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Biomedical subjects

J R Patsch

Publications and source records attributed to J R Patsch.

At least 73 records · Page 4Linked to original sources
PubMed1995

Sera from HIV-1 infected individuals in all stages of disease preferentially recognize the V3 loop of the prototypic macrophage-tropic glycoprotein gp120 ADA.

The outer membrane glycoprotein gp120 and the transmembrane glycoprotein gp41 are predominant targets of the humoral immune response to infection by human immunodeficiency virus type 1. The third hypervariable region (V3 loop) is the principal neutralizing domain and is the primary target of neutralizing antibodies directed against the envelope proteins of HIV-1. The V3 loop is also the major determinant for HIV-1 cell-specific tropism. To further characterize the humoral immune response directed against the gp120 envelope proteins, we expressed two prototypic gp120 envelope proteins (LAI/HXB2 and ADA) and chimeric gp120 envelope proteins in stable transfected Drosophila melanogaster Schneider 2 cells. Sera from four infected adults over the course of infection [McNearney et al. (1992) Proc. natn. Acad. Sci. U.S.A. 89, p. 10,242] were assayed for reactivity with the respective envelope proteins. Sera obtained at early stages preferentially recognized the gp120 envelope protein ADA, whereas in later stages of infection the sera showed diminished reactivity with both gp120 LAI/HXB2 and gp120 ADA. Chimeric envelope proteins revealed that the humoral response was directed primarily against the V3 loop of gp120 ADA. Furthermore, 22 sera from HIV-1 infected individuals in different stages of the disease were tested. Reactivity of sera with the gp120 envelope protein ADA was seven-fold higher than with the gp120 envelope protein LAI/HXB2. Our results suggest that the humoral immune response is preferentially elicited against the V3 loop of the prototypic macrophage-tropic gp120 envelope protein ADA.

Adult↗
PubMed1995

Post-prandial lipaemia.

Post-prandial lipaemia represents the state of absorption during which TG metabolic capacity is under challenge. Low TG metabolic capacity imparts the risk of development of atherosclerosis. TG-intolerance has been shown to be an independent risk factor for CAD and impaired TG metabolic capacity could underlie a common high risk lipoprotein constellation of low HDL cholesterol and small sized HDL and LDL. Magnitude and duration of post-prandial lipaemia determine how much cholesterol is diverted from LDL and HDL into TG-rich lipoproteins through which it causes atherosclerosis. Potential means of intervention are improvement of TG metabolic capacity by reducing obesity, prescription of aerobic exercise, reduction of oxidizability of post-prandial lipoproteins by antioxidants and TG-lowering drugs.

Arteriosclerosis↗
PubMed1995

Postprandial state and atherosclerosis.

Accumulating evidence suggests that triglyceride-rich lipoproteins are an independent risk factor for atherosclerosis. This epidemiological evidence first emerged as a result of studying postprandial lipaemia that characterized the metabolic capacity of triglycerides in the postabsorptive state, that is, under challenge. Studies of postprandial lipaemia were helpful to explain several effects of triglyceride-rich lipoproteins on cholesteryl-ester-rich lipoproteins. From these studies it became apparent that peculiarities of cholesteryl-ester-rich lipoproteins, such as small LDL and small HDL, which have been associated with risk for atherosclerosis, were caused by impaired triglyceride metabolism.

Arteries↗
PubMed1995

Exercise and postprandial lipaemia.

Postprandial hyperlipidaemia is a risk factor for atherosclerosis in multiple vascular beds, independently of high-density lipoprotein (HDL) cholesterol. An increased level of HDL cholesterol is a strong indicator of a low risk of atherosclerosis. Exercise decreases postprandial lipaemia and, in turn, increases levels of HDL cholesterol. The favourable effects of exercise on lipoprotein metabolism, particularly evident in the postprandial state, may thus help to decrease susceptibility to atherosclerosis in exercise-trained people.

Arteriosclerosis↗
PubMed1995

[Effectiveness, tolerance and safety of simvastatin in comparison with bezafibrate in treatment of hypercholesterolemia].

