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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell injury proceeds through a predictable series of stages as it progresses from reversible to irreversible injury (or "point of no return") and ends eventually in cell death. Ion deregulation is strongly implicated in this process and, in particular, the deregulation of cytosolic Ca2+ ([Ca2+]i) which is thought by most to be a critical step in the transition from reversible to irreversible injury. [Ca2+]i is normally maintained at approximately 100 microM, a level 10,000 times lower than for extracellular Ca2+ [( Ca2+]e). Deregulation may affect any of three Ca2+ buffering systems: the plasma membrane, the mitochondria, and the endoplasmic reticulum. Perturbation of [Ca2+]i is intimately related to perturbation of other ions, including, H+, Na+, and K+. In normal cells, [Ca2+]i elevation is also linked to activation of oncogenes as well as cell division, initiation, wound repair, differentiation, and possibly tumor promotion. In all models of acute injury for which we have measured [Ca2+]i, including ischemia, HgCl2 and calcium inophores, [Ca2+]i always became elevated. This elevation results from influx of [Ca2+]e (ionomycin), redistribution from intracellular stores (NEM, KCN), or from both sources (HgCl2). The degree of [Ca2+]i elevation is correlated with the degree of injury (as determined by blebbing and morphological changes) and cell killing. More recently, much work has been focused on the role of [Ca2+]i in neoplasia. Many stimuli, including the promoter TPA and transforming growth factor beta have been shown to affect normal and transformed cells differently. Both cause differentiation in normal human bronchial epithelial cells but stimulate growth in transformed cells. We propose that deregulation of ions, especially [Ca2+]i, plays an important role, if not a key role, in the initiation of acute and chronic cell injury, including neoplasia. Increases in [Ca2+]i appear to accelerate degradative processes and, unless regulated, lead to cell death.
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PMID:The relationship between cellular ion deregulation and acute and chronic toxicity. 264 22

Intravenous thrombolytic therapy with streptokinase in the setting of acute MI has been shown to be effective in improving left ventricular function, limiting infarct size, and improving early mortality. The benefit of this therapy is greatest when administered within 3 hours and is of minimal benefit when given more than 6 hours from symptom onset. Newer second generation thrombolytic agents such as intravenous r-TPA have been shown to be more effective at establishing patency of acutely thrombosed coronary arteries. TPA treatment produces patency rates similar to those observed with intracoronary administration of streptokinase (65 to 75 per cent). This agent will probably become standard therapy for patients with acute MI. Unfortunately, there are significant problems with systemic thrombolytic therapy. The potential for bleeding complications contraindicates the use of this therapy in patients with recent cerebrovascular events, recent surgery, or other possible bleeding problems. Acute angioplasty of the infarct-related artery has been shown to be effective in restoring blood flow in 85 per cent of patients with acute MI. Preliminary studies have suggested that this therapy, when administered within 4 hours from symptom onset, improves global and regional left ventricular function to a greater degree than intracoronary streptokinase. Patients receiving acute PTCA as a primary reperfusion modality have a lower incidence of post-infarction angina and provokable ischemia by exercise testing. If facilities and skilled personnel are available to perform PTCA within 4 hours from symptom onset, this therapy remains an alternative revascularization modality in patients with acute infarction and contraindications to systemic thrombolytic therapy. However, the benefit of PTCA with regard to reduction in mortality when used in this manner is unproven. PTCA can also be used as an adjunctive therapy administered at some time following systemic thrombolytic therapy. Performing PTCA acutely offers the potential to restore blood flow in 90 per cent of the patients that initially fail thrombolytic therapy. However, despite the use of PTCA in this subgroup, benefits with regard to improved ventricular function and decreased mortality have yet to be conclusively demonstrated. Performing acute PTCA following systemic thrombolytic therapy also incurs a high incidence of bleeding complications. If initial thrombolytic therapy reestablishes vessel patency, similar improvements in ventricular function can be expected even if PTCA is deferred until clinically indicated by evidence of recurrent ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Percutaneous transluminal coronary angioplasty during acute myocardial infarction. 297 41

