Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Glasgow Coma Scale (GCS) is the most frequently used tool worldwide for assessing the severity of neurologic injury after brain trauma, although applying this scale to infants and younger children can be problematic. The CHOP Infant Coma Scale, or Infant Face Scale (IFS), is a novel scale for children under 2 years of age which differs from other pediatric coma scales in the following ways: (1) it relies on objective behavioral observations; (2) it assesses cortical as well as brainstem function; (3) it parallels the GCS in scoring but is based on infant-appropriate behaviors; and (4) it can be applied to intubated patients. We report the results of a prospective study designed to compare interrater reliability between the IFS and GCS in children less than 2 years of age. Seventy-five hospitalized children less than 2 years of age were assessed simultaneously by a pair of observers, representing a spectrum of health care professionals, who scored the children using both the IFS and GCS. Interrater reliability for each pair of observers for each scale was assessed using the kappa statistic. A second series of 10 infants in the intensive care unit with specific diagnoses of acute traumatic or hypoxic/ischemic brain injury were similarly assessed. In the 75 hospitalized infants with a variety of diagnoses, interrater reliability for the GCS was in the "almost perfect," "slight," and "fair" range for the eye-opening, motor, and verbal subtests, respectively. In contrast, the IFS showed interrater reliability in the "almost perfect," "substantial," and "almost perfect" ranges for the three subtests. When applied to infants in an intensive care unit with acute traumatic brain injury or hypoxia/ischemia, the GCS interrater reliability scores were in the "fair" range, while the IFS scores were in the "almost perfect" range. The IFS demonstrates improved interrater reliability in direct comparison to the GCS, particularly in the "verbal/face" component where most pediatric coma scales are deficient. The IFS may prove to be a simple and practical bedside index of brain injury severity in children less than two years of age.
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PMID:CHOP Infant Coma Scale ("Infant Face Scale"): a novel coma scale for children less than two years of age. 1101 13

Excessive nitric oxide (NO) has been implicated in neurotoxicity after stresses such as ischemia. NO toxicity is generally thought to be mediated by the DNA damage-p53 pathway or mitochondrial dysfunction. We investigated the mechanism of NO toxicity by using murine microglial MG5 cells established from p53-deficient mice. When MG5 cells were exposed to bacterial lipopolysaccharide plus interferon-gamma, mRNA and protein for inducible NO synthase (iNOS) were markedly induced, and apoptosis occurred. Under these conditions, we found that mRNA and protein for CHOP/GADD153, a C/EBP family transcription factor which is involved in endoplasmic reticulum (ER) stress-induced apoptosis, are induced. iNOS mRNA was induced 2 h after treatment, whereas CHOP mRNA began to increase at 6 h with a time lag. CHOP mRNA was also induced by NO donors S-nitroso-N-acetyl-DL-penicillamine (SNAP) or NOC18, or a peroxynitrite generator 3-(4-morpholinyl)-sydnonimine hydrochloride (SIN-1). Bip/GRP78, an ER chaperone which is known to be induced by ER stress, was also induced by SNAP or SIN-1, indicating that NO causes ER stress. These results suggest that NO-induced apoptosis in MG5 cells occurs through the ER stress pathway involving CHOP, but is independent of p53.
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PMID:Induction of CHOP and apoptosis by nitric oxide in p53-deficient microglial cells. 1159 87

