Biomedical subjects
Publications and source records attributed to R Shankar.
Although families have traditionally been the caregivers for mentally ill relatives in India, this situation is changing, creating a need for more structured interventions with families. Interventions appropriate to families in India are discussed here.
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Injury to the vascular endothelium and the subsequent inflammatory response are considered prerequisites for the development of atherosclerosis. Platelet-derived growth factor (PDGF) production by and monocyte adhesion to aortic endothelial cells (EC) may participate in this inflammatory process and therefore are two potential targets for control by anti-inflammatory agents. Our previous studies have demonstrated that monocyte adhesion and PDGF production are stimulated by thrombin in EC. Here, we provide evidence that treatment of EC with the anti-inflammatory agent 3-deazaadenosine (c3Ado) effectively abolished thrombin-stimulated PDGF production and monocyte adhesion. c3Ado had no significant effect on either basal monocyte adhesion or constitutive PDGF production. c3Ado was also effective in negating monocyte adhesion induced by other agonists, such as interleukin-1, phorbol 12-myristate 13-acetate (PMA), and lipopolysaccharide. Northern analysis demonstrated that c3Ado significantly reduced thrombin- and PMA-stimulated steady-state levels of PDGF-A chain, PDGF-B chain, and endothelial-leukocyte adhesion molecule-1 (ELAM-1) mRNAs. Nuclear run-on studies demonstrated that a marked transcriptional activation of these genes by thrombin and PMA was abrogated by c3Ado treatment. The transcriptional rate of the alpha-tubulin gene was unaffected by the drug. Antibody binding studies with an anti-ELAM-1 monoclonal antibody 7A9 revealed that thrombin-stimulated EC expression of ELAM-1 was abolished by c3Ado, indicating that the suppression of ELAM-1 expression on EC surface may be a mechanism by which c3Ado interferes with monocyte adhesion. Experiments with the nucleoside transport inhibitor nitrobenzylthioinosine suggested that the transport of c3Ado into EC was required for its inhibitory activity. In addition, L-homocysteine thiolactone was found to potentiate the inhibitory activity of c3Ado, suggesting that the accumulation of intracellular c3Ado homocysteine may be the underlying mechanism by which c3Ado inhibits thrombin-induced EC function. Taken together, these results indicate that c3Ado may prove effective against vascular injury and inflammation through its ability to inhibit induction of both monocyte adhesion and PDGF production.
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Thrombin stimulates multiple functions in cultured endothelial cells (EC), including an increase in cell surface adhesion sites for monocytes and the production of platelet-derived growth factor (PDGF). We have initiated studies to define the intracellular signaling pathways involved in these two thrombin-induced EC functions by focusing on the possible roles of the Na(+)-H+ antiporter and guanine nucleotide-binding proteins (G proteins). Amiloride suppressed thrombin-stimulated PDGF production by human aortic EC without affecting either basal PDGF production or overall protein synthesis. The steady-state mRNA levels of PDGF-A and PDGF-B chain were not reduced by amiloride. In replicate EC cultures, amiloride had no effect on thrombin-stimulated monocyte adhesion. In addition, thrombin induction of PDGF production, but not monocyte adhesion, was abrogated in the absence of extracellular sodium. Thrombin stimulation of both monocyte adhesion and PDGF production appeared to involve a pertussis toxin-insensitive G protein. Thrombin induced an increase in [35S]guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) binding to human EC membranes. GTP gamma S, in the presence of a suboptimal concentration of thrombin, caused maximal stimulation of both monocyte adhesion and PDGF production. The effect of GTP gamma S on PDGF production was at the level of transcription. These results indicate that the EC is capable of responding to a pluripotent agonist such as thrombin through multiple signaling pathways, which converge and diverge to achieve differential cellular responses.
Human aldose reductase (EC 1.1.1.21) and aldehyde reductase (EC 1.1.1.2) are implicated in the development of diabetic complications by a variety of mechanisms, and a number of drugs to inhibit these enzymes have been proposed for the therapy and prevention of these complications. To probe the structure and function of these two enzymes, we used site-directed mutagenesis in the cDNAs of both enzymes to replace lysine 262 with methionine. Wild-type and mutant enzymes were overexpressed in Escherichia coli and purified by anion exchange and affinity chromatography. N-terminal sequence analysis, Western blots, and kinetic studies confirmed the identity of the recombinant wild-type enzymes with the native human placental and liver enzymes. Recombinant aldose reductase (hAR) and aldehyde reductase (hGR) have apparent kinetic constants virtually identical to their respective native enzymes. The mutant aldose reductase (hARK262 greater than M) shows a 66-fold increase in Km for NADPH with respect to the wild type (1.9 +/- 0.4 microM versus 125 +/- 14 microM), whereas the Km for DL-glyceraldehyde increased 35-fold (20 +/- 2 versus 693 +/- 41 microM). The same constants for the mutant aldehyde reductase (hGRK262 greater than M) increased 97- and 86-fold, respectively (from 2.0 +/- 0.4 to 194 +/- 16 microM and from 1.6 +/- 0.4 to 137 +/- 3 mM). These results indicate that lysine 262 in aldose reductase and aldehyde reductase is crucial to their catalytic activity by affecting co-factor binding.
