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The positional distributions of stable isotopes in metabolites provide specific fingerprints of the pathways and fluxes that have occurred in the organisms under study. In particular, modern nuclear magnetic resonance (NMR) spectroscopy enables the detailed assignment of isotope patterns in natural products, for example, in metabolites obtained from labelling experiments using13C-enriched precursors, such as glucose, acetate or CO2. In this study, the transient13C-isotopologue composition of blood glucose from an adult human volunteer after intravenous supply of [U-13C6]glucose was determined by high-resolution13C NMR spectroscopy. The non-linear progression curves displaying the relative amounts of eight13C-glucose isotopologues reflected the contributions of glucose metabolism by glycolytic cycling, the pentose phosphate pathway and anaplerotic reactions involving the citric acid cycle. The pilot study suggests that the experimental setting can be useful in analysing under non-invasive conditions the impact of physiological and pharmacological constraints on glucose turnover in humans. [ABSTRACT FROM AUTHOR]

Background We investigated in a longitudinal, multicenter, cohort study whether combined lipid apheresis and lipid-lowering medication can reduce extremely high levels of lipoprotein(a) (Lp[a]) and thus prevent major adverse coronary events (MACE) more efficaciously than lipid-lowering medication alone. Methods Eligible patients had coronary artery disease and Lp(a) levels ≥ 2.14 µmol/l (95th percentile). All patients received lipid-lowering medications alone until maximally tolerated doses were no longer effective, followed by combined lipid apheresis and lipid-lowering medication. The rates of the primary outcome, MACE, were recorded for both periods. Results A total of 120 patients were included. The mean duration of lipid-lowering therapy alone was 5.6 ± 5.8 years, and that of apheresis was 5.0 ± 3.6 years. Median Lp(a) concentration was reduced from 4.00 µmol/1 to 1.07 µmol/l with apheresis treatment (P<0.0001); the corresponding mean annual MACE rate per patient was 1.056 versus 0.144 (P<0.0001). Conclusions Lowering of Lp(a) levels by apheresis was efficacious and safe, and we recommend this therapy for patients in whom maximally tolerated doses of medication alone have failed to control coronary artery disease-associated events. [ABSTRACT FROM AUTHOR]

Background/Aims: Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown to inhibit growth and to induce apoptosis in human hepatocellular carcinoma (HCC) cells. However, the potential benefit of pravastatin in HCC patients has still not been characterized, which prompted us to test the efficacy of pravastatin in patients with advanced HCC. Methods: We investigated prospectively a cohort of 183 HCC patients who had been selected for palliative treatment by transarterial chemoembolization (TACE). Fifty-two patients received TACE combined with pravastatin (20–40 mg/day) and 131 patients received chemoembolization alone. Six independent predictors of survival according to the Vienna survival model for HCC were equally distributed in both groups. Results: During the observation period of up to 5 years, 31 (23.7%) out of 131 patients treated by TACE alone and 19 (36.5%) out of 52 patients treated by TACE and pravastatin survived. Median survival was significantly longer in HCC patients treated by TACE and pravastatin (20.9 months, 95% CI 15.5–26.3, p = 0.003) than in HCC patients treated by TACE alone (12.0 months, 95% CI 10.3–13.7). Conclusion: Combined treatment of chemoembolization and pravastatin improves survival of patients with advanced HCC in comparison to patients receiving chemoembolization alone. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Nucleosomes, complexes of DNA and histone proteins, are released during cell death into the blood circulation. Elevated serum and plasma levels have been found in various forms of cancer, but also in autoimmune diseases and acute situations such as stroke, trauma, and during sepsis. Here, the clinical relevance of circulating nucleosomes for diagnosis, staging, prognosis, and therapeutic monitoring of cancer is reviewed. Several studies have shown that levels of nucleosomes are significantly higher in serum and plasma of cancer patients in comparison to healthy controls. However, because of elevations of nucleosome levels in patients with benign diseases relevant for differential diagnosis, they are not suitable for cancer diagnosis. Concerning tumor staging, nucleosome levels correlate with tumor stage and presence of metastases in gastrointestinal cancer, but not in other tumor types. Prognostic value of circulating nucleosomes is found in lung cancer in univariate analyses, but not in multivariate analyses. Circulating nucleosomes are most informative for the monitoring of cytotoxic therapy. Strongly decreasing levels are mainly found in patients with remission of disease, whereas constantly high or increasing values are associated with progressive disease during chemo- and radiotherapy. In addition, therapy outcome is already indicated by the nucleosomal course during the first week of chemo- and radiotherapy in patients with lung, pancreatic, and colorectal cancer as well as in hematologic malignancies. Despite their non-tumor-specificity, kinetics of nucleosomes are valuable markers for the early estimation of therapeutic efficacy and may be helpful to adapting early cancer therapy in the future. [ABSTRACT FROM AUTHOR]

