Peripheral nerve disease in SARS:: report of a case.
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Acute Disease↗
Biomedical subjects
M T Tseng
Publications and source records attributed to M T Tseng.
Preischemic hyperglycemia-aggravated damage: evidence that lactate utilization is beneficial and glucose-induced corticosterone release is detrimental.
Aerobic lactate utilization is crucial for recovery of neuronal function posthypoxia in vitro. In vivo models of cerebral ischemia pose a conceptual challenge when compared to in vitro models. First, the glucose paradox of cerebral ischemia, namely, the aggravation of delayed neuronal damage by preischemic hyperglycemia, cannot be reproduced in vitro. Second, in vitro elevated glucose levels protect against ischemic (hypoxic) damage, an outcome that has seldom been reproduced in vivo. Employing a rat model of cardiac-arrest-induced transient global cerebral ischemia (TGI), we found that hyperglycemic conditions, when induced 120-240 min pre-TGI, significantly reduced post-TGI neuronal damage as compared to normoglycemic conditions. In contrast, hyperglycemia, when induced 15-60 min pre-TGI, significantly aggravated post-TGI neuronal damage. Brain lactate levels in rats loaded with glucose either 15 min or 120 min pre-TGI were significantly and equally higher than those of control, saline-injected rats. The beneficial effect of 120 min pre-TGI glucose loading was abolished by lactate transport inhibition. A significant increase in blood corticosterone (CT) levels was observed upon glucose loading that peaked at 15-30 min and returned to baseline levels by 60-120 min. When rats loaded with glucose 15 min pre-TGI were treated with metyrapone, a CT synthesis inhibitor, a significantly lower degree of delayed neuronal damage in comparison to both untreated, 15 min glucose-loaded rats and normoglycemic, control rats was observed. Thus, although elevated levels of brain lactate cannot explain the glucose paradox of cerebral ischemia, hyperglycemia-induced, short-lived elevation in CT blood levels could. More importantly, lactate appears to play a crucial role in improving postischemic outcome.
Adenosine Diphosphate↗
Excitotoxic preconditioning elicited by both glutamate and hypoxia and abolished by lactate transport inhibition in rat hippocampal slices.
Ischemic preconditioning (PC) of heart and brain is a well-documented phenomenon. However, the mechanism underlying the increased resistance to severe ischemia by a preceding mild ischemic exposure remains unclear. Over a decade ago, we demonstrated the existence of hypoxic PC in the hippocampal slice preparation. Here we report the ability of a short exposure to toxic levels of glutamate to heighten the tolerance of hippocampal slices to a subsequent, longer exposure to the excitotoxin. Glutamate PC could also be induced by a short hypoxic exposure, suggesting a common mechanistic pathway for all PC stimuli. Since glutamate receptor activation and hypoxia increase tissue lactate production, a-cyano-4-hydroxycinnamate was applied during the PC period to completely abolished PC. These results indicate that excitotoxic PC and hypoxic PC share similar mechanisms that possibly involve lactate production and its neuronal utilization.
Action Potentials↗
Blockade of lactate transport exacerbates delayed neuronal damage in a rat model of cerebral ischemia.
Studies over the past decade have demonstrated that lactate is produced aerobically during brain activation and it has been suggested to be an obligatory aerobic energy substrate postischemia. It has been also hypothesized, based on in vitro studies, that lactate, produced by glia in large amounts during activation and/or ischemia/hypoxia, is transported via specific glial and neuronal monocarboxylate transporters into neurons for aerobic utilization. To test the role of lactate as an aerobic energy substrate postischemia in vivo, we employed the cardiac-arrest-induced transient global cerebral ischemia (TGI) rat model and the monocarboxylate transporter inhibitor alpha-cyano-4-hydroxycinnamate (4-CIN). Once 4-CIN was establish to cross the blood--brain barrier, rats were treated with the inhibitor 60 min prior to a 5-min TGI. These rats exhibited a significantly greater degree of delayed neuronal damage in the hippocampus than control, untreated rats, as measured 7 days post-TGI. We concluded that intra-ischemically-accumulated lactate is utilized aerobically as the main energy substrate immediately postischemia. Blockade of lactate transport into neurons prevents its utilization and, consequently, exacerbates delayed ischemic neuronal damage.
