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Biomedical subjects

E Friedman

Publications and source records attributed to E Friedman.

At least 775 records · Page 43Linked to original sources
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Decreased phospholipase C-beta immunoreactivity, phosphoinositide metabolism, and protein kinase C activation in senescent F-344 rat brain.

Phosphoinositide metabolism, phospholipase C immunoreactivity, and protein kinase C translocation were measured in brain slices of 6- and 24-month-old F-344 rats. Basal phosphoinositide labeling and accumulation of [3H]inositol phosphates were reduced in the 24-month-old rats. The cholinergic agonist, carbachol, induced lower net accumulations of inositol phosphates in striatal, hippocampal, and cortical slices of the aged rats. The dose-response curve for carbachol showed a significantly lower maximal response in the striatum of senescent rats, whereas the time course of [3H]inositol incorporation into inositol metabolites and the accumulation of free [3H]inositol in tissues from young and old animals were not different. Quantitative analyses showed marked reductions in endogenous brain levels of the phosphoinositides and in phospholipase C-beta 1 immunoreactivity, but no marked reductions in endogenous brain levels of the phosphoinositides and in phospholipase C-beta 1 immunoreactivity, but no changes in phospholipase C-gamma levels in aged animals. Moreover, basal protein kinase C activity and carbachol-mediated translocation of the enzyme were significantly reduced in the cerebral cortex of the senescent animals. These findings imply that aging is associated with alterations in the brain content, metabolism, and activity of phosphoinositide-derived second messengers in the F-344 rat brain.

Aging↗
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Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients.

BACKGROUND: recent investigations have suggested that the phosphoinositide (PI) signal transduction system may be involved in the pathophysiology of bipolar affective disorders. Earlier studies in our laboratory have implicated altered PKC-mediated phosphorylation in bipolar affective disorder and in the clinical action of lithium. In the present study, we compared PKC activity and its translocation in platelets from subjects with bipolar affective disorder and three other groups. METHODS: subjects included 44 with bipolar disorder (acute manic episode), 25 with acute major depression, 23 with schizophrenia in acute exacerbation and 43 controls free of personal or family history of an Axis I disorder. Blood platelet membrane and cytosol PKC activity was measured before and after in vitro stimulation with serotonin (5-HT), thrombin and the direct PKC activator, PMA. In addition, we examined 5-HT-, thrombin- and PMA-elicited translocations of PKC isozymes from cytosol to the membrane in platelets of control subjects. RESULTS: in the basal state, manic subjects demonstrated higher membrane PKC activity than depressive and control subjects. The ratio of membrane to cytosol PKC activity was significantly higher in manic (1.10), as compared to control (0.84), depressed (0.93) or schizophrenic (0.93) subjects. Stimulation of platelets with 5-HT in vitro, resulted in greater membrane to cytosol ratio in the manic subjects compared to the three other groups. The responsiveness of platelets to PMA and thrombin was greater for manic subjects than for depressed and schizophrenic subjects, but not greater than the controls. In this measure both the schizophrenic and depressive groups were less active than controls. The results also demonstrate that platelets contain alpha-, beta-, delta- and zeta-PKC isozymes. While alpha- and beta-PKC isoforms were translocated from cytosol to membrane in response to serotonin, PMA and thrombin, serotonin also elicited the redistribution of delta-PKC and thrombin also activated zeta-PKC. CONCLUSION: the results demonstrate that a heightened PKC-mediated signal transduction is associated with acute mania and suggest a decreased transduction in patients with unipolar depression or schizophrenia.

Acute Disease↗
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Attenuation of cocaine-induced genomic and functional responses in prenatal cocaine-exposed rabbits.

The effects of in utero cocaine exposure on cocaine-induced genomic and functional responses in postnatal life were examined. Pregnant Dutch Belted rabbits were injected intravenously, twice daily, with cocaine hydrochloride (4 mg/kg) or saline from day 8 through day 29 of pregnancy. Prenatally exposed kits were challenged with cocaine on postnatal day 20. In prenatal saline-exposed kits, cocaine induced time- and dose-dependent c-fos gene expression in both frontal cortex and striatum. Prenatal cocaine exposure reduced cocaine-induced c-fos responses by 35-58% in the frontal cortex and 37-41% in the striatum. Cocaine-induced functional responses that included head bobbing, seizure, and locomotor activity were also attenuated in prenatal cocaine-exposed kits. Cocaine-induced c-fos expression and functional responses were blocked by the D(1) dopamine receptor antagonist, SCH23390, or by the serotonin receptor antagonist, methysergide, but not by the D(2) dopamine receptor antagonist, L-sulpride. The results indicate that in utero cocaine exposure leads to diminished responses to cocaine challenge in the offspring, which may be mediated by prenatal cocaine-induced alterations in one or more components of the D(1) dopamine and/or serotonin receptor signaling systems during early postnatal life.

