Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892

On application of Liouville type equations to constructing B\"acklund transformations

It is shown how pseudoconstants of the Liouville-type equations can be exploited as a tool for construction of the B\"acklund transformations. Several new examples of such transformations are found. In particular we obtained the B\"acklund transformations for a pair of three-component analogs of the dispersive water wave system, and auto-B\"acklund transformations for coupled three-component KdV-type systems.Comment: 11 pages, no figure

Genetic loci on chromosome 5 are associated with circulating levels of interleukin-5 and eosinophil count in a European population with high risk for cardiovascular disease

IL-5 is a Th2 cytokine which activates eosinophils and is suggested to have an atheroprotective role. Genetic variants in the IL5 locus have been associated with increased risk of CAD and ischemic stroke. In this study we aimed to identify genetic variants associated with IL-5 concentrations and apply a Mendelian randomisation approach to assess IL-5 levels for causal effect on intima-media thickness in a European population at high risk of coronary artery disease. We analysed SNPs within robustly associated candidate loci for immune, inflammatory, metabolic and cardiovascular traits. We identified 2 genetic loci for IL-5 levels (chromosome 5, rs56183820, BETA = 0.11, P = 6.73E−5 and chromosome 14, rs4902762, BETA = 0.12, P = 5.76E−6) and one for eosinophil count (rs72797327, BETA = −0.10, P = 1.41E−6). Both chromosome 5 loci were in the vicinity of the IL5 gene, however the association with IL-5 levels failed to replicate in a meta-analysis of 2 independent cohorts (rs56183820, BETA = 0.04, P = 0.2763, I2 = 24, I2 − P = 0.2516). No significant associations were observed between SNPs associated with IL-5 levels or eosinophil count and IMT measures. Expression quantitative trait analyses indicate effects of the IL-5 and eosinophil-associated SNPs on RAD50 mRNA expression levels (rs12652920 (r2 = 0.93 with rs56183820) BETA = −0.10, P = 8.64E−6 and rs11739623 (r2 = 0.96 with rs72797327) BETA = −0.23, P = 1.74E−29, respectively). Our data do not support a role for IL-5 levels and eosinophil count in intima-media thickness, however SNPs associated with IL-5 and eosinophils might influence stability of the atherosclerotic plaque via modulation of RAD50 levels

Localized induction equation and pseudospherical surfaces

We describe a close connection between the localized induction equation hierarchy of integrable evolution equations on space curves, and surfaces of constant negative Gauss curvature.Comment: 21 pages, AMSTeX file. To appear in Journal of Physics A: Mathematical and Genera

Restrictive fluid management versus usual care in acute kidney injury (REVERSE-AKI) : a pilot randomized controlled feasibility trial

Purpose We compared a restrictive fluid management strategy to usual care among critically ill patients with acute kidney injury (AKI) who had received initial fluid resuscitation. Methods This multicenter feasibility trial randomized 100 AKI patients 1:1 in seven ICUs in Europe and Australia. Restrictive fluid management included targeting negative or neutral daily fluid balance by minimizing fluid input and/or enhancing urine output with diuretics administered at the discretion of the clinician. Fluid boluses were administered as clinically indicated. The primary endpoint was cumulative fluid balance 72 h from randomization. Results Mean (SD) cumulative fluid balance at 72 h from randomization was - 1080 mL (2003 mL) in the restrictive fluid management arm and 61 mL (3131 mL) in the usual care arm, mean difference (95% CI) - 1148 mL (- 2200 to - 96) mL, P = 0.033. Median [IQR] duration of AKI was 2 [1-3] and 3 [2-7] days, respectively (median difference - 1.0 [- 3.0 to 0.0], P = 0.071). Altogether, 6 out of 46 (13%) patients in the restrictive fluid management arm and 15 out of 50 (30%) in the usual care arm received renal replacement therapy (RR 0.42; 95% CI 0.16-0.91), P = 0.043. Cumulative fluid balance at 24 h and 7 days was lower in the restrictive fluid management arm. The dose of diuretics was not different between the groups. Adverse events occurred more frequently in the usual care arm. Conclusions In critically ill patients with AKI, a restrictive fluid management regimen resulted in lower cumulative fluid balance and less adverse events compared to usual care. Larger trials of this intervention are justified.Peer reviewe

