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Biomedical subjects

Jürgen Graf

Publications and source records attributed to Jürgen Graf.

At least 19 recordsLinked to original sources
PubMed2007

Endotoxin hypersensitivity in chronic heart failure.

BACKGROUND: Raised concentrations of endotoxin (lipopolysaccharides, LPS) have been demonstrated in patients with chronic heart failure (CHF). Tolerance of monocytes to LPS can be induced by negative feedback mechanism through LPS itself, resulting in a downregulation of cytokine response to LPS challenge. As endotoxin desensitization has also been suggested for CHF, we investigated the response to LPS challenge in CHF patients. METHODS: We prospectively studied 100 patients with CHF (62 +/- 13 years) and 21 controls (58 +/- 10 years, LVEF 60 +/- 3%). HLA-DR expression and TNFalpha generation of monocytes after ex vivo stimulation by LPS (stimulation with LPS 50 and 500 pg/ml) were determined. 46 CHF patients were in NYHA class II (LVEF 29 +/- 8%) and 54 in NYHA class III (LVEF 27 +/- 7%). RESULTS: HLA-DR expression in controls (25,837 +/- 7915 ABS/cell) was comparable to CHF NYHA II patients (23,720 +/- 8488 ABS/cell, n.s.), but lower in patients classified NYHA III (20,327 +/- 5073 ABS/cell, p < 0.01). Stimulated TNFalpha production ex vivo was higher in CHF NYHA III (LPS 50: 437 +/- 284; LPS 500: 946 +/- 500 pg/ml, each p < 0.05) and CHF NYHA II (LPS 50: 397 +/- 277; LPS 500: 933 +/- 483 pg/ml, each p < 0.05) compared to controls (LPS 50: 315 +/- 134; LPS 500: 715 +/- 339 pg/ml). CONCLUSIONS: In chronic heart failure TNFalpha generation capacity increases while HLA-DR expression decreases compared to controls. Thus patients with CHF display enhanced susceptibility to inflammatory stimuli.

Aged↗
PubMed2006

[Quality assurance and guidelines in intensive care medicine].

Although validated instruments are readily available for structured outcome assessment, this has been rarely employed in German intensive care units yet. Analysis of the effectiveness or efficiency of intensive care medicine without systematic assessment of outcomes and underlying structures and processes is impossible. Detailed knowledge of outcomes is mandatory, when continuous quality improvement is warranted. In the future, German intensive care units should implement regular outcome assessment to allow objective comparisons considering the particular case mix. Evidence-based guidelines may facilitate both, development of objectives, and assessment of outcomes. Owing to the advancement of medicine regular updates of guidelines are mandatory. Moreover, targets for the quality assessment need to be adjusted accordingly. This finally leads toward a continuous quality improvement process.

Germany↗
PubMed2006

Changes of the hepatic proteome in murine models for toxically induced fibrogenesis and sclerosing cholangitis.

We investigated the changes in the hepatic proteome in murine models for toxic-induced fibrogenesis and sclerosing cholangitis. A comprehensive comparison of protein changes observed is made and the mechanistical basis of the expression changes is discussed. Hepatic fibrosis was induced by repetitive intraperitoneal CCl4 treatment of BALB/c mice or developed spontaneously in BALB/c-ATP-binding cassette, subfamily B, member 4 (Abcb4) knock out mice. Fibrosis was verified by a morphometric score and assessment of hydroxyproline content of liver tissue, respectively. The innovative difference in-gel electrophoresis (DIGE) technique was used to analyse protein expression levels of the mouse proteome. Results were confirmed by Western blotting and real-time RT-PCR. In CCl4-induced fibrosis 20 out of 40 and in BALB/c-Abcb4(-/-) mice 8 out of 28 differentially expressed proteins were identified utilizing DIGE. Only two proteins, selenium-binding protein (Sbp2) and carbonic anhydrase 3, have been unidirectionally expressed (i.e. down-regulated) in both models. Relevant differences in the pathogenesis of toxically induced liver fibrosis and sclerosing cholangitis exist. The only novel protein with regard to liver fibrosis depicting a unidirectional expression pattern in both animal models was Sbp2. An explicit protein function could not be clarified yet.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

The value of cardiopulmonary exercise testing and brain natriuretic peptide plasma levels in predicting the prognosis of patients with chronic heart failure.

