Effects of clopidogrel with or without aspirin on the generation of extracellular vesicles in the microcirculation and in venous blood: A randomized placebo controlled trial.

BACKGROUND: Dual-antiplatelet therapy (DAPT) is a standard strategy in acute coronary heart disease; however, it confers a considerable bleeding risk. Single-antiplatelet therapy (SAPT) inhibits haemostatic system activation ex vivo to a similar extent as DAPT. Extracellular vesicles (EV) are procoagulant and contribute to haemostatic system activation. We aimed to investigate the effect of DAPT compared with SAPT on EV. METHODS: In a randomized, double-blind, placebo-controlled trial, 44 healthy volunteers received DAPT (clopidogrel + aspirin) or SAPT (clopidogrel + placebo) for 7 days. Blood was obtained from a standardized microvascular injury and through venipuncture at baseline (BL) and at 2 h, 24 h, and 8 days after treatment initiation. The number, origin, and surface expression of EV were assessed using flow cytometry. Data are given as median (quartiles). Non-parametric tests were used to evaluate the short-term (BL vs 2 h) and long-term differences (2 h to 8 days), as well as the differences between treatment groups. RESULTS: There was no difference either in the short-term effects on the number (×103 mL-1) of EV in microvascular blood between DAPT [BL: 1433 (653; 3184) vs 2 h: 862 (545; 2026), p = 0.39] and SAPT [(BL: 614 (552; 1402) vs 2 h: 1079 (781; 1538), p = 0.75)] or in the long-term effects. DAPT and SAPT did not exhibit differential short-term effects on the number and proportion (36% and 27% vs 55% and 36%) of platelet-derived EV. DAPT and SAPT resulted in a significant short-term increase in phosphatidylserine expression in microvascular blood. The effects of DAPT and SAPT on EV in venous blood were similar to those in microvascular blood. CONCLUSION: DAPT and SAPT have comparable effects on the amount, origin, and surface characteristics of EV.

Feasibility of a 'reversed' isolated forearm technique by regional antagonization of rocuronium-induced neuromuscular block: a pilot study.

BACKGROUND: The isolated forearm technique is used to monitor intraoperative awareness. However, this technique cannot be applied to patients who must be kept deeply paralysed for >1h, because the tourniquet preventing the neuromuscular blocking agent from paralysing the forearm must be deflated from time to time. To overcome this problem, we tested the feasibility of a 'reversed' isolated forearm technique. METHODS: Patients received rocuronium 0.6 mg kg(-1) i.v. to achieve muscle paralysis. A tourniquet was then inflated around one upper arm to prevent further blood supply to the forearm. Sugammadex was injected into a vein of this isolated forearm to antagonize muscle paralysis regionally. A dose titration of sugammadex to antagonize muscle paralysis in the isolated forearm was performed in 10 patients, and the effects of the selected dose were observed in 10 additional patients. RESULTS: The sugammadex dose required to antagonize muscle paralysis in the isolated forearm was 0.03 mg kg(-1) in 30 ml of 0.9% saline. Muscle paralysis was antagonized in the isolated forearm within 3.2 min in nine of 10 patients; the rest of the patients' bodies remained paralysed. Releasing the tourniquet 15 min later did not affect the train-of-four count in the isolated forearm but significantly increased the train-of-four count in the other arm by 7%. CONCLUSIONS: Regional antagonization of rocuronium-induced muscle paralysis using a sugammadex dose of 0.03 mg kg(-1) injected into an isolated forearm was feasible and did not have relevant systemic effects. CLINICAL TRIAL REGISTRATION: The trial was registered at EudraCT (ref. no. 2013-002164-53) before patient enrolment began.

Effects of P2Y12 receptor inhibition with or without aspirin on hemostatic system activation: a randomized trial in healthy subjects.

