Phase I study of the combination of losoxantrone and cyclophosphamide in patients with refractory solid tumours

Losoxantrone is a DNA intercalator that was developed with the potential to replace anthracyclines. The recommended single agent dose of losoxantrone is 50 mg m−2 every 3 weeks. We conducted a phase I study of losoxantrone and a fixed dose of cyclophosphamide on a q3 weekly schedule. Forty-nine patients were enrolled, of which 46 were evaluable for toxicity. The dose-limiting toxicity was neutropenia at the maximum tolerable losoxantrone dose of 45 mg m−2. With granulocyte colony-stimulating factor support, significant further dose escalation of losoxantrone was achieved. Cardiotoxicity was seen with cumulative dosing. Pharmacokinetics of losoxantrone revealed linear kinetics and triphasic clearance, with significant interpatient variability. No objective responses were seen in this study. Neutropenia was dose-limiting in this combination with or without granulocyte colony-stimulating factor support. The recommended dose for further testing is cyclophosphamide 500 mg m−2 followed by losoxantrone 95 mg m−2 with granulocyte colony-stimulating factor support

Effect of educational intervention on medication timing in Parkinson's disease: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Medicine usage in Parkinson's disease patients is often imperfect, in particular irregular timing of medication. The effect of informing Parkinson's disease patients about the continuous dopaminergic hypothesis (to encourage regular medicine intake) on medication adherence and motor control was tested.</p> <p>Methods</p> <p>Patients were randomised either to the active group (receiving the intervention) or control group (no extra information). Antiparkinson medicine usage was monitored for 3 months before and after the intervention using electronic pill bottles which record the date and time of opening (MEMS^®, Aardex, Switzerland) and data used to calculate the percentage of doses taken at correct time intervals.</p> <p>Results</p> <p>43 patients (52%) were randomised to active counselling, and 40 (48%) were controls (standard management). The intervention effect (difference in timing adherence pre- to post-intervention between the 2 groups) was 13.4% (CI 5.1 to 21.7), p = 0.002. Parkinson motor scores did not change significantly (active group 0.1, CI -3.4 to 3.7) versus controls (4.5, CI 1.6 to 7.1), p = 0.06.</p> <p>Conclusion</p> <p>Timing adherence, but not motor scores, improves by providing patients with extra information. Therapy timing is of potential importance in Parkinson's disease management.</p> <p>Trial registration number</p> <p>NCT00361205</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Modulation of the Akt/Ras/Raf/MEK/ERK pathway by A3 adenosine receptor

Downstream A3 receptor signalling plays an important role in the regulation of cell death and proliferation. Therefore, it is important to determine the molecular pathways involved through A3 receptor stimulation. The phosphatidylinositide-3-OH kinase (PI3K)/Akt and the Raf/mitogen-activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways have central roles in the regulation of cell survival and proliferation. The crosstalk between these two pathways has also been investigated. The focus of this review centres on downstream mediators of A3 adenosine receptor signalling

Physiological changes to the swallowing mechanism following (Chemo)radiotherapy for head and neck cancer: a systematic review

Emerging research suggests that preventative swallowing rehabilitation, undertaken before or during (chemo)radiotherapy ([C]RT), can significantly improve early swallowing outcomes for head and neck cancer (HNC) patients. However, these treatment protocols are highly variable. Determining specific physiological swallowing parameters that are most likely to be impacted post-(C)RT would assist in refining clear targets for preventative rehabilitation. Therefore, this systematic review (1) examined the frequency and prevalence of physiological swallowing deficits observed post-(C)RT for HNC, and (2) determined the patterns of prevalence of these key physiological deficits over time post-treatment. Online databases were searched for relevant papers published between January 1998 and March 2013. A total of 153 papers were identified and appraised for methodological quality and suitability based on exclusionary criteria. Ultimately, 19 publications met the study’s inclusion criteria. Collation of reported prevalence of physiological swallowing deficits revealed reduced laryngeal excursion, base-of-tongue (BOT) dysfunction, reduced pharyngeal contraction, and impaired epiglottic movement as most frequently reported. BOT dysfunction and impaired epiglottic movement showed a collective prevalence of over 75 % in the majority of patient cohorts, whilst reduced laryngeal elevation and pharyngeal contraction had a prevalence of over 50 %. Subanalysis suggested a trend that the prevalence of these key deficits is dynamic although persistent over time. These findings can be used by clinicians to inform preventative intervention and support the use of specific, evidence-based therapy tasks explicitly selected to target the highly prevalent deficits post-(C)RT for HNC

The Role of Aldosterone Blockade in Patients with Heart Failure

The mechanisms associated with aldosterone production both systemically and locally as well as the effects of aldosterone blockade on the pathophysiology of heart failure (HF) have been extensively reviewed in this series and elsewhere. This article will review the clinical evidence supporting the use of aldosterone blocking agents (AB)in patients with HF and speculate on some potential future uses.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45819/1/10741_2005_Article_2352.pd