Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivated prothrombin complex (Proplex) with a Kingdon time between 100 and 138 seconds effected functional recovery and adequate haemostasis in a haemophiliac with inhibitors of the high-responder type at comparatively low cost, and with no adverse effects. Home treatment was successful. Liver function remained normal during treatment. Statistically significant changes occurred in the prothrombin time (PT), fibrinogen levels and the thrombin time after each infusion. No evidence of diffuse intravascular coagulation (DIC) was ever detected. The inhibitor level decreased from 10 to 2 Bethesda units, and the radio-immunoassay (RIA) for Australia antigen remained negative.
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PMID:Inactivated Proplex for the haemophiliac with inhibitors. A case report. 49 25

Repeated fibrinogen determination were made in 24 patients suffering from subarachnoid hemorrhage(SAH), in order to know the influence of blood content of fibrinogen upon the ischemic complications following vasospasm. In 11 cases (group II) among those 24 patients admitted within two weeks after the last SAH due to ruptured intracrainal aneruysm, a rise in fibrinogen over 600 mg/dl occurred, while in remaining 12 cases (group I) the levels of fibrinogen were kept below 600 mg/dl during the acute stage. In cases of group II, fibrinogen began to increase in accordance with the augmentation of vasospasm and reached to peak within 4 to 9 days after the onset of SAH. Blood viscosity also increased showing positive correlation with the increase in fibrinogen, and rose over 1.5 times normal value when fibrinogen exceeded 600 mg/dl. Reduction of anti-thrombin III was also observed in group II patients previous to the increase in fibrinogen, suggesting the occurrence of hypercoagulability in association with the appearance of vasospasm. In most cases of group II, their neurological signs deteriorated markedly at the time when fibrinogen rose over 600 mg/dl. The mortality in group II whose fibrinogen increased over 600 mg/dl was of 6 of 11, with poor recovery of function among the survivors; of those with levels below 600 mg/dl (group I), only 1 of 12 died and all of remaining 11 made a reasonably good functional recovery. These facts suggest that the increase in fibrinogen would cause the aggression of the ischemic complications following vasospasm through the diminution the cerebral microcirculation induced by the raised blood viscosity, and the critical level of fibrinogen increase as the alarming sign for the ischemic complications was 600 mg/dl. One should attract attention to the changes of fibrinogen level as one of the risk risk factors in acute stage of SAH.
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PMID:[Studies on the fibrinolytic system in ruptured intracranial aneurysm.--Part 2: Fibrinogen changes in acute stage of SAH as a risk factor of the ischemic complications following vasospasm (author's transl)]. 67 36

The current study examines nestin expression after intracerebral hemorrhage (ICH), the role of different blood components in nestin upregulation, and the possibility that low doses of thrombin that induce tolerance to brain injury (thrombin preconditioning) might also induce nestin expression. Adult male Sprague-Dawley rats received an intracaudate injection of either whole blood, thrombin (1 or 5 U) or red blood cells (RBCs). Animals were sacrificed for single and double labeling immunohistochemistry to identify which cells express nestin, and for Western blotting to quantify nestin expression. By immunohistochemistry, nestin immunoreactivity was present in large numbers of astrocytes, surrounding the hematoma from day 3 to 1 week after ICH. After 2 weeks, nestin immunoreactivity was co-localized with a neuronal marker (neuronal specific enolase). By Western blot analysis, nestin was strongly expressed at day 3 (P<0.01) and 1 week (P<0.01), and expression persisted for at least 1 month (P<0.05). Intracerebral injection of thrombin or lysed RBCs resulted in a marked increase in nestin expression. Interestingly, injection of a low dose of thrombin that induces brain tolerance also upregulated nestin. The ICH-induced nestin expression in astrocytes may reflect an early response of these cells to injury, while the delayed expression in neurons might be a part of the adaptative response to injury perhaps leading to recovery of function. Nestin induction by a low dose of thrombin suggests that specific receptor-mediated pathways are involved in inducing nestin expression and that nestin may play a role in thrombin preconditioning.
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PMID:Nestin expression after experimental intracerebral hemorrhage. 1288 31

