Advanced glycation end products as a biomarker for incisional hernia.

BACKGROUND: Incisional hernia is one of the most frequent complications after abdominal surgery, with incidences up to 30%. A reliable biomarker for the prediction of this complication is lacking. Advanced glycosylation end products (AGEs), also known as non-enzymatic collagen crosslinks, are correlated with aging, smoking, hyperglycemia, hyperlipidemia and oxidative stress. In this study the accumulation of AGEs and the relation between AGEs and incisional hernia were investigated. MATERIALS AND METHODS: In an exploratory case-control study, 23 patients with incisional hernia after midline incision were compared with 17 patients without clinical or radiological signs of incisional hernia after midline incision, AGEs were measured using a Skin Auto Fluorescence (SAF)-reader. RESULTS: Twenty-three patients with a clinically significant incisional hernia and 17 control patients were included. The study groups had significant differences in mean BMI. There was a significant difference between mean AGEs in patients with and without incisional hernia after midline incision (3.00 ± 0.15 vs. 2.56 ± 0.11, T test p = 0.03). CONCLUSION: AGE accumulation measured in the skin indirectly with autofluorescence might be associated with incisional hernia. Prospective larger trials should confirm this finding.

Methods to assess impaired post-prandial metabolism and the impact for early detection of cardiovascular disease risk.

Post-prandial lipaemia has emerged as a key contributor to cardiovascular disease (CVD) risk and progression. Specifically, delayed clearance of chylomicrons (CM) and their remnants increase the delivery of triglyceride and cholesteryl ester to the vessel wall and can accelerate the progression of atherosclerosis, which may be particularly pertinent to individuals with insulin resistance and/or obesity. As the number of studies linking post-prandial metabolism and chronic disease increases, interest has grown in the use of parameters reflecting CM metabolism as a possible indicator of early CVD risk. This, in turn has raised the question of what method might be most appropriate to detect CM and their remnants in plasma accurately. However, the handful of techniques able to measure CM metabolism (triglyceride-rich lipoprotein fractions; remnant-lipoprotein cholesterol; retinyl esters, CM-like emulsion; sodium dodecyl sulphate-polyacrylamide gel electrophoresis; immunoblotting, enzyme-linked immunoabsorbent assays; C(13) breath test; capillary finger prick) differ in their specificity, cost and applicability in research and in the clinical setting. In this review, we explore the scientific and clinical implications of CM methodology to better understand early risk assessment of CVD. We raise ongoing issues of the need to appreciate differential separation of very low-density lipoprotein and CM fractions, as well as to identify the technical basis for imprecision between assays for apolipoprotein B48. We also highlight emerging issues with respect to the practicality of measuring post-prandial metabolism in large clinical studies and offer opinions on the appropriateness of existing techniques in this field.

Insulin mediated inhibition of hormone sensitive lipase activity in vivo in relation to endogenous catecholamines in healthy subjects.

The regulation of hormone-sensitive lipase activity in vivo has not been studied in detail before. We have performed noninvasive in vivo tests to measure hormone-sensitive lipase activity under high plasma levels of endogenous insulin and catecholamines. For this purpose, two mental stress tests were carried out at random in 13 healthy volunteers. The subjects ingested 200 ml of a placebo solution or 20% glucose, followed by 1 h of rest, 20 min of mental stress, and 40 min of rest. Twenty minutes after the ingestion of glucose, insulin levels increased from 6.8 +/- 1.6 to a maximum of 30.5 +/- 4.8 mU/liter (P < 0.01), whereas the increase in insulin was significantly less after placebo (from 5.7 +/- 0.9 to 9.5 +/- 1.5 mU/liter; P < 0.01). The increase in heart rate, as an estimate of the amount of stress, was similar in both tests (12% increase). During stress, plasma norepinephrine and epinephrine concentrations increased by 24% and 44%, respectively, after glucose and by 4% and 21%, respectively, after placebo (n = 6). Fasting plasma FFA were similar in both tests (placebo, 0.35 +/- 0.07 mM; glucose, 0.46 +/- 0.08 mM). Forty minutes after ingestion of placebo, plasma FFA concentrations decreased to 0.27 +/- 0.07 mM, compared with a stronger suppression to 0.11 +/- 0.02 mM after ingestion of glucose (P < 0.01). By 10 min after mental stress, plasma FFA concentrations increased by 53% after placebo (P < 0.01), in contrast to unchanged FFA concentrations after ingestion of glucose. Taken together, these results suggest that the suppression of hormone-sensitive lipase by endogenous insulin in healthy, insulin-sensitive subjects is stronger than the stimulation by endogenous catecholamines.