The prognostic relevance of blood markers in cerebral stroke is still a matter of controversial debate. In sera of 63 patients, nucleosomes, neuronspecific enolase (NSE), S100 protein, and C-reactive protein (CRP) were determined daily during the first week after cerebral stroke. Infarction volume was quantified by CT or MRI and the clinical status by Barthel Index (BI) at admission, discharge, and after 12 months (prognosis). All markers were evaluated by univariate and multivariate analysis on their prognostic relevance. During observation time (12 months), three patients died and 33 reached complete recovery. Infarction volume, nucleosomes, NSE, S100, and CRP correlated significantly with clinical status at admission. The same markers except CRP and initial BI correlated with recovery after 12 months. Almost all patients with initial BI ‡ 50 reached complete recovery. In patients with initially severe defects (BI < 50), nucleosomes and S100, both at day 3, were found to be prognostically relevant. At 100%-specificity for non-recovery, only nucleosomes maintained their prognostic power (sensitivity 52.6%; p = 0.014), whereas S100 did not (sensitivity 16.7%; p = 0.25). In multivariate analysis, nucleosomes and BI at admission showed independent prognostic relevance (p = 0.039). Circulating nucleosomes and clinical scores provide independent prognostic information concerning the later outcome in patients with initially severe defects after stroke. [ABSTRACT FROM AUTHOR]

Abstract: Preeclampsia is a pregnancy-related hypertensive disease resulting in substantial maternal and neonatal morbidity and mortality. Until today there is no satisfactory treatment to stop disease progression except immediate delivery of the fetus. Heparin-mediated extracorporeal low density lipoprotein (LDL) precipitation (H.E.L.P.) apheresis removes simultaneously circulating LDL, lipoprotein(a) [Lp(a)], fibrinogen, C-reactive protein (CRP) and various proinflammatory and procoagulatory factors. This study was to test the feasibility of H.E.L.P. apheresis in preeclamptic patients and its potential effects on blood and placental markers of preeclampsia. We applied H.E.L.P. apheresis to nine preeclamptic patients and it was well tolerated. Their gestational ages could be continued by 17.7 (3–49) more days. Eight of the nine neonates did well during their neonatal stage. One infant died of late-onset sepsis. H.E.L.P. apheresis reduced significantly circulating levels of triglycerides, total and LDL-cholesterol, Lp(a), fibrinogen, hs-CRP, TNFα, sVCAM-1, E-selectin, lipopolysaccharide binding protein (LBP), homocysteine and plasma viscosity. We conclude that H.E.L.P. apheresis reduced maternal circulating levels of proinflammatory and coagulatory markers and plasma viscosity without overt maternal or neonatal clinical side effects. [Copyright &y& Elsevier]

Facing an era of promising new antitumor therapies, predictors of therapy response are needed for the individual management of treatment. In sera collected prospectively from 311 patients with advanced non-small cell lung cancer receiving first-line chemotherapy, changes in nucleosomal DNA fragments, cytokeratin-19 fragments (CYFRA 21–1), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and progastrin-releasing peptide (ProGRP) were investigated and correlated with therapy response. In univariate analysis, high levels, slower and incomplete decline in nucleosomal DNA, CYFRA 21–1, and CEA predicted poor outcome. DNA concentrations at day 8 of the first therapeutic cycle and CYFRA 21–1 before start of the second cycle were identified as best predictive variables. In multivariate analysis, they predicted progression with a specificity of 100% in 29% of the cases earlier than imaging techniques. Thus, nucleosomal DNA and CYFRA 21–1 specifically identify a subgroup of patients with insufficient therapy response at the early treatment phase and showed to be valuable for disease management. [ABSTRACT FROM AUTHOR]

