Intracarotid administration of human bone marrow mononuclear cells in rat photothrombotic ischemia

Background: Increasing evidence suggests that cell therapy improves functional recovery in experimental models of stroke and myocardial infarction. So far only small pilot trials tested the effects of cell therapy in stroke patients, whereas large clinical trials were conducted in patients with ischemic heart disease. To investigate the therapeutic benefit of cell therapy to improve the recovery after stroke, we determined the efficacy of bone marrow derived mononuclear cells, which were shown to improve the recovery in experimental and clinical acute myocardial infarction studies, in a rat stroke model. Methods: Adult male Wistar rats were randomly assigned to receive either five million human bone marrow mononuclear cells (hBMC) or placebo intraarterially 3 days after photothrombotic ischemia. For immunosuppression the animals received daily injections of cyclosporine throughout the experiment, commencing 24 hours before the cell transplantation. A battery of behavioural tests was performed before and up to 4 weeks after ischemia. Results: Body temperature and body weight revealed no difference between groups. Neurological deficits measured by the Rotarod test, the adhesive-removal test and the cylinder test were not improved by hBMC transplantation compared to placebo. Conclusions: This study demonstrates that hBMC do not improve functional recovery when transplanted intraaterially 3 days after the onset of focal cerebral ischemia. A possible reason for the failed neurological improvement after cell therapy might be the delayed treatment initiation compared to other experimental stroke studies that showed efficacy of bone marrow mononuclear cells

Granulocyte-colony stimulating factor in experimental stroke and its effects on infarct size and functional outcome: a systematic review

Background Granulocyte-colony stimulating factor (G-CSF) shows promise as a treatment for stroke. This systematic review assesses G-CSF in experimental ischaemic stroke. Methods Relevant studies were identified with searches of Medline, Embase and PubMed. Data were extracted on stroke lesion size, neurological outcome and quality, and analysed using Cochrane Review Manager using random effects models; results are expressed as standardised mean difference (SMD) and odds ratio (OR). Results Data were included from 19 publications incorporating 666 animals. G-CSF reduced lesion size significantly in transient (SMD -1.63, p4 weeks post ischaemia) was not (SMD 0.76, p=0.35). Death (OR 0.27, p<0.0001) was reduced with G-CSF. Median study quality was 4 (range 0-7/8); Egger’s test suggested significant publication bias (p=0.001). Conclusions G-CSF significantly reduced lesion size in transient but not permanent models of ischaemic stroke. Motor impairment and death were also reduced. Further studies assessing dose-response, administration time, length of ischaemia and long-term functional recovery are needed

Bone marrow-derived mononuclear cells do not exert acute neuroprotection after stroke in spontaneously hypertensive rats

Bone marrow-derived mononuclear cells (BM-MNCs) were shown to improve the outcome in animal stroke models and clinical pilot studies on BM-MNCs for stroke patients were already conducted. However, relevant aspects of pre-clinical evaluation, such as the use of animals with comorbidities and dose-response studies, were not thoroughly addressed so far. We therefore investigated different BM-MNC doses in the clinical meaningful stroke model of spontaneously hypertensive (SH) rats. Three hours after the onset of transient middle cerebral artery occlusion (MCAO) animals received either one of three syngeneic BM-MNC doses or placebo intravenously. The primary endpoint was the infarct size. Secondary endpoints included functional outcome, mortality, inflammatory processes, and the dose-response relationship. In contrast to previous studies which used healthy animals no beneficial effect of BM-MNCs was found. Infarct volumes, mortality, behavioral outcomes, and the extent of the inflammatory response to cerebral ischemia were comparable in all groups. In conclusion, we could not demonstrate that early BM-MNC treatment improves the outcome after stroke in SH rats. Whether BM-MNCs improve neurological recovery after delayed treatment initiation was not investigated in the present study, but our data indicates that this should be determined in co-morbid animal stroke models before moving to large-scale clinical studies. Future preclinical stroke studies on co-morbid animals should also include groups of healthy animals in order to determine whether negative results can be attributed to the comorbid condition

G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial

Background: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.Methods: Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 mu g/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.Results: Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.Conclusions: Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors

Erythropoietin for stroke treatment: dead or alive?