Effects of different nutrient intakes on daytime triacylglycerolemia in healthy, normolipemic, free-living men.

BACKGROUND: Postprandial studies with standardized mixed meals have shown that ingestion of high-carbohydrate diets is associated with elevated plasma triacylglycerol (TG) concentrations. OBJECTIVE: We evaluated the effects of different nutritional components on daytime triacylglycerolemia in 58 healthy, free-living, normolipemic men. DESIGN: Capillary TG (TGc) was self-measured at 6 fixed time points over 3 d. Daytime TGc profiles were calculated as areas under the curve (AUCs) for absolute and incremental changes in TGc concentrations (TGc-AUC and DeltaTGc-AUC, respectively). Food intake was recorded in a diary. RESULTS: The mean (+/-SD) fasting TGc concentration, TGc-AUC, and DeltaTGc-AUC were 1.20 +/- 0.41 mmol/L, 24.1 +/- 6.9 mmol x h/L, and 7.3 +/- 4.5 mmol x h/L, respectively. Mean total energy intake was 10881 +/- 2536 kJ/d. Total intakes of fat, carbohydrate, and protein were 95 +/- 25 (33% of energy), 304 +/- 69 (48% of energy), and 101 +/- 27 (16% of energy) g/d, respectively. Fasting TGc concentrations and TGc-AUC were not related to dietary intake. The mean DeltaTGc-AUC was significantly related to total carbohydrate (r = 0.38, P < 0.005), protein (r = 0.29, P < 0.05), and energy (r = 0.28, P < 0.05) intakes. Fat intake (as a % of energy) was negatively associated with the mean DeltaTGc-AUC (r = -0.30, P < 0.05). When the study group was subdivided into tertiles on the basis of fat intake (27.2%, 33.5%, and 39.1% of energy, respectively), carbohydrate intake was 50.9%, 48.1%, and 44.6% of energy, respectively. DeltaTGc-AUC was significantly lower at the highest tertile of fat intake (4.8 +/- 4.3 mmol x h/L) than at the lowest (8.2 +/- 4.0 mmol x h/L) and intermediate (8.9 +/- 4.3 mmol x h/L) tertiles (P < 0.05 for each). CONCLUSION: DeltaTGc-AUC is associated with the carbohydrate content of the diet in free-living men.

High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH) and disturbances in postprandial lipoprotein metabolism are both associated with premature atherosclerosis. The effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors on plasma cholesterol levels in patients with FH is well established; however, it is not known whether postprandial lipoproteins are also influenced. In this case-controlled intervention study, we investigated the effects of high-dose simvastatin on postprandial lipoproteins. We used a new method to analyze remnant lipoproteins based on the immunoseparation principle (remnant-like particle cholesterol [RLP-C] assay) and the well-established measurement of retinyl ester (RE) analysis in plasma and in the Svedberg flotation unit (Sf)<1000 fraction. Seven heterozygous FH patients and 7 control subjects matched for sex, age, body mass index, triglycerides, and apolipoprotein E genotype were enrolled in the study. An oral vitamin A (RE) fat-loading test was performed at baseline in both groups and after 3 months of high-dose simvastatin (80 mg/d) treatment in the FH patients. Before treatment, FH patients had significantly higher fasting and postprandial concentrations of lipoprotein remnants (plasma RLP-C 42+/-19 mg/dL and area under the RLP-C curve 415+/-82 mg. L(-1). h(-1), respectively) than did control subjects (7+/-3 mg/dL and 101+/-35 mg. L( -1). h(-1), respectively; P<0.05), suggesting a delayed clearance of chylomicron remnant particles in the FH patients. Treatment with simvastatin significantly reduced fasting and postprandial remnant lipoprotein cholesterol concentrations (13+/-3 mg/dL and 136+/-53 mg. L(-1). h(-1), respectively; P<0.05 for both). Postprandial RE in the Sf<1000 fraction, not total RE in plasma, was also significantly higher in FH patients than in control subjects (24+/-10 versus 6.3+/-5.9 mg. L( -1). h(-1), P<0.05), but treatment with simvastatin did not result in improvement of the postprandial RE response, either in the Sf<1000 fraction or in plasma. It is concluded that heterozygous FH patients have increased fasting and postprandial remnant lipoprotein concentrations. Treatment with simvastatin significantly reduced the fasting and postprandial RLP-C concentrations but did not result in improved postprandial RE response.

