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Biomedical subjects

F C Luft

Publications and source records attributed to F C Luft.

At least 289 records · Page 16Linked to original sources
PubMed1997

The role of the general clinical research center in promoting patient-oriented research into the mechanisms of disease.

Patient- and proband-oriented research (POR) into the mechanisms of disease has been most successful in the United States over the past 50 years. To foster POR in universities across the country the National Institutes of Health (NIH) instituted 5-year renewable competitive grants for the establishment of General Clinical Research Centers (GCRCs). The number of GCRCs grew from 5 in 1960 to a maximum of 93 in 1969. Currently 74 GCRCs are in operation at 47 of more than 120 medical schools in the United States. They range in size from 4 to 30 beds, with an average of about 10. Each GCRC supports a Program Director, diet kitchens, core laboratory, biostatistical and computing support, nursing staff, and an administrative assistant. The GCRC is available to enable and facilitate POR of faculty investigators based at the parent university. Investigators make applications to the GCRC for support of a given project, the project is evaluated by the GCRC institutional advisory committee and ethics committee, and if found acceptable the resources of the GCRC including bed space, nursing support, laboratory, and statistical capabilities are made available. The GCRC grant supplies the university with overhead support, but more importantly GCRC-supported investigators regularly bring in grant support from NIH far and above that provided by the GCRC grant itself. NIH also provide for research fellowships through the GCRC, including salary support to encourage young physicians to participate in basic POR. These grants are competitive and last for a 3-year funding cycle. The costs of the GCRCs in terms of beds per day are less than those of the Clinical Center at NIH and the overall scientific productivity has been greater. Further, the prestige of having a GCRC and the resources a GCRC provides, have been a major impetus for university support. Despite general problems in terms of recruiting young physicians to careers in basic POR, the GCRC has been a stellar success scientifically, fiscally, and also in facilitating the separation between patient care costs and those engendered by research.

Academies and Institutes↗
PubMed1996

Anti-endothelial cell antibodies in Takayasu arteritis.

BACKGROUND: Although a specific etiology for Takayasu arteritis has not been found, the bulk of evidence favors an autoimmune mechanism. We examined the sera of 19 patients with Takayasu arteritis for antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), anti-DNA antibodies, antibodies to extractable nuclear antigens (ENA), anti-Ro anti-bodies, anticardiolipin antibodies, circulating immune complexes, and anti-endothelial cell antibodies (AECA). METHODS AND RESULTS: We used enzyme-linked immunoassays, immunofluorescence, counterimmunoelectrophoresis, fluorescent-activated cell sorter (FACS) analysis, and confocal microscopy. We found that although no patient had positive ANCA, ANA, anti-DNA antibodies, ENA antibodies, anti-Ro antibodies, or anticardiolipin antibodies, 18 of the 19 patients had AECA. The AECA titers of the patients were 2561 +/- 1458 compared with 126 +/- 15 arbitrary units in a normal group of control subjects (P < .001). To verify the specificity of AECA, we performed cytofluorimetry on human endothelial cells with the sera from patients and control subjects. Two entirely separate patterns of fluorescence intensity were identified. We next performed immunocytochemistry and confocal microscopy with human endothelial cells subjected to patients' sera and to sera from normal subjects. The cells subjected to sera from patients with Takayasu arteritis demonstrated specific immunofluorescent staining of their plasma membrane and cytosol. CONCLUSIONS: AECA are frequently present in patients with Takayasu arteritis. They may play a role in the pathogenesis. Furthermore, they may be useful as an additional diagnostic tool.

Adolescent↗
PubMed1996

Angiotensin-converting enzyme and heart chymase gene polymorphisms in hypertrophic cardiomyopathy.

We examined the insertion/deletion polymorphism in the angiotensin-converting enzyme gene and identified polymorphisms in the heart chymase gene to test the hypothesis that these angiotensin II-producing enzymes are associated with a monogenic cardiac disease (50 patients and 50 control subjects) as a model of cardiac hypertrophy. We found that the angiotensin-converting enzyme DD genotype was present more often in patients than in control subjects and identified a possible interaction with 1 of the chymase polymorphisms.

Adult↗
PubMed1996

Familial and genetic influences on heart rate variability.

