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)

In the elderly, asymptomatic white matter hyperintensities are common on T2-weighted magnetic resonance imaging (MRI). In symptomatic patients, such MRI appearances correlate with varied postmortem findings including demyelination or stroke. What structural correlates underlie the T2 hyperintensities in patients whose lesions are asymptomatic is controversial. Therefore, in order to investigate the underlying metabolism and perfusion in white matter lesions (exhibiting T2 hyperintensity), 13 patients underwent proton magnetic resonance spectroscopy and dynamic gadolinium-DTPA perfusion-weighted MR imaging. N-acetyl aspartate (NA) levels were reduced in the lesions compared with age-matched controls (P = 0.031), implying neuronal/axonal loss. Creatine levels were also reduced (P = 0.001). Choline levels were unchanged in the lesions. Lactate was identified in the lesions of 5 of the 13 patients. Although not statistically significant, perfusion studies exhibited a trend toward lower cerebral blood volumes in patients with high grade extracranial carotid stenosis and lactate-containing lesions. These findings suggest that neuronal/axonal loss underlies the majority of T2-weighted asymptomatic lesions in the older population, and in many cases these changes may be due to chronic ischemia.
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PMID:Proton magnetic resonance spectroscopy and gadolinium-DTPA perfusion imaging of asymptomatic MRI white matter lesions. 789 36

We studied the effect of high thoracic aorta cross-clamping, complete transverse section of the spinal cord at Th6 level, and combined hemisection at Th6 level followed later by high thoracic aorta cross-clamping upon the morphology and number of identified presynaptic knobs in lumbosacral segments in dogs. In animals surviving 48-72 hours after high thoracic aorta cross-clamping the occurrence of an unusual form of boutons accompanied by periboutonal halo in L3-S1 segments was found. According to the bouton size and light as well as electron microscopic appearance, four types, i.e., light giant (T1), dark enlarged (T2), light giant with periboutonal halo (T3), and giant disintegrating (T4) boutons were detected after 48 and 72 hour reperfusion. The appearance of four boutonal types in the lumbosacral segments is caused by spinal cord ischemia secondary to high thoracic aorta cross-clamping followed by 48 or 72 hour reperfusion. At the end of the sixth reperfusion day no signs of enlarged and giant boutons were detected in L3-S1 segments. A statistically significant increase of enlarged and giant boutons was noted at the end of the third reperfusion day in comparison with 48 hour survival. After spinal cord transection at midthoracic (Th6) level, followed by 72 hour survival, no such unusual synaptic knobs could be found in L3-S1 segments. The laminar distribution pattern of T1-T4 types based on light microscopic analysis and confirmed electron microscopically is characteristic and strictly bound to those spinal cord gray matter layers which serve as main termination sites of the descending cortical, brain stem, as well as long propriospinal projections in the lumbosacral segments (laminae V-VII). A statistically significant increase of enlarged and giant boutons was found in the intermediate zone (lamina VII). Hemisection at midthoracic level (Th6) followed later by 30 minute high thoracic aorta cross-clamping and 48 hour reperfusion caused a marked decrease of enlarged and giant boutons in L3-S1 segments on the hemisectioned side in comparison with the contralateral one. Large amounts of irregularly arranged round vesicles and tubular profiles were disclosed in the boutonal matrix of T1, T3, and T4 types in L3-S1 segments of animals subjected to 30 minute high thoracic aorta cross-clamping followed by 72 hour reperfusion. Accumulation of tubular and membranous materials was invariably seen in the bulbous enlargement of the terminal axonal branch.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Ischemia-induced delayed-onset paraplegia is accompanied by an unusual form of synaptic degeneration in the lumbosacral segments: an experimental light and electron microscopic study in dogs. 806 85

