Biomedical subjects
E Friedman
Publications and source records attributed to E Friedman.
Reduced G protein function in desensitized rat aorta.
These studies investigated the role of G proteins in vascular desensitization. Rats were infused with norepinephrine (NE) subcutaneously (0.1 mg/kg/hr) for 6 days using osmotic minipumps and aortas were obtained. NE-stimulated contraction was blunted in aortas obtained from NE infused rats compared to aortas from vehicle infused controls. Contractile responses to KCl and serotonin (5-HT) were not affected by NE infusion indicating desensitization was specific to certain receptors. Dose response curves for NaF-stimulated contraction were right-shifted in aortas from NE infused rats suggesting reduced G protein function in these vessels. G protein function was studied further by assessing G protein activation in response to receptor stimulation. This was done by measuring agonist-stimulated increases in 35S-GTP gamma S binding to G protein alpha subunits in aortic membranes. The alpha 1 adrenergic agonist phenylephrine stimulated GTP tau S binding to Gs and Gi in aortic membranes and the degree of stimulation was reduced in desensitized vessels. 5-HT stimulated binding to Gi and Go in aortic membranes and the response was not altered in desensitized vessels. Thus, vascular desensitization produced by NE infusion involves selective reductions in the ability of alpha 1 receptors to activate Gs and Gi.
Protein kinase activity changes in the aging brain.
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Effect of aging and diet restriction on monoamines and amino acids in cerebral cortex of Fischer-344 rats.
The effect of chronic diet restriction on amino acids and monoamines in cerebral cortex was studied in young and old male Fischer-344 rats. The effect of restricted feeding (60% of ad lib diet) was compared at 6 and 24 months of age. The results indicate that aging did not significantly alter the levels of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in frontal (FCX), parietal (PCX) and occipital cortices (OCX). On the other hand, the effect of age on serotonin (5HT) was found to be regionally specific. The level of 5HT was 43% higher, while the ratio of 5HIAA/5HT was decreased 26% in OCX of 24 months old animals. In the FCX 5HIAA/5HT ratio was increased 27%. Diet restriction in old rats increased DA level markedly in FCX, and attenuated the age-related increase of 5HT level in OCX. The ratios of 5HIAA/5HT in FCX and OCX of DR animals were maintained at those found in the young ad lib (AL) group. The cortical neurotransmitter amino acids (aspartate, glutamate, gamma-aminobutyric acid, glycine and taurine) were well maintained during aging and dietary manipulation. Age-related reduction of cortical tryptophan and plasma ratio of tryptophan to large neutral amino acids in old animals were attenuated by chronic DR. The results suggest that serotonergic neurons are more susceptible to change during aging than are the catecholaminergic neurons. Diet restriction during the life of the animals appears to protect or attenuate the age-related changes in cortical serotonergic system while FCX dopamine concentrations were dramatically increased.
Cocaine acts in the central nervous system to inhibit sympathetic neural activity.
Cocaine was administered i.v. to decerebrate cats while monitoring cardiac preganglionic sympathetic nerve activity (SNA), arterial blood pressure (BP) and heart rate (HR). Cocaine, 4 mg/kg i.v., reduced SNA by 55 +/- 6%, but did not significantly affect BP or HR. Cocaine, in doses that were ineffective by the i.v. route, was administered into the vertebral artery and produced decreases in SNA, BP and HR in anesthetized cats. Administration of cocaine into the carotid artery was without effect. Topical administration of cocaine to the intermediate area of the ventrolateral medullary surface (25 micrograms/side) evoked hypotension and bradycardia. Nisoxetine, an inhibitor of norepinephrine uptake, applied bilaterally to the intermediate area (30 micrograms/side) exerted a similar hypotensive effect. Lidocaine administered in doses equivalent to those of cocaine had no significant effect on SNA when given i.v. or on BP when given into the vertebral artery. These results indicate that cocaine inhibits central sympathetic outflow and that the site of action appears to be in the hindbrain at a site that is reached by placement of the drug at the intermediate area of the ventrolateral medulla. The data also indicate that the mechanism of action of cocaine to inhibit sympathetic outflow may be unrelated to its local anesthetic action and may involve inhibition of catecholamine uptake in the ventrolateral medulla.