The efficacy, tolerability and safety of simvastatin was compared to that of bezafibrate in a randomized placebo controlled double-blind trial including 64 patients with primary hypercholesterolemia with total cholesterol levels above 240 mg/dl and low-density lipoprotein (LDL) cholesterol above 195 mg/dl. During a placebo period of four weeks patients were counselled for a diet low in cholesterol (< 300 mg/day) and saturated fat (< 10% of calories). This period was also used for randomization of the individuals into the bezafibrate and simvastatin group, respectively. Patients assigned to bezafibrate treatment took bezafibrate at 600 mg/day throughout the entire 12 weeks of active treatment. Patients assigned to simvastatin took simvastatin at 10 mg/day when LDL-cholesterol was below 195 mg/dl, and at 20 mg/day when LDL-cholesterol was above 195 mg. To compare the lipid lowering effect of both substances total cholesterol, LDL- and high-density lipoprotein (HDL)-cholesterol were measured as well as triglycerides, very low density lipoprotein (VLDL)-cholesterol and the concentrations of apolipoproteins (apo)-AI, apo-AII and apo-B, respectively. These variables were compared between the two study groups with respect to the percentage change from baseline levels obtained during the placebo period. After a 12 week treatment period mean percent reduction of total cholesterol in the simvastatin group was 24% and that of LDL-cholesterol was 36%, both more pronounced than the respective reductions (14% and 17%) observed in the bezafibrate group. The mean percent increase in HDL-cholesterol was similar in both treatment groups (simvastation by 20% vs. bezafibrate by 17%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Effect of pancreas transplantation on lipoprotein lipase, postprandial lipemia, and HDL cholesterol.

Pancreas transplantation with systemic venous drainage of the graft causes elevated plasma levels of insulin, known to be a potent regulator of plasma lipoprotein metabolism. We studied 11 post-type I diabetic pancreas-kidney transplant recipients, 9 type I diabetic kidney transplant recipients displaying peripheral hyperinsulinemia due to subcutaneous insulin treatment, 11 nondiabetic kidney transplant recipients as controls for the effects of immunosuppressive medication, and 11 healthy control subjects, all matched for age, sex, and body mass index. We determined fasting lipids, lipoproteins and lipolytic enzymes, as well as postprandial lipid metabolism after a standardized oral fat load. High-density lipoprotein (HDL) cholesterol averaged 1.98 (0.40) mmol/L in pancreas-kidney transplant patients, clearly higher than that of kidney transplant recipients (1.52 (0.36) mmol/L, P < 0.05) or of controls (1.50 (0.38) mmol/L, P < 0.05). In pancreas-kidney transplant patients postprandial lipemia was lowest and lipoprotein lipase activity was highest (average 32% and 154%, respectively, of the mean of the controls) compared with nondiabetic kidney transplant recipients (P < 0.005, P < 0.05) and healthy controls (P < 0.001, P < 0.01). In type I diabetic kidney transplant recipients the levels of HDL cholesterol (1.88 (0.63) mmol/L), postprandial lipemia, and lipoprotein lipase activity were intermediate between pancreas-kidney transplant patients and healthy controls. The distinctly elevated HDL cholesterol in pancreas-kidney transplant patients can be readily explained by the low postprandial triglyceride levels resulting from a high activity of lipoprotein lipase. The very favorable lipid profile in post-diabetic pancreas-kidney transplant recipients could be expected to counteract the severe atherosclerotic risk of long-standing diabetes.

Adult↗
PubMed1994

Fenofibrate improves postprandial chylomicron clearance in II B hyperlipoproteinemia.

