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Biomedical subjects

M L Kashyap

Publications and source records attributed to M L Kashyap.

At least 37 records · Page 2Linked to original sources
PubMed1995

A rapid flow cytometric assay for low-density lipoprotein receptors in human peripheral blood mononuclear cells.

Receptor-dependent uptake of low density lipoproteins (LDLs) labeled with the fluorescent probe 3,3'-dioctadecylindocarbocyanine iodide (DiI) by human lymphocytes was measured by flow cytometry. Freshly isolated lymphocytes showed very little uptake, whereas the cells cultured in lipoprotein-free medium for 48 hours showed about a 10-fold increase in the uptake of DiI-LDL. The uptake was inhibited by excess unlabeled LDL, heparin, and ethyleneglycol-bis-(beta-aminoethylether)-N,N, N',N'-tetraacetic acid (EGTA) but not by acetylated LDL, and therefore it appears to be very specific. Comparative studies with iodine 125-labeled LDL showed that there is correlation between the uptake of DiI-LDL and degradation of 125I-labeled LDL by the lymphocytes. The assay was carried out with lymphocytes from several normal healthy individuals and some clinically diagnosed heterozygous familial hypercholesterolemic patients. The results indicate that this assay can be used to distinguish patients with LDL receptor-defective familial hypercholesterolemia from normal individuals.

Adolescent↗
PubMed1995

Elevated plasma lipoprotein(a) levels and hypoalbuminemia in peritoneal dialysis patients.

Plasma lipoprotein(a), Lp(a), is strongly and independently associated with atherosclerosis, and levels are elevated in hemodialysis (HD) patients and in some studies of those on peritoneal dialysis (PD). We hypothesized that protein losses and hypoalbuminemia could stimulate hepatic Lp(a) synthesis, and this effect would be accentuated in PD patients with malnutrition. The PD subjects (n = 24) had higher plasma Lp(a) levels than those (n = 10) on HD (median 34.4 vs 21.0 mg/dl, p < 0.05), and values exceed normal in 62.5% vs 20% of the subjects (p < 0.03), respectively. The serum albumin levels inversely correlated with concentrations of Lp(a) and apolipoprotein B, as well as the apolipoprotein B/AI ratio. In conclusion, plasma Lp(a) concentrations are frequently elevated in PD as well as HD patients. Measuring Lp(a) levels is useful in identifying patients at increased atherogenic risk, which may not be reflected in routine lipid profiles. The negative correlation between plasma Lp(a) and albumin levels suggests that the latter may be linked pathophysiologically to hepatic Lp(a) production. The association of hypoalbuminemia with higher Lp(a) values is of particular concern because malnutrition frequently occurs in PD patients.

Adult↗
PubMed1994

Efficacy and safety of controlled-release niacin in dyslipoproteinemic veterans.

