Protocol for a randomised control trial of methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients (MOTION)

Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood-brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid-induced constipation and gastrointestinal dysmotility.This is a single-centre, multisite, double-blind, randomised, placebo-controlled trial. 84 patients will be recruited from 4 intensive care units (ICUs) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects.The trial protocol, the patient/legal representative information sheets and consent forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. On completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.2014-004687-37; Pre-results

The dermomyotome ventrolateral lip is essential for the hypaxial myotome formation

Background The myotome is the primitive skeletal muscle that forms within the embryonic metameric body wall. It can be subdivided into an epaxial and hypaxial domain. It has been shown that the formation of the epaxial myotome requires the dorsomedial lip of the dermomyotome (DML). Although the ventrolateral lip (VLL) of the dermomyotome is believed to be required for the formation of the hypaxial myotome, experimentally evidence for this statement still needs to be provided. Provision of such data would enable the resolution of a debate regarding the formation of the hypaxial dermomyotome. Two mechanisms have been proposed for this tissue. The first proposes that the intermediate dermomyotome undergoes cellular expansion thereby pushing the ventral lateral lip in a lateral direction (translocation). In contrast, the alternative view holds that the ventral lateral lip grows laterally. Results Using time lapse confocal microscopy, we observed that the GFP-labelled ventrolateral lip (VLL) of the dermomyotome grows rather than translocates in a lateral direction. The necessity of the VLL for lateral extension of the myotome was addressed by ablation studies. We found that the hypaxial myotome did not form after VLL ablation. In contrast, the removal of an intermediate portion of the dermomyotome had very little effect of the hypaxial myotome. These results demonstrate that the VLL is required for the formation of the hypaxial myotome. Conclusion Our study demonstrates that the dermomyotome ventrolateral lip is essential for the hypaxial myotome formation and supports the lip extension model. Therefore, despite being under independent signalling controls, both the dorsomedial and ventrolateral lip fulfil the same function, i.e. they extend into adjacent regions permitting the growth of the myotome

Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia

Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6–239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0–10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%–84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62–341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13–7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought

Green synthesis and biological evaluation of novel 5-fluorouracil derivatives as potent anticancer agents

This study reports the formation of 5-FU co-crystals with four different pharmacologically safe co-formers; Urea, Thiourea, Acetanilide and Aspirin using methanol as a solvent. Two fabrication schemes were followed i.e., solid-state grinding protocol, in which API and co-formers were mixed through vigorous grinding while in the other method separate solutions of both the components were made and mixed together. The adopted approaches offer easy fabrication protocols, no temperature maintenance requirements, no need of expensive solvents, hardly available apparatus, isolation and purification of the desired products. In addition, there is no byproducts formation, In fact, a phenomenon embracing the requirements of green synthesis. Through FTIR analysis; for API the Nsingle bondH absorption frequency was recorded at 3409.02 cm−1 and that of single bondCdouble bondO was observed at 1647.77 cm−1. These characteristics peaks of 5-FU were significantly shifted and recorded at 3499.40 cm−1 and 1649.62 cm−1 for 5-FU-Ac (3B) and 3496.39 cm−1 and 1659.30 cm−1 for 5-FU-As (4B) co-crystals for Nsingle bondH and single bondCdouble bondO groups respectively. The structural differences between API and co-crystals were further confirmed through PXRD analysis. The characteristic peak of 5-FU at 2θ = 28.79918o was significantly shifted in the graphs of co-crystals not only in position but also with respect to intensity and FWHM values. In addition, new peaks were also recorded in all the spectra of co-formers confirming the structural differences between API and co-formers. In addition, percent growth inhibition was also observed by all the co-crystals through MTT assay against HCT 116 colorectal cell lines in vitro. At four different concentrations; 25, 50, 100 and 200 µg/mL, slightly different trends of the effectiveness of API and co-crystals were observed. However; among all the co-crystal forms, 5-FU-thiourea co-crystals obtained through solution method (2B) proved to be the most effective growth inhibitor at all the four above mentioned concentrations