We have studied ischemic tolerance induced by the serine protease thrombin in two different models of experimental ischemia. In organotypic hippocampal slice cultures, we demonstrate that incubation with low doses of thrombin protects neurons against a subsequent severe oxygen and glucose deprivation. L-JNKI1, a highly specific c-jun N-terminal kinase (JNK) inhibitor, and a second specific JNK inhibitor, SP600125, prevented thrombin preconditioning (TPC). We also show that the exposure to thrombin increases the level of phosphorylated c-jun, the major substrate of JNK. TPC, in vivo, leads to significantly smaller lesion sizes after a 30-min middle cerebral artery occlusion (MCAo), and the preconditioned mice were better off in the three tests used to evaluate functional recovery. In accordance with in vitro results, TPC in vivo was prevented by administration of L-JNKI1, supporting a role for JNK in TPC. These results, from two different TPC models and with two distinct JNK inhibitors, show that JNK is likely to be involved in TPC.
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PMID:Thrombin-induced ischemic tolerance is prevented by inhibiting c-jun N-terminal kinase. 1736 85

Myocardial ischemia/reperfusion (I/R) injury is partly mediated by thrombin. In support, the functional inhibition of thrombin has been shown to decrease infarct size after I/R. Several cellular responses to thrombin are mediated by a G-protein coupled protease-activated receptor 1 (PAR1).However, the role of PAR1 in myocardial I/R injury has not been well characterized. Therefore, we hypothesized that PAR1 inhibition will reduce the amount of myocardial I/R injury. After we detected the presence of PAR1 mRNA and protein in the rat heart by RT-PCR and immunoblot analysis,we assessed the potential protective role of SCH 79797, a selective PAR1 antagonist, in two rat models of myocardial I/R injury. SCH 79797 treatment immediately before or during ischemia reduced myocardial necrosis following I/R in the intact rat heart. This response was dose-dependent with the optimal dose being 25 microg/kg IV. Likewise, SCH 79797 treatment before ischemia in the isolated heart model reduced infarct size and increased ventricular recovery following I/R in the isolated heart model with an optimal concentration of 1 microM. This reduction was abolished by a PAR1 selective agonist. SCH 79797-induced resistance to myocardial ischemia was abolished by wortmannin, an inhibitor of PI3 kinase; L-NMA, a NOS inhibitor; and glibenclamide, a nonselective K(ATP) channel blocker. PAR1 activating peptide,wortmannin, L-NMA and glibenclamide alone had no effect on functional recovery or infarct size. A single treatment of SCH 79797 administered prior to or during ischemia confers immediate cardioprotection suggesting a potential therapeutic role of PAR1 antagonist in the treatment of injury resulting from myocardial ischemia and reperfusion.
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PMID:SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts. 1746 33

The current study examined 3CB2, a marker of radial glia, expression after intracerebral hemorrhage (ICH) and intracerebral thrombin injection. Adult male Sprague-Dawley rats received an intracaudate injection of 100 microl autologous whole blood or 5 U thrombin (50 microl). Animals were sacrificed for Western blotting to quantify 3CB2 expression, and for single and double labeling immunohistochemistry to identify which cells express 3CB2. Behavioral examinations (forelimb placing test and corner turn test) were performed as an evaluation of function. By Western blot analysis, 3CB2 was strongly expressed at day 3 and the expression persisted for at least 1 month. Intracerebral injection of thrombin also upregulated 3CB2. Hirudin, a thrombin inhibitor, reduced ICH-induced 3CB2 expression. By immunohistochemistry, 3CB2 immunoreactivity was present in large numbers of glial cells surrounding the hematoma at 1 day after ICH. One month later, 3CB2 immunoreactivity was co-localized with a neuronal precursor marker, TUC-4. ICH-induced behavioral deficits were severe at 1, 3 and 7 days, with recovery at 1 month. The forelimb placing test score paralleled changes in 3CB2 expression. ICH-induced 3CB2 expression in glial cells may reflect an early response of these cells to injury, while the delayed expression in neurons might be a part of the adaptative response to injury perhaps participating in recovery of function. Thrombin has a role in 3CB2 expression in ICH.
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PMID:3CB2, a marker of radial glia, expression after experimental intracerebral hemorrhage: role of thrombin. 1858 41

Components of the blood have been proposed as potential therapeutic targets for improving cellular regeneration after injury and neurodegenerative disease. In this work, thrombin is shown to increase endogenous neural progenitor proliferation in the intact murine spinal cord. A local injection of heparin before a spinal cord injury reduces cell proliferation and astrogliogenesis associated with scarring. We sought to create depot-formulations of PLGA microsphere and Pluronic F-127 for sustained local delivery of two thrombin inhibitors, heparin and hirudin. Each hydrogel depot-formulation showed delayed drug release compared to microspheres or hydrogel alone. Animals with a lateral demyelination lesion showed a reduction in CD68+ macrophages when treated with hirudin-loaded PLGA/F-127 gels compared to control and heparin-treated animals. Moreover, hirudin-loaded materials showed an accelerated recovery in coordinated stepping and increased oligodendrocyte densities. Together, these data demonstrate that controlled delivery of hirudin accelerates functional recovery from a demyelination lesion in the spinal cord.
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PMID:Poly(lactic-co-glycolic) acid microspheres encapsulated in Pluronic F-127 prolong hirudin delivery and improve functional recovery from a demyelination lesion. 2506 4

Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4 deficiency on cardioprotection after myocardial ischemia-reperfusion (IR) injury in mice. When challenged by in vivo or ex vivo IR, PAR4 knockout (KO) mice exhibited increased tolerance to injury, which was manifest as reduced infarct size and a more robust functional recovery compared to wild-type mice. PAR4 KO mice also showed reduced cardiomyocyte apoptosis and putative signaling shifts in survival pathways in response to IR. Inhibition of PAR4 expression in isolated cardiomyocytes by shRNA offered protection against thrombin and PAR4-agonist peptide-induced apoptosis, while overexpression of wild-type PAR4 significantly enhanced the susceptibility of cardiomyocytes to apoptosis, even under low thrombin concentrations. Further studies implicate Src- and epidermal growth factor receptor-dependent activation of JNK on the proapoptotic effect of PAR4 in cardiomyocytes. These findings reveal a pivotal role for PAR4 as a regulator of cardiomyocyte survival and point to PAR4 inhibition as a therapeutic target offering cardioprotection after acute IR injury.
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PMID:Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury. 2664 15

Spontaneous intracerebral hemorrhage (SICH) continues to be a significant cause of neurologic morbidity and mortality throughout the world. Although recent advances in the treatment of SICH have significantly decreased mortality rates, functional recovery has not been dramatically improved by any intervention to date. There are 2 predominant mechanisms of brain injury from intracerebral hemorrhage: mechanical injury from the primary hematoma (including growth of that hematoma), and secondary injury from perihematomal inflammation. For instance, in the hours to weeks after SICH as the hematoma is being degraded, thrombin and iron are released and can result in neurotoxicity, free radical damage, dysregulated coagulation, and harmful inflammatory cascades; this can clinically and radiologically manifest as perihematomal edema (PHE). PHE can contribute to mass effect, cause acute neurologic deterioration in patients, and has even been associated with poor long-term functional outcomes. PHE therefore lends itself to being a potential therapeutic target. In this article, we will review 1) the pathogenesis and time course of the development of PHE, and 2) the clinical series and trials exploring various methods, with a focus on minimally invasive surgical techniques, to reduce PHE and minimize secondary brain injury. Promising areas of continued research also will be discussed.
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PMID:Treatment Strategies to Attenuate Perihematomal Edema in Patients With Intracerebral Hemorrhage. 2737 15

The Plasticity Related Gene family covers five, brain-specific, transmembrane proteins (PRG1-5, also termed LPPR1-5) that operate in neuronal plasticity during development, aging and brain trauma. Here we investigated the role of the PRG family on axonal and filopodia outgrowth. Comparative analysis revealed the strongest outgrowth induced by PRG3 (LPPR1). During development, PRG3 is ubiquitously located at the tip of neuronal processes and at the plasma membrane and declines with age. In utero electroporation of PRG3 induced dendritic protrusions and accelerated spine formations in cortical pyramidal neurons. The neurite growth promoting activity of PRG3 requires RasGRF1 (RasGEF1/Cdc25) mediated downstream signaling. Moreover, in axon collapse assays, PRG3-induced neurites resisted growth inhibitors such as myelin, Nogo-A (Reticulon/RTN-4), thrombin and LPA and impeded the RhoA-Rock-PIP5K induced neurite repulsion. Transgenic adult mice with constitutive PRG3 expression displayed strong axonal sprouting distal to a spinal cord lesion. Moreover, fostered PRG3 expression promoted complex motor-behavioral recovery compared to wild type controls as revealed in the Schnell swim test (SST). Thus, PRG3 emerges as a developmental RasGRF1-dependent conductor of filopodia formation and axonal growth enhancer. PRG3-induced neurites resist brain injury-associated outgrowth inhibitors and contribute to functional recovery after spinal cord lesions. Here, we provide evidence that PRG3 operates as an essential neuronal growth promoter in the nervous system. Maintaining PRG3 expression in aging brain may turn back the developmental clock for neuronal regeneration and plasticity.
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PMID:Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury. 2774 21


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