In vivo evidence of defective postprandial and postabsorptive free fatty acid metabolism in familial combined hyperlipidemia.

Overproduction of very low density lipoprotein (VLDL) is the major characteristic of subjects with familial combined hyperlipidemia (FCHL). As enhanced free fatty acid (FFA) flux to the liver may be one of the determinants of VLDL overproduction, we studied FFA changes and products of hepatic FFA metabolism in response to a 24-h oral fat loading test (50 g/m(2)) in 7 FCHL subjects and 7 matched control subjects. The response to the meal was subdivided into a postprandial (up to 8 h after ingestion of the meal) and postabsorptive period (from 8 to 24 h). Although postheparin plasma lipolytic activities were not different between both groups, the postprandial FFA area under the curve (FFA-AUC) and FFA incremental area under the curve (FFA-dAUC) were higher in FCHL subjects than in control subjects (6.05 +/- 0.45 vs. 3.43 +/- 0.46 and 2.60 +/- 0.49 vs. 0.96 +/- 0.31 mmol. h/L, respectively; P < 0.01 for each). The postprandial increase in ketone bodies was almost four times higher in FCHL patients. As ketogenesis occurs predominantly in hepatocytes, these findings suggest that during the postprandial period in FCHL an increased flux of FFA to the liver occurs, possibly because of inadequate incorporation of FFA into triglycerides (TGs) in adipocytes. In the postabsorptive period, FFA and ketone bodies significantly decreased in FCHL subjects, in contrast to control subjects, in whom both increased. These results may represent a diminished release of FFA from adipocytes by hormone-sensitive lipase (HSL) in FCHL patients. The decrease in postabsorptive FFA and ketone bodies in FCHL patients could not be explained by insulin-mediated inhibition of HSL, as both FCHL subjects and control subjects had similar postabsorptive insulin concentrations, which were below fasting concentrations. This study provides in vivo evidence of impaired metabolism of postprandial FFA in FCHL, which may explain in part the hepatic VLDL overproduction characteristic of FCHL subjects.

Growth hormone (GH) treatment decreases postprandial remnant-like particle cholesterol concentration and improves endothelial function in adult-onset GH deficiency.