BACKGROUND: A peak VO2 above 14 ml/min/kg at cardiopulmonary exercise testing and brain natriuretic peptide (BNP) levels is used to estimate survival in patients with chronic heart failure (CHF). Limited data, however, exist comparing the prognostic value of both markers simultaneously in patients with mild to moderate CHF. METHODS: We prospectively studied 85 consecutive patients (59+/-13 years, 63 men) with CHF (mean LVEF 26+/-6%). All patients underwent cardiopulmonary exercise testing with determination of peak VO2 and measurement of plasma BNP at rest. The incidence of cardiac decompensation and cardiac death was recorded in the follow-up. RESULTS: During a mean follow-up of 427+/-150 days, four deaths and ten cardiac decompensations occurred. Kaplan-Meier estimates of freedom from clinical events differed significantly for patients above and below the median BNP of 292 pg/ml and also for patients above and below a peak VO2 of 14 ml/min/kg (p<0.05 each). BNP and peak VO2 (area under the ROC 0.75 vs. 0.72) showed a comparable discrimination of CHF patients with adverse cardiac events. The prognostic information of BNP was at least as powerful as that derived from peak VO2. A BNP above 324 pg/ml was associated with a risk ratio of 8.8 for adverse cardiac events. CONCLUSIONS: In patients with mild to moderate CHF, BNP measurements appear to be an alternative to peak VO2 determined by cardiopulmonary exercise testing for the assessment of prognosis in CHF. BNP may facilitate the ambulatory management of patients with mild to moderate CHF since it is less expensive, less time-consuming, and free of procedural risk compared to exercise testing.

Journal Article↗
PubMed2006

Enhanced expression of MMP-7 and MMP-13 in inflammatory bowel disease: a precancerous potential?

Matrix metalloproteinases (MMPs) are responsible for the turnover and degradation of extracellular matrix. They play a crucial role in the growth and migration of colorectal carcinoma cells. Colorectal carcinomas are characterized by enhanced expression of MMP-2, MMP-9, MMP-7, and MMP-13. The aim of this study was to determine the expression levels of MMP-2, MMP-9, MMP-7, MMP-13, and MMP-14 and their specific inhibitor TIMP-1 in inflammatory bowel diseases and precancerous lesions of the colon, i.e., Crohn's disease and ulcerative colitis, and in adenomatous polyps (APs) for comparison. Biopsy samples of pathological and healthy tissue were obtained from 40 patients with inflammatory bowel disease (ulcerative colitis, n = 17; Crohn's disease, n = 23) and from 19 patients with APs. mRNA was measured by quantitative real-time polymerase chain reaction to study MMP and TIMP-1 gene expression in both pathological and normal mucosal specimens. For MMP-2, MMP-9, and TIMP-1, protein expression also was quantified with sandwich enzyme-linked immunosorbent assay. In biopsy specimens of Crohn's disease and ulcerative colitis, significantly increased levels of MMP-2, MMP-7, and MMP-13 mRNA were found. MMP-2 and MMP-9 showed enhanced secretion on the protein level. AP revealed an increased transcription of MMP-7 and MMP-13 genes. MMP-14 mRNA was decreased in APs. MMPs, especially MMP-7 and MMP-13, which are expressed primarily on the tumor cell surface, are elevated in inflammatory bowel disease, which may have more chance to evolve into malignancy than normal tissue. In APs, increased expression of MMP-7 and MMP-13 may serve as an early indicator for colorectal carcinogenesis.

Adenomatous Polyps↗
PubMed2005

Experimental support for the "E pathway hypothesis" of coupled transmembrane e- and H+ transfer in dihemic quinol:fumarate reductase.