Background: Nucleosomes are cell death products that are elevated in serum of patients with diseases that are associated with massive cell destruction. We investigated the kinetics of circulating nucleosomes after cerebral stroke and their correlation with the clinical status. Methods: In total, we analyzed nucleosomes by ELISA in sera of 63 patients with early stroke daily during the first week after onset. For correlation with the clinical pathology, patients were grouped into those with medium to slight functional impairment (Barthel Index BI ≥50) and those with severe functional impairment (BI <50). Results: Patients with BI ≥50 showed a continuous increase in nucleosomes until day 5 (median: 523 arbitrary units, AU) followed by a slow decline. In contrast, patients with BI <50 showed a steeper initial increase reaching a maximum already on day 3 (869 AU). Both, days after stroke (p < 0.001) and BI (p < 0.001), had a significant influence on nucleosome concentrations, respectively. Consistently, patients with BI <50 had a significantly larger area under the curve (AUC/day) of nucleosome values during the first week after stroke (800 AU) than patients with BI ≥50 (497 AU; p = 0.031). Concerning the infarction volume, nucleosomes showed significant correlations for the concentrations on day 3 (r = 0.43; p = 0.001) and for the area under the curve (r = 0.34; p = 0.016). Conclusion: Even if nucleosomes are nonspecific cell death markers, their release into serum after cerebral stroke correlates with the gross functional status as well as with the infarction volume and can be considered as biochemical correlative to the severity of stroke. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Elevated levels of nucleosomal DNA fragments can be detected in plasma and sera of patients with malignant diseases. Methods: We investigated the course of nucleosomal DNA, thymidine kinase, lactate dehydrogenase and leukocytes in sera of 25 patients with acute myeloid leukemia during the first cycle of induction chemotherapy and tested their power to distinguish between patients with complete remission and those with no remission. Results: Almost all patients showed strongly decreasing levels of nucleosomal DNA during the first week, in some cases after initial peaks. In overall analysis of variance, DNA levels could clearly distinguish between patients with complete remission, who had higher DNA values, and those with insufficient response (p = 0.017). The area under the curve of DNA values of days 2-4 after start of therapy (AUC 2-4) discriminated between both groups with a sensitivity of 56% at a specificity of 100%. Further, pretherapeutic levels and AUC 2-4 of nucleosomal DNA correlated significantly with blast reduction after 16 days. A tendency to higher levels in patients with complete response was also found for thymidine kinase, lactate dehydrogenase and leukocytes, however the difference did not reach the level of significance (p = 0.542, p = 0.260, and p = 0.144, respectively). Conclusion: Our results indicate that nucleosomal DNA fragments are valuable markers for the early prediction of therapeutic efficacy in patients with acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Background: Given the central importance of the microvasculature in heart transplant recipients, we investigated the possibility of increasing cardiac perfusion after reduction of low-density lipoprotein (LDL)-cholesterol, lipoprotein (a), C-reactive protein (CRP) and fibrinogen plasma levels after apheresis treatment in transplanted patients. Methods: Ten long-term heart transplant recipients were examined with positron emission tomography (PET) to measure myocardial perfusion before and after a single heparin-mediated extracorporeal LDL/fibrinogen precipitation (HELP)-apheresis treatment. PET studies were performed the mornings before and after the apheresis treatment. Myocardial blood flow at rest and during adenosine-induced hyperemia was measured using 13N-ammonia. Results: HELP-apheresis reduced the plasma levels of LDL-cholesterol, lipoprotein (a) and C-reactive protein by 48% (p < 0.001), fibrinogen by 42% (p = 0.02), plasma viscosity by 14% (p = 0.004) and erythrocyte aggregation by 28% (p < 0.02). Osmolality (<1%) and hematocrit (<2%) remained stable. A single apheresis treatment increased median corrected rest flow by 17.5% (p = 0.007) and median hyperemic flow by 27% (p = 0.02). Median coronary flow reserve increased by 8.1% (p = 0.09). Hyperemic flow after adenosine infusion increased plasma vascular endothelial growth factor levels only before HELP-apheresis (+60%), indicating better ischemic tolerance after apheresis (p = 0.01). Conclusions: Myocardial perfusion in transplanted hearts increases significantly after single HELP-apheresis treatment. The present study is only a proof of concept, providing complementary evidence to clinical long-term studies showing that cholesterol reduction either with statins and/or apheresis improves heart transplant outcome. [Copyright &y& Elsevier]

