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Biomedical subjects

F C Luft

Publications and source records attributed to F C Luft.

At least 163 records · Page 9Linked to original sources
PubMed1999

Angiotensin inhibition and atrial natriuretic peptide release after acute volume expansion in rats with aortocaval shunt.

OBJECTIVE: In heart failure atrial natriuretic peptide (ANP) release in response to volume expansion is impaired while the renin-angiotensin system is activated. This study was designed to test the hypothesis that ANP release in heart failure is dependent on an activated angiotensin system. METHODS: We studied the ANP and renin-angiotensin systems in a rat model of shunt-induced high-output heart failure, in which we rapidly increased circulating fluid volume with a 5 ml, hyperoncotic infusion, and evaluated the effects of acute inhibition of the angiotensin converting enzyme as well as of the blockade of the angiotensin II type 1 receptors on the ANP release and on renal excretory function. RESULTS: ANP and angiotensin II plasma concentrations prior to volume expansion were elevated (p < 0.05) in rats with aortocaval shunt compared to controls. The diuretic response to acute volume expansion (18.5 +/- 1.5 vs. 48.2 +/- 2.4 microliters/min, p < 0.001) was markedly blunted. ANP release was attenuated in rats with aortocaval shunt, as was the increase of its second messenger cGMP in plasma and urine. The blunted increase in ANP plasma levels was not due to depleted cardiac stores as cardiac ANP content, as well as ANP synthesis, were increased (p < 0.05). Acute inhibition of the angiotensin converting enzyme as well as blockade of the angiotensin II type 1 receptors restored ANP release in response to volume expansion (p < 0.01). Moreover, acute inhibition of the renin-angiotensin system completely normalized the diuretic response. CONCLUSIONS: Our data suggest that the ANP system is impaired in rats with aortocaval shunt. The activation of the angiotensin system contributes to the impairment of the ANP system. Acute inhibition of the angiotensin II system significantly improved the ability of the ANP system to respond to acute volume expansion. Our findings indicate a hitherto fore unappreciated interaction between both systems and suggest additional mechanisms for the beneficial effects of angiotensin converting enzyme inhibition or angiotensin II type 1 receptor antagonists in heart failure.

Angiotensin II↗
PubMed1999

Bad genes, good people, association, linkage, longevity and the prevention of cardiovascular disease.

1. Cardiovascular disease, the most common cause of death, is the product of risk factors such as hypertension, lipid disturbances, diabetes mellitus, left ventricular hypertrophy and nicotine smoking, all of which are influenced by genetic variance. Thus, genes that influence these factors have a considerable bearing on longevity. 2. Although mortality rates increase exponentially with increasing age, an interesting tendency towards a plateau occurs, suggesting that old individuals are somewhat protected from the propensity to die. This phenomenon is difficult to explain. 3. One possibility is a model of repair, in which certain alleles exert a beneficial influence at an advanced age. 4. An alternative explanation might be a mutation that exerts both negative and positive effects. 5. The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene exerts was observed to have an effect on heart size. The D allele was linked to a greater heart size, compared with the I allele in a modified sibpair model. This potentially deleterious effect was counter-balanced by linkage of the D allele to increased heart rate variability, which is potentially a beneficial attribute. Furthermore, in a cohort of the German population over age 80 years, it was observed that the D allele occurred at a frequency higher than would be expected. 6. The present study discusses the hypothesis that the ACE gene I/D polymorphism may be a genetic variant with both negative and positive effects.

Adult↗
PubMed1999

Extracellular matrix regulates apoptosis in human neutrophils.

