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Biomedical subjects

G Freund

Publications and source records attributed to G Freund.

18 recordsLinked to original sources
PubMed1992

Use of annexin-V to demonstrate the role of phosphatidylserine exposure in the maintenance of haemostatic balance by endothelial cells.

Annexin-V (PAP-I, lipocortin-V) acts as a potent anticoagulant in vitro by binding to negatively charged phospholipids with higher affinity than vitamin K-dependent proteins, with a Kd in the 10(-10) M range. The purpose of the present study was to use annexin-V as a probe to assess the catalytic potential of phospholipids in pro- and anti-coagulant reactions in purified systems and at the surface of endothelial cells in culture after stimulation. Procoagulant tissue factor and anticoagulant thrombomodulin activities were compared by using specific two-stage amidolytic assays performed with purified proteins. Procoagulant activity was estimated by the generation of Factor Xa by the Factor VII(a)-tissue factor complex. Anticoagulant activity was estimated by the generation of activated protein C by either the thrombin-thrombomodulin complex or Factor Xa. Annexin-V induced a decrease of 70% of thrombomodulin activity when thrombomodulin (5.4-214 nM) was reconstituted into phosphatidylcholine/phosphatidylserine (1:1, mol/mol) vesicles at 37.5 or 75 microM-phospholipid concentration, the apparent Ki being 0.5 microM at 75 microM-lipid. The saturating concentration of annexin-V was dependent on phospholipid concentration, but was independent of the phospholipid/thrombomodulin ratio. By contrast, when thrombomodulin was not reconstituted in vesicles, annexin-V had no effect. At 2 microM, annexin-V totally inhibited the generation of activated protein C by Factor Xa in the presence of 75 microM-lipid, the saturating inhibitory concentration being dependent on phospholipid concentration. At 0.1 microM, annexin-V totally inhibited tissue-factor activity present in crude brain thromboplastin. In the absence of stimulation, human endothelial cells in culture expressed significant thrombomodulin activity and no detectable tissue-factor activity. Basal thrombomodulin activity was only slightly inhibited (less than 15%) by 0.5 microM-annexin-V. Phorbol myristate acetate (PMA) induced the expression of tissue-factor activity and decreased thrombomodulin activity at the endothelial-cell surface. Annexin-V, at a concentration of 16 microM, caused an 80% decrease of tissue-factor activity induced by PMA at 10 ng/ml, whereas it inhibited thrombomodulin activity by only 15% on the same stimulated cells. Our results confirm that annexin-V inhibits, in vitro, procoagulant tissue-factor activity and anticoagulant activities (activation of protein C by the thrombin-thrombomodulin complex and by Factor Xa), through phospholipid-dependent mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)

Annexin A5↗
PubMed1992

Insulin-like growth factor I receptor binding in brains of Alzheimer's and alcoholic patients.

Patients with chronic alcoholism and/or Alzheimer's disease show degenerative changes in the cerebral cortex and hippocampus. To investigate possible changes in insulin-like growth factor I receptor binding sites in brain tissue of patients with these pathological conditions, the number of 125I-insulin-like growth factor I binding sites was determined in tissues obtained from control patients and those with Alzheimer's and/or with a history of alcoholism. The four experimental groups examined consisted of patients from similar age groups. Postmortem histology and a clinical history were used for the diagnosis of Alzheimer's disease and alcoholism, respectively. Careful clinical records were kept concerning other variables such as immediate cause of death and medications administered before death. Specific binding of 125I-insulin-like growth factor I to homogenates prepared from cerebral cortex of Alzheimer's, alcoholic, alcoholic Alzheimer's, and age-matched control patients was similar, although Alzheimer's patients tended to have slightly higher binding values. No significant differences in insulin-like growth factor I binding in cerebral cortex were found with regard to age of patients, the interval between death and autopsy, and CNS-active medications. No statistical differences in 125I-insulin-like growth factor I binding were noted in hippocampal tissue from the four patient groups. Thus, human insulin-like growth factor I binding sites in cerebral cortex and hippocampus appear unaffected by several variables.

Alcoholism↗
PubMed1991

Binding of [125I]-insulin-like growth factor-1 (IGF-1) in brains of Alzheimer's and alcoholic patients.

Patients with chronic alcoholism and/or Alzheimer's disease suffer from degenerative changes in the cerebral cortex and hippocampus. To investigate possible changes in IGF-1 receptor binding sites in brain tissue of patients with these pathological conditions, the binding of [125I]-IGF-1 was determined in tissues obtained from control, Alzheimer's and/or patients with a history of alcoholism. The four experimental groups examined consisted of patients from similar age groups. Specific binding of [125I]-IGF-1 to cerebral cortical membranes from Alzheimer's patients had significantly more binding sites than age-matched controls, alcoholic patients and alcoholic patients with Alzheimer's disease. Regression analyses indicated that there were no significant differences in [125I]-IGF-1 binding in cerebral cortex with regard to age of patients (1.1% of total variance with a range of 52 to 92 years). Likewise, the time interval between death and autopsy contributed only 1.4% to the total variance in IGF-1 binding. No statistical differences in [125I]-IGF-1 binding were noted in hippocampal tissue from the various patient groups. Thus, human IGF-1 binding sites in cerebral cortex and hippocampus appear to be relatively stable for a number of variables. The increase in cerebral cortical [125I]-IGF-1 binding sites could be due to upregulation of IGF-1 receptors resulting from a decrease in IGF-1 levels in Alzheimer's patients.