The role of gastric mucus was evaluated in a rat model of gastric epithelial damage induced by local ischemia/reperfusion (I/R) stress. In this model, blood-to-lumen chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) clearance served as an index of injury. Tetraprenyl acetone (TPA; 100 mg, 200 mg/kg IP) was used to stimulate mucus production. Administration of TPA increased both the hexosamine content in gastric tissue and the amount of alcian blue-periodic acid Schiff (AB-PAS) stained mucus in the mucosa in a dose-dependent manner. Increases in 51Cr-EDTA clearance induced by I/R were significantly attenuated by TPA in a dose-dependent manner. N-acetyl-L-cysteine (NAC; 0.6%, 0.8%) was perfused into the gastric lumen to assess the effect of reduction in mucus on the injury induced by I/R. Although mean values of hexosamine content were increased by perfusion with NAC, AB-PAS-stained mucus in the mucosa was significantly decreased in a dose-dependent manner. Perfusion of NAC did not change basal 51Cr-EDTA clearance but significantly exacerbated the increase in clearance induced by I/R in a dose-dependent manner. These results indicate that gastric mucus protects the gastric mucosa against I/R stress in vivo.
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PMID:Role of mucus in gastric mucosal injury induced by local ischemia/reperfusion. 766 77

Ischemic brain injury is exacerbated by leukocyte infiltration and formation of vasogenic edema. In this study we demonstrate that intercellular adhesion molecule-1 (ICAM-1) is dramatically (3 to 15-fold) up-regulated in human cerebromicrovascular endothelial cells (HCEC) by a 16 h exposure to the cytokine, IL-1 beta (50-200 u/ml), the phorbol ester, TPA (1-100 nM), or by simulated in vitro ischemia/reperfusion. These treatments also significantly increased the adhesion of allogeneic neutrophils to HCEC monolayers. Both IL-1 beta- and TPA-induced expression of ICAM-1 and increased neutrophil adhesion to HCEC were inhibited by the transcriptional inhibitor, actinomycin D (AcD; 1-10 micrograms/ml), and by an anti-ICAM-1 antibody (ICAM-1 Ab). By contrast, ischemia-induced neutrophil adhesion was only slightly affected by AcD and ICAM-1 Ab alone, but it was abolished by the combination of anti-ICAM-1 and anti-CD18 antibodies. The increase in surface expression of ICAM-1 and neutrophil adhesion by IL-1 beta, TPA and ischemia were significantly reduced by the cyclo-oxygenase (COX) inhibitors, indomethacin (100-300 microM) and dexamethasone (10-50 microM). These results indicate that ICAM-1 expression in HCEC can lead to enhanced neutrophil adhesion and that COX activation in HCEC likely plays a role in the processes by which leukocyte adhesion and recruitment take place in the brain during inflammation and ischemia in vivo.
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PMID:The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion. 918 51