UNLABELLED: ESSENTIALS: In acute coronary syndromes, dual antiplatelet therapy inhibits platelets but confers a bleeding risk. Healthy male volunteers received clopidogrel or ticagrelor plus aspirin or clopidogrel or ticagrelor alone. The decrease in ß-thromboglobulin in shed blood was comparable after single and dual antiplatelet therapy. We hypothesize that patients with acute coronary syndromes may not require dual antiplatelet therapy. BACKGROUND: Dual antiplatelet therapy with a P2Y12 inhibitor and aspirin is standard in acute coronary syndromes. Dual antiplatelet therapy causes more bleeding than single antiplatelet therapy with a P2Y12 inhibitor. OBJECTIVES: To compare the effects of dual and single antiplatelet therapies on hemostatic system activation. PATIENTS/METHODS: In a randomized, parallel-group, double-blind, placebo-controlled study, 44 healthy volunteers received clopidogrel (600 mg, then 150 mg d(-1) ) and aspirin (100 mg d(-1) ) or placebo for 7 days; An additional 44 volunteers received single-dose ticagrelor (180 mg) and aspirin (300 mg) or placebo. ß-Thromboglobulin (ß-TG [IU L(-1) ]) and prothrombin fragment 1.2 (f1.2 [nmol L(-1) ]) were measured in blood obtained from bleeding time incisions. Data are given as geometric mean ratio (GMR [95% confidence interval]) to describe the differences in the first 2 h and as mean differences (Δ [95% confidence interval]) in area under the curve (AUC) to discriminate differences in effects over the total observation time. RESULTS: Clopidogrel plus aspirin and clopidogrel plus placebo reduced ß-TG by a GMR of 0.51 (0.42-0.63) and 0.54 (0.46-0.64) at 2 h. Ticagrelor plus aspirin and ticagrelor plus placebo decreased ß-TG by a GMR of 0.38 (0.26-0.57) and 0.47 (0.31-0.72). Ticagrelor plus aspirin and ticagrelor plus placebo reduced f1.2 by a GMR of 0.58 (0.45-0.75) and 0.55 (0.38-0.80); clopidogrel did not. Over 24 h, no difference in ß-TG occurred between clopidogrel plus aspirin and clopidogrel plus placebo (ΔAUC = -2.9 [-9.9 to 4.1]) or between ticagrelor plus aspirin and ticagrelor plus placebo (ΔAUC = -3.5 [-11.8 to 4.7]). No difference in f1.2 occurred between clopidogrel plus aspirin and clopidogrel plus placebo (ΔAUC = -4.2 [-10.2 to 1.8]) or between ticagrelor plus aspirin and ticagrelor plus placebo (ΔAUC = -3.6 [-10.9 to 3.7]). CONCLUSIONS: P2Y12 inhibitor monotherapy and dual antiplatelet therapy inhibit hemostatic system activation to a comparable extent.

Estimation of severe drug-drug interaction warnings by medical specialist groups for Austrian nationwide eMedication.

OBJECTIVE: The objective of this study is to estimate the amount of severe drug-drug interaction warnings per medical specialist group triggered by prescribed drugs of a patient before and after the introduction of a nationwide eMedication system in Austria planned for 2015. METHODS: The estimations of interaction warnings are based on patients' prescriptions of a single health care professional per patient, as well as all patients' prescriptions from all visited health care professionals. We used a research database of the Main Association of Austrian Social Security Organizations that contains health claims data of the years 2006 and 2007. RESULTS: The study cohort consists of about 1 million patients, with 26.4 million prescribed drugs from about 3,400 different health care professionals. The estimation of interaction warnings show a heterogeneous pattern of severe drug-drug-interaction warnings across medical specialist groups. CONCLUSION: During an eMedication implementation it must be taken into consideration that different medical specialist groups require customized support.

JADE: a tool for medical researchers to explore adverse drug events using health claims data.

