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Biomedical subjects

P Scheinberg

Publications and source records attributed to P Scheinberg.

At least 19 recordsLinked to original sources
PubMed2003

Stem-cell transplantation for autoimmune diseases.

The use of intensive immunosuppressive treatment coupled with BM stem-cell transplantation (SCT) to treat human autoimmune diseases (AID) follows anecdotal observations of responses of AID to allogeneic SCT and an extensive background of experience with SCT in animals with AID. In the last decade, numerous clinical trials have been initiated to explore a potential benefit of (mainly autologous) SCT in advanced and debilitating cases of rheumatoid arthritis, scleroderma, systemic lupus erythematosis and multiple sclerosis. In this review the etiology of AID and the experimental basis of SCT is presented, together with recent clinical results of SCT for AID. While much has been learned about the risks and benefits of SCT in AID, the underlying mechanisms regulating remission and relapse of AID after treatment remain largely unknown.

Autoimmune Diseases↗
PubMed1994

Stroke: the way things really are.

BACKGROUND: To comply with governmental requirements regarding the validity of therapeutic modalities and for medico-legal purposes, it is important to distinguish between what has been scientifically proven and what is anecdotal in the prevention and management of stroke. SUMMARY OF REVIEW: This review summarizes the evidence for many of the modalities used to prevent stroke in high-risk patients, including antiplatelet drugs, anticoagulants, and endarterectomy, and the limitations of each. Controversial therapeutic modalities for which no scientific proof exists, such as anticoagulation of progressing stroke, are also discussed. The term "standard of care" should apply to modalities proven to be effective by scientifically controlled studies, not because they are used by many physicians. Treatment of acute stroke is still disappointing despite the development of many promising pharmacological strategies in experimental animals. An important part of the reason may be that the window of therapeutic opportunity is much shorter than the usual entry time of patients in most clinical trials. This logistic problem merits serious attention. CONCLUSIONS: Numerous controlled, randomized, multiple-center clinical trials have demonstrated that the efficacy or lack thereof of various therapies directed at preventing or treating stroke can be determined and that anecdotal data may be misleading and harmful. At the least we should be aware of what we know and what we do not.

Anticoagulants↗
PubMed1991

Transient ischemic attacks: an update.

This is a review of extant concepts of transient ischemic attacks (TIAs), their definitions, prognostic significance, pathogenesis, physiology, and management. The natural history of TIAs depends upon the risk factors of the population group studied, so that therapeutic trials should be controlled and randomized and not dependent upon published natural history data. A strong association between TIAs and coronary artery disease has now been established. It may be difficult to establish the cause or pathogenesis of TIAs in any given patient in view of the relatively poor correlation between the patient's symptoms and location of arterial plaques. Recent studies have suggested mechanisms aside from impaired perfusion or embolization from carotid plaques or vertebral basilar disease. There are no proven indications for carotid endarterectomy, a procedure which has been excessively used in the United States, but presently ongoing prospective, randomized, controlled multi-center studies will likely resolve this important issue. Neither is there scientific validation for the use of long-term anticoagulants, but data support the efficacy of ASA in reducing the incidence of stroke and myocardial infarction in patients with TIAs.

Anticoagulants↗
PubMed1991

The biologic basis for the treatment of acute stroke.

This is a review of therapeutic modalities that have been utilized in the treatment of stroke. Each is based upon data obtained from the study of the biologic events that occur during experimentally induced cerebral ischemia in animals. The type of information obtained from these studies could not have been obtained in any other manner. Despite the apparent effectiveness of some of these modalities in modifying stroke in animals, their application to humans with stroke has been disappointingly ineffectual. The delay between onset of stroke symptoms and initiation of treatment is usually several hours or more, which may be too late to rescue ischemic neurons. In order to be effective, treatment will have to be initiated as early as possible (preferably within 1 hour) to take advantage of the biologic window of opportunity. There is evidence that this can be accomplished by proper planning and training of personnel.

Acidosis, Lactic↗
PubMed1988

Dementia due to vascular disease--a multifactorial disorder.

This review was undertaken to evaluate critically the literature pertaining to vascular dementia with the objective of determining a more useful and scientifically supported definition of vascular dementia, its relation to other causes of dementia, and the biologic mechanisms involved in its causation.

Alzheimer Disease↗
PubMed1988

Pentoxifylline in acute nonhemorrhagic stroke. A randomized, placebo-controlled double-blind trial.