Animals↗
Comparison of university of wisconsin, euro-collins, low-potassium dextran, and krebs-henseleit solutions for hypothermic lung preservation.
OBJECTIVE: We sought to test the effectiveness of 4 different solutions for hypothermic rat lung preservation. METHODS: One hundred ninety-two rats were used. The rats were divided into 4 groups, and University of Wisconsin, Euro-Collins, low-potassium dextran, or Krebs-Henseleit solution was used in each group. They were further divided into 6 subgroups of 8 rats each. The lungs were preserved at 4 degrees C for 0, 4, 6, 8, 12, or 24 hours, respectively, and lung function was studied by using a living rat perfusion model. RESULTS: Pulmonary arterial flow decreased in each group after 4 to 6 hours of preservation; the low-potassium dextran group decreased the least and the Krebs-Henseleit group decreased the most. Pulmonary vascular resistance increased in each group after 6 hours of preservation; the Krebs-Henseleit group increased the most. Although airway pressure increased, static lung compliance and gas exchange capacity decreased after 8 hours of preservation; the Krebs-Henseleit group exhibited the worst values. Lung tissue wet/dry weight ratio increased gradually during preservation; the University of Wisconsin group exhibited the least increase. An ultrastructural study indicated the least morphologic changes in the low-potassium dextran group at 24 hours. CONCLUSIONS: At 4 degrees C, all solutions preserved rat lungs for 4 hours with acceptable function. However, 6 hours of preservation resulted in damaged pulmonary function in some lungs, and this damage increased when preservation time was extended. The lungs preserved in low-potassium dextran solution had the best overall function, but the lungs preserved in University of Wisconsin solution had less edema.
Adenosine↗
LC-MS/MS detection of peroxynitrite-derived 3-nitrotyrosine in rat microvessels.
3-Nitrotyrosine (3NT) is used as a biomarker of nitrative pathology caused by peroxynitrite (PN), myeloperoxidase (MPO)-, and/or eosinophil peroxidase (EPO)-dependent nitrite oxidation. 3NT measurements in biological materials are usually based on either antibody staining, HPLC detection, or GC detection methodologies. In this report, a procedure is described for the measurement of 3NT and tyrosine (TYR) by LC-MS/MS that is simple, direct, and sensitive. Though highly specialized in its use as an assay, LC-MS/MS technology is available in many research centers in academia and industry. The critical assay for 3NT was linear below 100 ng/ml and the limit of detection was below 100 pg/ml. Regarding protein digested samples, we found that MRM was most selective with 133.1 m/z as the daughter ion. In comparison, LC-ECD was 100 times less sensitive. Basal levels of 3NT in extracted digests of rat brain homogenate were easily detected by LC-MS/MS, but were below detection by LC-ECD. The LC-MS/MS assay was used to detect 3NT in rat brain homogenate that was filtered through a 180 micron nylon mesh. Three fractions were collected and examined by phase contrast microscopy. The mass ratio (3NT/TYR) of 3NT in fractions of large vessel enrichment, microvessel enrichment, and vessel depletion was 0.6 ng/mg, 1.2 ng/mg, and 0.2 ng/mg, respectively. Ultimately, we found that the basal 3NT/TYR mass ratio as determined by LC-MS/MS was six times greater in microvessel-enriched brain tissue vs. tissue devoid of microvessels.
Animals↗
A case study of ligation induced calcification in middle cerebral artery in rat.
A 90 min ligation of the middle cerebral artery (MCA) followed by 72-hour reperfusion appeared to cause calcium deposition in vascular myocytes of the tunica media and the perivascular tissue of the Sprague Dawley rat. The presence of small ovoid to large irregularly shaped intracellular opaque deposits were demonstrated by light and electron microscopy. Using X-ray elemental analysis the chemical nature of the deposits was found to be calcium phosphate. The functional significance of this first demonstration of acute calcification following transient ligation of the rodent MCA invites further studies.
Animals↗
Ultrastructural localization of hippocampal TNF-alpha immunoreactive cells in rats following transient global ischemia.