In 11 patients with IIB hyperlipoproteinemia we studied fasting lipids, lipoproteins, lipoprotein-modifying enzymes, and postprandial lipid metabolism after a standardized oral fat load supplemented with vitamin A before and 12 weeks after treatment with fenofibrate, a third-generation fibric acid derivative. Fasting plasma cholesterol, triglycerides, low-density lipoprotein cholesterol decreased significantly (P < 0.05, P < 0.01, P < 0.01), high-density lipoprotein subfraction 3 cholesterol increased significantly (P < 0.05), and high-density lipoprotein subfraction 2 cholesterol remained unchanged. Postprandial lipemia, i.e., the integrated postprandial triglyceride concentrations corrected for the fasting triglyceride level, and postprandial chylomicron concentrations, as assessed by biosynthetic labeling of chylomicrons with retinyl palmitate, decreased by 40.6% and 60.1% (P < 0.05; P < 0.05), respectively. The activity of lipoprotein lipase (LPL) increased by 33.6% (P < 0.05); the increase in LPL during fenofibrate treatment was positively correlated with the increase in high-density lipoprotein cholesterol (r = 0.84; P < 0.005). Hepatic lipase and cholesteryl ester transfer protein mass and activity remained unchanged. We conclude that lipid-lowering therapy with fenofibrate ameliorates fasting and, more profoundly, postprandial lipoprotein transport in hypertriglyceridemia by curbing postprandial triglyceride and chylomicron accumulation, at least in part, through an increase in LPL activity.

Adult↗
PubMed1994

The immunosuppressive substance 2-chloro-2-deoxyadenosine modulates lipoprotein metabolism in a murine macrophage cell line (P388 cells).

A recently developed immunosuppressive substance, 2-chloro-2-deoxyadenosine (2-CdA), was reported to inhibit monocyte functions at low concentration. Because macrophages play a key role in the formation of atherosclerotic plaques, it was of interest to study the effect of 2-CdA on cellular lipid metabolism. For this purpose we have used a macrophage cell line (P388) to perform incubation studies in the presence of acetylated low density lipoprotein (Ac-LDL) and 2-CdA. The addition of 2-CdA, in concentrations ranging from 5-20 nM, induced a dose-dependent decrease in cellular cholesterol content and in the amount of extracellular [14C]oleic acid (OA) incorporated into the cholesteryl ester (CE) fraction. The effect was maximized at 20 nM 2-CdA with an 86% reduction in cholesterol esterification compared to controls (P < 0.008). To evaluate the mechanism of interaction of 2-CdA with cellular lipid metabolism, deoxycytidine (dCyt) and 3-methoxybenzamide (3-MOB), substances known to antagonize the effect of 2-CdA in different ways, were co-administered with 2-CdA. dCyt, a competitive inhibitor of dCyt kinase, which catalyzes phosphorylation to the active metabolite, antagonized the effects of 20 nM 2-CdA, producing significantly greater incorporation of extracellular [14C]OA into the CE fraction than in the presence of 2-CdA alone (P < 0.0086). Co-incubation with 2-CdA and the poly-ADP-ribose synthetase inhibitor 3-MOB, which is known to render cells resistant to 2-CdA toxicity by preventing cellular nicotinamide adenine dinucleotide (NAD)- and adenosine triphosphase-depletion, also reversed the effect of 2-CdA on lipid accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1994

Triglyceride-rich lipoproteins and atherosclerosis.

Plasma triglyceride (TG)-rich lipoproteins are related to high density lipoprotein (HDL)-cholesterol and risk of coronary artery disease (CAD). Two major hypotheses on the role of HDL in the development of CAD have been proposed: a 'causalist' view assigns a protective effect against atherosclerosis to HDL and a 'non-causalist' view states that HDL do not interfere directly with development of atheroma but reflect metabolism of TG-rich lipoproteins. HDL exist as two major subfractions: small, lipid-poor, dense HDL3, and larger, lipid-rich, less dense HDL2, with variable levels of total-HDL cholesterol. Rapid lipolysis of TG-rich lipoproteins produces increased lipid uptake, formation of HDL2 and may protect the arterial wall; delayed lipolysis increases transfer of TG from TG-rich lipoproteins into HDL. Cholesteryl ester transfer protein (CETP) catalyzes lipid exchange and may be the mechanism for switching 'good cholesterol' into 'bad cholesterol'. According to this view, the driving force for the switch is the metabolism of TG-rich lipoproteins. Rapid clearance of TG-rich lipoproteins promotes formation of HDL2, low levels of TG-rich lipoproteins prevent transfer of HDL-cholesteryl esters into TG-rich lipoproteins keeping HDL-cholesterol high. The net effect is antiatherogenic. Accumulation of TG-rich lipoproteins leads to transfer of cholesteryl esters from HDL into lipoprotein fractions associated with high CAD risk.