Animals↗
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Germline mutational analysis of presenilin 1 and APP genes in Jewish-Israeli individuals with familial or early-onset Alzheimer disease using denaturing gradient gel electrophoresis (DGGE).

Germ line mutations in three genes have been detected in patients with familial Alzheimer's disease (FAD) and sporadic, early onset disease: amyloid precursor protein (APP), presenilin 1 (PS-1), and presenilin 2 (PS-2). The relative proportions in which mutations in these genes occur among AD patients in Israel has not been evaluated. To that end, we screened 52 Jewish-Israeli patients with AD: 22 with sporadic, early-onset disease (below 65 years), and 30 with FAD. Mutation screen employed denaturing gradient gel electrophoresis (DGGE) of exon-specific PCRs and restriction enzyme digest. Five patients from three different families displayed mutations within the PS-1 gene: three patients of one family showed a mis-sense mutation in codon 120 (Glu 120Lys), and two other unrelated patients showed an identical mis-sense mutation in codon 318 (Glu318Gly). No patient showed an abnormal migration on DGGE (for APP) or mutant restriction digest pattern (for PS-2) genes. These data may indicate the existence of another familial Alzheimer disease (FAD) gene locus in the Israeli Jewish population.

Adult↗
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Codon 72 polymorphism of p53 in Israeli Jewish cervical cancer patients and healthy women.

Recently it has been found that the presence of homozygous arginine polymorphism at codon 72 of p53, represents a significant risk factor in the development of HPV-associated cervical cancer. The incidence of cervical carcinoma is persistently very low in Israeli Jewish women for unknown reasons. The incidence among those of North African origin is relatively higher. The aim of the present study was to assess the frequency distribution of the p53 homozygous arginine polymorphism in cervical cancer patients and in a population sample of healthy Israeli Jewish women in order to determine whether the incidence pattern among them is genetically based. The cases consisted of 23 Israeli Jewish patients with histologically confirmed squamous cell carcinoma of the cervix. A group of 162 randomly chosen Israeli Jewish healthy participants, considered to represent the general population, comprised the controls. The germline p53 polymorphism at codon 72 was determined by PCR in DNA obtained from a blood sample taken from each subject. Homozygous arginine was found in 34.8% of cases and in only 14.8% of controls. This difference was statistically significant (P = 0.01). The frequency of homozygous arginine polymorphism in controls was lower than in any other population hitherto reported. It was significantly more common among those of North African than among those of other origin (30.3% vs. 10.8%; P < 0.01). It may be assumed that the low incidence of cervical cancer in Israeli Jewish women and the differences between the ethnic groups may be related to the frequency pattern of the homozygous arginine p53 polymorphism

Adult↗
PubMedDate not supplied

Analyses of p53 expression pattern and BRCA mutations in patients with double primary breast and ovarian cancer.

OBJECTIVE: To analyze the somatic pattern of p53 expression and BRCA germline mutation status in Israeli patients with both ovarian (OvCa) and breast cancer (BrCa). METHODS: The study group comprised 43 Israeli patients with OvCa, all of whom had previous primary BrCa. p53 immunohistochemistry (IHC) on all available archival tissues and genotyping for the three predominant Jewish germline BRCA1-2 mutations were carried out. Samples from 64 patients with solitary OvCa and 61 with solitary BrCa were similarly analyzed as controls. RESULTS: p53 expression pattern and the immunopositivity rate were similar in the ovarian and breast tumors within the study group and in the two control groups: positive p53 staining was detected in 68% of ovarian tumors in the study group compared with 71.9% in the controls, and in 19.4% of the BrCa tissues versus 21.3% in the controls. Within the study group, advanced stage OvCa had a higher rate of p53 expression (84%) compared to early stage disease (38.5%) (P = 0.006). This difference was not apparent in the solitary OvCa control group. OvCa in BRCA1-2 mutation carriers from the study group were more likely to display positive p53 staining (79%), especially in tumors diagnosed before the age of 60 (90%) compared with the OvCa of noncarriers (60%), but this difference was statistically insignificant. The p53 expression rate in BrCa samples from the study group was not associated with BRCA1-2 mutation status. CONCLUSIONS: Positive p53 expression, detected by IHC, in OvCa patients with previous primary BrCa is significantly higher in advanced stage disease in BRCA1-2 mutation carriers. There is a higher positive p53 expression somatically in OvCa in BRCA1-2 carriers in whom OvCa was diagnosed before the age of 60 years, although this trend is not statistically significant. These observations suggest that somatic p53 inactivation may be an important event in ovarian tumorigenesis in this subset of patients.