Alcoholism↗
PubMed1991

Unrecognized left ventricular dysfunction in an apparently healthy alcohol abuse population.

To examine effects of chronic alcohol abuse on left ventricular function, 162 otherwise relatively healthy alcohol abusers, having been admitted to a rehabilitation program, underwent cardiac evaluation including chest X-ray, electrocardiogram, and radionuclide angiography after 2 weeks abstinence. Twenty-nine of the 162 alcoholic subjects (18%) with left ventricular dysfunction were identified. Twenty-two had regional wall motion abnormalities, suggesting a localized process, of whom 12 also had depressed ejection fractions. Seven others had a depressed ejection fraction alone with a more global myopathic process. Only 4 of these 29 patients had any history suggesting prior heart disease. Two of the 29 had Q-waves greater than or equal to 0.4 s and 8 had an abnormal cardiothoracic ratio on chest X-ray. Chronic alcohol abusers appear to be at relatively high risk for left ventricular dysfunction; most of which is unrecognized. Routine screening methods failed to identify 85% of our subjects who later were recognized by radionuclide angiography. Since historical and electrocardiographic abnormalities are often absent in this population, detection of left ventricular dysfunction by other methods such as radionuclide angiography must be used.

Adult↗
PubMed1991

Loss of synaptic receptors can precede morphologic changes induced by alcoholism.

Neuropsychological deficits including dementia in some alcoholics may potentially result from progressive, submicroscopic loss of synaptic receptors in the absence of morphological lesions. The densities of two types of synaptic receptors were determined in autopsy brain homogenates from several brain regions of not grossly demented alcoholics and non-alcoholic controls. In alcoholics, muscarinic cholinergic receptors were decreased by 40% in frontal cortex, temporal cortex and putamen and by 30% in hippocampus. Benzodiazepine receptors were decreased by 30% in hippocampus and by 25% in frontal cortex but not in temporal cortex or putamen. These changes occurred in histologically normal brains in the absence of Wernicke's encephalopathy, coma, liver cirrhosis and cholinergic or benzodiazepine medications. A computer data base matched for differences in death-autopsy time intervals, age and hypoxia. We conclude that chronic exposure to alcohol results in a loss of synaptic receptors with their synapses. To what extent such receptor losses could result in impairment of cognitive function is currently unknown but will depend on other factors such as the availability of spare receptors and what subtypes of receptors are involved. A rationale may emerge for using in alcoholics the cholinergic treatments currently being developed for the cognitive deficits of Alzheimer's disease.

Alcoholism↗
PubMed1979

Reflections on the topics: EEG frequency bands and regulation of vigilance.

A critical analysis of quantitative pharmaco-electroencephalography begins with parametrization into variables. The determination of frequency bands according to clinical criteria should be reconsidered. Alternatives may be the determination of factor scores or the definition of frequency bands based on factor analysis. If the latter procedure is used, the clinical alpha-band is subdivided into a lower (alpha 1F = 8,5-10.5 HZ) and an upper (alpha 2F = 10.5-12.5 HZ) part. Furthermore parts of the clinical theta-band (and the delta-band are combined into the delta F-band (1.5-6.0 HZ), for awake healthy volunteers with an occipital alpha-rhythm. Existing concepts of vigilance for the awake stages are not contradictory to the following observations: the factor structure of EEG relative power spectrum variables shows a negative correlation of slow alpha-frequencies with those in the delta F- and beta 3F-band. There is also a negative correlation between slow and fast alpha-wave relative power values.

Arousal↗
PubMed1979

Possible relationships of alcohol in membranes to cancer.

Ethanol can be used as a chemical tool to alter membrane fluidity or composition, or both, and to study the effects on induction, growth, spread, or treatment of cancers. Ethanol rapidly equilibrates with total body water and enters all cell membranes. Ethanol molecules are intercalated between the lipids of the bilayer membranes. This expands membranes and increases their fluidity, which in turn affects cell agglutination, phagocytosis, membrane transport, membrane enzyme activities, and many other membrane functions. After 3 to 5 days of continuous ethanol administration, the original membrane fluidity is restored by the incorporation of "stiffening" lipids, such as cholesterol, into the bilayer and by the increase of the chain length and saturation of fatty acids. The desired membrane effects (increased fluidity or altered membrane composition) can be obtained by adjusting time-dose relationships of ethanol administration. There may be an important role of moderate alcohol consumption in cancer biology that is not presently recognized by epidemiological studies because both cancers and moderate alcohol consumption are very prevalent in the general adult population. Moderate, social alcohol use could potentially either suppress or enhance the induction, growth, spread, or therapy of cancers. Such potential roles of alcohol in cancer biology could easily be tested in animals by incorporating the feeding of alcohol-containing diets into experiments that follow standard cancer protocols.