Using a polyclonal antibody against rat TNF-alpha, we have identified specific intracellular immunoreactive sites in hippocampal pyramidal cells, astroglia, and in microglia within 72 h after a period of ischemia. Electron opaque immunoreactive products in pyramidal cells were found mainly in somata and dendrites. Astrocytes and microglia were nearly devoid of such complexes. These findings demonstrate the presence of TNF-alpha in hippocampal neurons and its enhancement by ischemic stress.
Animals↗
Correlates of delayed neuronal damage and neuroprotection in a rat model of cardiac-arrest-induced cerebral ischemia.
Numerous studies over the past three decades have used rodent models of cerebral ischemia. To measure the postischemic outcome, the majority of these studies used histopathology as the method of choice both quantitatively and qualitatively. No functional measure of postischemic outcome has been proved to correlate well with the histopathological one. The rat chest compression model of cardiac-arrest-induced global cerebral ischemia was used in the present study. Two separate measures of neuronal damage at 7 days postischemia were performed: (a) histologically, by counting normal pyramidal cell bodies in the mid-CA1 hippocampal region of the rat brain, in hematoxylin-eosin-stained, paraffin-embedded 6-microm sections, and (b) electrophysiologically, by counting the number of 400 microm hippocampal slices in which it was possible to evoke a normal (>/=10 mV) CA1 population spike by orthodromic stimulation of the Schaffer collaterals. The correlation between these two measures was tested in the following groups of rats: (a) control, untreated group, (b) MK-801-treated groups (0.03 to 1.0 mg/kg given i.p. shortly after ischemia), (c) diltiazem-treated (DILT) groups 1.0 to 30 mg/kg, given i.p. shortly after ischemia, and (d) a group treated with a combination of the two drugs together (0.1 mg/kg MK-801+3.0 mg/kg DILT given i.p. shortly after ischemia). The two measures of postischemic outcome were highly correlated in all groups studied. Both MK-801 and DILT exhibited a dose-dependent neuroprotective effect. When administered together, a synergy between the neuroprotective effect of MK-801 and DILT was observed. At the doses used, minimal or no side effects of either MK-801 or DILT were observed.
Animals↗
The glucose paradox in cerebral ischemia. New insights.
The present in vivo findings that lactate, accumulated during an ischemic episode, is an essential aerobic energy substrate during the initial postischemic period are in full agreement with out in vitro findings. Moreover, the beneficial effects of hyperglycemia are also in agreement with our and others' in vitro results that have demonstrated a neuroprotective effect of glucose against hypoxic change. The aggravation of ischemic delayed neuronal damage by glucose loading 15 min prior to the ischemic insult is likely the result of glucose induction of a short-acting (30 to 60 min) systemic factor (hormonal?) that, when combined with an ischemic insult, potentiates the ischemic damage.
Animals↗
Analysis of pulmonary microvasculature changes after photodynamic therapy delivered to distant sites.
Photodynamic therapy (PDT) can exert local damage by direct tumor cytotoxicity, by disruption of the microvasculature or by a combination of these effects. Although systemic effects after PDT of small tissue areas (< 1% total body surface area) are unlikely, treatment of larger areas may result in an accumulated effect leading to toxicity. Several investigators have described animal death after high dose PDT to tumors on the hind limb of animals and hypothesized that a toxic shock syndrome caused by vasoactive agents released after PDT is responsible. Because one of the most vulnerable organs to toxic shock injury is the lung, we studied the systemic effects of local PDT to this organ by intravital microscopy using a pulmonary window chamber. The PDT treatment conditions (25 mg/kg Photofrin, 24 h, 150 J/cm2 630 nm, maximum area 6.28 cm2) were chosen that produce systemic toxicity and lethality in rats. Adhesion of leukocytes in the lung was monitored in vivo using anti-CD-13-labeled microspheres. The progression of pulmonary edema was assessed by monitoring the leakage of rhodamine-labeled albumin and by wet-to-dry lung weight ratios. Although an increased leukocyte adherence was observed and a significant number of animals died after the extensive PDT treatment, no biologically significant lung edema could be demonstrated. These data indicate that lung edema and acute respiratory distress syndrome is not the cause of death in these animals and that the toxicity is related to other mechanisms including circulatory shock after extensive muscle damage.