OBJECTIVE: The objective of our project was to create a tool for physicians to explore health claims data with regard to adverse drug reactions. The Java Adverse Drug Event (JADE) tool should enable the analysis of prescribed drugs in connection with diagnoses from hospital stays. METHODS: We calculated the number of days drugs were taken by using the defined daily doses and estimated possible interactions between dispensed drugs using the Austria Codex, a database including drug-drug interactions. The JADE tool was implemented using Java, R and a PostgreSQL database. RESULTS: Beside an overview of the study cohort which includes selection of gender and age groups, selected statistical methods like association rule learning, logistic regression model and the number needed to harm have been implemented. CONCLUSION: The JADE tool can support physicians during their planning of clinical trials by showing the occurrences of adverse drug events with population based information.

Association of nutritional risk index with metabolic biomarkers, appetite-regulatory hormones and inflammatory biomarkers and outcome in patients with chronic heart failure.

AIMS: We aimed to evaluate the association of the nutritional status by using the nutritional risk index (NRI) with metabolic and inflammatory biomarkers, and appetite-regulatory hormones in a cohort of stable patients with heart failure (HF), and to analyse its prognostic value. METHODS AND RESULTS: In this prospective observational cohort study, we included 137 stable chronic HF patients (median age, 60 years; median body mass index, 27 kg/m(2) ) with optimised medical treatment. Baseline NRI of < 113 (n = 45) was associated with a significant increase in the levels of ghrelin (p < 0.001), peptide YY (p = 0.007), pentraxin-3 (p = 0.001), tumour necrosis factor-alpha (p = 0.018), adiponectin (p < 0.0001) and the N-terminal prohormone of brain natriuretic peptide (NT-proBNP; p < 0.0001) compared with those in patients with NRI of ≥ 113. The NRI was found to be correlated with the homoeostasis model assessment of insulin resistance index (r = 0.444; p < 0.0001) and inversely correlated with the NT-proBNP level (r = -0.410; p < 0.0001). The overall mortality rate was 20%. A baseline NRI of < 113 was associated with a higher risk of all-cause mortality (log rank = 0.031). CONCLUSION: We propose that the NRI is a useful and easily applicable tool for the early identification of nutritional depletion in patients with chronic HF as it discriminates metabolic changes prior to the clinical manifestation of body wasting. Furthermore, poor nutritional status, represented as a low NRI, is associated with an increased incidence of death in such cases.

Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects.

BACKGROUND: Patients with acute coronary syndrome and concomitant atrial fibrillation may require antithrombotic triple therapy but clinical evidence of safety and efficacy is poor. We have therefore studied the combination of different antithrombotic medicines for coagulation activation in an in vivo model in the skin microvasculature. METHODS AND RESULTS: Platelet activation (ß-thromboglobulin [ß-TG]) and thrombin generation (prothrombin fragment 1 + 2 [F1+2 ], thrombin-antithrombin complex [TAT]) were studied in an open-label, randomized, parallel group trial in 60 healthy male subjects (n = 20 per group) who received ticagrelor and acetylsalicylic acid (ASA) in combination with dabigatran (150 mg bid), rivaroxaban (20 mg od) or phenprocoumon (INR 2.0-3.0). Coagulation biomarkers in shed blood were assessed at 3 h after monotherapy with the medicines under study, at 3 h after triple therapy dosing and at steady state trough conditions. Single doses of ticagrelor, dabigatran or rivaroxaban caused comparable decreases in shed blood ß-TG and were more pronounced than phenprocoumon at an INR of 2.0-3.0. In contrast, thrombin generation was more affected by rivaroxaban and phenprocoumon than by dabigatran. During triple therapy a similarly sustained inhibition of platelet activation and thrombin generation with a maximum decrease of ß-TG, F1+2 and TAT at 3 h post-dosing was noted, which remained below pre-dose levels at trough steady state. CONCLUSION: A triple therapy at steady state with ticagrelor plus ASA in combination with dabigatran or rivaroxaban is as effective as a combination with phenprocoumon for platelet activation and thrombin generation in vivo.