BACKGROUND: During inflammation, polymorphonuclear neutrophils (PMNs) migrate into the affected tissue interacting with extracellular matrix (ECM) proteins. We tested the hypothesis that PMN-matrix interaction affects PMN apoptosis. METHODS: Apoptosis of human PMNs was detected by DNA-fragmentation assay and was quantitated by flow cytometry, ultraviolet and light microscopy. Cell adhesion was assessed by a toluidine blue assay, and cell spreading was detected by phase contrast microscopy. Protein tyrosine phosphorylation was studied using Western blotting and confocal microscopy. RESULTS: PMN apoptosis was not different in unstimulated cultures on either surface-adherent fibronectin or on PolyHema, a surface that prevents cell adherence. However, tumor necrosis factor-alpha (TNF alpha) treatment significantly increased apoptosis on fibronectin (37 +/- 4%) compared with PolyHema (20 +/- 3%). Tests on other matrix substances revealed that the percentage of apoptotic PMNs in the presence of TNF alpha was 8 +/- 1% on PolyHema, 26 +/- 4% on fibronectin, 17 +/- 2% on collagen I, 16 +/- 2% on collagen IV, and 16 +/- 3% on laminin (P < 0.05 for all matrices compared with PolyHema). Preincubation with genistein (50 microM) significantly inhibited TNF alpha-mediated apoptosis on fibronectin (39 +/- 4% to 21 +/- 4%) but not on PolyHema (21 +/- 4% to 16 +/- 4%). Genistein also reduced PMN spreading on fibronectin. In contrast, inhibitors of mitogen-activated protein kinase and protein kinase C showed no effect on PMN apoptosis. Fibronectin strongly increased tyrosine phosphorylation of three 102, 63, and 54 kDa proteins. Five newly tyrosine-phosphorylated 185, 85, 66, 56, and 42 kDa bands were also visible. Using confocal microscopy, highest tyrosine phosphorylation was localized to sites of cell-matrix interaction. CONCLUSIONS: ECM influences apoptosis in TNF alpha-activated, adherent, spreading PMNs. The process is regulated by tyrosine phosphorylation. Acceleration of apoptosis may shorten the PMN lifespan and thereby locally regulate inflammation.

Apoptosis↗
PubMed1999

Differential expression of protein kinase C isoforms in streptozotocin-induced diabetic rats.

BACKGROUND: The cellular effects of hyperglycemia are mediated by protein kinase C (PKC). However, PKC consists of several distinct isoforms, and their contribution to the pathogenesis of diabetic complications in different organs is not clear. We investigated the expression and translocation of PKC isoforms alpha, betaI, betaII, delta, epsilon, and zeta in kidney, heart, and aorta from diabetic rats. METHODS: Hyperglycemia was induced with streptozotocin (70 mg/kg) in the rat. After four weeks, PKC isoform expression was assessed by Western blot after tissue fractionation and by immunohistochemistry. RESULTS: Streptozotocin increased blood glucose from 117.0 +/- 3.6 to 510.0 +/- 19.4 mg/dl (N = 8, P < 0.01) and induced albuminuria. PKC isoforms alpha, beta, delta, epsilon, and zeta were all detected in control animals. Western blot showed increased PKC alpha expression in kidney and heart (160% and 170%, respectively). PKC betaI, betaII, and delta expression was not influenced by hyperglycemia. PKC zeta was decreased in diabetic animals in both tissues by 60%. The membrane association of PKC alpha and PKC epsilon was increased; however, the relative amount of PKC in the particulate fraction was not influenced by hyperglycemia. Immunohistochemistry revealed a marked increase in PKC alpha immunoreactivity in renal glomeruli and interstitial capillaries, cardiac capillaries, and skeletal muscle, as well as in the endothelial cells of larger arteries. PKC beta showed a small decrease in the glomeruli. PKC epsilon was increased in renal tubules in diabetic rats but was decreased in the myocardium. PKC zeta was expressed in both myocardial and glomerular cells but was decreased during hyperglycemia. Our results demonstrate that PKC isoforms are differentially regulated in kidney and heart in diabetes. High glucose increases PKC alpha expression, whereas PKC zeta is down-regulated. The finding that PKC alpha is mostly increased in endothelial cells supports a role for PKC alpha in functional endothelial disturbances observed in diabetes.

Animals↗
PubMed1999

Near infra-red interactance for nutritional assessment of dialysis patients.