Abstract: Acute occlusion of a peripheral artery is a serious complication in peripheral arterial disease (PAD). Traditionally open surgical intervention in combination with antithrombotic therapy is the choice for treatment but the beneficial effects of both strategies are limited often by the patient''s situation and therapeutic side effects. Heparin-mediated extracorporeal low-density lipoprotein precipitation (H.E.L.P.) apheresis efficiently removes circulating atherogenic lipoproteins, fibrinogen and C-reactive proteins as well as various proinflammatory and procoagulatory factors. We first report H.E.L.P. apheresis treating a PAD patient suffering from repeated postoperative femoropopliteal bypass graft occlusion, first, intensively, followed by weekly intervals. Limb amputation was avoided and the patient is doing well now. Angiography revealed bypass graft remained patent half a year after operation. This case report might help to design the regime for preventing postoperative bypass occlusion in patients with hyperlipidemia or hyperfibrinogenemia. [Copyright &y& Elsevier]

In addition to hypercholesterolemia, proinflammatory and prothrombotic markers have been suggested to play an important role in atherogenesis. We examined whether heparin-mediated extracorporeal low-density lipoprotein precipitation (HELP) therapy modulates the circulating levels of proinflammatory and prothrombotic markers. Twenty-two coronary heart disease (CHD) patients undergoing regular HELP-apheresis (18 males, 4 females, mean age 57.3±10.9 years) were enrolled in this study. A single HELP therapy treatment significantly decreased the circulating levels of high sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin, lipopolysaccharide binding protein (LBP), endothelin-1 (ET-1), and monocyte chemoattractant protein-1 (MCP-1) on average by 67, 37, 24, 27, 24, and 15%, respectively. Prothrombotic factors including fibrinogen, tissue factor (TF), soluble CD40 ligand (sCD40L), and homocysteine were decreased by 66, 27, 16, and 22%, respectively. In accordance with previous studies HELP therapy reduced total cholesterol, low density lipoprotein (LDL) cholesterol, and Lp(a) mass by 50, 61, and 62%, respectively. Our data suggest that simultaneous reduction of proinflammatory and prothrombotic factors together with atherogenic lipoproteins by HELP-apheresis may contribute to improvement of endothelial dysfunction and thereby inhibit progression of atherosclerotic lesions and stabilize the existing plaque. [Copyright &y& Elsevier]

Various radical measures for the treatment of severe hypercholesterolemia such as partial ileal bypass, portocaval shunt, liver transplantation and plasma exchange have been tested in patients in whom drug and diet failed or were insufficient. Although effective, most of these treatments have severe side effects and are not routinely used. For hypercholesterolemic patients LDL-apheresis has proved to be the most promising and safe way as an adjuvant therapy. Several LDL-apheresis procedures with a varying degree of selectivity and efficiency have subsequently been developed. One of them is the H.E.L.P. system which was introduced in 1984 and has now been widely used. Besides the marked reduction of LDL particles by all techniques it has become apparent that only the H.E.L.P. system results in an equally significant change in hemostaseology, hemorheology and vasomotion because of its simultaneously removal of LDL, Lp(a), fibrinogen and CRP. This contribution reviews the application of the H.E.L.P. system as a valuable therapeutic tool for the treatment of various atherothrombotic and microcirculatory disorders such as prevention of early graft occlusion after coronary artery bypass grafting, treatment of peripheral vascular disease, stroke and preeclampsia. [Copyright &y& Elsevier]

Objective: Interest has recently focused on the use of neurohormonal markers such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) as indices of left ventricular systolic dysfunction and prognosis in heart failure. Also, peptides belonging to the interleukin-6 (IL-6) family have been shown to induce ANP and BNP secretion. We hypothesized that BNP and ANP spillover in the peripheral circulation reflects left ventricular dysfunction and IL-6 production in septic shock.Design and Setting: Retrospective, clinical study in the medical intensive care unit of a university hospital.Patients and Participants: 17 patients with septic shock and 19 control subjects.Interventions: Collection of clinical and demographic data in relation to ANP, BNP, IL-6, and soluble TNF receptors (sTNF-R-p55, sTNF-R-p75) in plasma over a period of 4 days.Measurements and Results: In septic shock we found a significant increase in ANP (82.7+/-9.9 vs. 14.9+/-1.2 pg/ml) and BNP (12.4+/-3.6 vs. 5.5+/-0.7 pg/ml). Plasma ANP peaked together with IL-6. Peaks of ANP and IL-6 were significantly correlated (r=0.73; p<0.01). BNP was inversely correlated to cardiac index (r=-0.56; p<0.05).Conclusions: ANP and BNP increase significantly in patients with septic shock. BNP reflects left ventricular dysfunction. ANP is related to IL-6 production rather than to cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]