Premature atherosclerosis is a clinical feature in adult-onset GH deficiency. Evidence is accumulating that disturbances in triglyceride metabolism, reflected by abnormalities in circulating remnant lipoproteins, are associated with increased atherogenic potential. In a case-controlled intervention study, we investigated postprandial lipoprotein metabolism using a new remnant lipoprotein method based on immunoseparation principle [RLP-cholesterol (RLP-C)]. In addition, we analyzed retinyl ester (RE) analysis in plasma and in Sf < 1000 fraction. Endothelial function was assessed as flow-mediated dilatation (FMD). Eight patients diagnosed with acquired adult-onset GH deficiency and eight controls matched for gender, age, body mass index, and apolipoprotein (apo) E genotype were enrolled in the study. Oral vitamin A fat loading tests were performed at baseline in both groups and after 6 months of treatment with recombinant human GH (rh-GH) in the adult-onset GH-deficient patients. Adult-onset GH-deficient patients had significantly higher fasting RLP-C, postprandial RLP-C concentrations (plasma RLP-C, 0.29 +/- 0.14 mmol/L; and incremental area under the curve-RLP-C, 2.13 +/- 1.60 mmol*h/L, respectively) than controls (0.19 +/- 0.06 mmol/L and 1.05 +/- 0.72 mmol*h/L (P: < 0.05), respectively). They also had significantly higher postprandial RE in plasma and Sf < 1000 fraction. Treatment with rh-GH significantly reduced postprandial RLP-C concentrations (incremental area under the curve-RPL-C 0.73 +/- 0.34 mmol*h/L; P: < 0.05) but had no effects on the fasting RLP-C concentrations (0.317 +/- 0.09 mmol/L, P: < 0.05), or on the postprandial RE in plasma and in Sf < 1000 fraction. Endothelial function measured as FMD was improved from 5.9 +/- 3.3% to 10.2 +/- 4.0% (P: < 0.05) in patients treated with rh-GH. It is concluded that patients with adult-onset GH deficiency have increased levels of fasting and postprandial RLP-C and an impaired endothelial function as measured as FMD. Treatment with rh-GH resulted in a decrease of postprandial RLP-C concentration, thereby improving the postprandial atherogenic lipoprotein profile and improvement of endothelial function, however, the clearance of large chylomicron particles as reflected by RE remained disturbed.

Delayed chylomicron remnant clearance in subjects with heterozygous familial hypercholesterolaemia.

OBJECTIVES: To study the role of the LDL receptor in the clearance of chylomicron remnants in humans. DESIGN: Chylomicron remnant clearance was studied in five untreated subjects with heterozygous familial hypercholesterolaemia (FH) and nine normolipidaemic controls, by oral retinyl palmitate-fat loading tests. Fasting plasma triglycerides (TG), which are important determinators of chylomicron and remnant clearance, were not significantly different between FH (1.76+/-0.32 mmol L(-1), mean+/-SEM) and controls (1.26+/-0.18 mmol L(-1). Chylomicrons (Sf > 1000) and their remnants (Sf < 1000) were separated by flotation and their clearance was estimated by calculating the area under the 24 h-retinyl palmitate curve (AUC-RP). The factors determining chylomicron and remnant clearance were studied by univariate and multiple regression analysis. RESULTS: Triglyceride clearance in plasma, Sf > 1000 fractions and Sf < 1000 fractions was not significantly different between FH subjects and controls. In subjects with heterozygous FH, chylomicron remnant clearance was two-fold delayed (AUC-RP, 49.39+/-11.61 h.mg L(-1) compared to controls (27.45+/-3.95 h.mg L(-1); P = 0.048). Moreover, 28.4% higher fasting plasma TG in FH resulted in 44.4% higher areas under the remnant-curves compared to controls. The clearance of chylomicron RP was associated to plasma apo E (beta = 0.73, P = 0.011), plasma LDL cholesterol (beta = 0.62, P = 0.018) and plasma TG (beta = 0.58, P = 0.029). The clearance of remnant RP was associated to the diagnosis (FH vs. non-FH), but not to the well-known determinants of remnant clearance like plasma TG. CONCLUSIONS: The clearance of chylomicrons and large remnants isolated in the Sf > fraction depends primarily on the apo B, E (LDL) receptor and to a lesser extent on plasma triglycerides. The clearance of smaller chylomicron remnants isolated in the Sf < 1000 depends to a large extent on the apo B, E (LDL) receptor.

Postural myoclonus induced by phenytoin.

Involuntary movements are an infrequent complication of treatment with phenytoin and include tremor, asterixis, myoclonus, parkinsonism, and dyskinesias. The mechanism by which phenytoin exerts its actions is unclear. Phenytoin has been observed to exert variable effects on dopamine metabolites and also may induce changes in serotonergic activity. In this report, we discuss the available experimental evidence concerning the possible mechanisms of involuntary movements induced by phenytoin. We describe a case of postural myoclonus during treatment with phenytoin.