BACKGROUND: Malnutrition is a common problem in dialysis patients and may affect up to one-third of patients. Near-infrared interactance (NIR) is a novel approach to estimate body composition and per cent total body fat. METHODS: We used near-infrared interactance (Futrex 5000) to estimate the body composition including body fat percentage, as well as subjective global assessment (SGA), anthropometric measurements including mid-arm circumference (MAC), triceps and biceps skinfold thickness, calculated mid-arm muscle circumference (MAMC), body mass index (BMI), and laboratory values. NIR score, SGA assessment and anthropometric parameters were measured shortly after the end of a dialysis session. NIR measurement was made by placing a Futrex sensor on the nonaccess upper arm for several seconds. Serum albumin, transferrin (reflected by total iron binding capacity), and total cholesterol concentrations were performed as well. RESULTS: Thirty-four patients (20 men and 14 women) were selected from a pool of 120 haemodialysis patients. Their ages ranged from 26 to 86 years (58+/-14 years). Time on dialysis ranged from 8 months to 19 years (4.5+/-4.6 years). NIR scores were significantly different in three SGA groups: (A) well-nourished, 32.5+/-6.9%; (B) mildly to moderately malnourished, 29.2+/-5.3%; and (C) severely malnourished, 23.2+/-10.2% (P<0.001). Pearson correlation coefficients (r) between the NIR score and nutritionally relevant parameters were significant (P<0.001) for body mass index (r=+0.81), mid-arm circumference (r=+0.74), triceps skin fold (r=+0.54), biceps skin fold (r=+0.55), and mid-arm muscle circumference (r=+0.54). An inverse correlation was also found between NIR and years dialysed (r=-0.49, P=0.004), denoting a lesser body fat percentage according to NIR for patients dialysed longer. NIR was correlated with serum transferrin (r=+0.41, P=0.016) and cholesterol (r=+0.39, P=0.022) and marginally with serum albumin (r=+0.29, P=0.097). CONCLUSIONS: We conclude that NIR, which can be performed within seconds, may serve as an objective indicator of nutritional status in haemodialysis patients. More comparative and longitudinal studies are needed to confirm the validity of NIR measurements in nutritional evaluation of dialysis patients.

Adipose Tissue↗
PubMed1999

A modified quantitative subjective global assessment of nutrition for dialysis patients.

BACKGROUND: Malnutrition, a predictor of increased mortality in dialysis patients, can be estimated using the subjective global assessment (SGA), a semiquantitative scale with three severity levels. This semiquantitative feature restricts the SGA's reliability and precision. METHODS: Using the components of the conventional SGA, we developed a fully quantitative scoring system (the dialysis malnutrition score) consisting of seven variables: weight change, dietary intake, gastrointestinal symptoms, functional capacity, comorbidity, subcutaneous fat and signs of muscle wasting. Each component was assigned a score from 1 (normal) to 5 (very severe). The sum of all seven components in this malnutrition score lies between 7 (normal) and 35 (severely malnourished). To evaluate nutritional status in chronic dialysis patients, anthropometric measurements including mid-arm circumference (MAC), triceps skin-fold thickness, calculated mid-arm muscle circumference (MAMC), body mass index (BMI, ratio of weight to square of height) and laboratory parameters were used. Forty-one patients (20 men and 21 women) were randomly selected from a pool of 120 haemodialysis patients. Patients were aged between 26 and 81 years (mean SD, 57 +/- 12 years) and had undergone haemodialysis for between 7 months and 12 years (mean +/- SD, 3.0 +/- 2.1 years). RESULTS: The malnutrition score of each patient was assessed by a dietitian within 5-20 min (12.0 +/- 3.5 min) with no knowledge of anthropometric findings. Pearson correlation coefficients between the malnutrition score and biceps skin-fold (r= -0.32) MAC (r= -0.55), MAMC (r= -0.66), BMI (r= -0.35), total iron-binding capacity (TIBC, r= -0.77), the serum albumin concentration (r= -0.36) and total protein (r= -0.33) were all significant, whereas the conventional SGA had significant correlation only with TIBC (r= -0.35) and MAMC (r= -0.37). Malnutrition score showed a significant correlation with age (r= +0.34) and years dialysed (r= +0.28). Multiple regression analysis showed a significant correlation between the malnutrition score and the combination of the MAMC, BMI, serum albumin concentration and TIBC (r= 0.81, P<0.001). There was no correlation between the malnutrition score and sex, urea reduction ratio, protein catabolic rate, and the absolute lymphocyte count. CONCLUSIONS: We conclude that our invented malnutrition score, which can be performed in minutes, reliably assesses the nutritional status of haemodialysis patients. We suggest that our malnutrition score may be superior to the SGA. More comparative and longitudinal studies are needed to confirm the validity of this scoring system in nutritional evaluation of dialysis patients.

