Quest for Quality in Translational Stroke Research—A New Dawn for Neuroprotection?

Despite tremendous progress in modern-day stroke therapy, ischemic stroke remains a disease associated with a high socioeconomic burden in industrialized countries. In light of demographic change, these health care costs are expected to increase even further. The current causal therapeutic treatment paradigms focus on successful thrombolysis or thrombectomy, but only a fraction of patients qualify for these recanalization therapies because of therapeutic time window restrictions or contraindications. Hence, adjuvant therapeutic concepts such as neuroprotection are urgently needed. A bench-to-bedside transfer of neuroprotective approaches under stroke conditions, however, has not been established after more than twenty years of research, albeit a great many data have demonstrated several neuroprotective drugs to be effective in preclinical stroke settings. Prominent examples of substances supported by extensive preclinical evidence but which failed clinical trials are tirilazad and disodium 2,4-sulphophenyl-N-tert-butylnitrone (NXY-059). The NXY-059 trial, for instance, was retrospectively shown to have a seriously weak study design, a trial of insufficient quality and a poor statistical analysis, although it initially met the recommendations of the STAIR committee. In light of currently ongoing novel neuroprotective stroke trials, such as ESCAPE-NA, and to avoid the mistakes made in the past, an improvement in study quality in the field of stroke neuroprotection is urgently needed. In the present review, animal models closely reflecting the “typical” stroke patient, occlusion techniques and the appropriate choice of time windows are discussed. In this context, the STAIR recommendations could provide a useful orientation. Taking all of this into account, a new dawn for neuroprotection might be possible.     

Characterisation of Extracellular Vesicles from Equine Mesenchymal Stem Cells

Extracellular vesicles (EVs) are nanosized lipid bilayer-encapsulated particles secreted by virtually all cell types. EVs play an essential role in cellular crosstalk in health and disease. The cellular origin of EVs determines their composition and potential therapeutic effect. Mesenchymal stem/stromal cell (MSC)-derived EVs have shown a comparable therapeutic potential to their donor cells, making them a promising tool for regenerative medicine. The therapeutic application of EVs circumvents some safety concerns associated with the transplantation of viable, replicating cells and facilitates the quality-controlled production as a ready-to-go, off-the-shelf biological therapy. Recently, the International Society for Extracellular Vesicles (ISEV) suggested a set of minimal biochemical, biophysical and functional standards to define extracellular vesicles and their functions to improve standardisation in EV research. However, nonstandardised EV isolation methods and the limited availability of cross-reacting markers for most animal species restrict the application of these standards in the veterinary field and, therefore, the species comparability and standardisation of animal experiments. In this study, EVs were isolated from equine bone-marrow-derived MSCs using two different isolation methods, stepwise ultracentrifugation and size exclusion chromatography, and minimal experimental requirements for equine EVs were established and validated. Equine EVs were characterised using a nanotracking analysis, fluorescence-triggered flow cytometry, Western blot and transelectron microscopy. Based on the ISEV standards, minimal criteria for defining equine EVs are suggested as a baseline to allow the comparison of EV preparations obtained by different laboratories.     

Using fiber optics to tap the sun's power

This paper discusses a solar energy collection system in which optical fibers are used to transport energy from a single-stage and a double-stage, three-dimensional Compound Parabolic Concentrator (CPC). After developing a thermo-mathematical model for the assembly of CPC and fibers, numerical simulations are used to optimize the system design. The modules filled with plastic and glass are shown to perform considerably better than those filled with air. A two-stage system performs better than a single-stage module. CPC surface reflectance improves the yield but an increase in fiber length decreases the performance.     

Stand und Auswirkungen der globalen Harmonisierung der Einstufung und Kennzeichnung gefährlicher Stoffe und Güter

In Chapter 19 of Agenda 21 regarding the worldwide environmentally sound management of toxic (dangerous) chemicals the UN Conference on Environment and Development (UNCED) in June 1992 in Rio de Janeiro agreed to adopt — amongst others — the global harmonization of classification and labelling of chemicals by the year 2000. Under the name of »global harmonization« this programme has made considerable progress, but it is not generally known in detail — except by those directly involved — what has happened, and what will still happen, what harmonization in this context means, and what the consequences will be when this ambitious goal is finally reached. The submitted contribution attempts as far as possible to overcome this information deficit.     

Posttraumatic Inflammation as a Key to Neuroregeneration after Traumatic Spinal Cord Injury

Pro- and anti-inflammatory cytokines might have a large impact on the secondary phase and on the neurological outcome of patients with acute spinal cord injury (SCI). We measured the serum levels of different cytokines (Interferon-γ, Tumor Necrosis Factor-α, Interleukin-1β, IL-6, IL-8, IL-10, and Vascular Endothelial Growth Factor) over a 12-week period in 40 acute traumatic SCI patients: at admission on average one hour after initial trauma; at four, nine, 12, and 24 h; Three, and seven days after admission; and two, four, eight, and twelve weeks after admission. This was done using a Luminex Performance Human High Sensitivity Cytokine Panel. SCI was classified using the American Spinal Injury Association (ASIA) Impairment Scale (AIS) at time of admission and after 12 weeks. TNFα, IL-1β, IL-6, IL-8, and IL-10 concentrations were significantly higher in patients without neurological remission and in patients with an initial AIS A (p < 0.05). This study shows significant differences in cytokine concentrations shown in traumatic SCI patients with different neurological impairments and within a 12-week period. IL-8 and IL-10 are potential peripheral markers for neurological remission and rehabilitation after traumatic SCI. Furthermore our cytokine expression pattern of the acute, subacute, and intermediate phase of SCI establishes a possible basis for future studies to develop standardized monitoring, prognostic, and tracking techniques.     