Crude myocardial sarcolemmal membrane fractions were prepared from rat hearts subjected to total global ischemia with and without normoxic reperfusion, or global anoxic (N2) perfusion with and without normoxic reperfusion. The direct effects on beta-adrenoceptor number, G-protein levels and stimulation of the adenylate cyclase (AC) complex were assessed. In terms of AC activation, ischemia led to a marked increase (4-fold) in sensitivity to terbutaline (beta2-agonist) and phorbol ester (tetradecanoyl phorbol acetate = TPA) stimulation, whereas the dobutamine (beta1) responsiveness and Gpp(NH)p activation through G(s)alpha/G(i2)alpha remained unaltered. However, forskolin-elicited holoenzyme activity fell markedly during normoxic reperfusion. Ischemia did not change the beta1-adrenoceptor number, while beta2-receptor population increased by approximately 45%. Western blots of myocardial G(s)A and G(i2)alpha contents revealed that ischemia selectively diminished G(i2)alpha levels only by some 50-70%. Contrastingly, anoxia selectively increased the AC sensitivity (2-fold) to beta1-adrenergic stimulation. As subsequent to ischemia, anoxia also increased the sensitivity to TPA stimulation, however, only 2-fold. Gpp(NH)p activation was unchanged, while forskolin-enhanced activity gradually declined, also during ensuing normoxic reperfusion. Anoxia brought about a 75% enhancement in beta1-receptor number, while beta2-receptors remained unaffected. However, altered receptor number normalized on termination of normoxic reperfusion. Finally, anoxia led to a 50-60% decimation of myocardial G(i2)alpha levels, while G(s)alpha was only marginally reduced. Despite the fact that the ischemia and anoxia effectuated a similar deterioration of physiological heart parameters, myocardial contents of energy rich phosphate moieties and loss of G(i2)alpha, ischemia rendered the most profound increase in responsiveness of the sarcolemmal AC system.
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PMID:Enhanced responsiveness of the myocardial beta-adrenoceptor-adenylate cyclase system in the perfused rat heart (I). 1019 81

ST-segment elevation acute myocardial infarction (AMI) in patients who have undergone previous coronary artery bypass grafting (CABG) is associated with low reperfusion rates and poor outcome after fibrinolytic therapy. The efficacy of a combination strategy (reduced fibrinolytic plus platelet glycoprotein IIb/IIIa agent) in this setting is unknown. In the Global Use of Streptokinase and TPA for Occluded coronary arteries V (GUSTO V) trial, 553 patients with a history of CABG were treated with standard-dose reteplase (n = 273), or half-dose reteplase and full-dose abciximab (n = 280) in the first 6 hours of evolving ST-segment elevation MI. Mortality at 30 days was significantly higher in patients who underwent prior CABG compared with patients with no prior CABG (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.21 to 2.24, p = 0.001). In patients who underwent prior CABG, mortality at 7 days was reduced 15% with combination therapy compared with reteplase alone, which was not statistically significant (OR 0.85, 95% CI 0.40 to 1.81, p = 0.66). Patients who underwent prior CABG treated with the combination therapy had fewer episodes of recurrent ischemia (OR 0.60, 95% CI 0.37 to 0.96, p = 0.02), high degree atrioventricular block (OR 0.17, 95% CI 0.02 to 0.82, p = 0.01), and ventricular tachycardia (OR 0.29, 95% CI 0.07 to 0.96, p = 0.04). There was a trend toward reduced urgent revascularization (OR 0.61, 95% CI 0.36 to 1.03, p = 0.06) but no significant difference in reinfarction (OR 0.61, 95% CI 0.31 to 1.52, p = 0.40). In the GUSTO V trial, patients who underwent prior CABG had significantly higher event rates compared with patients without CABG. As in the overall trial, combination therapy in patients who underwent prior CABG led to a consistent reduction in key secondary complications of AMI, including recurrent ischemia and a trend toward reduced urgent revascularization.
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PMID:Outcome of acute myocardial infarction in patients with prior coronary artery bypass grafting treated with combination reduced fibrinolytic therapy and abciximab. 1245 May 98

Presented are the clinical data of 18 consecutive patients who were treated by IV recombinant tissue plasminogen activator (r-TPA) for suspected vertebrobasilar (VB) acute ischemia within 7 hours. The mean delay for treatment was 5 +/- 3.6 hours. Mean baseline NIH Stroke Scale score was 17 +/- 4. At 3 months, 10 patients were independent (modified Rankin Scale [mRS] score = 0 to 2), whereas 8 patients showed a poor outcome (mRs = 3 to 6). IV r-TPA in VB ischemia in a 7-hour window may be safe and efficient.
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PMID:Intravenous r-TPA in vertebrobasilar acute infarcts. 1515 94

