the Proteotoxic Stress Response, HSF1 Activation and Heat Shock Protein Synthesis

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    The target of rapamycin (TOR) is a high molecular weight protein kinase that regulates many processes in cells in response to mitogens and variations in nutrient availability. Here we have shown that mTOR in human tissue culture cells plays a key role in responses to proteotoxic stress and that reduction in mTOR levels by RNA interference leads to increase sensitivity to heat shock. This effect was accompanied by a drastic reduction in ability to synthesize heat shock proteins (HSP), including Hsp70, Hsp90 and Hsp110. As HSP transcription is regulated by heat shock transcription factor 1 (HSF1), we examined whether mTOR could directly phosphorylate this factor. Indeed, we determined that mTOR could directly phosphorylate HSF1 on serine 326, a key residue in transcriptional activation. HSF1 was phosphorylated on S326 immediately after heat shock and was triggered by other cell stressors including proteasome inhibitors and sodium arsenite. Null mutation of S326 to alanine led to loss of ability to activate an HSF1-regulated promoter-reporter construct, indicating a direct role for mTOR and S326 in transcriptional regulation of HSP genes during stress. As mTOR is known to exist in at least two intracellular complexes, mTORC1 and mTOR2 we examined which complex might interact with HSF1. Indeed mTORC1 inhibitor rapamycin prevented HSF1-S326 phosphorylation, suggesting that this complex is involved in HSF1 regulation in stress. Our experiments therefore suggest a key role for mTORC1 in transcriptional responses to proteotoxic stress

    Lysyl hydroxylase 3 localizes to epidermal basement membrane and Is reduced in patients with Recessive Dystrophic Epidermolysis Bullosa

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    Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1 resulting in reduced or absent type VII collagen, aberrant anchoring fibril formation and subsequent dermal-epidermal fragility. Here, we identify a significant decrease in PLOD3 expression and its encoded protein, the collagen modifying enzyme lysyl hydroxylase 3 (LH3), in RDEB. We show abundant LH3 localising to the basement membrane in normal skin which is severely depleted in RDEB patient skin. We demonstrate expression is in-part regulated by endogenous type VII collagen and that, in agreement with previous studies, even small reductions in LH3 expression lead to significantly less secreted LH3 protein. Exogenous type VII collagen did not alter LH3 expression in cultured RDEB keratinocytes and we show that RDEB patients receiving bone marrow transplantation who demonstrate significant increase in type VII collagen do not show increased levels of LH3 at the basement membrane. Our data report a direct link between LH3 and endogenous type VII collagen expression concluding that reduction of LH3 at the basement membrane in patients with RDEB will likely have significant implications for disease progression and therapeutic intervention
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