OBJECTIVE: To evaluate the safety and efficacy of controlled-release niacin in patients with hyperlipoproteinemia. DESIGN: A retrospective cohort study. SETTING: A Department of Veterans Affairs Medical Center. PATIENTS: A consecutive sample of 969 predominantly elderly male veterans treated for dyslipoproteinemia with controlled-release niacin between October 1988 and October 1991. MAIN OUTCOME MEASURES: Primary outcomes were lipid levels and lipoprotein cholesterol response, alternations in levels of hepatic enzymes and blood chemistry test results, and characterization of niacin-induced hepatotoxicity abstracted from the patient's medical, laboratory, and pharmacy records. RESULTS: 93% (896 of 969) of the cohort was evaluable. Patients (age, 61.7 years [9.4 years], mean [SD]) were treated for 1 to 36 months (13.0 months [9.7 months]) with an average maintenance dose of 1.67 g/d (0.8 g/d). Niacin was discontinued in 48.5% (435 of 896) of the patients primarily because of adverse effects. Poor glycemic control led to discontinuation in 40.6% (43 of 106) of the patients with diabetes mellitus. The lipoprotein response was dose-related and favorable (levels of total cholesterol, -19.1%; low-density lipoprotein cholesterol, -24.0%; high-density lipoprotein cholesterol, +5.7%; and triglycerides, -32.5%). Statistically but not clinically meaningful dose-related increases were seen in levels of liver enzymes and serum glucose (aspartate aminotransferase, +29%; alanine aminotransferase, +23%; alkaline phosphatase, +25%; and glucose, +7%; P = 0.0001). Twenty of 896 (2.2%) and 42 of 896 (4.7%) patients met biochemical criteria for probable and for possible or probable niacin-induced hepatotoxicity, respectively. Predisposing factors included high dose, alcohol use, preexisting liver disease, and concurrent oral sulfonylurea therapy. CONCLUSIONS: Controlled-release niacin is effective in treating dyslipoproteinemia in selected middle-aged and elderly veterans, but approximately one half of patients discontinued the drug because of adverse effects or other causes including noncompliance. Niacin should be avoided in patients with hepatic dysfunction or a history of liver disease, patients with diabetes mellitus, and patients who abuse alcohol. Because controlled-release niacin seems to be more potent than crystalline niacin, product substitution without dose adjustment should be avoided.

Aged↗
PubMed1994

Alterations in reverse cholesterol transport associated with programmable implantable intraperitoneal insulin delivery.

Our previous studies have suggested that intraperitoneal (IP) insulin delivery may be associated with alterations of reverse cholesterol transport (RCT). We thus studied two parameters of RCT. We performed RCT studies in 10 C-peptide-negative type I diabetic patients who were randomized into two groups. The experimental (A) and control (B) groups were studied at -3 and 0 months before and +3 and +6 months after IP pump subcutaneous (SC) insulin use. The first step in RCT was estimated by measuring patient serum-mediated 3H-cholesterol efflux from cultured fibroblasts. Cholesteryl ester transport protein (CETP) activity was assessed by a solid-phase assay. No changes in glucose control occurred during the study. Total low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, apoprotein B, and apoprotein A-I remained unchanged during the study. Cholesterol efflux from group A increased from baseline after 3 months of IP insulin by 9.5% +/- 3.4% (mean +/- SE, P < .05), whereas in group B patients it decreased negligibly by 1.5% +/- 2.9% (P = .045 for changes between groups). CETP activity increased from baseline by 25.3% +/- 7.7% (P < .05) in group A after 3 months of IP insulin, whereas in group B it changed little, -1.5% +/- 7.9%, with modest differences between groups (P = .16). These data indicate that (1) serum from patients treated long-term with IP insulin delivery may enhance cholesterol efflux from fibroblasts and CETP activity, and (2) these effects appear independent from glucose control, implying a direct effect by IP insulin.

Adult↗
PubMed1994

High density lipoproteins stimulate the production and secretion of endothelin-1 from cultured bovine aortic endothelial cells.

The concentration of HDL in the blood inversely correlates with the incidence of cardiovascular disease, probably related to the ability of these lipoproteins to efflux cholesterol from vascular cells. it is also possible that HDL affect the production or action of vasoactive peptides implicated in the development of vascular diseases. Therefore, we determined the effects of human HDL on the production and secretion of endothelin-1 (ET-1) from cultured bovine aortic endothelial cells. HDL produced a highly significant stimulation of endothelin secretion (maximum 240% of control), even at very low levels of lipoproteins (1 microgram/ml). HDL also stimulated the translation of ET-1 by twofold in the bovine aortic endothelial cells. In contrast, HDL had no significant effect on steady state mRNA levels, transcript degradation, or transcription. Stimulation of ET-1 secretion by HDL was dependent on protein kinase C activation. Purified apo A-I, the major apoprotein of HDL, increased ET-1 secretion and translation approximately 85% as potently as HDL. Our results indicate that low concentrations of human HDL strongly stimulate the production of ET-1, a powerful vasoconstrictor and mitogen for the vascular smooth muscle cell. We propose that HDL may participate in the regulation of vasomotor tone through this potentially important effect in the vasculature.