Effect of systemic high dose vitamin C therapy on forearm blood flow reactivity during endotoxemia in healthy human subjects.

OBJECTIVE: Acute inflammation induced by administration of Escherichia coli lipopolysaccharide endotoxin (LPS) reduces plasma concentrations of vitamin C and impairs vascular endothelium-derived nitric oxide (NO) bioactivity. We tested the hypothesis that systemically administered high dose vitamin C restores the endogenous anti-oxidant potential and improves NO-dependent vasodilatation in the forearm vasculature. DESIGN & SETTING: 36 male subjects were enrolled in this balanced, placebo controlled cross-over study. Forearm blood flow (FBF) reactivity to acetylcholine (ACh) and glyceryl-trinitrate (GTN), a sensitive test for endothelial function, was assessed at baseline and 4h after LPS-administration (20 IU/kg i.v). The effect of two different doses of intravenous vitamin C (Vitamin C-Injektopas®), 320 mg/kg and 480 mg/kg over 2h, or placebo on forearm vascular function was studied after LPS. MAIN RESULTS: LPS caused transient flu-like symptoms, decreased plasma vitamin C concentrations and reduced the ACh-dependent increase in FBF by up to 76%. Vitamin C at a mean plasma concentration of 3.2 or 4.9 mmol/L restored the response to ACh compared to baseline. CONCLUSION: High dose systemic vitamin C recovers LPS-induced endothelium-dependent vasodilation in the forearm resistance vasculature. This provides a rationale for a further clinical study of the systemic vitamin C effect under inflammatory conditions.

Hypertensive emergencies are associated with elevated markers of inflammation, coagulation, platelet activation and fibrinolysis.

Data from in vitro and animal experiments suggest that progressive endothelial damage with subsequent activation of coagulation and inflammation have a key role in hypertensive crisis. However, clinical investigations are scarce. We hypothesized that hypertensive emergencies are associated with enhanced inflammation, endothelial- and coagulation activation. Thus, we enrolled 60 patients admitted to an emergency department in a prospective, cross-sectional study. We compared markers of coagulation, fibrinolysis (prothrombin fragment F(1+2), plasmin-antiplasmin complexes, plasmin-activator inhibitor, tissue plasminogen activator), platelet- and endothelial activation and inflammation (P-selectin, C-reactive protein, leukocyte counts, fibrinogen, soluble vascular adhesion molecule-1, intercellular adhesion molecule-1, myeloperoxidase and asymmetric dimethylarginine) between hypertensive emergencies, urgencies and normotensive patients. In hypertensive emergencies, markers of inflammation and endothelial activation were significantly higher as compared with urgencies and controls (P<0.05). Likewise, plasmin-antiplasmin complexes were 75% higher in emergencies as compared with urgencies (P<0.001), as were tissue plasminogen-activator levels (∼30%; P<0.05) and sP-selectin (∼40%; P<0.05). In contrast, similar levels of all parameters were found between urgencies and controls. We consistently observed elevated markers of thrombogenesis, fibrinolysis and inflammation in hypertensive emergencies as compared with urgencies. Further studies will be needed to clarify if these alterations are cause or consequence of target organ damage.

Corneocyte quantification by NIR densitometry and UV/Vis spectroscopy for human and porcine skin and the role of skin cleaning procedures.

Optical methods of corneocyte quantification during tape stripping experiments on the skin are useful tools for the rapid evaluation of the skin penetration potential of dermally applied substances. However, a comparative investigation of the different methods proposed for this task, namely NIR densitometry and UV/Vis spectroscopy, is still missing. Thus, the aim of the present work was to employ these two techniques in comparative tape stripping experiments both in vivo on human forearm skin and in vitro on porcine ear skin. Standard tape stripping experiments were performed in the absence and presence of a marketed formulation containing flufenamic acid as a model drug. In the context of these methodological investigations, different methods of skin cleaning prior to the tape stripping procedure were evaluated to identify the most appropriate working protocol among the approaches proposed in the respective literature. The results showed that the investigated methods of NIR densitometry and UV/Vis spectroscopy deliver highly comparable results. Both optical methods are suitable to determine the skin penetration profiles of active substances during in vivo and in vitro tape stripping, especially if a simple working protocol without any cleaning procedures is maintained.