Nuku, a family of primate retrocopies derived from KU70

The gene encoding the ubiquitous DNA repair protein, Ku70p, has undergone extensive copy number expansion during primate evolution. Gene duplications of KU70 have the hallmark of long interspersed element-1 mediated retrotransposition with evidence of target-site duplications, the poly-A tails, and the absence of introns. Evolutionary analysis of this expanded family of KU70-derived &ldquo;NUKU&rdquo; retrocopies reveals that these genes are both ancient and also actively being created in extant primate species. NUKU retrocopies show evidence of functional divergence away from KU70, as evinced by their altered pattern of tissue expression and possible tissue-specific translation. Molecular modeling predicted that amino acid changes in Nuku2p at the interaction interface with Ku80p would prevent the assembly of the Ku heterodimer. The lack of Nuku2p-Ku80p interaction was confirmed by yeast two-hybrid assay, which contrasts the robust interaction of Ku70p-Ku80p. While several NUKU retrocopies appear to have been degraded by mutation, NUKU2 shows evidence of positive natural selection, suggesting that this retrocopy is undergoing neofunctionalization. Although Nuku proteins do not appear to antagonize retrovirus transduction in cell culture, the observed expansion and rapid evolution of NUKUs could be being driven by alternative selective pressures related to infectious disease or an undefined role in primate physiology. &nbsp;</p

Methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients. Results from the MOTION trial

Purpose: Constipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of bowel dysfunction. We tested if methylnaltrexone, a pure peripheral mu-opioid receptor antagonist, could reverse opioid-induced constipation. Methods: The MOTION trial is a multi-centre, double blind, randomised placebo-controlled trial to investigate whether methylnaltrexone alleviates opioid-induced constipation (OIC) in critical care patients. Eligibility criteria included adult ICU patients who were mechanically ventilated, receiving opioids and were constipated (had not opened bowels for a minimum 48 h) despite prior administration of regular laxatives as per local bowel management protocol. The primary outcome was time to significant rescue-free laxation. Secondary outcomes included gastric residual volume, tolerance of enteral feeds, requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day, escalation of opioid dose due to antagonism/reversal of analgesia, incidence of ventilator-associated pneumonia, incidence of diarrhoea and Clostridium difficile infection and finally 28 day, ICU and hospital mortality. Results: A total of 84 patients were enrolled and randomized (41 to methylnaltrexone and 43 to placebo). The baseline demographic characteristics of the two groups were generally well balanced. There was no significant difference in time to rescue-free laxation between the groups (Hazard ratio 1.42, 95% CI 0.82–2.46, p = 0.22). There were no significant differences in the majority of secondary outcomes, particularly days 1–3. However, during days 4–28, there were fewer median number of bowel movements per day in the methylnaltrexone group, (p = 0.01) and a greater incidence of diarrhoea in the placebo group (p = 0.02). There was a marked difference in mortality between the groups, with ten deaths in the methylnaltrexone group and two in the placebo group during days 4–28 (p = 0.007). Conclusion: We found no evidence to support the addition of methylnaltrexone to regular laxatives for the treatment of opioid-induced constipation in critically ill patients; however, the confidence interval was wide and a clinically important difference cannot be excluded

Support for UNRWA's survival

The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides life-saving humanitarian aid for 5·4 million Palestine refugees now entering their eighth decade of statelessness and conflict. About a third of Palestine refugees still live in 58 recognised camps. UNRWA operates 702 schools and 144 health centres, some of which are affected by the ongoing humanitarian disasters in Syria and the Gaza Strip. It has dramatically reduced the prevalence of infectious diseases, mortality, and illiteracy. Its social services include rebuilding infrastructure and homes that have been destroyed by conflict and providing cash assistance and micro-finance loans for Palestinians whose rights are curtailed and who are denied the right of return to their homeland

High frequency of central nervous system involvement in transformed Waldenstrom macroglobulinemia

Histologicaltransformation (HT) to diffuse large B-cell lymphoma (DLBCL) is a rare event in Waldenström macroglobulinemia (WM) and is associated with a poor prognosis.1-4 It confers an inferior outcome compared with WM patients without HT.2,3 Most transformed WM patients present with elevated serum lactate dehydrogenase (LDH) levels and extranodal disease.1 Among extranodal sites, the central nervous system (CNS) is one of the most frequently involved sites identified at diagnosis of transformed WM (ranging from 13% to 18%).1,3 However, the prognostic value of CNS involvement is unknown, and the rate of CNS involvement at relapse has not been previously reported in this setting.This work was supported by Cancer Research UK [C355/A26819], FC AECC, and AIRC under the “Accelerator Award Program” [EDITOR] to M.A. and R.G.-S

Modelling and simulation techniques for supporting healthcare decision making : a selection framework

The development of this workbook has been led by a team of researchers from five UK universities with a grant from the UK Engineering and Physical Sciences Research Council (EPSRC). They are investigating the use of modelling and simulation in healthcare as part of the RIGHT (Research Into Global Healthcare Tools) project. The workbook was developed following an extensive review of literature on the application of modelling and simulation in healthcare and other safety- critical industries, supplemented by the team’s extensive expertise of modelling and simulation in healthcare. In order to produce this summary guide, thousands of articles were categorised according to the techniques used, when they were used, and with what resources.peer-reviewe