Animals↗
PubMed1994

Uremic serum subfraction inhibits apolipoprotein A-I production by a human hepatoma cell line.

Abnormalities in lipoprotein metabolism are common in uremic patients and may represent an additional risk factor for the development of atherosclerosis. Despite the frequent occurrence of lipoprotein abnormalities, the role of various serum toxins and subfractions that accumulate in uremic patients on lipoprotein metabolism is not clearly understood. This study addressed the role of uremic toxins on lipoprotein metabolism by examining the effect of a 500 to 2,000-d subfraction obtained from the serum of uremic and control subjects on the synthesis of apolipoprotein (apo) A-I in a human hepatoma cell line (Hep-G2). Serum subfractions obtained from uremic patients inhibited apo A-I synthesis and secretion by Hep-G2 cells in a dose-dependent manner as measured by (3H)leucine incorporation into apo A-I, immunoprecipitation, and ELISA. The uremic serum subfraction decreased the mRNA expression for apo A-I in Hep-G2 cells when compared with controls. These observations suggest that a component of uremic serum can have the potential to inhibit hepatic apo A-I synthesis and may adversely influence high-density lipoprotein metabolism, thus increasing the risk for the development of atherosclerotic vascular complications in uremic patients.

Apolipoprotein A-I↗
PubMed1993

Apolipoproteins A-I and B and cholesterol in synovial fluid of patients with rheumatoid arthritis.

Synovial fluid (SF) of patients with rheumatoid arthritis (RA) has been noted to contain cholesterol crystals and increased amounts of cholesterol compared with normal SF. SF, plasma apolipoproteins (apos) A-I and B, and cholesterol in 12 untreated classic RA patients (inflammatory arthritis) and eight untreated degenerative joint disease ([DJD] noninflammatory arthritis) patients were analyzed. Results showed that mean apo A-I, apo B, and cholesterol levels of RA SF were significantly higher than those of DJD SF (apo A-I, P = .004; apo B, P = .0008; cholesterol, P = .0004). Regression analyses of plasma and SF apo A-I and apo B (r = .72, P = .008 and r = .63, P = .02, respectively) suggested an increased permeability for these lipoprotein constituents across RA synovial membrane that was not observed in DJD synovial membrane. These data suggest that RA synovium but not DJD synovium is more permeable to major apoproteins of low- and high-density lipoproteins (LDL and HDL). These apolipoproteins have been shown to influence the immune response and may therefore be involved in the pathogenesis of RA.

Adult↗
PubMed1993

Increased reverse cholesterol transport in athletes.

Proposed mechanisms for the cardioprotective benefits of exercise include decreased lipid deposition and increased reverse cholesterol transport (RCT). RCT involves the efflux of tissue free cholesterol into high-density lipoprotein (HDL) particles, esterification by lecithin:cholesterol acyltransferase (LCAT), transfer to other lipoproteins by cholesterol ester transfer proteins (CETP), and liver excretion. We tested the hypothesis that RCT is enhanced in athletes and that this can occur without large increases in plasma HDL cholesterol (HDL-C) mass levels. Fasting venous blood was drawn from 13 sedentary men and 11 athletes exercising at the rate of 5,185 +/- 501 kcal/wk. Compared with controls, athletes had similar age, body mass index (BMI), HDL-C (P > .1) and apolipoprotein (apo) A-1 (P > .5) levels, and lower low-density lipoprotein cholesterol (LDL-C) (P < .05) and apo B (P < .03) levels. The net mass of free cholesterol transported (NMCT) out of cultured human fibroblasts into the athletes' serum was greater than that for controls (25.5 +/- 8.0 v 7.1 +/- 2.6 micrograms/mL/h, P = .048). The efflux component of this transport correlated with HDL-C and apo A-1 levels and was similar between groups (P = .24), suggesting that athletes' antiatherogenic NMCT findings were due to decreased cholesterol influx into the cells. Athletes had increased plasma LCAT (20.3 +/- 2.1 v 13.9 +/- 1.5 micrograms/mL/h, P = .028) and CETP activities (69.7 +/- 4.5 v 21.5 +/- 4.8%/mL/h, P < .001). The NMCT positively correlated with CETP and LCAT activities and inversely with apo B levels and the cardiac risk ratio apo B/A-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Synovial fluid lipoproteins: review of current concepts and new directions.