Kidney biopsy in patients with diabetes mellitus.

BACKGROUND: The clinical consequences of the results obtained by kidney biopsy in patients with diabetes mellitus Type 1 or Type 2 have been controversial. Our study was conducted to assess clinical symptoms and histological diagnoses in patients with diabetes mellitus Type 1 and Type 2 undergoing kidney biopsy. DESIGN, SETTING AND PATIENTS: Observational study. The study included data from 567 consecutive renal biopsies of patients with diabetes mellitus Type 1 or 2 and chronic kidney disease (CKD) examined by standard histopathological procedures. The main outcome measures were incidence of diabetic nephropathy (DN) and glomerulonephritis (GN), predictors for the presence of both DN or GN. RESULTS: Approximately 70% of patients with diabetes mellitus Type 1 or 2 and evidence for CKD had DN. Glomerular diseases present in approximately 30% of patients with diabetes were predominantly immune complex GN and secondary focal glomerulosclerosis, followed by IgA-GN, which was associated with microhematuria (p = 0.01) and hypertension (p = 0.04). Only a minority had membranous GN, which was associated with nephrotic syndrome (p = 0.004). Progressive CKD predicted the presence of GN in diabetes mellitus Type 2 (r = -0.98; p = 0.02). CONCLUSION: GN is not uncommon in patients with diabetes and evidence for CKD. Kidney biopsy should therefore be considered in patients with diabetes and progressive CKD.

Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux.

Edoxaban, an oral direct factor Xa (FXa) inhibitor, is in phase III clinical development for stroke prevention in atrial fibrillation and treatment of venous thromboembolism. The shed blood model allows for study of activated coagulation at a site of standardised tissue injury due to local release of tissue factor. The objective of this study was to evaluate the effect of three doses of edoxaban on markers of coagulation in shed and venous blood versus placebo and a standard prophylactic dose of fondaparinux. A total of 100 healthy male subjects were randomised to receive single doses of one of five treatments: subcutaneously administered fondaparinux 2.5 mg; orally administered edoxaban 30, 60, or 120 mg; or placebo. The primary objective was measurement of blood coagulation markers prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin (TAT) complex, and platelet activation marker ß-thromboglobulin (ß-TG), in venous and shed blood. Secondary objectives included pharmacokinetics, shed blood volume, and safety of edoxaban. Single doses of edoxaban caused rapid and significant decreases of F1+2, TAT, and ß-TG in the shed blood model, indicating inhibition of thrombin generation and platelet activation. Inhibition was significantly less for fondaparinux versus edoxaban. Baseline-corrected F1+2, TAT, and ß-TG values demonstrated sustained inhibition up to 24 hours for shed blood in the edoxaban groups but no significant inhibition in venous blood. Overall, edoxaban treatments were well tolerated. In conclusion, single oral doses of edoxaban 30, 60, or 120 mg caused rapid and sustained inhibition of coagulation up to 24 hours in the shed blood model.

Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes.

