Dose escalation of desmoteplase for acute ischemic stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset

<p><b>Background and Purpose:</b> Desmoteplase is a novel plasminogen activator with favorable features in vitro compared with available agents. This study evaluated safety and efficacy of intravenous (IV) desmoteplase in patients with perfusion/diffusion mismatch on MRI 3 to 9 hours after onset of acute ischemic stroke.</p> <p><b>Methods:</b> DEDAS was a placebo-controlled, double-blind, randomized, dose-escalation study investigating doses of 90 μg/kg and 125 μg/kg desmoteplase. Eligibility criteria included baseline National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch. The safety end point was the rate of symptomatic intracranial hemorrhage. Primary efficacy co-end points were MRI reperfusion 4 to 8 hours after treatment and good clinical outcome at 90 days. The primary analyses were intent-to-treat. Before unblinding, a target population, excluding patients violating specific MRI criteria, was defined.</p> <p><b>Results:</b> Thirty-seven patients were randomized and received treatment (intent-to-treat; placebo: n=8; 90 μg/kg: n=14; 125 μg/kg: n=15). No symptomatic intracranial hemorrhage occurred. Reperfusion was achieved in 37.5% (95% CI [8.5; 75.5]) of placebo patients, 18.2% (2.3; 51.8) of patients treated with 90 μg/kg desmoteplase, and 53.3% (26.6; 78.7) of patients treated with 125 μg/kg desmoteplase. Good clinical outcome at 90 days occurred in 25.0% (3.2; 65.1) treated with placebo, 28.6% (8.4; 58.1) treated with 90 μg/kg desmoteplase and 60.0% (32.3; 83.7) treated with 125 μg/kg desmoteplase. In the target population (n=25), the difference compared with placebo increased and was statistically significant for good clinical outcome with 125 μg/kg desmoteplase (P=0.022).</p> <p><b>Conclusions:</b> Treatment with IV desmoteplase 3 to 9 hours after ischemic stroke onset appears safe. At a dose of 125 μg/kg desmoteplase appeared to improve clinical outcome, especially in patients fulfilling all MRI criteria. The results of DEDAS generally support the results of its predecessor study, Desmoteplase in Acute Ischemic Stroke (DIAS).</p&gt

The Desmoteplase In Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase

Background and Purpose: Most acute ischemic stroke patients arrive after the 3-hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose-finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI. Methods: DIAS was a placebo-controlled, double-blind, randomized, dose-finding phase II trial. Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight-adjusted doses escalating through 62.5 μg&#8260;kg, 90 μg&#8260;kg, and 125 μg&#8260;kg were subsequently investigated in 57 patients (referred to as Part 2). The safety endpoint was the rate of sICH. Efficacy endpoints were the rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days. Results: Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7%). In Part 2, the sICH rate was 2.2%. No sICH occurred with placebo in either part. Reperfusion rates up to 71.4% (P=0.0012) were observed with desmoteplase (125 μg/kg) compared with 19.2% with placebo. Favorable 90-day clinical outcome was found in 22.2% of placebo-treated patients and between 13.3% (62.5 μg&#8260;kg; P=0.757) and 60.0% (125 μg&#8260;kg; P=0.0090) of desmoteplase-treated patients. Early reperfusion correlated favorably with clinical outcome (P=0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6% of patients without reperfusion. Conclusions: Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion/diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 μg&#8260;kg.</p

Rehabilitation of Patients with Acid-base and Fluid Balance Disorders with Short Bowel Syndrome after Ileostomies

Background: Patients with ileostomies regularly suffer from short bowel syndrome or high volume output associated with loss of absorptive surface and subsequent impairment of absorption for drugs and different nutrients resulting in electrolyte and fluid balance disorders as well as renal insufficiency. Adaptation of these fundamental functions of the gut with adequate fluid uptake, absorption of sufficient different nutrients and vitamins represents a major challenge to rehabilitate these patients shortly after surgery. Patients with ileostomy often develop metabolic acidosis with normal anion gap. In our retrospective study we would like to draw attention to these metabolic disorders in patients with ileostomy in comparison to patients with colostomy and patients undergoing gastrectomy for gastric cancer. Methods: In the period from 2005 to 2012 we examined 164 patients with ileostomy in our rehabilitation clinic, 109 patients with colostomy and 193 patients after surgery for gastric cancer of the possible presence of metabolic acidosis by using capillary blood gas analysis (metabolic acidosis was anticipated, if base excess was <= -3,0 mmol/l). Patients are treated as inpatients both in early stage and for follow-up rehabilitation. The length of time in our rehabilitation clinic lies inbetween 24-28 days. On the basis of random samples we tested blood samples in 19 patients with ileostomy in succession for ferritin, folic acid, zinc, selenium and vitamin B12. Statistical analysis comprised the classical intervals (mean and standard deviation, range and T-test for dependent and indipendent samples). Results: In total we tested 164 inpatients with ileostomy in our rehabilitation clinic (median age 67.4 years, range 19-79 years). The time for surgery for ileostomy took place about 1.4 months on average ago (range 1/4-56 months). 60 (36.5 %) inpatients suffered from metabolic acidosis often combined with renal insufficiency. Supportive therapy intravenously administered in 10 patients and sodium bicarbonate given by mouth in 40 patients significantly improved metabolic acid (base excess improved on average from -7.2 to -3.2 mmol/l, p < 0.00138) and renal function calculated on the basis of serum creatinine (serum creatinine decreased from 1.49 on average to 1.34 mg/dl, p < 0.04039). Body weight remained constant over the whole period on average with 74 kg. Diuretics did not show any influence on the base excess. In 19 patients with ileostomy who did not take any kind of supplements, among the parameters tested were a high percentage of zinc (9 of 19 patients, 47 %) and selenium deficiency (13 of 19 patients, 68 %). 50 patients with ileostomy were younger than 65 years of age and thus in the working age population. In the group of patients after gastrectomy because of gastric cancer (n = 193, median age 69.1 years, range 36-82 years), the time for surgery for gastrectomy took place about 1.8 months on ave-rage ago and in this group only 14 patients (7 %) showed metabolic acidosis. In the group of patients with colostomy (n = 109, median age 69.5 years, range 39-82 years), the time for surgery for colostomy took place about 2.1 months on average ago and in this group only 6 patients (5.5 %) suffered from metabolic acidosis. Conclusion: Medical rehabilitation is indicated for patients with enterostoma. Acceptance of the enterostoma by the patient himself, psychological stabilization, achievement of self-sufficiency in stoma care, improvement of physical abilities and finally being fit for full or limited employment are the most important objectives in rehabilitation medicine. Metabolic acidosis was often found in patients with ileostomy and was an important clinical appearance. Blood gas analysis is recommended to verify metabolic acidosis and if confirmed sodium bicarbonate and in cases of high volume output salt-depleting ileostomy additionally intravenous fluid support should be offered controlling body weight in the follow-up. As could be shown by our analysis patients with ileostomy should also be tested for zinc and selenium deficiency

