Biomedical subjects
D E Levy
Publications and source records attributed to D E Levy.
Clinical predictors of outcome in ischemic stroke.
Stroke is the most common neurologic disorder of adults and one of the three leading causes of death in North America. Results of a study suggest that inexpensive and easily obtained clinical variables can be used to predict which patients with stroke will do well and which will not. This capability is invaluable to physicians, patients with stroke and their families, and future investigators.
Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia.
Progressive brain damage after transient cerebral ischemia may be related to changes in postischemic cerebral blood flow and metabolism. Regional cerebral blood flow (rCBF) and cerebral glucose utilization (rCGU) were measured in adult rats prior to, during (only rCBF), and serially after transient forebrain ischemia. Animals were subjected to 30 minutes of forebrain ischemia by occluding both common carotid arteries 24 hours after cauterizing the vertebral arteries. Regional CBF was measured by the indicator-fractionation technique using 4-iodo-[14C]-antipyrine. Regional CGU was measured by the 2-[14C]deoxyglucose method. The results were correlated with the distribution and progression of ischemic neuronal damage in animals subjected to an identical ischemic insult. Cerebral blood flow to forebrain after 30 minutes of moderate to severe ischemia (less than 10% control CBF) was characterized by 5 to 15 minutes of hyperemia; rCBF then fell below normal and remained low for as long as 24 hours. Post-ischemic glucose utilization in the forebrain, except in the hippocampus, was depressed below control values at 1 hour and either remained low (neocortex, striatum) or gradually rose to normal (white matter) by 48 hours. In the hippocampus, glucose utilization equaled the control value at 1 hour and fell below control between 24 and 48 hours. The appearance of moderate to severe morphological damage in striatum and hippocampus coincided with a late rise of rCBF above normal and with a fall of rCGU; the late depression of rCGU was usually preceded by a period during which metabolism was increased relative to adjacent tissue. Further refinement of these studies may help identify salvageable brain after ischemia and define ways to manipulate CBF and metabolism in the treatment of stroke.
A genetic locus regulates the expression of tissue-specific mRNAs from multiple transcription units.
129 GIX- mice, unlike animals of the congeneic partner strain GIX+, do not express significant amounts of the retroviral antigens gp70 and p30. Evidence is presented indicating that the GIX phenotype is specified by a distinct regulatory gene acting on multiple transcription units to control the levels of accumulation of specific mRNA species. The steady-state levels of retroviral-homologous mRNA from the tissues of GIX+ and GIX- mice were examined by blot hybridization using as probes DNA fragments from cloned murine leukemia viruses. RNA potentially encoding viral antigens was reduced or absent in GIX- mice, even though no differences in integrated viral genomes were detected between these congeneic strains by DNA blotting. Tissue-specific patterns of accumulation of these RNA species were detected in brain, epididymis, liver, spleen, and thymus, and several distinct RNA species were found to be coordinately regulated with the GIX phenotype. Measurements of RNA synthesis suggest a major role for transcriptional control in the regulation of some retroviral messages.
Experimental cerebral ischemia produced by extracranial vascular injury: protection with indomethacin and prostacyclin.
To determine whether the production of brain ischemia is modified by antiplatelet agents administered at the time of extracranial endothelial injury, we modified a four-vessel occlusion rat model so that an electrogenic platelet thrombus in one carotid artery produced cerebral ischemia. DC current was passed through an anode around the left carotid artery of 11 rats with preoccluded vertebral and contralateral carotid arteries. Five of six untreated rats became unresponsive because of carotid occlusion and resultant cerebral ischemia; none of five animals pretreated with indomethacin and infused with prostacyclin (PGI2) were clinically affected. Light- and electronmicroscopic studies showed arterial platelet-fibrin thrombi and ischemic brain damage in untreated rats. All rats had received radiolabeled platelets; radioactivity was increased in the electrogenically injured left carotid arteries from treated and untreated rats, but counts were reduced by more than 80% in indomethacin/PGI2-treated rats (p less than 0.01).
Comparison of radio-labeled butanol and iodoantipyrine as cerebral blood flow markers.
Cerebral blood flow (CBF) techniques based on the principle of indicator fractionation rely upon free diffusibility of the blood flow indicator into brain (i.e. complete cerebral extraction). Extraction of two commonly-used indicators, iodoantipyrine and n-butanol, was evaluated in rats by measuring torcular venous efflux after systemic injection of the indicator under conditions of normal and high CBF. The extraction of n-butanol was found to be virtually complete at all blood flows examined; iodoantipyrine, on the other hand, was completely extracted only at flows under 180 ml/100 g/min, despite the fact that the oil: water partition coefficient for iodoantipyrine exceeds that for n-butanol. Brain uptake indices for the two indicators were also measured: brain uptake of n-butanol was greater than that of iodoantipyrine, and the difference was more marked if the indicator entered brain mixed with blood than if it entered as a bloodless bolus. Blood components may thus interact with iodoantipyrine to retard its movement across the blood-brain barrier and thereby limit extraction of this lipid-soluble substance. Inasmuch as iodoantipyrine is diffusion-limited at blood flows above 180 ml/100 g/min, butanol is a more accurate CBF indicator above the normal flow range in the rat.