Reconciliation of apparently contradictory experimental results obtained on the quinol:fumarate reductase, a diheme-containing respiratory membrane protein complex from Wolinella succinogenes, was previously obtained by the proposal of the so-called "E pathway hypothesis." According to this hypothesis, transmembrane electron transfer via the heme groups is strictly coupled to cotransfer of protons via a transiently established pathway thought to contain the side chain of residue Glu-C180 as the most prominent component. Here we demonstrate that, after replacement of Glu-C180 with Gln or Ile by site-directed mutagenesis, the resulting mutants are unable to grow on fumarate, and the membrane-bound variant enzymes lack quinol oxidation activity. Upon solubilization, however, the purified enzymes display approximately 1/10 of the specific quinol oxidation activity of the wild-type enzyme and unchanged quinol Michaelis constants, K(m). The refined x-ray crystal structures at 2.19 A and 2.76 A resolution, respectively, rule out major structural changes to account for these experimental observations. Changes in the oxidation-reduction heme midpoint potential allow the conclusion that deprotonation of Glu-C180 in the wild-type enzyme facilitates the reoxidation of the reduced high-potential heme. Comparison of solvent isotope effects indicates that a rate-limiting proton transfer step in the wild-type enzyme is lost in the Glu-C180 --> Gln variant. The results provide experimental evidence for the validity of the E pathway hypothesis and for a crucial functional role of Glu-C180.

Cell Membrane↗
PubMed2005

Selective increase of cardiac neuronal sympathetic tone: a catheter-based access to modulate left ventricular contractility.

OBJECTIVES: This study was designed to develop a technique to selectively increase the sympathetic tone to the heart by cardiac sympathetic nerve stimulation (SNS). BACKGROUND: Access to the cardiac sympathetic neurons may allow modulating the adrenergic tone of the heart while avoiding systemic side effects. METHODS: Cardiac sympathetic nerves course within neural sleeves along the subclavian artery. Because of this proximity, transvascular SNS was attempted with electrode catheters inside the subclavian artery in 16 pigs. RESULTS: Right/left (R-/L-) SNS (20 Hz) during ventricular pacing at 200/min evoked a >100% increase of left ventricular systolic pressure (baseline: 51 +/- 1 mm Hg; L-SNS: 118 +/- 26 mm Hg; R-SNS: 116 +/- 33 mm Hg; p < 0.001) while systemic vascular resistance remained unchanged. There was a sigmoid dose-response curve with rapid on- and offset of the effect during SNS initiation/cessation. Positive inotropic effects persisted for 12 h of continued SNS (n = 4). Besides positive dromotropic effects, L-SNS/R-SNS yielded a 41% and 77% sinus rate increase, respectively. CONCLUSIONS: The neural adrenergic tone to the heart can be selectively increased by catheter stimulation of cardiac efferent sympathetic nerves.

Animals↗
PubMed2005

Statin treatment after onset of sepsis in a murine model improves survival.

BACKGROUND: HMG-CoA-reductase inhibitors have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering. We have recently demonstrated that pretreatment with simvastatin profoundly improves survival in a cecal ligation and perforation (CLP) model of sepsis. Here, we studied whether treatment with simvastatin after onset of sepsis-induced hemodynamic alterations is beneficial and whether prolonged survival can also be achieved with other statins. METHODS AND RESULTS: Mice were rendered septic by CLP. At 6 hours after sepsis induction, when profound hemodynamic alterations were manifest, treatment with atorvastatin, fluvastatin, pravastatin, simvastatin, or placebo was initiated. Except for fluvastatin (27+/-2.3 hours), survival time was extended from 23+/-1.2 hours for placebo-treated mice to 37+/-3.6 hours for simvastatin-treated, to 40+/-4.2 hours for atorvastatin-treated, and to 39+/-3.9 hours for pravastatin-treated mice. This profound improvement is based on the preservation of cardiac function and hemodynamic status in statin-treated animals, both of which are severely impaired in untreated CLP mice. As underlying mechanisms, improved susceptibility to endothelial nitric oxide synthase stimulation and reduced endothelial adhesion of leukocytes could be demonstrated after statin treatment. CONCLUSIONS: Well established in the treatment of lipid disorders and coronary artery disease, statins harbor the additional and novel potential of effective sepsis treatment. This benefit extends to several but not all statins tested.

Animals↗
PubMed2005

An expandable percutaneous catheter pump for left ventricular support: proof of concept.