We report the first experiences with HELP apheresis as an emergency treatment for acute cardiovascular syndromes; two patients who were not eligible for lysis therapy and catheter intervention were treated with HELP apheresis instead. Both patients had a most severe, generalized atherosclerosis and reached the hospital too late for conventional measures. In both cases, the use of the apheresis dramatically improved the clinical situation to such an extent that the possibilities of this apheresis system urge further investigation. [ABSTRACT FROM AUTHOR]

Approximately 30% of myeloma patients express cyclin D1 RNA and protein. The low incidence of translocation t(11; 14) detected by conventional cytogenetics suggests that the up-regulation of cyclin D1 protein might result from other mechanisms as well as from gene amplification. Therefore, the frequency and the clinical and prognostic implications of cyclin D1 amplification were examined. We highly purified myeloma cells from bone marrow by magnetic cell sorting and analysed 50 myelomas by fluorescence in situ hybridization (FISH) using probes specific for cyclin D1 and 20 samples by immunoblotting to detect cyclin D1 expression. The amplification of cyclin D1 gene was found in 19 of 50 analysed patients and was associated with expression of cyclin D1 protein. The amplification correlated significantly with the bone marrow infiltration, plasma cell morphology and labelling index as well as serum β2-microglobulin, C-reactive protein (CRP) and creatinine levels. In univariate analysis, the amplification of the cyclin D1 gene was a significantly unfavourable parameter with regard to overall survival (P = 0·0064) and progression-free survival (P = 0·0005). In multivariate analysis, cyclin D1 amplification and serum β2-microglobulin were independent and well-suited parameters for predicting survival. The detection of cyclin D1 amplification seems to be of promising prognostic value in multiple myeloma. [ABSTRACT FROM AUTHOR]

There is increasing evidence that atherogenic risk factors largely contribute to the pathogenesis of graft vessel disease (GVD) after heart transplantation. Initial endothelial damage of the transplant heart derives from reperfusion ischemia during operation, repeated infections, and rejection episodes. Immunosuppressive medication considerably increases low density lipoprotein (LDL) cholesterol, lipoprotein(a), and fibrinogen blood levels, which in turn further damage the endothelium of the graft coronaries. Probably, this interplay of immunological and atherogenic factors accounts for the rapid development of GVD and its poor prognosis. The rapidity of the disease process makes it necessary to eliminate important risk factors as early and as efficiently as possible. Therefore, we studied whether heart transplant patients could benefit from a combined treatment of statins and apheresis heparin extracorporeal LDL/fibrinogen precipitation (HELP), which has already been shown to be beneficial for the treatment of advanced coronary artery disease. Such a combined treatment allows simultaneous and drastic reduction of LDL, lipoprotein(a), and fibrinogen blood levels and significantly prevented GVD. Moreover, it did not affect the prevention of rejections and infections, respectively. [ABSTRACT FROM AUTHOR]

Although the pathogenesis of sudden hearing loss (SHL) is not as yet known, the clinical picture and the frequent association with vascular risk factors make an ischaemic event likely. This study aimed to assess the effect of an extracorporeal procedure (H.E.L.P.) in removing LDL-cholesterol, fibrinogen and lipoprotein (a) from the plasma, on the recovery of hearing SHL. This procedure using the HELP-system was compared with the usual standard treatment with prednisolone, dextranes and pentoxifyllin. We undertook a single centre, prospective, randomized study in which 18 patients were assigned to H.E.L.P.-apheresis and 9 patients were assigned to standard treatment (2:1 randomization). Audiometric and laboratory testing was performed at baseline, 24 h and 6 weeks after start of treatment. Primary endpoint was the improvement of the average pure-tone threshold between 0,125 and 8 kHz after 24 h. Twenty-four hours after H.E.L.P. treatment average pure-tone threshold recovered by 10.4 dB and by 26.4 dB after 6 weeks. The recovery of hearing of the standard treated patients was 5.8 dB and 16.8 dB after 24 h and 6 weeks respectively. LDL-cholesterol, fibrinogen and lipoprotein (a) were significantly reduced in the HELP treated patients compared with standard therapy, resulting in a significant improve in plasma viscosity, erythrocyte aggregation and resistance to oxidative stress of LDL particles. Our results suggest that the clinical outcome of SHL after a single extracorporeal LDL-apheresis is superior or at least equal to the more expensive standard treatment with prednisolone, dextranes and pentoxifyllin. Re-establishment of vascular endothelial function and improved blood rheology may be the underlying cause. These results must be confirmed in larger-scale trials. [ABSTRACT FROM AUTHOR]