OBJECTIVE: in type 2 diabetic patients and their first-degree relatives, insulin resistance (IR) is associated with impairment of insulin-stimulated myocellular glucose-6-phosphate (g6p) and unidirectional flux through ATP synthase (fATP), suggesting the presence of inherited abnormal mitochondrial oxidative fitness. We hypothesized that patients with long-standing type 1 diabetes may also exhibit insulin resistance as well as lower fATP. DESIGN: this single-centre trial was registered at ClinicalTrials.gov (NCT00481598). SUBJECTS: we included eight nonobese type 1 diabetic patients (mean diabetes duration: 17 years) with near-target glycaemic control [haemoglobin A1c (HbA1c): 6.8 ± 0.4%] during treatment with continuous subcutaneous insulin infusion pumps and eight healthy volunteers (HbA1c: 5.4 ± 0.2%) of comparable age, body mass and level of physical activity. OUTCOME MEASURES: myocellular fATP, g6p and intramyocellular lipid content (IMCL) were measured with (1) H/(31) P magnetic resonance spectroscopy during fasting and hyperinsulinaemic-euglycaemic clamp tests. RESULTS: fasting fATP, g6p and IMCL did not differ between groups. During stimulation by insulin, type 1 diabetic patients exhibited approximately 50% (P < 0.001) lower whole-body glucose disposal along with approximately 42% (P = 0.003) lower intramyocellular g6p and approximately25% (P = 0.024) lower fATP. Insulin-stimulated fATP correlated positively with whole-body insulin sensitivity (R = 0.706, P = 0.002) and negatively with HbA1c (R = -0.675, P = 0.004). CONCLUSIONS: despite documented near-target glycaemic control for 1 year, nonobese patients with long-standing type 1 diabetes can exhibit insulin resistance. This associates with lower insulin-stimulated flux through muscular ATP synthase which could result from glucose toxicity.

Haem arginate infusion stimulates haem oxygenase-1 expression in healthy subjects.

BACKGROUND AND PURPOSE: Haem oxygenase 1 (HO-1) is an inducible protein that plays a major protective role in conditions such as ischaemia-reperfusion injury and inflammation. In this study, we have investigated the role of haem arginate (HA) in human male subjects in the modulation of HO-1 expression and its correlation with the GT length polymorphism (GT(n)) in the promoter of the HO-1 gene. EXPERIMENTAL APPROACH: In a dose-escalation, randomized, placebo-controlled trial, seven healthy male subjects with a homozygous short (S/S) and eight with a long (L/L) GT(n) genotype received intravenous HA. HO-1 protein expression and mRNA levels in peripheral blood monocytes, bilirubin, haptoglobin, haemopexin and haem levels were analysed over a 48 h observation period. KEY RESULTS: We found that the baseline mRNA levels of HO-1 were higher in L/L subjects, while protein levels were higher in S/S subjects. HA induced a dose-dependent increase in the baseline corrected area under the curve values of HO-1 mRNA and protein over 48 h. The response of HO-1 mRNA was more pronounced in L/L subjects but the protein level was similar across the groups. CONCLUSIONS AND IMPLICATION: HA is an effective inducer of HO-1 in humans irrespective of the GT(n) genotype. The potential therapeutic application of HA needs to be evaluated in clinical trials.

Reduction of both number and proliferative activity of human endothelial progenitor cells in obesity.

OBJECTIVE: Circulating endothelial progenitor cells (EPCs), responsible for neoangiogenesis and vascular repair, negatively correlate with vascular dysfunction and atherosclerotic risk factors. Because obesity may have a crucial role in the development of endothelial dysfunction, this study evaluated the number and proliferative activity of circulating human EPCs in obese (body mass index (BMI)=48+/-9, n=45) compared with lean (23+/-2, n=45) volunteers. METHODS: EPCs were quantified after isolation of peripheral blood mononuclear cells (PBMCs) using fluorescence-activated cell sorting analyses. In addition, plated PBMCs developed colony-forming units (CFUs) from which 'outgrowth' endothelial cells (OECs) sprouted and differentiated into mature endothelial cells. Growth rates were monitored by periodical microscopic evaluation. Cell-cycle protein expression was determined by western blot analyses. RESULTS: BMI negatively correlated (P<0.01) with the number of CD34(+)/CD133(+)/KDR(+) (r=-0.442), CD34(+)/KDR(+) (r=-0.500) and CD133(+)/KDR(+) (r=-0.282) EPCs. Insulin, leptin, HbA(1c), high-sensitivity C-reactive protein and hypertension, as well as diminished high-density lipoprotein and apolipoprotein A1, were not only associated with obesity but also with significantly reduced EPC levels. Applying selective culture conditions, EPC-CFUs differentiated into OECs that proliferated more slowly when derived from obese compared with lean subjects (obese: 19.9+/-2.2% vs lean: 30.9+/-3.2% grown area per week, P<0.01). The reduced proliferation was reflected by decreased (P<0.05, n=24 for each group) expression of cell-cycle-promoting cyclins and E2F-1, by hypophosphorylation of retinoblastoma protein and by increased (P<0.05, n=24 for each group) expression of the cell-cycle inhibitor p21(WAF-1/Cip1). CONCLUSIONS: Reduced numbers of EPCs along with their premature senescence, as shown in this study, could function as early contributors to the development and progression of vascular dysfunction in obesity.

