Matrix metalloproteinases in human spontaneous intracerebral hemorrhage: an update

Background: In default of a plausible and satisfactory causal treatment for hemorrhagic stroke, a role of matrix metalloproteinases (MMPs) in the pathogenesis of cerebrovascular diseases has recently been widely discussed. The well-known impact of MMPs on extracellular matrix destruction triggered by inflammation as a foundation for several diseases, including stroke, is very much in evidence. Newly, some additional aspects of MMP function considering their intracellular activity crucial for neuronal death following ischemic brain damage have emerged. The effect of blood-brain barrier disruption caused by MMPs on the prognosis in patients suffering from spontaneous intracerebral hemorrhage (ICH) has been of interest since it throws a new light upon the pathogenesis, course and possible therapeutic approaches for this least treatable and at the same time most life-threatening form of stroke. Hence, we primarily aimed to review the current clinical knowledge on the significance of metalloproteinase activation in the course of spontaneous intracranial hemorrhage in humans. We also provide a brief characterization of the MMP enzyme family and report on the latest findings on issues arising from experimental studies. Methods: A Medline search using the following key words was performed: matrix metalloproteinases + spontaneous intracerebral hemorrhage/intracranial hemorrhage/bleeding/hemorrhagic stroke. We accepted studies reporting on MMP expression in adult patients with spontaneous ICH, as well as its relation to radiological and clinical features and patients’ outcome. For the final review, 18 clinical studies were considered. MMP inhibition was reviewed on the basis of 11 relevant experimental studies. Also, some relevant reports on the biology of MMPs and their pathophysiology in ICH were reviewed. Results and Conclusions: Many studies provide convincing evidence of a detrimental role of MMPs in ICH, stressing their association with neuroinflammation. The role of MMPs in hemorrhagic stroke appears critical for hematoma and brain edema growth as well as for neuronal death, which are understood as secondary brain injury and may have a considerable clinical impact. Although data on human spontaneous ICH are scarce and mostly based on small populations, they reveal the apparent correlation between MMPs and clinical and radiological ICH features as well as the functional outcome, which might rationalize future therapeutic strategies. However, attempts at MMP inhibition in spontaneous ICH have solely been made under experimental conditions and were associated with a wide range of possible side effects. Therefore, further comprehensive, elucidating investigations in this field are vital before any conclusions could be translated to humans. Copyright (C) 2012 S. Karger AG, Base

European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage

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Junction formation by Zn(O,S) sputtering yields CIGSe-based cells with efficiencies exceeding 18%

In an effort to reduce the complexity and associated production costs of Cu(In,Ga)Se2 (CIGSe)-based solar cells, the commonly used sputtered undoped ZnO layer has been modified to eliminate the requirement for a dedicated buffer layer. After replacing the ZnO target with a mixed ZnO/ZnS target, efficient solar cells could be prepared by sputtering directly onto the as- grown CIGSe surface. This approach has now been tested with high-quality lab- scale glass/Mo/CIGSe substrates. An efficiency of 18.3% has been independently confirmed without any post-deposition annealing or light soaking

Prothrombin complex concentrate versus placebo, no intervention, or other interventions in critically bleeding patients associated with oral anticoagulant administration: a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis

Background: Acute critical bleeding is one of the most feared complications during treatment with oral anticoagulating agents. As more patients undergo treatment with anticoagulating agents, critically bleeding episodes in patients with vitamin K antagonists, thrombin inhibitor, or factor Xa inhibitor-inducted coagulopathy will be encountered frequently by physicians. Hence, an effective treatment capable of reversing the iatrogenic coagulopathy in the acute setting is needed. In randomised clinical trials and observational studies, prothrombin complex concentrate has been reported to be superior to other acute interventions, and many guidelines recommend prothrombin complex concentrate in treatment of critically bleeding patients. The aim of this systematic review is to synthesise the evidence of the effects of prothrombin complex concentrate compared with placebo, no intervention, or other treatment options in critically bleeding patients treated with oral anticoagulants. Methods/design: A comprehensive search for relevant published literature will be undertaken in Cochrane Central Register of Controlled Trials, MEDLINE, Embase, WHO International Clinical Trials Registry Platform, Science Citation Index, regulatory databases, and trial registers. We will include randomised clinical trials comparing prothrombin complex concentrate versus placebo, no intervention, or other interventions in critically bleeding patients with oral anticoagulant-induced coagulopathy. Data extraction and risk of bias assessment will be handled by two independent review authors. Meta-analysis will be performed as recommended by Cochrane Handbook for Systematic Reviews of Interventions, bias will be assessed with domains, and trial sequential analysis will be conducted to control random errors. Certainty will be assessed by GRADE. Discussion: As critical bleeding in patients treated with oral anticoagulants is an increasing problem, an up-to-date systematic review evaluating the benefits and harms of prothrombin complex concentrate is urgently needed. It is the hope that this review will be able to guide best practice in treatment and clinical research of these critically bleeding patients. Systematic review registration: PROSPERO CRD4201808437

Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .)