Periventricular white matter injury, the principal variety of brain injury of the human premature infant, involves differentiating oligodendroglia. Nothing is known of the biochemical mechanism of oligodendroglial death in this disorder. Because an early event in periventricular white matter injury is ischemia-induced axonal disruption and because such axonal destruction could lead to a marked increase in local concentrations of glutamate, we evaluated the vulnerability of differentiating oligodendroglia to glutamate in a culture model. Oligodendroglia were isolated from mixed-glial primary cultures by a selective detachment technique and grown in a primary culture under conditions that lead to differentiation. These oligodendroglia were found to be highly vulnerable to glutamate-induced cell death. The EC50 for glutamate for a 24 hr exposure was approximately 200 microM, comparable to the value reported for neurons in conventional cerebral cortical cultures. Astrocytes, in contrast, were shown to be resistant to as much as 5 mM glutamate. Study of glutamate receptor antagonists and glutamate transport substrates showed that the glutamate-induced oligodendroglial death was not related to a receptor mechanism, as operates in neurons, but rather was secondary to glutamate uptake by the oligodendroglia. Glutamate transport by high-affinity, sodium-dependent and by sodium-independent systems was shown. The central importance of glutamate uptake for the toxic effect of glutamate was shown by total prevention of the oligodendroglial toxicity by the simultaneous inhibition of glutamate uptake by the specific inhibitor D,L-threo-beta-hydroxyaspartate. Subsequent observations showed that the toxicity of glutamate was mediated by free radical attack, the consequence of glutathione depletion, apparently caused by the action of a glutamate-cystine exchange mechanism that results in cystine and thereby glutathione depletion. Thus, addition of cystine or cysteine totally prevented the glutamate toxicity to oligodendroglia. Second, glutamate exposure led to cystine efflux. Third, glutathione levels decreased markedly in cells exposed to glutamate, and this marked decrease preceded the loss of cell viability. Fourth, glutamate toxicity could be prevented totally by exposure to different free radical scavengers, vitamin E and idebenone. The data thus show that glutamate is highly toxic to oligodendroglia. Moreover, the findings raise the possibilities that such glutamate toxicity is operative in the oligodendroglial cell death associated with ischemic processes that disrupt axons, such as periventricular white matter injury of the premature infant, and that novel therapies directed against glutamate transport, glutathione depletion, and free radical attack might be beneficial in prevention of that injury.
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PMID:Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. 809 41

Insulin-like growth factors (IGFs) are involved in cell growth and differentiation. In muscle tissue they regulate axonal in growth and maintain the connection. They also play a role in regeneration of the peripheral nerve system. We hypothesized that IGFs might also be important factors in the recovery of central nervous tissue after traumatic damage such as perinatal asphyxia. Our group developed a rat model to mimic the resulting damage and test the changes of expression of IGF-1, -2 and several of their binding proteins. We also examined the influence of exogenous IGF-1 and -2 after asphyxia in the same model. Rats underwent a unilateral ligation of the A. carotis followed by a 15 or 90 min inhalational hypoxia (8% O2). The treatment resulted in a mild or severe damage in the ligated hemisphere with either selective neuronal loss or complete infarction of the volume, respectively. The treatment induced expression of both IGFs and binding protein 2, 3 and 5. Binding protein 1 is not expressed and binding protein 4 is suppressed soon after hypoxia-ischemia. We conclude that both IGFs and several of their binding proteins are involved in response and wound healing after hypoxic brain damage. This was further tested in a second experiment. Rats were injected with IGF-1 or IGF-2 intra-ventricular soon after the hypoxic damage. IGF-1 treatment significantly reduced neuronal loss, IGF-2 had no effect. Behaviour tests, however, showed no difference between IGF-1 treated rats and controls. Our studies show interesting aspects for further investigation and a possible treatment of perinatal asphyxia and traumatic damage of nerve tissue.
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PMID:[Somatomedins and their binding proteins are involved in wound healing after hypoxia of the central nervous system]. 812