Protein synthesis inhibition occurs in neurons immediately on reperfusion after ischemia and involves at least alterations in eukaryotic initiation factors 2 (eIF2) and 4 (eIF4). Phosphorylation of the alpha subunit of eIF2 [eIF2(alphaP)] by the endoplasmic reticulum transmembrane eIF2alpha kinase PERK occurs immediately on reperfusion and inhibits translation initiation. PERK activation, along with depletion of endoplasmic reticulum Ca2+ and inhibition of the endoplasmic reticulum Ca2+ -ATPase, SERCA2b, indicate that an endoplasmic reticulum unfolded protein response occurs as a consequence of brain ischemia and reperfusion. In mammals, the upstream unfolded protein response components PERK, IRE1, and ATF6 activate prosurvivial mechanisms (e.g., transcription of GRP78, PDI, SERCA2b ) and proapoptotic mechanisms (i.e., activation of Jun N-terminal kinases, caspase-12, and CHOP transcription). Sustained eIF2(alphaP) is proapoptotic by inducing the synthesis of ATF4, the CHOP transcription factor, through "bypass scanning" of 5' upstream open-reading frames in ATF4 messenger RNA; these upstream open-reading frames normally inhibit access to the ATF4 coding sequence. Brain ischemia and reperfusion also induce mu-calpain-mediated or caspase-3-mediated proteolysis of eIF4G, which shifts message selection to m 7 G-cap-independent translation initiation of messenger RNAs containing internal ribosome entry sites. This internal ribosome entry site-mediated translation initiation (i.e., for apoptosis-activating factor-1 and death-associated protein-5) can also promote apoptosis. Thus, alterations in eIF2 and eIF4 have major implications for which messenger RNAs are translated by residual protein synthesis in neurons during brain reperfusion, in turn constraining protein expression of changes in gene transcription induced by ischemia and reperfusion. Therefore, our current understanding shifts the focus from protein synthesis inhibition to the molecular pathways that underlie this inhibition, and the role that these pathways play in prosurvival and proapoptotic processes that may be differentially expressed in vulnerable and resistant regions of the reperfused brain.
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PMID:Molecular pathways of protein synthesis inhibition during brain reperfusion: implications for neuronal survival or death. 1182 11

Up-regulation of several stress proteins such as heat-shock proteins and glucose-regulated proteins participate in tolerance against environmental stress. Previously, we found that protein-disulfide isomerase (PDI) is specifically up-regulated in response to hypoxia/brain ischemia in astrocytes. In addition, the overexpression of this gene into neurons protects against apoptotic cell death induced by hypoxia/brain ischemia. To address the detailed function of PDI, we screened for proteins that interact with PDI using the yeast two-hybrid system. We report here that PDI interacts with ubiquilin, which has a ubiquitin-like domain and a ubiquitin-associated domain. Interestingly, ubiquilin is also up-regulated in response to hypoxia in glial cells with a time course similar to that of PDI induction. In hypoxia-treated glial cells, the endogenous ubiquilin and PDI were almost completely co-localized, suggesting that ubiquilin is an endoplasmic reticulum-associated protein. Overexpression of this gene in neuronal cells resulted in significant inhibition of the DNA fragmentation triggered by hypoxia, but not that induced by nitric oxide or staurosporine. Moreover, ubiquilin has the ability to attenuate CHOP induction by hypoxia. These observations suggested that ubiquilin together with PDI have critical functions as regulatory proteins for CHOP-mediated cell death, and therefore up-regulation of these proteins may result in acquisition of tolerance against ischemic stress in glial cells.
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PMID:Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death. 1209 88

In intravascular lymphoma (IVL) tumor cells are initially restricted to vascular lumina. Neurological syndromes predominate and are caused by ischemia as well as tumor infiltration into the nervous system. Ante mortem diagnosis is challenging and frequently impossible. Chemotherapy is effective if started prior to ischemic damage. Over a three year period, we have diagnosed IVL in seven patients. Tissue diagnosis could be accomplished in only three cases. Forthose in whom tissue diagnosis failed we based our diagnosis on clinical presentation, typical magnetic resonance imaging findings, spinal fluid cytopathology, and molecular analyses. Six patients were treated with methotrexate chemotherapy alone or in combination with CHOP. Three patients are in complete remission 9-20 months after initial diagnosis. Another patient achieved a partial response. Two patients died due to progressive disease shortly after initiation of treatment. Grade III toxicity was observed in only 4 of 61 cycles. Based on a small retrospective series of patients, we conclude that methotrexate is a well tolerated and effective agent for the treatment of IVL.
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PMID:A new approach to the diagnosis and treatment of intravascular lymphoma. 1267 17