Hybrid system for simultaneous fluorescence and X-Ray computed tomography.

A hybrid imaging system for simultaneous fluorescence tomography and X-ray computed tomography (XCT) of small animals has been developed and presented. The system capitalizes on the imaging power of a 360 degrees-projection free-space fluorescence tomography system, implemented within a microcomputed tomography scanner. Image acquisition is based on techniques that automatically adjust a series of imaging parameters to offer a high dynamic range dataset. Image segmentation further allows the incorporation of structural priors in the optical reconstruction problem to improve the imaging performance. The functional system characteristics are showcased, and images from a brain imaging study are shown, which are reconstructed using XCT-derived priors into the optical forward problem

Optimized dualCEST-MRI for imaging of endogenous bulk mobile proteins in the human brain

Recently we demonstrated that a selective detection of endogenous bulk mobile proteins in living tissue can be realized by the novel approach of dual-frequency irradiation CEST (dualCEST)-MRI1 without contamination of saturation transfer effects of metabolites, lipids and semi-solids. For this approach, specificity is achieved by measuring the intramolecular magnetization transfer (i.e. saturation crosstalk T) between CEST signals resonating at two different frequency offsets Δω and Δωc (Fig. 1a). Such a non-invasive imaging technique may be of particular interest for the detection of pathological alterations of protein expression, such as in neurodegenerative diseases or cancer. Until now, application in clinical trials was prevented by the inherently small signal-to-noise ratio (SNR) in comparison to conventional CEST approaches. Here, we present further developments in signal preparation, image acquisition and post-processing techniques enabling dualCEST examinations in a reasonable and clinicallyrelevant time frame

Relaxation‐compensated APT and rNOE CEST‐MRI of human brain tumors at 3 T

Purpose: Relaxation‐compensated CEST‐MRI (i.e., the inverse metrics magnetization transfer ratio and apparent exchange‐dependent relaxation) has already been shown to provide valuable information for brain tumor diagnosis at ultrahigh magnetic field strengths. This study aims at translating the established acquisition protocol at 7 T to a clinically relevant magnetic field strength of 3 T. Methods: Protein model solutions were analyzed at multiple magnetic field strengths to assess the spectral widths of the amide proton transfer and relayed nuclear Overhauser effect (rNOE) signals at 3 T. This prior knowledge of the spectral range of CEST signals enabled a reliable and stable Lorentzian‐fitting also at 3 T where distinct peaks are no longer resolved in the Z‐spectrum. In comparison to the established acquisition protocol at 7 T, also the image readout was extended to three dimensions. Results: The observed spectral range of CEST signals at 3 T was approximately ±15 ppm. Final relaxation‐compensated amide proton transfer and relayed nuclear Overhauser effect contrasts were in line with previous results at 7 T. Examination of a patient with glioblastoma demonstrated the applicability of this acquisition protocol in a clinical setting. Conclusion: The presented acquisition protocol allows relaxation‐compensated CEST‐MRI at 3 T with a 3D coverage of the human brain. Translation to a clinically relevant magnetic field strength of 3 T opens the door to trials with a large number of participants, thus enabling a comprehensive assessment of the clinical relevance of relaxation compensation in CEST‐MRI

Entwicklung von Schutzschichten fuer Turbinenteile durch Kombination verschiedener Beschichtungsverfahren Abschlussbericht. Abschlussdatum des Vorhabens: Juni 1986

With photosTIB: RN 3754 (85/903) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Bioinformatic approaches for functional annotation and pathway inference in metagenomics data

Metagenomic approaches are increasingly recognized as a baseline for understanding the ecology and evolution of microbial ecosystems. The development of methods for pathway inference from metagenomics data is of paramount importance to link a phenotype to a cascade of events stemming from a series of connected sets of genes or proteins. Biochemical and regulatory pathways have until recently been thought and modelled within one cell type, one organism, one species. This vision is being dramatically changed by the advent of whole microbiome sequencing studies, revealing the role of symbiotic microbial populations in fundamental biochemical functions. The new landscape we face requires a clear picture of the potentialities of existing tools and development of new tools to characterize, reconstruct and model biochemical and regulatory pathways as the result of integration of function in complex symbiotic interactions of ontologically and evolutionary distinct cell type