Besides distal symmetrical sensory polyneuropathy (DSSP), middle-aged diabetic patients may present with focal or multifocal neuropathies, including proximal neuropathy of the lower limbs, the pathophysiological features of which are uncertain. We studied 10 non-insulin-dependent diabetic patients, 45 to 72 years of age, who developed a painful proximal neuropathy of the lower limbs for which other causes of neuropathy were carefully excluded. The proximal neuropathy was asymmetrical in all patients, sensory in 4, motor and sensory in the others. Signs of DSSP were present in all. A sample of the intermediate cutaneous nerve of the thigh, a sensory branch of the femoral nerve, was taken by biopsy and examined by light and electron microscopy. Examination of the nerve specimens revealed ischemic nerve lesions in 3 patients. Nerve ischemia was associated with vasculitis and inflammatory infiltration in 2 of them. In the other patients the lesions of the cutaneous nerve of the thigh included a varying incidence of axonal and demyelinative lesions similar to those observed in DSSP, with mild inflammatory infiltration in 4 of them. The density of myelinated and of unmyelinated was variably decreased. This study shows that axonal and demyelinative lesions similar to those found in diabetic DSSP are present in proximal nerves in mild forms of proximal diabetic neuropathy; while nerve ischemia, inflammatory infiltration, and vasculitis are encountered in the most severe forms of proximal diabetic neuropathy.
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PMID:Nerve biopsy findings in different patterns of proximal diabetic neuropathy. 817 2

Although specific patterns of cellular vulnerability have been identified in experimental models of cerebral ischemia, there is little data on the occurrence of similar abnormalities in human ischemia. We therefore used a variety of histochemical methods to define changes affecting specific classes of cells in post-mortem specimens from seven patients with hippocampal and neocortical ischemic lesions. In acute lesions, staining with SMI-32, an antibody directed against nonphosphorylated neurofilaments that labels pyramidal projection neurons, was prominently depleted even when conventional Nissl staining revealed only mild pyknosis. In contrast, staining for other markers such as microtubule-associated protein 2 (MAP-2), another cytoskeletal protein, or parvalbumin, a calcium-binding protein found in gamma-aminobutyric acid (GABA)-ergic interneurons, were relatively preserved. SMI-32 antibody also labeled dystrophic axons and axonal retraction balls in and around acute ischemic lesions. The pattern of differential changes in immunoreactivity was essentially the same in all acute ischemic injuries, including both diffuse lesions in the CA1 field (Sommer's sector) and discrete infarcts in CA1 and neocortex. In addition, immunoreactivity for the immediate early gene product c-fos was enhanced in and around the acute ischemic lesions that we studied. In some very acute lesions, immunoreactivity for glial fibrillary acidic protein (GFAP) was depleted in areas of severe ischemia and necrosis, but, as expected, GFAP immunoreactivity was increased in lesions more than a few days old. In contrast, the loss of SMI-32 immunoreactivity persisted in chronic lesions. These findings are consistent with those of experimental ischemia in animals and confirm the relevance of these studies for human cerebral ischemia. The pattern of selective changes also resembles that of injuries induced directly by excitatory amino acids, which may play a significant role in the pathogenesis of ischemic damage.
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PMID:Immunohistochemical patterns of selective cellular vulnerability in human cerebral ischemia. 827 38

The present study has examined certain metabolic markers in fetal neocortical tissue transplanted to the cortex, hippocampus, striatum, or ventricle. Particularly, the immunocytochemical expression of neuron-specific enolase (NSE) was studied in a series of host rats ranging between 10 days and 15 months postoperative. NSE is a major glycolytic pathway enzyme found in all neurons. The antibody to NSE is a very reliable marker for neuronal functional metabolic activity and developmental status and its onset has been shown to coincide with synaptic connections. In some grafts oxidative metabolic status was investigated using cytochrome oxidase (CO) histochemistry. In addition, the normal development of NSE expression in rat neocortex was also examined. In normal development, NSE was weakly expressed in fetal brain, but by 1-2 weeks postnatal the enzyme was strongly expressed in all neurons. Typical cortical laminar patterns were evident at 30 days with neurons in layer V and scattered interneurons the most strongly stained. In cortex-cortex transplants NSE expression was very weak; at 1-3 weeks postoperative, it was practically nonexistent; and at all later times only a minority of neurons had normal expression when compared to that in normal development even though by Nissl staining standards in adjacent sections they appeared "normal." Labeling indices ranged between 30 and 49%. Intraventricular grafts had consistently low NSE expression with labeling indices ranging between 18 and 46%. However, when the neocortical tissue was placed in other regions, neuronal NSE appeared only slightly below normal. CO histochemistry corroborated the NSE activity with regards to graft placement. Several possibilities that may account for reduced NSE profile in transplanted neurons include incomplete migration patterns, reduced synaptic connectivity, and potential ischemia causing lowered protein synthesis during reestablishment of vascular connections. If neuronal glycolysis is weakened, it is possible that neurotransmitter production or axonal transport are reduced. Since most energy capacity in brain is dependent on the glycolytic sequence for oxidative metabolism, reduced glycolytic capacity, as depicted by NSE expression, may suggest the presence of transplanted neurons that have adapted to their new environment with a relatively immature profile.
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PMID:Developmental expression of neuron-specific enolase immunoreactivity and cytochrome oxidase activity in neocortical transplants. 828 24