Alcohol Drinking↗
PubMed1977

[An electroencephalographic comparison of fentanyl and sulfentanil (author's transl)].

Equipotent analgesic doses of sulfentanil and fentanyl showed similar effects in 281 cases of clinical neuroleptanalgesia. In rabbits equimolecular doses of sulfentanil induced a deeper narcotic effect (burst suppression) than fentanyl. This supports the thesis of a coincidental increase of analgesic potency and narcotic effect in agonistic opioids. In equipotent doses the conventional EEG and the amplitude-frequency-spectra are equal. Quantificated analyses and statistical calculations show essentially similar changes in animal: - Fentanyl as well as sulfentanil changes only the dominant frequency in the theta-bands. - The percentage value increases only in the sigma-band, doesn't change in the alpha- and beta1-band and decreases in the theta-band, beta2--and beta3-band. - The power of sigma rises by a potency of ten in both substances; the change in the other frequencies shows similar sizes. Fentanyl and sulfentanil do not coure differences in the EEG.

Adult↗
PubMed1975

Induction of physical dependence on alcohol in rodents.

An ethanol withdrawal syndrome consisting of tremors and seizures can be induced in rats and mice. This syndrome closely resembles the physical signs observed in human patients during alcohol withdrawal. The criteria for an animal model of a human disease appear to be fulfilled regarding the etiological agent, course of illness, the similarity of physical and electrophysiological manifestations and response to therapeutic agents. Therefore these models should lend themselves for the elucidation of the pathogenesis at the molecular level of biological organization and for the development of new therapeutic approaches. Criteria for an optimal animal model of ethanol dependence are outlined. Withdrawal signs are classified into minor (startle threshold and exploratory behavior) and major types (tremors and seizures). Methods for quantification of tremors and seizures are described. The procedures for induction of the major withdrawal signs are classified according to the mode of ethanol administration designed to circumvent the animal's inherent aversion to the taste of ethanol: Oral (free feeding, behavioral modifications of free feeding and force feeding), parenteral and inhalation. Auxiliary procedures consist of pyrazole administration and weight reduction resulting in a decreased rate of ethanol metabolism. Exposure to low environmental temperatures increases consumption of ethanol containing diets without proportionately increasing the rate of ethanol metabolism. Auxiliary procedures for the induction of seizures during withdrawal consist of handling the animals and audiogenic stimuli. Advantages and limitations of various rodent models are evaluated in terms of the procedures (practicability, compounding variables) and their results (reproducibility, severity and yield of major withdrawal signs, objective quantification). It is concluded that none of the current methods fulfill all requisites for all types of experiments. The selection of methods best suited for a particular experiment depend upon its objectives.

Acoustic Stimulation↗
PubMedDate not supplied

Physical dependence on ethanol: conceptual considerations.

The mechanism of physical dependence is defined as a chain of events that begins at the physical level of membrane organization and that progresses through the various levels of biological organization to the behavioral level. An ethanol-induced alteration may be (1) cause, (2) effect, (3) an unrelated covariate of physical dependence, or (4) an experimental artifact. A variety of criteria in addition to correlation must be met before the significance of an ethanol-induced effect can be assessed. The reasons are summarized for assuming that physical effects of ethanol on membranes are the primary initiators of the cascade of events that leads to physical dependence.

Alcoholism↗
PubMedDate not supplied

Alzheimer's disease and alcoholism: possible interactions.

The purpose of this investigation was to test the hypothesis that chronic exposure to alcohol may accelerate Alzheimer's disease (AD), either by independently adding receptor losses or by accelerating the AD disease process itself. Muscarinic [3H]quinuclidinyl benzilate and benzodiazepine [3H]-flunitrazepam receptor binding in homogenates of human autopsy brains were determined in four nonalcoholic and seven alcoholic AD brains and in histologically normal brains from 20 alcoholics and 20 nonalcoholics. Muscarinic binding was decreased in alcoholic AD compared with nonalcoholic AD in the parahippocampal region of frontal cortex, premotor temporal cortex, and amygdala, but not in the hippocampus. Benzodiazepine receptors were lost from the temporal cortex and amygdala, but the difference in the amygdala was not statistically significant. Plaque counts considered a marker of the severity of AD were not increased in the brains of alcoholics compared with nonalcoholics. Larger receptor losses in some alcoholic AD were associated with low plaque counts. Since all of these patients were severely demented, it is tentatively suggested that the receptor losses resulting from alcoholism may have contributed to the dementia in these AD patients.

Aged↗