Animals↗
Fosphenytoin reduces hippocampal neuronal damage in rat following transient global ischemia.
Fosphenytoin, a water-soluble disodium phosphate ester of phenytoin, is a phenytoin prodrug with similar anticonvulsant properties. In this study, we evaluated its neuroprotective properties in a cardiac arrest-induced global ischemia model. After 12 minute ischemia, Long-Evans hooded rats were resuscitated, given fosphenytoin (30 mg/kg, i.m.) or saline 5 minutes after the ischemic episode, and killed on day 7. Brains were removed, fixed, and vibratome sectioned to assess the numbers of normal appearing CAI pyramidal neurons and for immunohistological staining of glial fibrillary acidic protein (GFAP). After global ischemia, the number of hippocampal CA1 pyramidal neurons decreased significantly (from 14.33 +/- 1.73 to 2.19 +/- 0.16 per 100 micron 2). Most hippocampal CA1 pyramidal neurons showed signs of injury and GFAP immunoreactivity of the region increased. With fosphenytoin treatment 5 min after ischemia, hippocampal CA1 pyramidal neurons remained at near control level (13.90 +/- 0.92), however, GFAP staining was not significantly changed. Our data, although indicating different neuronal and glial responses following fosphenytoin treatment, nevertheless, suggest that fosphenytoin is an effective neuroprotectant against ischemia-induced damage.
Analysis of Variance↗
Fos-like immunoreactivity in rat hippocampal neurons following transient global ischemia.
Immediate early genes are expressed following ischemia in many tissues including the brain. Using a chest compression global ischemia model that produced delayed neuronal degeneration in surviving rats, we examined the hippocampal Fos response to ischemia/reperfusion by immunohistochemistry and electron microscopy. Immunostained nuclei were seen in a few CA1 pyramidal cells 1-3 h after reperfusion while the entire dentate granular cell population was immunoreactive. By electron microscopy, subcellular Fos-like immunoreactive sites were found both in the cell nuclei and on segments of endoplasmic reticulum. These findings indicate that transient global ischemia differentially affects the early response genes in neurons of the hippocampal subfields and that such difference may be related to the adult neuroplasticity of the brain.
Animals↗
Post-ischemic treatment with a lazaroid (U74389G) prevents transient global ischemic damage in rat hippocampus.
The ability of an experimental lazaroid, U74389G, to prevent damage to hippocampal CA1 cytoarchitecture due to transient global ischemia was studied by light and electron microscopy. Post-ischemic rats were given a single i.p. dose of lazaroid (6 or 18 mg kg-1) at 5 min after revival by cardiopulmonary resuscitation (CPR). Without lazaroid treatment the number of normal-appearing neurons in the CA1 region declined from a normal value of 15.49 +/- 2.21 to 8.40 +/- 10.08 per 100 microns2 on day 7 after the ischemic episode, and there was extensive damage visible in the cytoarchitecture of this region. In lazaroid treated rats, the normal cytoarchitecture was retained and the number of normal-appearing cells was maintained at 15.10 +/- 2.22 per 100 microns2. Ultrastructure studies indicated that pyknotic pyramidal cells laden with lysosomal aggregates were common in untreated post-ischemic rats but rare in lazaroid-treated rats. These results indicate that U74389G maintained the structural integrity of this region of the brain after transient global ischemia and suggest that this lazaroid may be an effective neuroprotectant.
Animals↗
Cardiac arrest-induced global cerebral ischemia studied in vitro.