Cholesterol, HDL↗
PubMed1994

Kinetics of lipids, apolipoproteins, and cholesteryl ester transfer protein in plasma after a bicycle marathon.

The short-term effects of prolonged intense exercise on plasma lipid transport parameters including cholesterol, triglycerides (TGs), low-density lipoprotein (LD) cholesterol, high-density lipoprotein (HDL) cholesterol, and its subfractions HDL2 cholesterol and HDL3 cholesterol, on apolipoproteins (apos) A-I, A-II, and B, and on mass and activity of cholesteryl ester transfer protein (CETP) were studied in eight male endurance-trained athletes over the first week after a bicycle marathon. CETP mass concentration in plasma was quantified by a newly developed immunoradiometric assay (IRMA). Plasma concentrations of cholesterol, TGs, LDL cholesterol, apo B, CETP, and cholesteryl ester transfer activity (CETA) were significantly reduced in the recovery period compared with pre-exercise values (cholesterol by 20%, P < .05; TGs by 63%, P < .05; LDL cholesterol by 32%, P < .05; apo B by 18%, P < .05; CETP mass by 29%, P < .05; and CETA by 14%, P < .05). HDL cholesterol and HDL2 cholesterol, in contrast, were significantly increased in the post-exercise period (HDL cholesterol by 12%, P < .05, and HDL2 cholesterol by 96%, P < .05), whereas HDL3 cholesterol showed a tendency to decrease in the late recovery period (by 8%, NS). Although changes in cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apo B, and CETP mass and activity were already evident in the early recovery period, HDL2 cholesterol showed a delayed response, reaching its maximum 72 hours after initiation of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Low-density lipoproteins of the postprandial state induce cellular cholesteryl ester accumulation in macrophages.

Chemically or biologically modified low-density lipoproteins (LDL) but not native unmodified LDL lead to foam cell formation in monocyte-derived macrophages. Since the magnitude of postprandial lipemia after a challenge test seems to be associated with coronary artery disease, we tested the hypothesis that in the course of postprandial lipemia, LDL appear in plasma that are capable of leading to foam cell formation even without prior modification. We incubated the macrophage-like cell line P388 with unmodified postabsorptive and postprandial LDL from 17 healthy donors and measured the cellular cholesterol and triglyceride contents and amounts of exogenous [14C]oleic acid incorporated into the cholesteryl ester fraction. Postprandial LDL induced a significantly more pronounced cholesteryl ester accumulation than did postabsorptive LDL (477 +/- 286% versus 212 +/- 173%, respectively; P < .003). The increase in cellular total cholesterol was significantly higher as a result of cell incubation with postprandial LDL (107 +/- 61%) than with postabsorptive LDL (54 +/- 40%, P < .003), whereas no increase in triglyceride content was observed (P < .589) in either case. After CuSO4 incubation and incubation with P388 cells, postprandial LDL revealed more thiobarbituric acid-reacting substances than did postabsorptive LDL (55 +/- 10 versus 28 +/- 9 nmol/mg protein, P < .018; 28 +/- 4 versus 20 +/- 3 nmol/mg protein). The increase in cellular cholesteryl ester synthesis caused by postprandial LDL was reduced by more than 50% when lipoproteins and cells were incubated in the presence of ascorbic acid (P < .007).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Lipoprotein lipase deficiency due to a 3' splice site mutation in intron 6 of the lipoprotein lipase gene.