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Electrical impedance plethysmography has been evaluated for early detection of peripheral atherosclerosis. A pressure cuff was wrapped around the lower leg and the cuff pressure increased. Two circumferential electrodes glued in the middle of the cuff recorded the impedance pulse, from which the arterial pulse volume was calculated. The ratio of maximal arterial volume change to the pulse pressure was determined as a measure of maximal compliance Cp. Based on the data from 118 human subjects, Cp was found to correlate well with known cardiovascular risk factors. For example, Cp decreased on the average from 3.08 to 1.92 microL.mm Hg-1.cm-1 (1 microL.mm Hg-1.cm-1 = 7.5 x 10(-10) m4.N-1) in groups of subjects of increasing age from 22 to 70 years. Subjects on a regular exercise program had an average value of 3.86, while those with proven peripheral vascular disease had a value of 0.70. In a related pathologic validation study on 15 monkeys fed a cholesterol-control diet a good correlation was found between the limb peak compliance and morphometric data obtained from iliac and carotid arteries.
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Fifteen cynomolgus monkeys were fed a control (n = 3) or cholesterol-containing diet (n = 12) for 26 months. An impedance plethysmograph and a calibrated volume plethysmograph were used to determine femoral arterial volume change, delta V, from femoral arteries. Abdominal aorta pulse pressure was measured directly. The ratio of delta V to pulse pressure, delta P, defined femoral artery compliance. At necropsy, sections of pressure fixed common iliac, external iliac, femoral and carotid arteries were obtained for measurements. The site of the largest atherosclerotic lesion was chosen for histologic measurement. The percentage intima in arterial tissue (PIAT) was determined at the site of the largest atherosclerotic lesions in iliac arteries and averaged. Peak compliance was inversely correlated with the PIAT (Pearson correlation -0.39, P less than 0.10, n = 21) which improved to r = -0.52, P less than 0.01 (n = 27) when the PIAT also included the carotid atherosclerosis. The correlation coefficients were comparable to those obtained for total plasma cholesterol concentration, and direct systolic and diastolic blood pressure. Peak compliance and alpha-cholesterol concentrations provided the best multiple linear regression fit for the prediction of PIAT.
This paper presents an approach for adaptive control of blood pressure using sodium nitroprusside. A modified stochastic model reference adaptive control algorithm with a time varying reference model is developed and used for this purpose. An automatic adjustment of the reference model is proposed in order to optimize the performance of the closed loop system while meeting clinical constraints imposed on the infusion rate and the mean arterial pressure. Extensive computer simulations show the robustness of the proposed controller in the presence of relatively high noise levels, over the full range of plant parameters and for large parameter variations.
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A possible cellular action for probucol in early atherogenesis was investigated. In diet-induced hypercholesterolemic rats, probucol reduced aortic accumulation of cholesterol without ameliorating monocyte attachment to the arterial endothelium. Under the imposed conditions, circulating cholesterol levels were not significantly altered by probucol. 125I-labeled acetyl LDL uptake and degradation studies with mouse peritoneal macrophages revealed that probucol had an inhibitory effect on the scavenger receptor pathway. The data suggested that the observed beneficial effects of probucol were not related to an early cholesterol-induced injury phase which might involve calcium. Instead, probucol probably through its free radical scavenging property, intervened at a subsequent cellular level to restrict lipid accumulation.
The protection afforded by phosphocitrate, a phosphorylated polycarboxylic acid, against crystal-induced membrane damage to polymorphonuclear leukocytes was studied in vitro. Membranolysis was assessed by nitro blue tetrazolium salt reduction, lactate dehydrogenase release, and scanning electron microscopy. Phosphocitrate protected strongly against hydroxyapatite crystal-induced damage, an action attributable to crystal surface binding of phosphocitrate rather than to the membrane. The ability of phosphocitrate to prevent hydroxyapatite crystallization, together with its membrane protective effect against preformed crystals, would suggest that the compound might have a useful future role against crystal-induced arthropathies.