Recent developments in plasma lipoprotein and apolipoprotein research have been striking, but few studies have focused on the analysis of lipoproteins in synovial fluid (SF). SF contains small amounts of lipoproteins and apolipoproteins. The lipid concentration of normal human SF is extremely low and is in sharp contrast to the concentrations found in plasma. Little is known about the lipids in pathological SF, but studies have noted increased cholesterol and lipoprotein content in rheumatoid arthritis (RA) SF ranging from 40% to 60% of the total plasma lipoproteins. Recently apolipoproteins AI, B and E have also been found to be in increased amounts in RA SF. Several theories have been proposed to account for the increased presence of SF lipids in RA. Animal and human studies indicate the SF cholesterol, lipoproteins, and apolipoproteins may aggravate the inflammatory reaction within the synovial space. Research suggests an immunologic role for plasma lipoproteins on lymphocyte and monocytes in the blood and lymph. SF lipoproteins and apolipoproteins should be studied to define their actions within the synovial space.

Animals↗
PubMed1992

Ethanol stimulates apolipoprotein A-I secretion by human hepatocytes: implications for a mechanism for atherosclerosis protection.

Ethanol intake in humans has been shown to have a protective effect against coronary heart disease. The specific mechanism by which ethanol is cardioprotective has not been elucidated. Apolipoprotein (apo) A-I, the major protein of high-density lipoprotein (HDL), takes up cellular cholesterol, thus initiating reverse cholesterol transport whereby excess tissue cholesterol is eliminated. Using highly specific antibodies, we have found that ethanol increases apo A-I secretion and the incorporation of radiolabeled leucine into apo A-I by human hepatocytes (Hep-G2 cells). In addition, we have found that apo A-I molecules induced by ethanol have the ability to efflux cholesterol from human fibroblasts in vitro, and that apo A-I mass directly correlates with cholesterol efflux levels. At 10, 20, and 100 mmol/L, ethanol stimulated apo A-I secretion by 130%, 136%, and 162% of control, respectively (control, 3.71 micrograms apo A-I/micrograms DNA), also stimulating the incorporation of 3H-leucine into newly synthesized apo A-I by 115%, 131%, and 159% of control (control, 111 cpm/micrograms DNA/h). The ethanol-induced apo A-I from Hep-G2 cells (incubated with 0, 10, 20, and 100 mmol/L ethanol) effluxed 2%, 14%, 16%, and 32% label (per h/mL incubation medium), respectively. Apo A-I mass correlated linearly with cholesterol efflux (r = .99, P less than .01). This data indicates that the cardioprotective role of moderate ethanol intake in humans is mediated by its stimulatory action on hepatic apo A-I secretion, thus defining the physiological basis for increased plasma apo A-I levels in vivo.

Apolipoprotein A-I↗
PubMed1991

HDL metabolism in HDL deficiency associated with familial hypertriglyceridemia: effect of treatment with gemfibrozil.