The authors tested the hypothesis of a genetic influence on heart rate variability (HRV). This genetic influence was assessed in 62, twin pairs (30 monozygotic, 32 dizygotic). From all twins, long-term electrocardiographic records were obtained, edited, and analyzed. Heart rate variability analysis was performed on the basis of parameters from time-domain, frequency-domain, and nonlinear dynamics. First, the parameter distances between the two twins of a pair and between one of the two and a third randomly selected person of another age-matched twin pair (ST1) were compared. Second, the parameter distances between the two twins and the averaged parameter distances of these two twins to all other age-matched persons (ST2) were compared. Finally, the averaged differences in parameter values between monozygotic and dizygotic age-matched twin pairs were compared. For statistical analysis, the nonparametric Wilcoxon's matched-pair signed rank test and parametric t-test for paired samples were used. Twin pairs show a significant lower difference in parameter values than other randomly selected and age-matched couples (P < .001 in ST1 and ST2). This reflects a considerable familial influence. Most parameters of the time-domain, none of the frequency-domain, and half of the nonlinear dynamics show significant differences between twin pairs and nontwin pairs. As a result of the comparison between monozygotic and dizygotic twin pairs, a significant lower parameter difference in the monozygotic pairs (P < .05) is found. These results suggest that there is a genetic component in heart rate generation and HRV, in addition to family environmental influences. Analysis of HRV might become a useful method in phenotyping severe genetic changes in cardiovascular diseases.

Adult↗
PubMed1996

Disease activity and autoantibodies to endothelial cells in patients with Wegener's granulomatosis.

The purpose of this study was to assess the utility of antiendothelial cell antibodies (AECAs) in patients with active and inactive Wegener's granulomatosis. We studied 32 patients with Wegener's disease (clinical criteria and biopsy, as well as titers of antineutrophil cytoplasmic antibodies with a cytoplasmic pattern [cANCA]) over 4 years and compared their AECA values with those of 24 normal subjects similar in age and gender distribution, as well as with those of patients with chronic glomerulonephritis with or without dialysis and of patients with severe arteriosclerosis. We measured AECAs, cANCAs, C-reactive protein, erythrocyte sedimentation rate, proteinuria, and renal function in patients with active disease or in patients reactivating their disease. A time course with repeated AECAs was conducted over 27 months in 24 patients. The AECAs were measured with an enzyme-linked immunosorbent assay. The specificity was verified with immunofluorescent confocal microscopy, which showed the AECA epitopes to be within the cytoplasm of endothelial cells. Elevated AECA titers were found in all patients with active disease, not all of whom had positive cANCAs. Although elevated AECAs were also found in some patients with inactive disease, normal AECA values were seen only in patients with inactive disease. Patients with active disease entering remission showed a decrease in AECA titers, while patients entering a relapse increased their AECA titers. We conclude that AECAs are present in patients with Wegener's granulomatosis. To our knowledge, these are the first serial AECA observations. Our data suggest that AECAs are correlated with disease activity. Antiendothelial cell antibody values in the normal range strongly support remission. These findings may be of clinical utility in distinguishing relapse from concomitant illness.

Autoantibodies↗
PubMed1996

Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.

The purpose of this study was to assess the value of electron beam computed tomography in the detection of cardiac calcifications in coronaries and valves of dialysis patients and to determine the rate at which calcification progresses. Forty-nine chronic hemodialysis patients aged 28 to 74 years were compared with 102 non-dialysis patients aged 32 to 73 years with documented or suspected coronary artery disease, all of whom underwent coronary angiography. We used high-resolution electron beam computed tomography scanning to make 30 axial slices with a distance of 3 mm between each slice. The number of calcifications, the surface area, and the average and highest density values were measured. We calculated a quantitative coronary artery calcium score and assessed calcification of mitral and aortic valves. In dialysis patients, the measurements were repeated after 12 months. The coronary artery calcium score was from 2.5-fold to fivefold higher in the dialysis patients than in the non-dialysis patients. Hypertensive dialysis patients had higher calcium scores than non-hypertensive dialysis patients (P < 0.05). A stepwise, multiple regression analysis confirmed the importance of age and hypertension. No correlation between calcium, phosphate, or parathyroid hormone values and the coronary calcium score was identified; however, the calcium score was inversely correlated with bone mass in the dialysis patients (r = 0.47, P < 0.05). The mitral valve was calcified in 59% of dialysis patients, while the aortic valve was calcified in 55%. The coronary artery calcium score was correlated with aortic valvular, but not mitral valvular calcification. A repeat examination of the dialysis patients at an interval of 1 year showed a disturbing tendency for progression. Our data under-score the frequency and severity of coronary and valvular calcifications in dialysis patients, and illustrate the rapid progression of this calcification. Finally, they draw attention to hypertension as an important risk factor in this process.