Endothelial progenitor cell (EPC) mobilization from the bone marrow was considered to improve outcome after ischemic stroke. Erythropoietin (EPO) might be a potential candidate stroke drug that increases the number of circulating EPCs. In the previous issue of Critical Care, Yip and colleagues investigated the effect of EPO in stroke patients on both clinical outcome and EPC stimulation. Although beneficial effects of EPO were observed, several issues regarding EPO's suitability as a stroke drug remain

Case Study of Holistic Energy Management Using Genetic Algorithms in a Sliding Window Approach

Energy management systems are used to find a compromise between conflicting goals that can be identified for battery electric vehicles. Typically, these are the powertrain efficiency, the comfort of the driver, the driving dynamics, and the component aging. This paper introduces an optimization-based holistic energy management system for a battery electric vehicle. The energy management system can adapt the vehicle velocity and the power used for cabin heating, in order to minimize the overall energy consumption, while keeping the total driving time and the cabin temperature within predefined limits. A genetic algorithm is implemented in this paper. The approach is applied to different driving cycles, which are optimized by dividing them into distinctive time frames. This approach is referred to as the sliding window approach. The optimization is conducted with two separate driving cycles, the New European Driving Cycle (NEDC) and a recorded real-world drive. These are analyzed with regard to the aspects relevant to the energy management system, and the optimization results for the two cycles are compared. The results presented in this paper demonstrate the feasibility of the sliding window approach. Moreover, they reveal the differences in fundamental parameters between the NEDC and the recorded drive and how they affect the optimization results. The optimization leads to an overall reduction in energy consumption of "inline-formula" "math display="inline"" "semantics" "mrow" "mn"3.37"/mn" "mo"%"/mo" "/mrow" "/semantics" "/math" "/inline-formula" for the NEDC and "inline-formula" "math display="inline"" "semantics" "mrow" "mn"3.27"/mn" "mo"%"/mo" "/mrow" "/semantics" "/math" "/inline-formula" for the recorded drive, without extending the travel time. Document type: Articl

Experimental RNomics in Aquifex aeolicus: identification of small non-coding RNAs and the putative 6S RNA homolog

By an experimental RNomics approach, we have generated a cDNA library from small RNAs expressed from the genome of the hyperthermophilic bacterium Aquifex aeolicus. The library included RNAs that were antisense to mRNAs and tRNAs as well as RNAs encoded in intergenic regions. Substantial steady-state levels in A.aeolicus cells were confirmed for several of the cloned RNAs by northern blot analysis. The most abundant intergenic RNA of the library was identified as the 6S RNA homolog of A.aeolicus. Although shorter in size (150 nt) than its γ-proteobacterial homologs (∼185 nt), it is predicted to have the most stable structure among known 6S RNAs. As in the γ-proteobacteria, the A.aeolicus 6S RNA gene (ssrS) is located immediately upstream of the ygfA gene encoding a widely conserved 5-formyltetrahydrofolate cyclo-ligase. We identifed novel 6S RNA candidates within the γ-proteobacteria but were unable to identify reasonable 6S RNA candidates in other bacterial branches, utilizing mfold analyses of the region immediately upstream of ygfA combined with 6S RNA blastn searches. By RACE experiments, we mapped the major transcription initiation site of A.aeolicus 6S RNA primary transcripts, located within the pheT gene preceding ygfA, as well as three processing sites

Die deutsche Frage - Problemskizze und Thesen

Wohl mit keinem anderen Problem hat sich die marxistische Arbeiterbewegung so schwer getan wie mit dem der Nation. Die Annalen des Sozialismus und Kommunismus sind gefüllt mit unbewältigten theoretischen und praktischen Problemen im Umfeld des Begriffspaars Klasse-Nation, und Deutschland macht darin keine Ausnahme. Im Gegenteil: wenn schon ganz allgemein nicht von der marxistisch-sozialistischen Theorie der Nation gesprochen werden kann, so ergeben sich aus den Besonderheiten der deutschen Geschichte ganz spezifische Hindernisse für eine unbefangene Diskussion der nationalen Problematik auf der Linken. Eine sozialistische Analyse der »Deutschen Frage« nach 1945 muss sich deshalb zunächst auch der Frage stellen, welcher theoretische Nationen begriff und welches Verständnis der Nationalgeschichte Deutschlands ihr zugrundeliegen