Aged↗
PubMedDate not supplied

Modulation of aortic and cardiac G protein alpha subunits and their mRNAs during norepinephrine infusion in rats.

These studies examine the possibility that alterations in the expression of G protein alpha subunits occur during desensitization of adrenergic responses in the cardiovascular system. To desensitize adrenergic receptors, rats were infused with norepinephrine (NE) subcutaneously (0.1 mg/kg/h) for 3 or 6 days using osmotic minipumps. G protein alpha subunits and their mRNAs were then measured in the aorta and heart using selective antibodies and cDNA probes. Infusion of NE for 6 days significantly decreases the levels of Gs alpha, Gi alpha and Go alpha in the aorta. The mRNAs for the alpha subunits are not altered in the aorta after NE infusion for 3 or 6 days indicating that reduced mRNA expression does not account for the decreased proteins. In the atrium and ventricle the levels of Gs alpha decrease after NE infusion for 3 days but then return to control levels by day 6. The levels of atrial and ventricular Gi alpha are unaltered after NE infusion for 3 days but increase significantly by day 6. Go alpha levels do not change in the atrium or ventricle on either day. The level of Gi2 alpha mRNA increases after NE infusion for 6 days and may account for the increased alpha i protein. The levels of the other G alpha mRNAs do not change in the atrium or ventricle. These results demonstrate that expression of G protein alpha subunits is altered during cardiovascular desensitization, raising the possibility that modulation of the alpha subunits may contribute to reduced adrenergic responsiveness.

Animals↗
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Amino acid levels in elderly nursing home residents.

We have compared levels of albumin and serum amino acids in a group of 87 recent admissions to a nursing home, average age 83 years, with a group of healthy moderately old subjects, average age 69 years. We found that the nursing home group was characterized by decreased levels of albumin, by increased total levels of the measured amino acids, and by increased levels of the nonessential amino acids. In contrast, there were no significant group differences in the essential amino acids. Among the nursing home patients, there was a negative correlation between essential amino acids and disability, consistent with nutritional deficits in the more disabled patients, and a positive correlation between essential amino acids and subjective complaints of pain, suggesting that pain is associated with breakdown or mobilization of endogenous protein stores. Though the nursing home patients had decreased serum levels of tryptophan, there was no association between serum tryptophan or other variables that could be related to the availability of tryptophan for transport into brain, with ratings of either depression or pain. Glutamine levels were significantly increased in the nursing home residents, and among these patients they were positively correlated with measures of cognitive impairment.

Activities of Daily Living↗
PubMedDate not supplied

Failure to thrive in the elderly: exploration of the concept and delineation of psychiatric components.

Findings from an exploratory study of the relationships between routine clinical laboratory tests and the clinical status of elderly patients living in a nursing home or congregate housing facility demonstrate that low albumin and anemia are associated with decreased survival and with self-care deficits, cognitive impairment, depression, and summary measures of the severity of medical illness. The interrelationships observed among these variables support the usefulness of the concept of failure to thrive. Although albumin can serve as a nutritional marker, findings on its relationship with sedimentation rate, triiodothyronine uptake, fasting plasma amino acids, and retinol-binding protein levels suggest that the low albumin related to failure to thrive is not a simple reflection of steady-state deficits in protein-calorie nutrition; it appears to be sensitive to more direct effects of disease and inflammation or to the interactions between nutrition and illness.

Activities of Daily Living↗
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Doing it yourself.

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Ethics, Medical↗
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Is it worth it?

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Bioethics↗