Adult↗
PubMed1996

Antisense oligonucleotides for ICAM-1 attenuate reperfusion injury and renal failure in the rat.

The leukocyte adhesion molecule ICAM-1 is implicated in ischemic renal reperfusion injury. We tested the utility of an ICAM-1 antisense oligodeoxyribonucleotide (ODN) with lipofectin, six hours prior to 30 minutes of bilateral renal ischemia in the rat. We measured ICAM-1 expression by immunohistochemistry and Western blot. Our antisense ODN showed a specific ICAM-1 surface expression inhibition in vitro. We then assessed ICAM-1 expression, leukocyte infiltration, serum creatinine, serum urea concentration, and renal histology in rats subjected to renal ischemia and controls. Serum creatinine and urea concentrations 12 and 24 hours post-ischemia were increased in saline treated and reverse ODN treated rats, compared to antisense ODN treated or sham operated rats (P < 0.05). Western blotting showed decreased ICAM-1 protein in antisense ODN-treated kidneys, compared to reverse ODN treated and saline treated ischemic controls (P < 0.05). Antisense ODN also ameliorated the ischemia-induced infiltration of granulocytes and macrophages (P < 0.05), and resulted in less cortical renal damage as assessed by a quantitative pathological grading scale (P < 0.05), compared to reverse ODN or saline treatment. Thus, antisense ODN for ICAM-1 protected the kidney against ischemic renal failure. The clinical applicability of these findings extends beyond ischemic acute renal failure.

Acute Kidney Injury↗
PubMed1996

Signal transduction of erythropoietin in endothelial cells.

Erythropoietin (EPO) induces endothelin expression in endothelial cells (EC) and has angiogenic effects. We investigated the intracellular signal transduction of EPO in EC and tested the hypothesis that the proliferative effects of EPO may be mediated by cytosolic calcium, changes in intracellular pH, or tyrosine phosphorylation. Cytosolic calcium and pH were measured with fura-2 and BCECF. Protein phosphorylation was assessed with 32P-labeled EC and two-dimensional (2D) gel chromatography. Tyrosine phosphorylation was measured using specific antityrosine antibodies and confocal microscopy. Proliferation was measured by thymidine incorporation and cell count. No effects of EPO on cytosolic calcium and pH were observed. In contrast, erythropoietin increased phosphorylation of 94, 70, 42, 40, 29 and 25 kDa proteins at five minutes and 60 minutes. Most of the early proteins were tyrosine phosphorylated. Confocal microscopy showed cytosolic as well as membrane-bound tyrosine phosphorylation in resting cells and an EPO-induced translocation of immunoreactivity to the nucleus. Immunostaining for the transcription factor STAT-5 showed that EPO induced a nuclear translocation of STAT-5. EPO 0.5, 2, and 4 U/ml increased proliferation, an effect that was prevented by incubation with the tyrosine kinase inhibitor genistein. We conclude that EPO induces proliferation in EC initially via tyrosine phosphorylation of six distinct proteins, and that the phosphorylation and nuclear translocation of the transcription factor STAT-5 is important for the effects of EPO on EC.

Biological Transport, Active↗
PubMed1996

Oligonucleotide ligation assay (OLA) for the diagnosis of familial hypercholesterolemia.

More than half of all deaths in Western society are related to arteriosclerotic cardiovascular diseases. Inherited disturbances in the low-density-lipoprotein (LDL) receptor and similar lipid-related defects account for the majority of these deaths. Testing procedures thus far rely on total cholesterol, LDL cholesterol, high-density-lipoprotein cholesterol, and triglyceride determinations. These tests are not able to provide any genetic information. We have developed an oligonucleotide ligation assay (OLA) that enables us to screen for high-risk individuals by testing for 19 common mutations in the LDL receptor and the apolipoprotein B genes using an automated genotyping-based two-step protocol. The novel OLA uses oligomeric pentaethyleneoxide mobility modifiers. The automated test will be useful in screening large populations for genetic data to distinguish relative from absolute risk, as well as for cost-effective familial analysis.

Apolipoproteins B↗
PubMed1996

Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12.