Nursing: breaking the bonds?
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Nursing: new power, old problems.
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Protein kinase C activity and contractile responsiveness in senescent blood vessels.
To examine Ca2(+)-signaling receptor function in the aging vasculature, the status of the diacylglycerol/protein kinase C (DAG/PKC) arm of the signal transduction pathway was assessed. contractile responsiveness to the PKC activator, phorbol 12-myristate 13-acetate (PMA), is substantially reduced in aortae from 24-month-old Fischer 344 rats compared to 6-month-old rats. PKC activity is reduced in all senescent vessels yet studied including aorta, renal artery, iliac artery and vena cava. This may account for the reduced contractile responsiveness. Additionally, PMA-stimulated PKC translocation is substantially reduced in senescent aorta and this may also contribute to reduced contraction.
Troubled past of 'invisible' profession.
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Medicare and Medicaid at 25.
On July 30, the United States marked the 25th anniversary of the signing of the law that brought Medicare and Medicaid into existence. These programs continue to control health policy, determine the direction of health spending, and provide access to health care services for millions of Americans. Contributing editor Emily Friedman takes a look at the history of Medicare and its effect on the American public and hospitals.
Analysts differ over implications of more hospital closings than openings since 1987.
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On the front lines of policymaking.
We generally associate policies with specific issues. But policies are made by people--frequently by politicians. And the policymaking process is often best explored through the stresses and strains that the process exerts on policymakers. To illustrate more clearly the thinking processes of policymakers and the choices they must make daily, Hospitals' contributing editor Emily Friedman followed a respected health policy leader through a typical day.
Injury induced by fatty acids or bile acid in isolated human colonocytes prevented by calcium.
Measurement of the modulation of the growth fraction of isolated normal colonocytes from adult subjects in primary monolayer culture was used as a sensitive quantitative assay to evaluate toxic effects of several endogenous compounds found within the colon. This assay was used to study the role of CaCl2 in blocking cell injury. When added simultaneously with the injurious agent, 5-10 mM CaCl2 blocked the toxicity of physiological concentrations of deoxycholic acid, oleic acid, palmitic acid and linoleic acid.
Urokinase secretion from human colon carcinomas induced by endogenous diglycerides.
Colon tumor cells are more responsive to certain growth modulators in their local environment in vivo than are normal colonocytes. Examples of this class of compounds are the fecal diglycerides (DGs)(E. Friedman et al., Cancer Res., 49: 544-548, 1989), which may act as endogenous tumor promoters. At the concentration found in vivo, fecal DGs composed of oleic, myristic, and palmitic fatty acids induced mitogenesis of all classes of benign tumor cells and of half of the resected carcinomas tested in primary culture, but induced no detectable mitogenesis of normal colonocytes. Colon tumor cells also exhibit selective responses to these endogenous modulators as measured by another biological parameter, secretion of urokinase from carcinomas than from normal colonocytes. Fecal DGs also induced a 13-fold increase in urokinase mRNA synthesis in colon carcinoma cells and induced secretion of active urokinase from each of five resected carcinomas. Colon carcinomas, at both the primary site and metastatic to the liver, secreted the Mr 55,000 form of urokinase constitutively and secreted the same form upon treatment with fecal DGs. An increase in the steady-state level of urokinase secretion by saturated-chain DGs exhibited a strong dependency on the chain length of the fatty acid residues, those of 14 and 16 carbons having the greatest activity. Thus, fecal DGs composed of oleic, myristic, and palmitic acid residues induce two biological activities selectively in colon tumor cells, each of which would enhance tumor development. Selective mitogenesis would increase adenoma and carcinoma cell number relative to normal colonocyte number, and induction of the proteolytic enzyme urokinase would aid local invasion of the carcinoma within the bowel wall.
Role of transforming growth factor beta 1 in induction of colon carcinoma differentiation by hexamethylene bisacetamide.