Immunoglobulin-sulfated polysaccharide interactions. Binding of agaropectin and heparin by human IgG proteins.
The interaction of immunoglobulins with certain acidic polysaccharides was demonstrated by the binding of the sulfated glycans agaropectin and heparin by certain human IgG proteins. Heparin-binding IgG proteins can distinguish between the molecular forms of heparin derived from porcine intestine, bovine lung, and rat skin. The major specificity of these proteins is for native and certain high molecular weight subunit components of rat skin heparin. The interactions with multi-chain and single chain rat skin heparin are stable under physiological conditions and involve the Fab and, more specifically, the Fv region of the IgG molecule. These reactions occur as a result of an electrostatic interaction between cationic sites on certain IgG proteins and anionic sulfate resides of agaropectin or heparin. The characteristics of heparin-IgG interaction resemble those of heparin with other plasma proteins, the interactions of which have biological significance.
Hypoxic-ischemic brain injury and the vegetative state: clinical and neuropathologic correlation.
We studied 10 patients who survived for 2 to 8 weeks in a vegetative state, including 8 with cardiopulmonary failure and 2 with subarachnoid hemorrhage. Within days of onset, they regained brainstem function and awoke, but none had evidence of cognitive awareness. All patients opened their eyes within 2 weeks, and eight had roving conjugate eye movements. Pupillary and corneal responses were intact within 1 week, and seven patients had tonic oculovestibular responses (OVR) within 24 hours. By the end of 1 day, only three patients failed to move limbs in response to noxious stimuli. At postmortem, all patients had widespread ischemic neuronal damage in the cerebral hemispheres. The brainstems lacked morphologic abnormality, except that one patient had a single microinfarct in the superior colliculus.
Prognosis in nontraumatic coma.
We conducted serial neurologic examinations on 500 patients in nontraumatic coma to identify factors predicting recovery. Overall, 81 patients (16%) led an independent life at some point within the first year; the remainder either died without recovery from coma (61%), never improved beyond the vegetative state (12%), or regained consciousness but remained dependent on others for daily activities (11%). Functional recovery did not depend on age but was to some degree related to the cause of coma (subarachnoid hemorrhage and other cerebrovascular disease having the worst recovery; hypoxia-ischemia, intermediate; and hepatic and miscellaneous causes, best) and especially to early clinical signs of brain dysfunction. Even within hours of the onset of coma, only one of 120 patients lacking two of corneal, pupillary, and oculovestibular responses ever regained independent function. The study identifies clinical features of comatose patients that appear within the first week and that are important for predicting recovery and designing future therapeutic trials.
The importance of cerebral arterioles in alterations of the blood-brain barrier.
Light and electron microscopy and quantitative estimates of pinocytotic activity in cerebral arterioles and capillaries were performed in two different rat models of altered blood-brain barrier permeability in order to determine the side of initially increased vesicular transport. Seizures were produced by 20 consecutive electroshocks, and ischemic neuronal damage was produced by a 30-minute period of combined right common carotid artery occlusion and systemic hypoxia. Horseradish peroxidase was used to evaluate blood-brain barrier permeability. Serial 1micronm.sections showed an ateriole within most foci of horseradish peroxidase extravasation. There were areas of brain in both experimental groups in which the only permeable vessels were arterioles, and in one ischemic animal, the only permeable vessels were arterioles. Pinocytotic activity was determined in capillaries and arterioles and expressed as the number of horseradish peroxidase-containing pinocytotic vesicles per square millimeter of endothelial cytoplasmic area +/- standard error. The pinocytotic activity in capillaries and arterioles, respectively, was 12.2 +/- 5.4 and 6.7 +/- 3.0 in normal rats, 86.7 +/- 22.1 and 267 +/- 46.1 after seizures, and 52.7 +/- 10.6 and 91.2 +/- 33.2 following cerebral ischemia. These results indicate the importance of the arterioles in maintaining and altering the blood-brain barrier and suggest that abnormal blood-brain barrier permeability occurs first within the arteriole.
A mask for delivery of inhalation gases to small laboratory animals.
A mask was developed for the administration of volatile anesthetics and other gases to small, spontaneously breathing laboratory animals. A vacuum-powered venting system surrounding the inspiratory gas supply prevented potentially hazardous gases from escaping into the environment. This system was used to deliver nitrous oxide, halothane, and methoxyflurane to rats, gerbils, and newborn dogs. It was used to vary the oxygen and carbon dioxide concentrations inspired by spontaneously breathing animals undergoing physiological experiments.
Delayed pentobarbital administration limits ischemic brain damage in gerbils.