The goal of the present study was to characterize the effects of chest compression-induced global cerebral ischemia on the hippocampal slice preparation. One of the characteristics of rats exposed to such cardiac arrest is a high susceptibility to sound-induced seizures. We tested audiogenic seizures as an in vivo indicator of ischemic cerebral damage and as a possible small animal model of epilepsy. The results of these tests were reported elsewhere. Long-Evans male rats (200-350 g) were subjected to 7 min of chest compression sufficient to stop the pumping action of the heart. The rats were then revived using cardiopulmonary resuscitation. Evaluation of cerebral damage following cardiac arrest and resuscitation was performed in vitro, by testing neuronal responses to electrical stimulation in hippocampal slices prepared from these animals. Sham control animals were used for comparisons. Twenty-one to 146 days after rats were chest-compressed, hippocampal slices were prepared. Sham control rats, anesthetized but not chest-compressed, were sacrificed one week later for preparation of slices. Rats in a second group exposed to 7-min chest compression, were sacrificed at different time intervals after their resuscitation (from 1 h to 7 days); hippocampal slices were prepared for electrophysiological analysis of neuronal damage. The results of these studies indicate that 3 weeks or longer after chest compression the evoked CA1 population spike amplitude in hippocampal slices was significantly attenuated; in 60% of these slices an epileptiform response was evoked. An increased proportion of slices prepared from rats 1 to 48 h after chest compression showed an augmentation in the amplitude of the evoked population spike; 72 h and up to 7 days after chest compression, an attenuation in the evoked CA1 population spike amplitude was observed, signaling delayed neuronal damage.
Animals↗
Prediction of chemotherapy response in human leukemia using in vitro chemosensitivity test.
We performed the dye exclusion assay (DEA) and the MTT dye reduction assay to determine the drug sensitivity of acute leukemia using short-term microplate cultures. The in vitro results were compared with the clinical response of 31 patients with acute leukemia treated by combination chemotherapy. The true-positive rates of the DEA and MTT assays were 86.7 and 91.3%, respectively; the true-negative rates were 33.3 and 77.8%, respectively; and the predictive accuracy was 62.5 and 87.5%, respectively. The DEA and MTT assays gave comparable results in drug sensitivity testing of leukemic blast cells. Our data suggest that MTT assay is the more suitable for assessing chemosensitivity in acute leukemia.
Adult↗
Effects of taurine and ketamine on bovine retinal membrane lipid peroxidation.
Lipid peroxidation disrupts membrane integrity and causes structural and functional alterations in ischemic tissues. Taurine and ketamine are putative ischemic protectants that affect Ca2+ influx. Here we report the influence of these compounds on lipid peroxidation in subcellular fractions, isolated cells and intact tissue from bovine retinas. P2 membrane fractions and isolated cells were exposed to the lipid peroxidation inducers cadmium chloride (200 microM) or L-ascorbic acid (1 mM) in the presence of 0-50 mM taurine, 0-10 mM ketamine, 1 mM kynurenic acid or 1 mM dextromethorphan. The latter compounds are N-methyl-D-aspartate receptor antagonists. Lipid peroxidation in isolated eyes reperfused after 1 h of ischemia either with or without protectants was determined by thiobarbituric acid assay. Glutathione was measured in isolated retinas subjected in vitro to simulated ischemia (no glucose or oxygenation) for 60 min either alone or in the presence of taurine or ketamine. Ketamine inhibited chemical- or ischemia-induced lipid peroxidation as well as ischemic glutathione depletion. Under the same conditions, taurine failed to affect lipid peroxidation or glutathione. The data show a direct effect of ketamine on lipid peroxidation and point to separate mechanisms of action for ketamine and taurine.
Animals↗
The influence of photodynamic therapy on the ultrastructure of the normal rat bladder.
Reduced bladder capacity is a major side effect for patients receiving photodynamic therapy (PDT) for bladder cancer. A rat bladder model has been developed to address both the vascular and tissue effects of the photodynamic treatment of the urinary bladder. Bladders were exteriorized and positioned in a plexiglass tissue bath. Effects on microvasculature were assessed during PDT of the bladder by recording luminal diameter changes in arterioles and venules. Animals receiving Photofrin II (10 mg kg-1) 30 min prior to PDT scored a statistically significant reduction in the diameter of the red blood cell column in the vessels, whereas administration of Photofrin II 48 h prior to PDT was ineffective. Morphological changes included significant endothelial and vascular myocyte damage in the 30 min PDT group alone. Among the other tissue components, the mucosal lining was minimally affected and the response of the muscularis was highly variable. Smooth muscle cell changes ranged from mild contraction to frank necrosis with many of the affected cells located near the altered vascular beds. These data suggest that the clinical symptoms of reduced bladder capacity can be accounted for by vascular damage and myocyte sensitivity. Further refinements in the Photofrin II and light doses used in therapy may reduce bladder complications and allow for better management of bladder cancer.
Animals↗