In a patient with primary hyperchylomicronemia as a result of lipoprotein lipase (LPL) deficiency, we sequenced all translated exons and intron-exon boundaries of the LPL gene. We found a C-->A mutation in position -3 at the acceptor splice site of intron 6 which caused aberrant splicing. The major transcript showed a deletion of exons 6 through 9 and amounted to about 3% of the normal transcript of a healthy control individual. In addition to this major transcript, we found trace amounts of both a normally spliced LPL mRNA and a second aberrant transcript devoid of exon 7. On the same allele, we detected in the LPL gene of our patient four polymorphic variations, three of which have not as yet been described. A second patient from an unrelated family, but from the same geographic area, was also found to be homozygous for the same mutation. Of the relatives of the two probands studied, 11 were heterozygous and 5 were unaffected by the mutation. LPL activity in postheparin plasma was near zero in the probands and reduced in 4 of the 10 heterozygotes. A third hyperchylomicronemic patient from the same area was found to be a compound heterozygote who carried on one allele the 3' splice site mutation of intron 6 and on the other one an already described missense mutation resulting in Gly188-->Glu substitution.

Alleles↗
PubMed1994

High density lipoproteins with differing apolipoproteins: relationships to postprandial lipemia, cholesteryl ester transfer protein, and activities of lipoprotein lipase, hepatic lipase, and lecithin: cholesterol acyltransferase.

To gain insight into metabolic determinants of high density lipoproteins (HDL) containing apolipoproteins A-I and A-II (LpA-I/A-II) and those containing A-I, but devoid of A-II (LpA-I), the plasma concentration of LpA-I and LpA-I/A-II within the HDL2 and HDL3 density spectrum was measured in 14 normolipidemic male subjects on a standardized diet. Apolipoprotein plasma concentrations of HDL subspecies were compared with the magnitude of postprandial lipemia, activities of lipoprotein lipase and hepatic lipase in postheparin plasma, plasma lecithin:cholesterol acyltransferase (LCAT) activity, and cholesteryl ester transfer protein (CETP) mass. Plasma levels of LpA-I/A-II were 2.5 times higher than levels of LpA-I (123 +/- 20 vs. 48.3 +/- 22.1 mg protein/dl) and the partition of LpA-I and LpA-I/A-II between HDL2 and HDL3 differed in that the proportion of LpA-I associated with HDL2 was greater than that of LpA-I/A-II (23 +/- 19 vs. 6 +/- 6%, P < 0.002). With increasing levels of HDL2, the proportion of LpA-I in HDL2 increased (P < 0.002). Furthermore, levels of LpA-I and LpA-I/A-II were strongly correlated within the HDL2 but not within the HDL3 density region. Plasma levels of LpA-I, but not LpA-I/A-II, were inversely correlated with the magnitude of postprandial lipemia. However, activities of lipoprotein lipase and hepatic lipase tended to show stronger associations with the partition of LpA-I/A-II between HDL2 and HDL3 than with that of LpA-I. Within the HDL3, but not the HDL2 density spectrum, LpA-I/A-II exhibited a positive association with plasma LCAT activity, while LpA-I displayed an inverse association with plasma CETP mass. These results are consistent with differences in substrate properties of LpA-I and LpA-I/A-II for lipoprotein modifying enzymes and imply different, but overlapping metabolic pathways of LpA-I and LpA-I/A-II.

Adult↗
PubMed1994

[Hypertriglyceridemia].

The hypertriglyceridemias comprise a heterogenous group of lipoprotein disorders varying with respect to etiology, lipoprotein pattern, and its major clinical sequelae, i.e. pancreatitis and atherosclerosis. Therefore goals and modalities of treatment should be individualized to a large extent. Behavioral measures like diet, weight control, exercise, reduced alcohol consumption and smoking cessation form the cornerstone of medical management. Lipid lowering drugs should be considered when triglyceride levels exceed 1000 mg/dl to reduce the risk of pancreatitis and in patients at high risk for atherosclerosis, often characterized by a high total cholesterol/HDL ratio, to reduce cardiovascular endpoints.

Combined Modality Therapy↗