The efficacy and safety of pentoxifylline were assessed in 297 adult patients with ischemic stroke in a multicenter, double-blind, randomized and placebo-controlled trial. Treatment was started within 12 hours after the stroke onset. Study medication was administered intravenously continuously (16 mg/kg/day, maximum 1,200 mg/day) for 3 days and per os (400 mg t.i.d.) for the remainder of 28 days. Demographic data were comparable, and functional impairment and mortality (pentoxifylline 12%, placebo 10%) were not different between the two groups. Neurologic deficit scores improved from baseline admission scores during the 4-week study in both groups but did not differ between groups at admission or throughout the study except during the first few days when the consciousness level (Days 1 and 2), motor function (Days 1 and 2), cranial nerve function (Days 1-4), and total neurologic deficit scores (Days 1 and 2) were better in the pentoxifylline group than in the placebo group, especially in a subset of patients with severe deficits at admission. Laboratory values and side effects were also comparable between groups. Our study indicates that pentoxifylline can be given safely in patients with acute ischemic stroke. Although pharmacologic effects were present during the first few days, the clinical benefits were small and not sustained.

Acute Disease↗
PubMed1987

Substantia nigra lesion protects against ischemic damage in the striatum.

The role of striatal dopamine (DA) in mediating ischemic neuronal death was studied in the rat. Two weeks after unilateral substantia nigra lesion, rats were subjected to 20 min of forebrain ischemia by 4-vessel occlusion. Morphological changes and 45Ca uptake were evaluated after 3 days of survival. In the DA-depleted striatum, the degree of ischemic neuronal damage and 45Ca uptake were markedly attenuated compared to the contralateral side. This study is the first to demonstrate that the presence of DA is a prerequisite for the development of ischemic injury in the striatum and that DA depletion protects the striatum from ischemic damage.

Animals↗
PubMed1987

Photochemically induced cerebral infarction. II. Edema and blood-brain barrier disruption.

Alterations in the blood-brain barrier to proteins, and regional water and electrolyte content were documented in a rat model of photochemically induced small-vessel thrombosis leading to infarction. Horseradish peroxidase (HRP) or Evans blue was given immediately following a 2-min photochemical sensitization period. At 5 min following irradiation, multifocal sites of peroxidase extravasation were noted within the irradiated area. Ultrastructural examination revealed endothelial cells filled with HRP which in some cases extended into the basal lamina and extracellular spaces. At 15 min, protein leakage was more pronounced within the irradiated zone and reaction product was also apparent within the subarachnoid and perivascular spaces of brain regions remote from the site of irradiation. Widespread staining on the surface of the irradiated hemisphere was apparent in rats perfused 8 h following Evans blue infusion. Water content increased significantly by 15 min within the irradiated zone but not in brain regions remote from this site. Although vasogenic edema is an early event in this stroke model, increases in water content are restricted to the irreversibly damaged site. In contrast, protein tracer escaping from microvessels coursing within the irradiated zone was widely distributed. These findings implicate endothelial barrier dysfunction in the genesis of tissue injury in this model. Morphological evidence for the capability of macromolecules to escape from a site of evolving infarction and to migrate to distances remote from the area of primary microvascular damage is also discussed.

Animals↗
PubMed1987

Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury.

We have tested whether small intraischemic variations in brain temperature influence the outcome of transient ischemia. To measure brain temperature, a thermocouple probe was placed stereotaxically into the left dorsolateral striatum of rats prior to 20 min of four-vessel occlusion. Rectal temperature was maintained at 36-37 degrees C by a heating lamp, and striatal temperature prior to ischemia was 36 degrees C in all animals. Six animal subgroups were investigated, including rats whose intraischemic striatal brain temperature was not regulated, or was maintained at 33, 34, 36, or 39 degrees C. Postischemic brain temperature was regulated at 36 degrees C, except for one group in which brain temperature was lowered from 36 degrees C to 33 degrees C during the first hour of recirculation. Energy metabolites were measured at the end of the ischemic insult, and histopathological evaluation was carried out at 3 days after ischemia. Intraischemic variations in brain temperature had no significant influence on energy metabolite levels measured at the conclusion of ischemia: Severe depletion of brain ATP, phosphocreatine, glucose, and glycogen and elevation of lactate were observed to a similar degree in all experimental groups. The histopathological consequences of ischemia, however, were markedly influenced by variations in intraischemic brain temperature. In the hippocampus, CA1 neurons were consistently damaged at 36 degrees C, but not at 34 degrees C. Within the dorsolateral striatum, ischemic cell change was present in 100% of the hemispheres at 36 degrees C, but in only 50% at 34 degrees C. Ischemic neurons within the central zone of striatum were not observed in any rats at 34 degrees C, but in all rats at 36 degrees C. In rats whose striatal temperature was not controlled, brain temperature fell from 36 to 30-31 degrees C during the ischemic insult. In this group, no ischemic cell change was seen within striatal areas and was only inconsistently documented within the CA1 hippocampal region. These results demonstrate that (a) rectal temperature unreliably reflects brain temperature during ischemia; (b) despite severe depletion of brain energy metabolites during ischemia at all temperatures, small increments of intraischemic brain temperature markedly accentuate histopathological changes following 3-day survival; and (c) brain temperature must be controlled above 33 degrees C in order to ensure a consistent histopathological outcome. Lowering of the brain temperature by only a few degrees during ischemia confers a marked protective effect.