Fetal Immunomodulatory Environment Following Cartilage Injury—The Key to CARTILAGE Regeneration?

Fetal cartilage fully regenerates following injury, while in adult mammals cartilage injury leads to osteoarthritis (OA). Thus, in this study, we compared the in vivo injury response of fetal and adult ovine articular cartilage histologically and proteomically to identify key factors of fetal regeneration. In addition, we compared the secretome of fetal ovine mesenchymal stem cells (MSCs) in vitro with injured fetal cartilage to identify potential MSC-derived therapeutic factors. Cartilage injury caused massive cellular changes in the synovial membrane, with macrophages dominating the fetal, and neutrophils the adult, synovial cellular infiltrate. Correspondingly, proteomics revealed differential regulation of pro- and anti-inflammatory mediators and growth-factors between adult and fetal joints. Neutrophil-related proteins and acute phase proteins were the two major upregulated protein groups in adult compared to fetal cartilage following injury. In contrast, several immunomodulating proteins and growth factors were expressed significantly higher in the fetus than the adult. Comparison of the in vitro MSCs proteome with the in vivo fetal regenerative signature revealed shared upregulation of 17 proteins, suggesting their therapeutic potential. Biomimicry of the fetal paracrine signature to reprogram macrophages and modulate inflammation could be an important future research direction for developing novel therapeutics.     

Effect of alpha-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention

BACKGROUND: Polyamines (e.g., putrescine, spermidine, and spermine) are required for optimal cell growth. Inhibition of polyamine synthesis suppresses carcinogen-induced epithelial cancers, including colon cancer, in animal models. In a short-term phase IIa trial, we determined that low doses of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (an enzyme involved in polyamine synthesis), reduced the polyamine content of normal-appearing rectal mucosa of subjects with a prior history of resected colon polyps. In a follow-up study, we have attempted to determine the lowest dose of DFMO that can suppress the polyamine content of rectal mucosa over a course of 1 year with no or minimal side effects. METHODS: Participants were randomly assigned to daily oral treatment with a placebo or one of three doses (0.075, 0.20, or 0.40 g/m2) of DFMO. Baseline and serial determinations of polyamine levels in rectal mucosa and extensive symptom monitoring (including audiometric measurements, since DFMO causes some reversible hearing loss at higher doses) were performed over a 15-month period. RESULTS: DFMO treatment reduced putrescine levels in a dose-dependent manner. Following 6 months of treatment, doses of 0.20 and 0.40 g/m2 per day reduced putrescine levels to approximately 34% and 10%, respectively, of those observed in the placebo group. Smaller decreases were seen in spermidine levels and spermidine:spermine ratios. Polyamine levels increased toward baseline values after discontinuation of DFMO. Although there were no statistically significant differences among the dose groups with respect to clinically important shifts in audiometric thresholds and nonaudiologic side effects, statistically significant higher dropout and discontinuation rates were observed in the highest dose group. CONCLUSIONS: Polyamine levels in rectal mucosa can be continuously suppressed by daily oral doses of DFMO that produce few or no side effects. A dose of 0.20 g/m2 can be used safely in combination phase IIb or single-agent phase III chemoprevention trials.     

Composite expansions on forced convection over a flat plate with an unheated starting length

The elliptic energy equation for steady, two-dimensional incompressible flow over a flat plate with an unheated starting length is analyzed using matched asymptotic expansions where the boundary layer solution has been treated as the outer expansion corresponding to the leading-edge equation as the inner expansion. It has been revealed that the linear velocity profile of flow occurs near the leading-edge of the heated part of the plate. This new technique for solving elliptic-to-parabolic equations involves stretching two different scales for two independent variables in the inner expansion. Results are applicable to the region where boundary layer theory breaks down, which is particularly interesting in microscale heat transfer.     

坎皮拉办公楼 奥地利维亚纳新城

正坎皮拉公司办公楼由天然石材筑成,大厅宽敞,内设办公室和行政区域,安保仓库配有运输区、储藏区。我们把坎皮拉公司办公楼做了大规模翻修,采用高质量、具代表性内部固定设施。仓库是一座混凝土独立建筑,半开放式设计尤为引人注目,出于为仓储考虑,屋顶上的灯倾斜设置,天花板则形似漂浮在这些灯上一样,整栋建筑看起来似乎没有封闭,却充满活力。     

Integrated approach for disassembly processes generation and recycling evaluation of an end-of-life product

An integrated approach for noble recycling is presented that puts forward the functional value of products and components. In a first step, the approach determines all feasible automatic disassembly sequences and in a second step all applicable recycling activities. This allows one to determine the most appropriate recycling process for an end-of-life product considering concurrent recycling techniques. The feasible automatic disassembly sequences are established by simulation in a virtual environment. The required generic disassembly product model, as well as the generic disassembly activity model, is presented by means of static and dynamic object-oriented diagrams. The recycling evaluation establishes an efficient solution responding to economic and ecological decision criteria. It is calculated applying a Goal-Programming approach transforming the multi-objective linear problem into a monocriteria linear program. The techno-economic decision model applied is Linear Activity Analysis. It allows one to integrate the generated disassembly processes based on single disassembly activities as well as other recycling techniques.