Plasma high density lipoproteins (HDL) and their major proteins--apolipoprotein (apo) AI and apo AII--are subnormal in most patients with familial hypertriglyceridemia. However, the pathophysiology of low plasma apo AI and apo AII is unclear. The kinetic parameters (turnover) of HDL apo AI and apo AII were studied in six lean patients with primary HDL deficiency associated with familial hypertriglyceridemia and normolipidemic healthy controls. The radioactivity decay curve of 125I labelled HDL was used for assessment of kinetics. Mean plasma apo AI and apo AII were significantly lower (p less than 0.001) in patients than normals (70.4 +/- 2.7 v 106.9 +/- 7.0; 24.2 +/- 1.6 v 39.2 +/- 0.9 mg/dl, respectively). The mean fractional catabolic rates (FCR) obtained from plasma 125I-HDL, apo AI, apo AII radioactivity decay curves and by Berson and Yalow's method (urine/plasma radioactivity ratios) were significantly greater (p less than 0.05) in patients than in controls (0.387 v 0.299; 0.391 v 0.309; 0.361 v 0.275; 0.272 v 0.207/d; respectively). The synthetic rates (SR of apo AI and apo AII were significantly lower in patients than in controls (11.12 v 14.17 mg/kg body weight/d. p less than 0.05; 3.53 v 4.68 mg/kg body weight/d, p less than 0.05, respectively). Each patient was also investigated for HDL and triglyceride metabolism immediately before and after 8 wk of gemfibrozil (1200 mg/d) treatment. Gemfibrozil significantly increased plasma HDL cholesterol, apolipoprotein (apo) AI, and apo AII by 36%, 29%, and 38% from baseline, respectively. Plasma TG decreased by 54%. Gemfibrozil increased synthetic rates of apo AI and apo AII by 27% and 34%, respectively, without changing the FCR.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein A-I↗
PubMed1990

Relationship between post-heparin plasma lipases, triglycerides and high density lipoproteins in normal subjects.

The relationship between plasma lipids and lipoproteins and the lipolytic activities of post-heparin plasma lipoprotein lipase (LpL) and hepatic-triglyceride lipase (H-TGL) was examined in normal subjects. Seven males and six females were given a high fat diet [15% carbohydrate (CARB), 65% fat, 20% protein] for 2 weeks followed by 4 weeks of a high CARB diet (65% CARB, 15% fat, 20% protein). Changes in plasma triglyceride concentrations associated with diet were negatively correlated with changes in HDL-C (r = -0.533, P less than 0.001) and the HDL subfraction HDL2b (r = -0.308, P less than 0.001). The activity of LpL in post-heparin plasma was positively correlated with changes in plasma HDL-C (r = 0.668, P less than 0.001) and HDL2b (r = 0.457, P less than 0.001), and negatively with plasma triglycerides (r = -0.546, P less than 0.001). Changes in H-TGL activity were negatively correlated with changes in HDL2b (r = -231, P less than 0.05) and positively correlated with HDL-C (r = 0.326, P less than 0.01). These results in normal subjects provide further evidence that LpL and H-TGL are important enzymes in the metabolism of plasma lipoproteins and that changes in their activities contribute to plasma lipid and lipoprotein concentrations.

Adult↗
PubMed1989

Cardiovascular disease in the elderly: current considerations.

Today, elderly patients account for one-third of the total United States health care costs and for one-third of all drug prescriptions. As the United States population grows older, health care costs are expected to grow proportionately unless cost reduction strategies are developed. Cardiovascular disease is ranked as the primary cause of mortality and disability in this age group. It is estimated that 80% of cardiovascular disease in the elderly arises as complications of atherosclerosis. Whereas modern technologic advances--cardiac catheterization, coronary angiography, coronary angioplasty, coronary bypass surgery, pacemaker insertion--can help to treat the effects of atherosclerosis, such advances are costly. The most effective cost reduction strategy lies in prevention of atherosclerosis and its complications. A number of studies have linked reduction of risk factors for atherosclerosis to reduction of coronary disease events. However, it is not certain that these data apply directly to the elderly; more research is necessary to develop effective preventive and management strategies.

Age Factors↗
PubMed1989

Basic considerations in the reversal of atherosclerosis: significance of high-density lipoprotein in stimulating reverse cholesterol transport.