Haemostatic therapies for acute spontaneous intracerebral haemorrhage

Background: Outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume; up to one-third of ICHs enlarge within 24 hours of onset. Early haemostatic therapy might improve outcome by limiting haematoma growth. This is an update of a Cochrane Review first published in 2006, and last updated in 2009. Objectives: To examine 1) the effectiveness and safety of individual classes of haemostatic therapies, compared against placebo or open control, in adults with acute spontaneous intracerebral haemorrhage, and 2) the effects of each class of haemostatic therapy according to the type of antithrombotic drug taken immediately before ICH onset (i.e. anticoagulant, antiplatelet, or none). Search methods: We searched the Cochrane Stroke Trials Register, CENTRAL; 2017, Issue 11, MEDLINE Ovid, and Embase Ovid on 27 November 2017. In an effort to identify further published, ongoing, and unpublished randomised controlled trials (RCT), we scanned bibliographies of relevant articles and searched international registers of RCTs in November 2017. Selection criteria: We sought randomised controlled trials (RCTs) of any haemostatic intervention (i.e. pro-coagulant treatments such as coagulation factors, antifibrinolytic drugs, or platelet transfusion) for acute spontaneous ICH, compared with placebo, open control, or an active comparator, reporting relevant clinical outcome measures. Data collection and analysis: Two authors independently extracted data, assessed risk of bias, and contacted corresponding authors of eligible RCTs for specific data if they were not provided in the published report of an RCT. Main results: We included 12 RCTs involving 1732 participants. There were seven RCTs of blood clotting factors versus placebo or open control involving 1480 participants, three RCTs of antifibrinolytic drugs versus placebo or open control involving 57 participants, one RCT of platelet transfusion versus open control involving 190 participants, and one RCT of blood clotting factors versus fresh frozen plasma involving five participants. We were unable to include two eligible RCTs because they presented aggregate data for adults with ICH and other types of intracranial haemorrhage. We identified 10 ongoing RCTs. Across all seven criteria in the 12 included RCTs, the risk of bias was unclear in 37 (44%), high in 16 (19%), and low in 31 (37%). Only one RCT was at low risk of bias in all criteria. In one RCT of platelet transfusion versus open control for acute spontaneous ICH associated with antiplatelet drug use, there was a significant increase in death or dependence (modified Rankin Scale score 4 to 6) at day 90 (70/97 versus 52/93; risk ratio (RR) 1.29, 95% confidence interval (CI) 1.04 to 1.61, one trial, 190 participants, moderate-quality evidence). All findings were non-significant for blood clotting factors versus placebo or open control for acute spontaneous ICH with or without surgery (moderate-quality evidence), for antifibrinolytic drugs versus placebo (moderate-quality evidence) or open control for acute spontaneous ICH (moderate-quality evidence), and for clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use (no evidence). Authors' conclusions: Based on moderate-quality evidence from one trial, platelet transfusion seems hazardous in comparison to standard care for adults with antiplatelet-associated ICH. We were unable to draw firm conclusions about the efficacy and safety of blood clotting factors for acute spontaneous ICH with or without surgery, antifibrinolytic drugs for acute spontaneous ICH, and clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use

The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice

Background: Genome-wide association studies in asthma have repeatedly identified single nucleotide polymorphisms in the ORM (yeast)-like protein isoform 3 (ORMDL3) gene across different populations. Although the ORM homologues in yeast are well-known inhibitors of sphingolipid synthesis, it is still unclear whether and how mammalian ORMDL3 regulates sphingolipid metabolism and whether altered sphingolipid synthesis would be causally related to asthma risk. Objective: We sought to examine the in vivo role of ORMDL3 in sphingolipid metabolism and allergic asthma. Methods: Ormdl3-LacZ reporter mice, gene-deficient Ormdl3(-/-) mice, and overexpressing Ormdl3(Tg/wt) mice were exposed to physiologically relevant aeroallergens, such as house dust mite (HDM) or Alternaria alternata, to induce experimental asthma. Mass spectrometry-based sphingolipidomics were performed, and airway eosinophilia, T(H)2 cytokine production, immunoglobulin synthesis, airway remodeling, and bronchial hyperreactivity were measured. Results: HDM challenge significantly increased levels of total sphingolipids in the lungs of HDM-sensitized mice compared with those in control mice. In Ormdl3(Tg/wt) mice the allergen-induced increase in lung ceramide levels was significantly reduced, whereas total sphingolipid levels were not affected. Conversely, in liver and serum, levels of total sphingolipids, including ceramides, were increased in Ormdl3(-/-) mice, whereas they were decreased in Ormdl3(Tg/wt) mice. This difference was independent of allergen exposure. Despite these changes, all features of asthma were identical between wildtype, Ormdl3(Tg/wt), and Ormdl3(-/-) mice across several models of experimental asthma. Conclusion: ORMDL3 regulates systemic ceramide levels, but genetically interfering with Ormdl3 expression does not result in altered experimental asthma

Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

<div><p>Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. <i>GORAB</i>, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the <i>Gorab</i>^<i>Null</i> full knockout, <i>Gorab</i> was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only <i>Gorab</i>^Prx1 and <i>Gorab</i>^Runx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of <i>Gorab</i>^<i>Null</i> mutants and in bone of <i>Gorab</i>^Prx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from <i>Gorab</i>^<i>Null</i> mutants. In bone from <i>Gorab</i>^Prx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured <i>GORAB</i>-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-β in <i>Gorab</i>^Prx1 bone tissue leading to enhanced downstream signalling, which was reproduced in <i>GORAB</i>-deficient fibroblasts. Our data suggest that the loss of <i>Gorab</i> primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.</p></div