OBJECTIVES: We sought to evaluate the performance of a newly designed percutaneous catheter with expandable pump. BACKGROUND: The device was designed as a percutaneously insertable temporary support system for patients with acute left ventricular failure. METHODS: The pump catheter (introduction diameter 9-F) is positioned in the left ventricle. The rotor is driven by an external motor through a flexible drive shaft. A model circuit was used to assess pump performance, hemolysis tests, and particle image velocimetry. The feasibility of the catheter placement and pump operation were examined in 12 anesthetized sheep. Cardiogenic shock was induced in seven of the animals. Cardiac output (CO) and mean aortic blood pressure (MAP) were recorded before and during shock, and during catheter pump action. RESULTS: The catheter pump delivered a flow of 4.1 l/min at a differential pressure of 60 mm Hg. The average modified index of hemolysis was 11.6 (optimum, 1.8). Fluoroscopically and echocardiographically guided in vivo placement and deployment of the device were quick and uncomplicated. Under simulation of acute left ventricular failure (CO 43 +/- 22% and MAP 55 +/- 16% of the baseline value), the catheter pump significantly improved CO to 67 +/- 12% and MAP to 74 +/- 18%. Maximum in vivo duration of operation was 6 h (average, 3.1 +/- 1.4 h). These animal studies revealed: 1) no significant hemolysis (average plasma-free hemoglobin 26 +/- 4 mg/l after 3 h); 2) no thrombotic deposits at rotor or pump housing; and 3) no damage to the endocardium or aortic valve. CONCLUSIONS: A percutaneously insertable, expandable catheter pump is technically and clinically feasible. Our first experimental results are encouraging.

Animals↗
PubMed2005

Relationship of five inflammatory gene polymorphisms with morbidity and mortality in 533 patients admitted to an ICU.

BACKGROUND: The aim of this study was to analyze the association of polymorphisms of five candidate genes with the outcome of consecutive patients admitted to a medical ICU. MATERIALS AND METHODS: The study population was prospectively recruited. Inclusion criteria were admission to the ICU and written informed consent by the patients or their relatives. A total of 533 patients were recruited. The morbidity was assessed by SAPS II Score. Outcome data of in hospital mortality and length of ICU and hospital stay were obtained. Genotyping for genetic polymorphisms (CRP 1059, IL1B -511, CTGF -477, CCR2 64VI, IL6 -174) were performed by allele-specific fluorogenic oligonucleotide probes (TaqMan analysis). RESULTS: All of the investigated polymorphisms were not associated with an altered outcome. There was no difference in morbidity and ICU or in-hospital mortality (neither in cross tabs analysis nor in Kaplan Meier or Cox regression analysis including age, gender and diagnosis as covariates) between the different genotypes. CONCLUSIONS: Genotyping of the investigated polymorphism for risk stratification of patients admitted to ICU does not seem to be appropriated.

Aged↗
PubMed2005

CD14 gene -260 C/T polymorphism is associated with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) show inflammatory changes and elevated plasma levels of TNFalpha and endotoxins. However, the role of the CD14 C(-260)T polymorphism in patients with CHF is unclear. Therefore, we sought to determine whether the C=>T promoter polymorphism (position -260) of the CD 14 gene is associated with a higher risk for the development of CHF. METHODS: We studied 100 patients with CHF (mean age 62+/-3 years, LVEF 28+/-8%) and 100 healthy controls (59+/-10 years, p=NS; LVEF 60+/-4%, p<0.05). CD14 genotyping was performed using a PCR-RFLP technique. RESULTS: Among CHF patients, the frequency of the T allele was lower (38% vs. 48%, p<0.05) and the frequency of the C allele higher (62 % vs. 52 %, p<0.05) than among controls. The distribution of CD14 genotypes in healthy controls was as follows: CC 32%, CT 40%, and TT 28%. Among CHF patients, the TT genotype was significantly underrepresented compared to controls: CC 38%, CT 48%, and TT 14% (p<0.05). CONCLUSIONS: The C -260T polymorphism of CD14 seems to influence the susceptibility for the development of CHF. The T allele is less frequent among CHF patients than among controls. The TT genotype could be a new genetic protective factor against the development of CHF.

Journal Article↗
PubMed2005

Urotensin II in patients with chronic heart failure.