The capacity of delayed barbiturate administration to limit brain damage after unilateralcerebral ischemia was examined histologically in gerbils. The right common carotid artery was occluded in 50 animals under brief (3-minute) halothane anesthesia; 18 animals (36%) developed motor abnormalities consistent with stroke. The arterial clasps were removed after 1 hour and the abnormal animals were divided into treatment and placebo groups. Treated gerbils received sodium pentobarbital (70 mg/kg) intarperitoneally 1 hour after clasp removal and a smaller dose (50 mg/kg) 2 hours later; these animals lost corneal reflexes but retained spontaneous respiration and were kept normothermic. Animals in the placebo group received equivalent volumes of normal saline. Except for the period of anesthesia, both groups had similar postischemic motor behavior. Neuropathological examination of animals killed by perfusion-fixation after 24 hours revealed fewer pentobarbital-treated animals with shift of midline structures and with ipsilateral ischemic damage (including infarction). Compared with the placebo group, there was less extensive neuronal ischemic cell change in five regions of the ipsilateral cerebral hemispheres of the pentobarbital-treated animals (p less than 0.05). The results suggest that barbiturates administered as long as 1 hour after the end of an ischemic insult can still limit brain damage.
Selective chromatolysis of neurons in the gerbil brain: a possible consequence of "epileptic" activity produced by common carotid artery occlusion.
Unilateral (50 to 118 minutes) and bilateral (2 to 33 minutes) carotid artery occlusion in gerbils resulted in two distinct types of neuronal alteration: ischemic cell change (ICC) in selectively vulnerable brain regions, and selective chromatolysis (SC) confined to the deeper layers of the cortex, the Sommer sector of zone h-1, and the paramedian region (PM) of the hippocampus. In typical SC the nucleus was eccentric and the Nissl substance was lost in the central eosinophilic cytoplasm. In electron micrographs this area of cytoplasm showed disruption of smooth and rough endoplasmic reticulum with disaggregation of polyribosomes and accumulation of mitochrondria and various dense bodies. SC was identified at 2 to 3 hours and was still recognizable at five days. When bilateral carotid artery occlusion lasted 5 to 6 minutes, SC was seen in the hippocampal Sommer sector and cerebral cortex, while ICC was restricted to the endfolium (h3-5). Unlike ICC, the frequency of SC was not related to the duration of ischemia but probably to the epileptic seizures (overt and subclinical) initiated by ischemia in the gerbil. These changes must be considered when the gerbil is employed as a model of experimental stroke.
Experimental cerebral ischemia produces platelet aggregates.
Human studies indicate that transient platelet abnormalities accompany acute cerebral ischemia. Although these abnormalities may precipitate the ischemi process, ischemia could also alter platelet function. Platelets were therefore studied in gerbils subjected to 1 hour of unilateral carotid artery occlusion. Venous blood from five clinically affected gerbils contained more aggregated platelets (37.8% +/- 6.4) than did blood from eight unaffected animals (11.1% +/- 3.0; p less than 0.01). Platelets labeled with 3H-serotonin were increased in ischemic brain; the ratio of radioactivity in the ipsilateral versus contralateral hemisphere was greater in eight affected (1.09 +/- 0.03) than in 19 unaffected (1.00 +/- 0.01; p less than 0.02) animals. The radioactive serotonin was located predominantly within blood vessels. Cerebral ischemia thus stimulated the formation of platelet aggregates, a response which could contribute to the ischemic process.
Delayed postischemic hypoperfusion: a potentially damaging consequence of stroke.
Cerebral blood flow (CBF) was assessed with radioactive butanol and antipyrine during and after 1 hour of unilateral carotid artery occlusion in gerbils. Animals with clinical evidence of stroke demonstrated a marked fall in ipsilateral CBF during occlusion "no-reflow" phenomenon did not develop; instead, blood flow returned to normal 5 minutes after the termination of carotid occlusion. Flow subsequently fell to half the control value, however, and remained depressed for several hours despite local metabolic demands. This delayed imbalance in energy supply and demand creates a potential for additional brain damage that might be prevented by appropriate therapeutic intervention.
Outcome from severe neurological illness; should it influence medical decisions?
Most persons now accept the concept that when brain is dead, self is dead, and are willing to act accordingly. Much more difficult is to decide what to do when illness irreparably deprives the brain of cognitive functions. To facilitate less impassioned discussion of this question, 500 consecutive patients in coma from non-traumatic causes have been studied in the USA and Europe and the outcome has been compared against carefully selected early neurological signs. Medical coma was itself a dangerous sign, with only 15% of patients recovering independence within the first month. Within the first six hours, when most medical decisions are made about applying intensive care, neurological signs predicted with 95% confidence between the extremes of favourable and unfavourable outcomes in as many as a quarter of the patients. Only 5% of patients who failed to regain cognition by the end of one week regained any independence. Other more detailed guidelines were equally informative. If prognostic signs that confidently separate potentially favourable from unfavourable outcomes can be identified in severe neurological illness, perhaps society can more easily help medicine in reaching difficult ethical decisions.
The vegetative state and its prognosis following nontraumatic coma.
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Predicting prognosis in coma. Can one improve medical decisions?
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