The differentiation agent hexamethylene bisacetamide (HMBA) increased expression of transforming growth factor beta 1 (TGF beta 1) mRNA in HT29 colon carcinoma cells. The increase was evident after 24 h and was maintained at levels 4-5-fold the control levels for at least 5-13 days. No increase in expression of TGF beta 2 or TGF alpha mRNA was observed. Both TGF beta 1 and HMBA induced loss of expression of a cell surface malignancy marker on HT29 cells, and both decreased cell growth in serum-free medium. Exogenously applied TGF beta 1 mimicked the growth-arresting effect of HMBA on three surgically resected moderately differentiated colon carcinomas in serum-free primary culture. Both TGF beta 1 and HMBA increased the tumor growth fraction in a second group of three more aggressive colon carcinomas, while neither agent had any measurable growth-modulating activity on two other colon carcinomas. The induction of TGF beta 1 mRNA by HMBA along with the parallel biological effects of HMBA and exogenously applied TGF beta 1 on resected carcinomas and on HT29 cells suggest that the effects of HMBA on colon carcinoma cells may be mediated in part by induction of TGF beta 1.
Maternal phenylketonuria pregnancy outcome: a preliminary report of facial dysmorphology and major malformations.
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Protein kinase C translocation in human blood platelets.
Protein kinase C (PKC) activity and translocation in response to the phorbol ester, phorbol 12-myristate, 13-acetate (PMA), serotonin (5-HT) and thrombin was assessed in human platelets. Stimulation with PMA and 5-HT for 10 minutes or thrombin for 1 minute elicited platelet PKC translocation from cytosol to membrane. The catecholamines, norepinephrine or epinephrine at 10 microM concentrations did not induce redistribution of platelet PKC. Serotonin (0.5-100 microM) and the specific 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (10-100 microM) but not the 5-HT1A or 5-HT1B agonists, (+/-) 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT) or 5-methoxy-3-3-(1,2,3,6-tetrahydro-4-pyridin) 1H-indole succinate (RU 24969) induced dose-dependent PKC translocations. Serotonin-evoked PKC translocation was blocked by selective 5-HT2 receptor antagonists, ketanserin and spiroperidol. These results suggest that, in human platelets, PMA, thrombin and 5-HT can elicit PKC translocation from cytosol to membrane. Serotonin-induced PKC translocation in platelets is mediated via 5-HT2 receptors.
Decreased striatal release of acetylcholine following withdrawal from long-term treatment with haloperidol: modulation by cholinergic, dopamine-D1 and -D2 mechanisms.
The effect of chronic treatment with haloperidol (2.7-5.3 mumol/kg/day) on K(+)-evoked release of [3H]acetylcholine (ACh) from superfused slices of the striatum was assessed. Acute injections of haloperidol (0.7-13.3 mumol/kg) produced 5-54% increases in the release of [3H]ACh in the striatum. Chronic treatment with haloperidol for 2.5 and 5 months also resulted in enhanced release of [3H]ACh in the striatum (28-35%). However, withdrawal from 2.5 and 5 months of treatment produced 34 and 38% decreases in K(+)-evoked release of [3H]ACh in the striatum, respectively. The drug SKF 38393 (D1-agonist), produced concentration-dependent (0.1-10 microM) increases (24-59%) in the release of [3H]ACh in the striatum which were blocked by the selective D1-antagonist, SCH 23390. The effect of stimulation of D1-receptors was significantly reduced after 2.5 or 5 months of chronic treatment with haloperidol. Both LY171555 (D2-agonist) and carbachol (muscarinic agonist) produced concentration-dependent (0.1-10 microM) inhibitions of the release of [3H]ACh in the striatum (LY171555: 28-62%; carbachol: 23-63%). Long-term treatment with haloperidol (2.5 and 5 months) elicited increases in sensitivity to the effect of LY171555, while the effect of carbachol was diminished only after the 5-month treatment period. These findings demonstrate that withdrawal from chronic exposure to haloperidol in the rat results in a reduction in the release of acetylcholine in the striatum. This effect is accompanied by (1) attenuated dopaminergic D1 mechanisms which ordinarily facilitate evoked release of ACh, (2) enhanced D2 mechanism which elicits inhibition of the release of ACh in the striatum, and (3) diminished muscarinic inhibitory influence which regulates the release of ACh.