Finding genes that cause human hypertension is not straightforward, since the determinants of blood pressure in primary hypertension are multifactorial. One approach to identifying relevant genes is to elucidate rare forms of monogenic hypertension. A relevant mutation may provide a rational starting point from which to analyse the pathophysiology of a condition affecting 20% of the world's population. In 1973 a family with autosomal dominantly inherited brachydactyly and severe hypertension, where the two traits cosegregated completely, was described. We have now re-examined this kindred, and localized the hypertension and brachydactyly locus to chromosome 12p in a region defined by markers D12S364 and D12S87. As the renin-angiotensin-system and sympathetic nervous system respond normally in this form of hypertension, the condition resembles essential hypertension. This feature distinguishes this form of hypertension from glucocorticoid remediable aldosteronism and Liddle's syndrome, which are salt-sensitive forms of monogenic hypertension with very low plasma renin activity. We suggest that identification of the gene involved in hypertension and brachydactyly and its mutation will be of great relevance in elucidating new mechanisms leading to blood pressure elevation.

Adult↗
PubMed1996

Microalbuminuria screening by reagent strip predicts cardiovascular risk in hypertension.

OBJECTIVE: We tested the hypothesis that qualitative microalbuminuria (MAU) screening in a practice setting would identify non-diabetic hypertensive patients at high risk of developing cardiovascular disease. DESIGN: We enrolled general practitioners throughout Germany, who obtained histories, physical examinations, and routine laboratory values as clinically indicated on treated or non-treated hypertensive, non-diabetic patients. MAU was measured with a albumin-sensitive, immunoassay test strip. We studied 11 343 non-diabetic hypertensive patients. RESULTS: The patients' mean age was 57 years, 51% were men and mean hypertension duration was 69 months. Twenty-five per cent had coronary artery disease, 17% had left ventricular hypertrophy, 5% had had a stroke, and 6% had peripheral vascular disease. MAU was present in 32% of men and 28% of women (P < 0.05). In patients with MAU, 31% had coronary artery disease, 24% had left ventricular hypertrophy, 6% had had a stroke, and 7% had peripheral vascular disease. In patients without MAU, these rates were 22%, 14%, 4%, and 5% respectively: lower in every category (P < 0.001). Further, in patients with coronary artery disease, left ventricular hypertrophy, stroke, and peripheral vascular disease, MAU was significantly greater than in patients who did not have these complications (P < 0.001). MAU increased with age, severity of hypertension and duration of hypertension, was associated with higher plasma creatinine values, and was more common in patients with hyperlipidemia (P < 0.05). CONCLUSION: On the basis of our survey, we conclude that qualitative MAU determinations identify hypertensive patients with particular cardiovascular risk in a practice setting.

Aged↗
PubMed1996

Genetic influences on blood pressure with the cold-pressor test: a twin study.

OBJECTIVES: To determine the genetic and environmental contributions to resting blood pressure, the level of blood pressure during the cold-pressor test and the increase in blood pressure with the cold-pressor test in an adult cohort of normotensive twins. DESIGN AND METHODS: Ninety-one monozygotic and 41 dizygotic normal twin pairs were recruited by advertisement. The mean age was 34 +/- 14 years (mean +/- SD). Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were measured continuously at the finger (using a Finapres device) and verified at the upper arm oscillometrically (using a Dinamap device) every minute. The cold-pressor test was conducted by immersing the non-dominant hand into cold (< 4 degrees C) water for 2 min. Statistical analysis was performed by using the SPSS program; parameters of the quantitative genetic models were estimated by path-analysis techniques using the LISREL 8 program. RESULTS: Heritability estimates of additive genetic effects were statistically significant for SBP and DBP but not for heart rate during rest and during the cold-pressor test. Furthermore, the path analysis indicated shared as well as specific genetic components both for the blood pressure level at rest and for that during the cold-pressor test. However, the genetic influences on the blood pressure level at rest and on the increase in blood pressure during the cold-pressor test (the blood pressure level during the cold-pressor test minus that during rest) were entirely independent of one another. CONCLUSIONS: A significant genetic covariation exists for SBP and DBP during rest and during the cold-pressor test, as well as a significant genetic variation that is specific to the cold-pressor stress condition. These findings suggest that different genes or sets of genes contribute to blood pressure regulation during rest and to blood pressure reactivity to cold-pressor stress.

Adult↗