Adenosine Triphosphate↗
PubMed1985

Cerebral norepinephrine depletion enhances recovery after brain ischemia.

Monoamine neurotransmitters, especially norepinephrine (NE), may have an important role in the pathophysiological aspects of postischemic cerebral dysfunction. In previous studies of post-decapitation-induced ischemia, we found that NE depletion caused a delay in glycogen breakdown but did not influence any of the other known biochemical abnormalities that accompany brain ischemia. In this study, we have turned to a model of transient incomplete and diffuse forebrain ischemia in the rat to examine the effects of cerebral NE depletion on the recovery after brain ischemia of levels of high-energy phosphate compounds, products of intermediary oxidative metabolism, and free fatty acids. We found that a unilateral lesion of the locus ceruleus and the resultant depletion of NE in the ipsilateral cerebral cortex had no effect on sham-operated controls nor on rats subjected to ischemia alone. However, in rats subjected to ischemia followed by 15 minutes of recirculation, the NE-depleted cerebral cortex had significantly higher phosphocreatine and adenosine triphosphate levels and energy charge, and lower adenosine monophosphate and docosahexaenoic acid concentrations. With longer periods of recirculation, these side-to-side differences were not apparent. These results suggest that activity of the central NE systems during transient brain ischemia has deleterious effects on the biochemical recovery of the cerebral cortex from severe ischemic insults.

Adenosine Monophosphate↗
PubMed1985

Regional brain energy metabolism after complete versus incomplete ischemia in the rat in the absence of severe lactic acidosis.

Levels of energy metabolites were measured in forebrain regions in fasted rats subjected to 4-h recirculation after 1 h of either incomplete or complete ischemia. Both models of ischemia were produced by a procedure combining bilateral common carotid artery occlusion, systemic hypotension, and CSF pressure elevation; the degree of intracranial hypertension was varied to produce incomplete and complete ischemia. Levels of brain lactate at the end of ischemia ranged from 16 to 19 mmol/kg in incomplete ischemia and from 11 to 13 mmol/kg in complete ischemia. Energy metabolism recovered evenly in the neocortical and subcortical regions with recirculation after incomplete ischemia. The metabolic recovery in the cerebral cortex after complete ischemia was similar to that observed after incomplete ischemia; however, recovery in the subcortical regions after complete ischemia was less extensive, NADH fluorescence remained high, and there was a fall in total creatine. Intracellular pH in the dorsal thalamus was more alkalotic after complete than incomplete ischemia. Thus, in the absence of profound tissue lactic acidosis, residual CBF during prolonged ischemia helps postischemic restitution of brain energy metabolism in subcortical regions. The pattern of poor recovery in these regions after complete ischemia suggests inadequate reperfusion. The decreased total creatine and the severe tissue alkalosis may be biochemical markers of advanced tissue injury during reflow.

Acidosis↗
PubMed1983

Compression-induced brain edema: modification by prior depletion and supplementation of vitamin E.

We studied the degree of edema resulting from focal brain compression in rats raised on vitamin E-deficient, -normal, or -supplemented diets. After release of 24 hours of epidural compression, edema developed ipsilaterally and was characterized by extravasation of serum protein, increased water and sodium content, and little change in potassium. The degree of swelling and increase of sodium in the previously compressed area were most pronounced in the vitamin E-deficient group and mildest in the vitamin E-supplemented group. Degradative processes of biomembranes seem to participate in the pathogenesis of brain edema; vitamin E may stabilize membranes by physicochemical interactions between the phytyl side chain and polyunsaturated phospholipids, or vitamin E may disrupt chains of free radical reactions.

Animals↗