Triglyceride-rich lipoproteins in non-insulin-dependent diabetes mellitus: post-prandial metabolism and relation to premature atherosclerosis.

Non-insulin-dependent diabetes mellitus is frequently associated with premature atherosclerosis. Abnormalities in lipid and lipoprotein metabolism contribute to the increased risk of coronary heart disease. One of the most common lipid abnormalities in non-insulin-dependent diabetes mellitus is hypertriglyceridaemia. In the present paper, the authors review the metabolism of triglyceride-rich lipoproteins, with special emphasis on the post-prandial state. Several studies have demonstrated that levels of atherogenic post-prandial lipoproteins are increased in patients with non-insulin-dependent diabetes mellitus. An increased supply of glucose and free fatty acids contributes to overproduction of very low-density lipoproteins, increasing the burden of triglyceride-rich lipoproteins on the common lipolytic pathway at the level of lipoprotein lipase. Low lipoprotein lipase activity and increased amounts of lipolysis-inhibiting free fatty acids further impair lipolysis of post-prandial lipoproteins. The clearance of atherogenic remnants is also delayed in non-insulin-dependent diabetes mellitus. There is evidence that a relative hepatic removal defect exists, secondary to impaired remnant-receptor interaction and increased competition with very low density lipoprotein remnants. Correction of the increased post-prandial lipaemia in non-insulin-dependent diabetes mellitus is advisable, as it may contribute to attenuation of the risk on premature atherosclerosis. When dietary measures and hypoglycaemic agents have failed to achieve acceptable lipid levels, lipid-lowering drugs should be advised. Fibric acids and hydroxymethyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors are the drugs of choice.

Impaired chylomicron remnant clearance in familial combined hyperlipidemia.

Postprandial chylomicron remnant clearance was studied in six patients with familial combined hyperlipidemia (FCH) and seven control subjects by using an oral retinyl palmitate (RP) fat-loading test. The chylomicron remnant clearance (Sf < 1,000 fraction), expressed as the area under the RP curve (AUC-RP), was delayed in FCH subjects (65.05 +/- 12.84 hours x [mg/L]) compared with control subjects (25.1 +/- 5.4 hours x [mg/L]; p = 0.01). Postprandial lipoprotein particle size and composition in the Sf > 1,000 fraction were different between FCH and control subjects as analyzed by molecular-sieve chromatography. Fasting high density lipoprotein cholesterol was lower in FCH patients (0.54 +/- 0.09 mmol/L) than in control subjects (0.89 +/- 0.05 mmol/L; p < 0.01). Mean plasma postheparin lipoprotein lipase and hepatic lipase activities were similar between FCH patients (94 +/- 25 and 427 +/- 57 milliunits/mL, respectively) and control subjects (126 +/- 16 and 362 +/- 33 milliunits/mL, respectively). In FCH, a 54% reduction (p < 0.05) of plasma triglycerides to 2.63 +/- 0.41 mmol/L by drug treatment resulted in an enhanced, but not normalized, clearance of chylomicron remnants (39.4 +/- 6.0 hours x [mg/L]). Univariate regression analysis revealed that in FCH subjects the changes in fasting plasma apolipoprotein C-III concentrations after therapy were significantly associated with the changes in chylomicron remnant AUC-RP (r = 0.87; p = 0.02). Delayed elimination of atherogenic chylomicron remnants may contribute to the increased risk of premature atherosclerosis in FCH.

Simvastatin improves chylomicron remnant removal in familial combined hyperlipidemia without changing chylomicron conversion.