The management of acute ischemic stroke has not made significant strides since the introduction of recombinant tissue plasminogen activator (r-TPA) two decades ago. The use of other therapies, such as heparin, aspirin, dipyridamole, and/or clopidogrel, have only moderately aided in the treatment of this ischemic disease. Therefore, major medical innovative approaches are critically needed. Because of the side effects associated with r-TPA (specifically bleeding) and its limited 3-h therapeutic window, new studies using current developments encountered in the molecular biology of ischemia are being incorporated into the potential therapy of ischemic stroke. A review of the major advances in the field, including glutamate receptor blockade, magnesium infusion, inflammation blockade, apoptosis inhibition, and other therapies, is introduced with special emphasis on the molecular findings recognized as targets for a better and more effective treatment. As new therapies are being considered, the time of administration is becoming a central point of study for the application of novel therapeutic initiatives.
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PMID:Molecular mechanisms in the pathogenesis and treatment of acute ischemic stroke. 1612 32

Clomethiazole has been marketed for several years as a sedative/antiepileptic. Astra is now developing it for the potential treatment of stroke. An NDA is expected to be filed in 1999/2000. A North American phase III trial for large stroke has commenced. This will include 1200 patients. Two other smaller scale phase III studies with clomethiazole have also commenced in North America for intracerebral hemorrhage (n=200) and safety in combination with TPA (n=100 to 200) (Genentech). A large-scale phase III trial has been completed in which clomethiazole was evaluated for its ability to reduce nerve damage in acute cerebrovascular ischemia. The multicenter, international trial, called CLASS (Clomethiazole Acute Stroke Study), analyzed 1360 patients and found no significant treatment effect. However, a subgroup of patients who presented with large stroke, experienced a significant benefit. Of these (n=545), 41% treated patients were functionally independent after 90 days, compared to 30% patients on placebo. Clomethiazole reduced functional disability and brain damage in the marmoset permanent MCAO model. Clomethiazole is thought to act through a GABAergic pathway, whereby it augments GABA's depressive effect on the CNS, giving the drug both hypnotic and neuroprotectant properties.
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PMID:Clomethiazole (Astra Arcus AB). 1616 Sep 52

Several studies have stressed the involvement of inflammation in the pathophysiology of acute brain ischemia, but the role of immunoinflammatory activation in diabetic stroke patients has not yet been fully evaluated. The aim of our study was to evaluate immunoinflammatory activation of acute phase of stroke in relation to time of symptoms onset, diabetic state and diagnostic subtype. We enrolled 60 patients (32 diabetics; 28 non- diabetics) with acute ischemic stroke and 123 subjects without acute ischemic stroke, and measured levels of IL-1beta, TNF-alpha IL-6, IL-10, E-selectin, P-selectin, sICAM-1, sVCAM-1, VWF, 24-72 h and 7-10 days after stroke onset; TPA, PAI-1 plasma levels at 24-72h. Our stroke patients exhibited significantly higher plasma levels of cytokines, selectins, adhesion molecules and PAI-1, and diabetic stroke patients exhibited higher plasma levels of PAI-1 in comparison with non-diabetic ones. Lacunar strokes in comparison with those non-lacunar exhibited significantly lower levels of TNF-alpha and IL1-beta P-selectin and ICAM-1. Moreover, diabetic patients with lacunar strokes exhibited a minor grade of immunoinflammatory activation of the acute phase at 24-72h and 7-10 days after stroke onset. The minor grade of immunoinflammatory activation of patients with lacunar strokes, particularly diabetic ones, could be related to the minor extension of the infarct size, owing to the typical microvascular disease of diabetic subjects which could also explain the reported better outcome of this subtype of ischemic stroke.
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PMID:Immunoinflammatory activation during the acute phase of lacunar and non-lacunar ischemic stroke: association with time of onset and diabetic state. 1702 49


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