BACKGROUND: Human Urotensin II (hU-II) is the most potent vasoconstrictor known to date. HU-II receptors are predominant in the human heart and arterial vessels, suggesting hU-II to be of importance as a cardiovascular mediator. METHODS: We studied 32 consecutive patients (60+/-12 years) with chronic heart failure (CHF) and 10 control subjects (54+/-12 years, n.s.) with cardiopulmonary exercise testing. Blood samples for the measurement of plasma hU-II and big-endothelin-1 (big-ET1) were obtained at rest and at peak exercise. RESULTS: Peak VO(2) was significantly higher in controls than in CHF patients (19.8+/-3.8 vs. 14.7+/-3.6 ml min(-1) kg(-1), P<0.001). Big-ET1 levels were increased in CHF compared to controls at rest (2.8+/-1.8 vs. 1.7+/-0.1 fmol/ml, P<0.01) and at peak exercise (2.7+/-1.7 vs. 1.6+/-0.2 fmol/ml, P<0.005). HU-II concentrations were comparable in patients with CHF and controls at rest (2990+/-1104 vs. 3290+/-508 pg/ml, n.s.) and peak exercise (3063+/-1185 vs. 3213+/-1188 pg/ml, n.s.). Resting hU-II levels demonstrated no correlation with peak VO(2) in controls or CHF patients. CONCLUSIONS: The measurement of circulating plasma levels of hU-II does not seem to be very helpful in studying the effects of hU-II in human cardiovascular regulation. A local paracrine or autocrine mediator effect of hU-II in CHF is possible.

Aged↗
PubMed2005

Five-year survival, quality of life, and individual costs of 303 consecutive medical intensive care patients--a cost-utility analysis.

OBJECTIVE: To assess long-term survival, health-related quality of life, and associated costs 5 yrs after discharge from a medical intensive care unit. DESIGN: Prospective cohort study. SETTING: Medical intensive care unit of a German university hospital. PATIENTS: Three hundred and three consecutive patients with predominantly cardiovascular and pulmonary disorders admitted between November 1997 and February 1998 with an intensive care unit length of stay >24 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic data, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment, simplified Therapeutic Intervention Scoring System, and individual intensive care unit and hospital costs were prospectively recorded. Primary outcomes included 5-yr survival, functional status, health-related quality of life (Medical Outcome Short Form, SF-36), effective costs per survivor, and costs per life year and per quality-adjusted life year gained. Of 303 patients, 44 (14.5%) died in the hospital. Among the remaining 259 patients, 190 (73%) survived the 5-yr follow up and 173 patients (91%) completed the questionnaire. Baseline demographics including gender, age, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment, simplified Therapeutic Intervention Scoring System, and admission diagnosis were similar between hospital and long-term survivors (p > .05 for all). The health status index of those patients surviving the 5-yr follow-up was 0.88, independent of patients' severity of illness. The average effective costs per survivor were 8.827 for intensive care unit costs and 14.130 for intensive care unit and hospital costs. Mean costs per life year and per quality-adjusted life year gained amounted to 19.330 and 21.922 , respectively. Increasing severity of illness was associated with higher costs. CONCLUSIONS: Considering the severity of illness and the patients' outcome, the costs associated with both life year and quality-adjusted life year gained were within generally accepted limits for other potentially life-saving treatments.

APACHE↗
PubMed2004

Endotoxin sensitivity and immune competence in chronic heart failure.

BACKGROUND: Raised concentrations of endotoxin (lipopolysaccharide, LPS) are found in patients with chronic heart failure (CHF). Tolerance of monocytes to LPS can be induced by LPS itself resulting in a downregulation of cytokine response to LPS challenge. This phenomenon of LPS desensitization has also been suggested for CHF. METHODS: We investigated whether CHF patients really show a desensitization to LPS stimuli at rest or after physical exercise, which was used as a model of limited inflammatory reaction. Thirty-five patients with CHF (59+/-12 years, 8 women) and 30 healthy control subjects were prospectively studied with cardiopulmonary exercise testing. At rest and directly after exercise blood samples were taken for the quantitative determination of HLA-DR expression of monocytes as a measure for immune competence and for the measurement of TNFalpha generation after ex vivo stimulation by LPS. RESULTS: HLA-DR expression was comparable in CHF patients and controls at rest as well as after exercise. TNFalpha production by LPS-stimulated monocytes ex vivo was higher in CHF patients compared to controls at rest and after exercise. CONCLUSIONS: Thus, our data are the first to show that patients with stable CHF show a cellular hypersensitivity to LPS with a higher TNFalpha generation capacity at rest and after exercise compared to controls. CHF patients seem to have a marked susceptibility to low inflammatory stimuli and no desensitization to LPS.

Female↗