It is unknown whether the clearance of atherogenic chylomicron remnants and the postprandial lipoprotein metabolism in general can be improved by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in subjects with familial combined hyperlipidemia (FCH). Therefore, the postprandial chylomicron remnant clearance was studied in nine normolipidemic untreated controls and seven FCH patients before and after treatment with simvastatin using an oral vitamin A-fat load (24 hours, 50 g/m2). Treatment with simvastatin reduced plasma cholesterol level by 16% (mean +/- SEM, 8.1 +/- 0.8 v 6.8 +/- 0.8 mmol/L; P < .05) and plasma apolipoprotein (apo) B level by 19% (1.6 +/- 0.2 v 1.3 +/- 0.2 g/L; P < .05). Plasma apo E level (89.6 +/- 21.0 mg/L) was reduced by 29% (63.5 +/- 14.1 mg/L; P < .05). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels did not change; consequently, the reductions seen had been due to a decrease in very-low-density lipoprotein (VLDL) levels. Fasting plasma triglyceride (30% reduction) and plasma apo C-II (31% reduction) levels did not change significantly. Mean postheparin plasma lipoprotein lipase (LPL) activity increased by 13% after treatment (90.4 +/- 19.8 v 102.6 +/- 20.3 mU/mL; P < .05), but hepatic lipase (HL) activity was not altered. The clearance of chylomicrons (Sf > 1,000), expressed as the area under the 24-hour retinyl palmitate curve, did not change with simvastatin (52.8 +/- 12.9 v 51.8 +/- 13.4 h.mg-1/L).(ABSTRACT TRUNCATED AT 250 WORDS)

Reverse cholesterol transport: relationship between free cholesterol uptake and HDL3 in normolipidaemic and hyperlipidaemic subjects.

High density lipoproteins (HDL) are responsible for the Reverse Cholesterol Transport (RCT). The role of the composition of the HDL particle in RCT, involving free cholesterol (chol) uptake from cell membranes, is not completely understood. We have therefore studied the uptake capacity from subjects with a wide variety of plasma HDL cholesterol concentrations in an HDL-receptor free model consisting of bovine heart mitochondrial membranes labeled with [14C]cholesterol. HDL were isolated by molecular sieve chromatography from fresh plasma samples of eight subjects with low plasma HDL chol concentrations (< or equal to 1.0 mmol L-1) and 15 subjects with normal HDL chol concentrations. The latter were subdivided into an intermediate (HDL chol: 1.0-1.4 mmol L-1; n =9) and a high HDL chol group (> or equal to 1.4 mmol L-1; n = 6). In the HDL fractions isolated by chromatography (cHDL), total chol and apolipoprotein (apo) AI were measured. Free chol uptake was significantly decreased by 32% in the tertile with the lowest plasma HDL chol (49.1 +/- 15.8 arbitrary units; mean +/- SD), compared to the tertile with high HDL chol (72.1 +/- 16.6 au). Linear regression analysis showed a positive correlation between the free chol uptake and plasma HDL3 concentrations (r = 0.61; P < 0.01), HDL chol (r = 0.56; P < 0.01), HDL associated apo AI (R = 0.46; P < 0.05), cHDL apo AI (r = 0.56; P < 0.05) and cHDL chol (r = 0.46; P < 0.05) in all subjects combined. Stepwise multiple-regression analysis confirmed the association of [14C] cholesterol uptake with plasma HDL3 concentrations (beta, 0.61; P = 0.004). No correlations were found between free chol uptake and total plasma apo AI (r = 0.26. ns) or HDL2 (r = 0.27; ns). After an oral fat load in four FCH patients, free chol uptake paralleled the changes in plasma HDL 3 chol concentrations. We conclude that HDL3 is involved in the early steps of RCT and low HDL 3 levels may result in less efficient RCT in hypertriglyceridemia.

Teaching the plantar reflex.

The efficacy of an instructional videotape about the interpretation of the plantar response was evaluated during a two week neurological clerkship. Experimental groups saw the videotape, control groups did not. All students (n = 65) assessed plantar responses of two to four different patients. Their judgment was compared with that of one senior neurologist. Only the students who had seen the videotape showed a significant improvement in performance on a second test (t-test, t = -2.26, p = 0.031). In addition, these students more frequently took account of the flexion synergy (Fisher exact test, p less than 0.001). Video can be an efficient tool in medical education.