A variety of endoplasmic reticulum (ER) stresses trigger the unfolded protein response (UPR), a compensatory response whose most proximal sensors are the ER membrane-bound proteins ATF6, IRE1alpha, and PERK. The authors simultaneously examined the activation of ATF6, IRE1alpha, and PERK, as well as components of downstream UPR pathways, in the rat brain after reperfusion after a 10-minute cardiac arrest. Although ATF6 was not activated, PERK was maximally activated at 10-minute reperfusion, which correlated with maximal eIF2alpha phosphorylation and protein synthesis inhibition. By 4-h reperfusion, there was 80% loss of PERK immunostaining in cortex and 50% loss in brain stem and hippocampus. PERK was degraded in vitro by mu-calpain. Although inactive IRE1alpha was maximally decreased by 90-minute reperfusion, there was no evidence that its substrate xbp-1 messenger RNA had been processed by removal of a 26-nt sequence. Similarly, there was no expression of the UPR effector proteins 55-kd XBP-1, CHOP, or ATF4. These data indicate that there is dysfunction in several key components of the UPR that abrogate the effects of ER stress. In other systems, failure to mount the UPR results in increased cell death. As other studies have shown evidence for ER stress after brain ischemia and reperfusion, the failure of the UPR may play a significant role in reperfusion neuronal death.
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PMID:Dysfunction of the unfolded protein response during global brain ischemia and reperfusion. 1267 23

A 54-year-old man with a past history of gastric malignant lymphoma treated by the total gastrectomy and the chemotherapy, developed bilateral sudden deafness one year later. Two years after the gastrectomy he became abruptly paraplegic with sensory impairments of the lower extremities and neurogenic bladder. Serum LDH and soluble IL-2 receptor were high in titers (552 U/l and 1,090 U/l, normal range 145-519). Although the imaging studies of the spinal cord were negative, the myelopathic symptoms resolved dramatically after a course of pulse dose methylprednisolone therapy. However, he soon developed an abnormal behavior and mental deterioration in 3 weeks. The MRIs of the brain revealed abnormal signals compatible with multiple cerebral infarctions. As intravascular malignant lymphomatosis (IML) was suspected because of the laboratory and MRI findings, biopsies of the skin, the bone marrow, the muscle and the lymph node were carried out, without evidence of lymphoma. The brain biopsy ultimately confirmed the presence of IML. The patient remarkably responded to biweekly CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) therapy in terms of regaining the mental alertness and improved hearing. However, the CHOP therapy was prematurely interrupted prior to completion because of infective arthritis. The relapse soon ensued, and he died 6 months after admission. This case was of interest because a solid gastric lymphoma appears to have transformed into the form of intravascular lymphomatosis without mass formations or leukemic changes. Although the neurological symptoms in association with IML are thought to be the results of ischemic events, this case illustrates a remarkable reversibility of the symptoms. This implies that the cerebral symptoms are not necessarily the results of typical ischemic infarction, but due to relative ischemia because of chiefly capillary-venous occlusion by lymphoma cells. The majority of the symptoms is thus attributable to the functional impairment. Therefore, the therapeutic intervention may dramatically improve the symptoms due to IML.
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PMID:[Dramatic but temporary improvements in a case of CNS intravascular malignant lymphomatosis]. 1282 May 43