Postprandial blood glucose level in maintenance hemodialysis patients predicts post-transplant-diabetes-mellitus.

Post-transplant-diabetes-mellitus (PTDM) is a frequent complication after kidney transplantation. One-hundred-and-seven patients with kidney transplantation were screened for the occurrence of PTDM. Of these, full data sets from 49 subjects were available with documented glucose concentrations during maintenance hemodialysis (MHD) and regular clinical follow-up of 7-34 months. For assessment of glucose metabolism the response to a standard meal during MHD was used in normoglycemic patients based on fasting blood glucose. Abnormal postprandial blood glucose concentration was defined as >140 mg/dl 2 h after food intake.Twelve end stage renal disease patients had abnormal postprandial blood glucose on MHD. All 12 subjects but also four MHD patients with normal postprandial and fasting blood glucose values developed PTDM. Multivariate Cox-regression analysis revealed that abnormal postprandial blood glucose is a strong predictor for PTDM (Hazard ratio: 42.3 (IQR: 7.9-227.2); p<0.001). Fasting blood glucose (94 vs. 100 mg/dl) was not different between MHD patients who did (n=16) or did not (n=33) develop PTDM.This study suggests that measurement of postprandial blood glucose during MHD identifies patients who develop PTDM after kidney transplantation. It should be used for screening of patients at risk.

Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial.

OBJECTIVE: The aim of this study was to investigate the effect of alpha-lipoic acid (ALA) treatment on endothelium-dependent and -independent vasodilatation, assessed by forearm blood flow (FBF), in patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: A total of 30 subjects with type 2 diabetes were included in this randomized, controlled, double-blinded, parallel group study. FBF responses to intra-arterial acetylcholine (ACh) and glycerol trinitrate (GTN) were measured before and after 21 days of intravenous treatment with 600 mg alpha-lipoic acid or placebo. RESULTS: FBF responses were comparable at baseline. After treatment, FBF reactivity to ACh and GTN was unchanged in subjects receiving placebo. By contrast, ALA treatment increased endothelium-dependent vasodilatation to ACh (P < 0.05) but not to GTN compared with baseline. CONCLUSIONS: Intravenous ALA treatment improves endothelium-dependent vasodilatation in patients with type 2 diabetes, in the absence of effects on forearm vasomotor function. If this salutary action translates into vascular risk reduction remains to be established.

Alcohol acutely increases vascular reactivity together with insulin sensitivity in type 2 diabetic men.