Atherosclerotic cardiovascular disease in the elderly is the result of several decades of cholesterol accretion. Advanced lesions may not be amenable to treatment, but a reversal of cholesterol accumulation may be possible. High-density lipoproteins (HDL) could serve an important function in this reversal through their role in the process of reverse cholesterol transport, which removes cholesterol from the body. Reverse cholesterol transport could be stimulated by raising plasma HDL level, but the efficacy of the process may be determined by the way in which HDL level is elevated. The increase of HDL synthesis rate may be the best approach. The antiatherosclerotic effects of gemfibrozil, a lipid-lowering agent that appears to raise HDL synthesis rate, may be mediated through this mechanism.

Age Factors↗
PubMed1988

High-density lipoprotein apolipoprotein AI and AII turnover in moderate and severe proteinuria.

The kinetic parameters of high-density lipoprotein (HDL) and its major apolipoproteins (Apo) AI and Apo AII were studied in 2 patients with moderate and severe proteinuria and 2 normal controls after intravenous injection of autologous 125I-HDL. The fractional catabolic rates (FCR) of HDL estimated by urine/plasma radioactivity ratio, and FCR of Apo AI and Apo AII calculated from the radioactivity decay curves were higher in the patients. These results support the concept that high-density lipoproteinuria and renal parenchymal sequestration of HDL found in the nephrotic syndrome contribute to accelerated HDL catabolism.

Adult↗
PubMed1988

Identification of an apoC-II variant (apoC-IIBethesda) in a kindred with apoC-II deficiency and type I hyperlipoproteinemia.

Apolipoprotein (apo) C-II deficiency is characterized by elevated plasma triglycerides, chylomicrons, and very low density lipoproteins, as well as reduced levels of low density and high density lipoproteins. A subject with apoC-II deficiency has been identified with an apoC-II plasma level of less than 0.05 mg/dl. The plasma apoC-II in the proband was immunochemically similar to apoC-II in normal subjects when analyzed by Ouchterlony immunodiffusion, however the apoC-II had an apparently lower molecular weight and higher pI when analyzed by two-dimensional gel electrophoresis. This apoC-II variant, designated apoC-IIBethesda, was not affected by neuraminidase treatment or reduction. Two-dimensional gel electrophoresis of the plasma of the mother of the proband revealed both normal apoC-II and apoC-IIBethesda, whereas analysis of the father and two siblings revealed apoC-II of normal electrophoretic mobility. These results were interpreted as indicating that the proband was a compound heterozygote with one allele for apoC-IIBethesda inherited from the mother and an allele coding for an abnormality which results in the virtual or complete absence of plasma apoC-II from the father. This proband represents the first example of a compound heterozygote for an apolipoprotein defect associated with a dyslipoproteinemia.

Apolipoprotein C-II↗
PubMed1987

Human plasma lipid transfer protein catalyzes the speciation of high density lipoproteins.

The role of purified plasma lipid transfer protein complexes in determining the particle size distribution of human plasma high density lipoproteins (HDL) was examined in vitro. Incubation of HDL2 or HDL3, isolated from normolipemic subjects with very low density lipoproteins (VLDL) or VLDL-remnants and lipid transfer protein complex had little or no effect on HDL particle size. In contrast, HDL isolated from patients with hypertriglyceridemia, designated HDL3D, showed speciation of particle size distribution when incubated with VLDL-remnants and the transfer protein. Incubation of HDL3D with VLDL-remnants and lipid transfer complex resulted in the production of two particles of radius 4.3 and 3.7 nm; incubation with VLDL or in the absence of the transfer protein did not result in a redistribution of particle size. We suggest that the action of lipid transfer protein complex on triacylglycerol-rich lipoprotein remnants and HDL accounts for the low levels of HDL-cholesterol observed in subjects with severe hypertriglyceridemia.

Carrier Proteins↗