Spinal cord injury after operations on the descending thoracic and thoracoabdominal aorta remains a persistent clinical problem. Previous attempts to decrease the risk of this devastating complication by lowering the rate of metabolism of the spinal cord have met with varying success. We hypothesized that the tolerance of the spinal cord to an ischemic insult could be improved by means of adenosine. Twenty New Zealand white rabbits underwent 40 minutes of isolated infrarenal aortic occlusion after heparin anticoagulation. Clamps were placed both below the left renal vein and above the aortic bifurcation. In 10 rabbits (group A), a bolus of adenosine (100 mg) was infused into the isolated aortic segment immediately after crossclamping and this bolus was followed by a flush of hypothermic saline (8 degrees C, 30 ml/kg) over the first 10 minutes of ischemia. In one control group of five animals (group B), the descending infrarenal aorta was crossclamped without infusion of adenosine or saline. In another control group of five animals (group C), the aortic segment was flushed with normothermic saline (37 degrees C) in a fashion identical to that of the study group. The aortic clamps were removed after 40 minutes, the abdomen was closed, and the animals were allowed to recover from anesthesia. Spinal cord function was assessed 12, 24, 48, 72, and 96 hours after operation by the Tarlov scale. All animals were put to death at 96 hours after operation and spinal cords were harvested for histologic analysis. The spinal cord function of all group A animals was fully intact with Tarlov scores of 5; group B and group C animals were all paraplegic with Tarlov scores of 0 (p < 0.001, general linear models analysis of variance). Histologic examination of spinal cords from group A rabbits revealed no evidence of cord injury, whereas spinal cords from groups B and C had evidence of extensive cord injury with central gray necrosis, axonal swelling, dissolution of Nissl substance, and astrocyte and macrophage infiltration. Regional infusion of the crossclamped infrarenal rabbit aorta with hypothermic saline and adenosine completely prevented paraplegia in our model despite a 40-minute ischemic insult.
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PMID:Complete prevention of postischemic spinal cord injury by means of regional infusion with hypothermic saline and adenosine. 830 74

We describe a patient with Tangier disease and a peripheral neuropathy with an unusual acute onset. The morphological studies of sural nerve biopsy revealed both axonal degeneration and demyelination, and the fiber loss was preferentially restricted to two of ten nerve fascicles. The cytoplasm of Schwann cells, fibroblasts, macrophages and pericytes were vacuolated because of the presence of numerous lipid droplets. The clinical and morphological findings are consistent with the possibility that ischemia plays a major role in causing this neuropathy.
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PMID:Acute presentation of Tangier polyneuropathy: a clinical and morphological study. 783 35

Vasospasm associated with ergotamine is a well-known phenomenon. In this case report we present a rare drug interaction between erythromycin and ergotamine at normal doses causing lower extremity ischemia in a 36-year-old woman. Nitroprusside proved to be the treatment of choice. The response was dramatic and took place in a matter of hours in this patient. Ischemic monomelic neuropathy is a recently described entity in which axonal necrosis is caused by a loss of distal extremity blood flow. The association between erythromycin and ergotamine may be a dangerous pharmacologic combination; drugs that have a hepatic cycle with ergotamine derivatives must be used with caution.
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PMID:Erythromycin-associated ergotamine intoxication: arteriographic and electrophysiologic analysis of a rare cause of severe ischemia of the lower extremities and associated ischemic neuropathy. 839


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