Adult↗
PubMed1999

Linkage but lack of association for blood pressure and the alpha-adducin locus in normotensive twins.

BACKGROUND: alpha-adducin is a cytoskeletal protein involved with sodium-pump activity in the renal tubule. The alpha-adducin gene locus has been linked to hypertension and a polymorphism identified which is associated with hypertension; however, the role of the alpha-adducin gene locus in normal blood pressure regulation is not defined. We performed a combined linkage and association study in normotensive monozygotic (MZ) and dizygotic (DZ) twins and their parents to address this issue. METHODS: We studied 126 MZ and 70 DZ twin pairs and parents of DZ twins. Blood pressure values and responses to a cold pressor test were obtained. Cardiac dimensions were measured echocardiographically. Three microsatellites adjacent to the alpha-adducin gene were studied as well as the 460 Trp mutation in the alpha-adducin gene. RESULTS: We obtained strong evidence for linkage (P< 0.001) between the alpha-adducin gene locus and systolic blood pressure. However, we were not able to associate the 460 Trp mutation with higher blood pressures, cold pressor responses or cardiac dimensions. CONCLUSIONS: The alpha-adducin gene locus is relevant to blood pressure regulation in normal subjects. Failure to find an association between higher blood pressures and the 460 Trp mutation suggests that this mutation may become important only when hypertension is triggered, or that other variations in alpha-adducin are present which have not yet been discovered.

Adolescent↗
PubMed1999

Microalbuminuria as a predictive factor for cardiovascular events.

We tested the hypothesis that microalbuminuria screening in a general practice setting would identify high-risk nondiabetic hypertensive patients, and we measured microalbuminuria response to drug treatment. General practitioners were enrolled who had collected medical histories and performed physical examinations and routine laboratory tests in more than 11,000 untreated hypertensive, nondiabetic patients. Microalbuminuria was measured with an albumin-sensitive immunoassay test strip. The patients' mean age was 57 years, 51% were men, and mean duration of hypertension was 69 months. Twenty-five percent of patients had coronary artery disease (CAD), 17% had left ventricular hypertrophy (LVH), 5% had had a stroke, and 6% had peripheral vascular disease (PVD). Microalbuminuria was present in 32% of men and 28% of women. In patients with microalbuminuria, 31% had CAD, 24% had LVH, 6% had had a stroke, and 7% had PVD. In patients without microalbuminuria, all of these rates were significantly lower: 22%, 14%, 4%, and 5%, respectively (p < 0.001). Furthermore, in patients with CAD, LVH, stroke, or PVD, microalbuminuria was significantly greater than in patients who did not have these complications (p < 0.001). A multiple stepwise regression analysis with microalbuminuria as the dependent variable showed microalbuminuria depended on the following factors, in order of importance: systolic blood pressure, retinopathy, CAD, diastolic blood pressure, and LVH (all p < 0.0001). A multiple stepwise regression analysis with each of the concomitant diseases as the dependent variable showed that microalbuminuria was an independent and significant variable for each of the conditions. The patients were assigned to monotherapy with either angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium antagonists, or diuretics. All of the drugs reduced microalbuminuria, although the beta-blocker carvedilol was superior (p < 0.05). We concluded microalbuminuria is an important risk factor that can be influenced by treatment.

Albuminuria↗
PubMed1999

Regulation of MAC-1 (CD11b/CD18) expression on circulating granulocytes in endurance runners.