Moderate alcohol consumption is associated with increased insulin sensitivity and reduced cardiovascular risk. We hypothesized that this relates to a direct effect of alcohol and therefore investigated whether acute alcohol intake altered insulin sensitivity or endothelial function in patients with type 2 diabetes. In an open-label two period design, the effect of a single oral dose of 40 g of alcohol (168 ml 40% vodka) on an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and on endothelium-dependent (flow mediated, FMD) or endothelium-independent (glyceroltrinitrate (GTN)-induced) vasodilation of the brachial artery measured by ultrasound was studied. Experiments were carried out in twelve male patients with type 2 diabetes mellitus (64+/-6 years, body mass index 28.4+/-5.7 kg/m (2)). Baseline insulin sensitivity index (S (I)) was 1.10+/-0.34 min (-1).microU (-1).ml, baseline FMD was +4.1+/-3.0%, and GTN-induced vasodilation +7.4+/-2.3% from resting brachial artery diameter. Acute alcohol intake increased alcohol plasma levels to 0.33+/-0.04 per thousand, S (I) to 1.86+/-0.45 min (-1).microU (-1).ml (p<0.05), and FMD to +8.2+/-2.8% (p<0.05), while GTN-induced dilation remained unchanged. No relationship was detectable between the observed changes. We conclude that alcohol intake acutely increases endothelium-dependent brachial artery vasodilation in patients with type 2 diabetes together with insulin sensitivity. This acute effect might explain some beneficial effects of low alcohol consumption in epidemiological observations.

Persistent arterial stiffness and endothelial dysfunction following successful pancreas-kidney transplantation in Type 1 diabetes.

OBJECTIVE: Successful simultaneous pancreas-kidney transplantation (SPK) in Type 1 diabetic (T1DM) patients results in improved cardiovascular outcome and survival. However, it is doubtful whether the impairment of cardiovascular and endothelial function in T1DM can be completely reversed. METHODS: Pulse-wave velocity, stroke volume, heart rate, serological markers of endothelial dysfunction (soluble intercellular, vascular cell-adhesion molecules, E-selectin, and plasminogen-activator-inhibitor-1) were measured in 10 T1DM patients after SPK with non-diabetic glucose levels, 10 T1DM patients with poor [T1DM>8; glycated haemoglobin (HbA1c)>8%], and 10 with good glucose control (T1DM<7, HbA1c<7%), in 6 non-diabetic patients after kidney transplantation (KT) and 9 non-diabetic control subjects (CON), matching for major anthropometric characteristics. RESULTS: Pulse-wave velocity was increased in SPK (P < 0.02 vs. CON, KT, T1DM<7) and in T1DM>8 (P < 0.02 vs. T1DM<7). Systolic blood pressure was increased in SPK (P < 0.05 vs. CON). Stroke volume was reduced in SPK, T1DM>8 and T1DM<7 and KT (P < 0.01 vs. CON). Heart rate was elevated in SPK and in T1DM>8 (P < 0.0003 vs. CON and T1DM<7). In SPK, soluble intercellular and vascular cell-adhesion molecules were 100% and 44% higher (P < 0.03 vs. CON), respectively, while plasminogen-activator-inhibitor-1 was decreased in SPK (P < 0.02 vs. CON). CONCLUSION: T1DM patients after SPK experience arterial stiffness, a higher heart-rate and blood pressure, reduced stroke volume and serological signs of endothelial dysfunction. Thus, functional and structural cardiovascular alterations as a result of glucotoxicity, uraemia and hypertension in T1DM might not be completely resolved by SPK.

Research ethics committees in Europe: trials and tribulations.

INTRODUCTION: Ethics committees have been an integral part of clinical research since 1975, when they were introduced through the amendment of the Declaration of Helsinki. Every proposal for clinical research on human subjects has to be submitted to an independent ethics committee for review and approval. The European Clinical Trials Directive 2001/20/EC was implemented in 2004 to harmonise the legislative framework for clinical research in Europe in order to make Europe more competitive in clinical research while at the same time improving the protection of research participants. RESULTS: We have evaluated the situation of ethics committees in Europe five years after the implementation of the new law with special consideration of the number of Ethics Committees per European Member State and the number of members within the specific committees, including the selection of members, also in regard to gender aspects and training requirements, the remuneration or compensation of members in regard of their review obligations, and also issues of conflicts of interest. CONCLUSION: Inadequate remuneration for professional services and gender imbalance are universal concerns across Europe. As the position of ethics committees changes continuously towards greater responsibility, further guidance is needed to uniformly adapt their structures to those needs.