Brain ischemia induces apoptosis in neuronal cells, but the mechanism is not well understood. When wild-type mice were subjected to bilateral common carotid arteries occlusion (BCCAO) for 15 min, apoptosis-associated morphological changes and appearance of TUNEL-positive cells were observed in the striatum and in the hippocampus at 48 h after occlusion. RT-PCR analysis revealed that mRNAs for ER stress-associated proapoptotic factor CHOP and an ER chaperone BiP are markedly induced at 12 h after BCCAO. Immunohistochemical analysis showed that CHOP protein is induced in nuclei of damaged neurons at 24 h after occlusion. In contrast, ischemia-associated apoptotic loss of neurons was decreased in CHOP(-/-) mice. Primary hippocampal neurons from CHOP(-/-) mice were more resistant to hypoxia-reoxygenation-induced apoptosis than those from wild-type animals. These results indicate that ischemia-induced neuronal cell death is mediated by the ER stress pathway involving CHOP induction.
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PMID:Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. 1475 8

Hrd1p in yeast plays an important role in endoplasmic reticulum-associated degradation (ERAD). In the present study, we used an in vivo model of hypoxia-ischemia in mice to study the expression of murine HRD1. Hypoxia-ischemia induced a significant increase in mRNA levels of genes including GRP78, CHOP and MyD116, the expression of which are specifically activated under conditions associated with ER dysfunction. The level of mHRD1 mRNA was significantly increased after ischemia. Interestingly, induction of mHRD1 was elevated at a later time point (12-48 h) in the ischemic cortex, whereas it increased at an earlier time point (3-12 h) in the injured striatum. We also examined the changes of mHRD1 mRNA expression in neuroblastoma Neuro2a and primary glial cells exposed to hypoxia/reoxygenation. The expression of mHRD1 mRNA was remarkably up-regulated in glial cells subjected to 24 h hypoxia, whereas no significant changes were observed in Neuro2a cells under hypoxia/reoxygenation. In addition, the levels of mHRD1 mRNA were markedly elevated in glial cells exposed to treatment with tunicamycin (Tm, an ER stress inducer). These findings suggest that hypoxia-ischemia triggers ER dysfunction and mHRD1 may play a role in ischemia-induced ER dysfunction.
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PMID:Induction of murine HRD1 in experimental cerebral ischemia. 1551 74

Expression and activity of the germinal center kinase, Ste20-like kinase (SLK), are increased during kidney development and recovery from ischemic acute renal failure. In this study, we characterize the activation and functional role of SLK. SLK underwent dimerization via the C-terminal domain, and dimerization enhanced SLK activity. In contrast, the C-terminal domain of SLK did not dimerize with a related kinase, Mst1, and did not affect Mst1 activity. Phosphorylation/dephosphorylation of SLK were not associated with changes in kinase activity. SLK induced phosphorylation of apoptosis signal-regulating kinase-1 (ASK1) and increased ASK1 activity, indicating that ASK1 is a substrate of SLK. Moreover, SLK stimulated phosphorylation of p38 mitogen-activated protein kinase via ASK1, but not c-Jun N-terminal kinase nor extracellular signal-regulated kinase. Chemical anoxia and recovery during re-exposure to glucose (ischemia-reperfusion injury in cell culture) stimulated SLK activity. Overexpression of SLK enhanced anoxia/recovery-induced apoptosis, release of cytochrome c, and activities of caspase-8 and -9, and apoptosis was reduced significantly with p38 and caspase-9 inhibitors. Induction of the endoplasmic reticulum stress response by anoxia/recovery or tunicamycin (monitored by induction of Bip or Grp94 expression, phosphorylation of eukaryotic translation initiation factor 2alpha subunit, expression of CHOP, and activation of caspase-12) was attenuated in cells that overexpress SLK. Thus, SLK is an anoxia/recovery-dependent kinase that is activated via homodimerization and that signals via ASK1 and p38 to promote apoptosis. Attenuation of the protective aspects of the endoplasmic reticulum stress response by SLK may contribute to its proapoptotic effect.
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PMID:Induction of apoptosis by the Ste20-like kinase SLK, a germinal center kinase that activates apoptosis signal-regulating kinase and p38. 1631 99


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