PURPOSE: We tested the hypothesis that degranulation of granulocytes and upregulation of the granulocyte integrin MA-1 (CD11b/CD18) are related to exercise duration and/or intensity. We also investigated whether or not the expression of MAC-1 would be influenced by body temperature or dehydration. Moreover, we tested the hypothesis that changes in leukocyte counts and changes in MAC1 expression with endurance exercise are independently regulated. METHODS: In eight amateur runners, MAC-1 (CD11b/CD18) surface expression on granulocytes was determined by fluorescent antibody cell sorting, before and after an incremental maximal treadmill test, a moderate 3-h run, and a competitive marathon race. RESULTS: Expression CD11b on granulocytes was increased by 10+/-9.6% (P < 0.05) after the maximal treadmill test and by 84+/-76% (P < 0.01) after the marathon run. There was no change in CD11b expression after the moderate 3-h run. CD18 expression was not significantly changed after any of the exercise protocols. CONCLUSION: Expression of CD11b on granulocytes is increased with intense endurance exercise, either incremental maximal treadmill testing or competitive marathon running, but not in moderate endurance training. Thus, exhaustive exercise may be one mechanism for the upregulation of integrin adhesive receptors on granulocytes. This phenomenon could be in part responsible for increased adhesion of granulocytes to endothelial cells and could facilitate tissue infiltration after endurance exercise.

Adult↗
PubMed1999

The proliferative effect of vascular endothelial growth factor requires protein kinase C-alpha and protein kinase C-zeta.

The heparin-binding protein vascular endothelial growth factor (VEGF) is a highly specific growth factor for endothelial cells. VEGF binds to specific tyrosine kinase receptors, which mediate intracellular signaling. We investigated 2 hypotheses: (1) VEGF affects intracellular calcium [Ca2+]i regulation and [Ca2+]i-dependent messenger systems; and (2) these mechanisms are important for VEGF's proliferative effects. [Ca2+]i was measured in human umbilical vein endothelial cells using fura-2 and fluo-3. Protein kinase C (PKC) activity was measured by histone-like pseudosubstrate phosphorylation. PKC isoform distribution was observed with confocal microscopy and Western blot. Inhibition of PKC isoforms was assessed by specific antisense oligonucleotides (ODN) for the PKC isoforms. VEGF (10 ng/mL) induced a transient increase in [Ca2+]i followed by a sustained elevation. The sustained [Ca2+]i plateau was abolished by EGTA. Pertussis toxin also abolished the plateau phase, whereas the initial peak was not affected. The PKC isoforms alpha, delta, epsilon, and zeta were identified in endothelial cells. VEGF induced a translocation of PKC-alpha and PKC-zeta toward the nucleus and the perinuclear area, whereas cellular distribution of PKC-delta and PKC-epsilon was not influenced. Cell exposure to TPA led to a down-regulation of PKC-alpha and reduced the proliferative effect of VEGF. VEGF-induced endothelial cell proliferation also was reduced by the PKC inhibitors staurosporine and calphostin C. Specific down-regulation of PKC-alpha and PKC-zeta with antisense ODN reduced the proliferative effect of VEGF significantly. Our data show that VEGF induces initial and sustained Ca2+ influx. VEGF leads to the translocation of the [Ca2+]i-sensitive PKC isoform alpha and the atypical PKC isoform zeta. Antisense ODN for these PKC isoforms block VEGF-induced proliferation. These findings suggest that PKC isoforms alpha and zeta are important for VEGF's angiogenic effects.

Calcium↗
PubMed1999

Peroxisome proliferator-activated receptor gamma gene locus is related to body mass index and lipid values in healthy nonobese subjects.

The peroxisome proliferator-activated receptor gamma (PPARgamma) gene has been implicated in morbid obesity and is important to lipid and carbohydrate metabolism. However, the relevance of gene variations in healthy nonobese subjects has not been defined. We recruited monozygotic and dizygotic healthy nonobese twin subjects to test the hypothesis that the PPARgamma gene is important to body mass index and lipid concentrations in healthy nonobese subjects. Both linkage and association strategies were used in the same dizygotic twins. The PPARgamma gene locus was linked (P<0.01) to high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and body mass index as quantitative traits. A biallelic variant in the PPARgamma gene was associated with high-density lipoprotein cholesterol and body mass index (P<0.05). We also looked for linkage between the same variables and the retinoic X receptor gene locus. This locus was linked to total and low-density lipoprotein cholesterol as well as triglycerides. We conclude that the PPARgamma gene is highly relevant to lipid metabolism and body mass index, not only in the morbidly obese but also in healthy nonobese subjects. The same appears to be true for its binding partner. Sequencing these genes in twins would serve to identify gene variations contributing to body mass index and lipid concentrations in healthy nonobese subjects.

Adult↗