Pharmacogenetics of efficiency and tolerance of the peroral antidiabetic drug metformin

Elektroniskā versija nesatur pielikumusMetformīns ir pirmās izvēles medikaments jaundiagnosticētu 2.tipa cukura diabēta (T2DM) pacientu ārstēšanā. Mēs identificējām asociāciju starp metformīna blakusparādībām un 2 ģenētiskiem variantiem (rs628031 and rs36056065) Organisko Katjonu transportierī 1 (OCT1/SLC22A1). Polimorfismiem rs3119309, rs2481030 un rs7757336, lokalizētiem Organisko Katjonu transportieru 2 un 3 (OCT2/SLC22A2 un OCT3/SLC22A3) starpgēnu reģionā, tika noteikta būtiska asociācija ar metformīna īstermiņa terapijas efektivitāti. Divi no šiem variantiem tika analizēti replikācijas pētījumā ar 126 T2DM pacientiem no Slovākijas un farmakokinētikas pētījumā ar 15 veseliem brīvprātīgajiem. Visbeidzot, 33 ģenētiskas variācijas tika izpētītas ATM, STK11 un T2DM kandidātgēnos, bet tikai dažas no tām bija nomināli asociētas ar metformīna īstermiņa terapijas efektivitāti. Atslēgas vārdi: OCTs, metformīns, farmakoģenētika, blakusparādības, efektivitāte.Metformin is the first-line medication used in treatment of newly-diagnosticed Type 2 diabetes mellitus (T2DM). We show an association between metformin side-effects and two genetic variants (rs628031 and rs36056065) in Organic Cation Transporter 1 (OCT1/SLC22A1). Polymorphisms rs3119309, rs2481030 un rs7757336 in intergenic region between Organic Cation Transporter 2 and 3 (OCT2/SLC22A2 and OCT3/ SLC22A3) were found to be associated with short-term efficiency of metformin therapy. Two of these variants were analysed in replication study in 126 T2DM patients from Slovakia and in pharmacokinetic study with 15 healthy participants. At last, 33 genetic variants in ATM, STK11 and list of T2DM susceptibility genes were investigated, but only few showed a nominal association with short-term efficiency of metformin monotherapy. Keywords: OCTs, metformin, pharmacogenetics, side-effects, efficiency

Constructing global firms? National, transnational and neocolonial effects in international management consultancies

Drawing on an empirical study of four major international management consultancies, this article examines managerial efforts to construct ‘global’ organizations. We show how these efforts are undermined by inter-office conflicts over the staffing of client projects. We argue that such constraints cannot be adequately understood as an outcome of inappropriate organizational structures and incentives since this explanation ignores the important role of institutional contexts. In this vein, we outline and develop four different institutionalist lenses and apply them to the empirical findings. In so doing, we reveal the need to adopt a multi-dimensional institutionalist approach to the study of ‘global’ firms, one that can account for not only national effects but also transnational and neocolonial influences on these organizations

Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future

Mutations in Rb1 pathway-related genes are associated with poor prognosis in Anaplastic Astrocytomas

Anaplastic astrocytoma (AA, WHO grade III) is, second to Glioblastoma, the most common and most malignant type of adult CNS tumour. Since survival for patients with AA varies markedly and there are no known useful prognostic or therapy response indicators, the primary purpose of this study was to examine whether knowledge of the known genetic abnormalities found in AA had any clinical value. The survival data on 37 carefully sampled AA was correlated with the results of a detailed analysis of the status of nine genes known to be involved in the development of astrocytic tumours. These included three genes coding for proteins in the p53 pathway (TP53, p14ARF and MDM2), four in the Rb1 pathway (CDKN2A, CDKN2B, RB1 and CDK4) and PTEN and EGFR. We found that loss of both wild-type copies of any of the three tumour suppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4, disrupting the Rb1 pathway, were associated with shorter survival (P=0.009). This association was consistent in multivariate analysis, including adjustment for age (P=0.013). The findings suggest that analysis of the genes coding for Rb1 pathway components provides additional prognostic information in AA patients receiving conventional therapy