Telmisartan improves absolute walking distance and endothelial function in patients with peripheral artery disease

Background  

Peripheral artery disease (PAD) is associated with high cardiovascular mortality and a poor quality of life. The AT1-receptor blocker telmisartan has been shown to have pleiotropic effects and it may also improve endothelial function. The aim of this study was to analyze the effects of telmisartan on absolute walking distance (WD) and endothelial function in patients with PAD.     

Prognostic relevance of programmed death-ligand 1 expression and microsatellite status in small bowel adenocarcinoma

Abstract

Background: Small bowel adenocarcinoma (SBA) is a dreadful disease. Patient prognosis is limited due to late presentation and ineffective chemotherapy. PD-1/PD-L1 checkpoint immunotherapy is regarded as a promising approach in several cancer entities. The association of PD-1/PD-L1 expression and its impact on patient prognosis with SBA is unclear.

Material and methods: Seventy-five consecutive patients who underwent surgery for SBA were retrospectively analyzed and stained for PD-L1 expression in the tumour or the stroma. Analysis of mismatch repair genes was performed to determine microsatellite status. Kaplan–Meier estimate was used to analyze patient survival. Univariate and multivariable Cox regression-analyses were used to assess the impact of PD-L1 expression and microsatellite status on patient survival.

Results: PD-L1 was weakly upregulated within the tumour or the stroma and associated with prolonged survival (p?=?.0071 and p?=?.0472, respectively). Fifty-one tumours (68%) revealed microsatellite stability (MSS) and 24 tumours (32%) were microsatellite instable (MSI) without correlating with patient survival (p?=?.611). Neither PD-L1 expression in the tumour nor in the stroma was identified as an independent risk factor influencing survival (p?=?.572 and p?=?.3055).

Conclusion: Although PD-L1 expression is associated with prolonged survival, it was not identified as an independent prognostic marker. Microsatellite status did not influence long-term survival.     

Hemodynamic, antiischemic, and neurohumoral effects of enoximone in patients with coronary artery disease

To evaluate the risk of ischemia in 17 patients with significant coronary artery disease, the influence of enoximone was analyzed under the following conditions: (1) at rest (RC) and during exercise (ExC) under control conditions and (2) at rest (RE) and during exercise (ExE) after administration of enoximone (0.75 mg/kg, intravenously). During ExC all patients had ischemia (angina, and ST segment alterations); metabolic markers of ischemia (MMI) increased, as did the mean pulmonary artery pressure, from 19 to 41 mm Hg. However, during ExE ischemia was abolished (no angina, decrease in mean pulmonary artery pressure to 24 mm Hg, and improvement in MMI) and there was some improvement in left ventricular pump function, whereas pre- and afterload decreased (pulmonary artery pressure by 40%, systemic vascular resistance by 10%), and heart rate, arterial pressure, and myocardial oxygen consumption (MVO2) were all unchanged (p greater than 0.05). Comparative hemodynamics at RE vs RC showed a decrease in pulmonary artery pressure (by 25%) and pulmonary vascular resistance (by 19%) and an increase in heart rate (by 11%), whereas arterial pressure and MVO2 were unchanged (p greater than 0.05). Enoximone did not induce changes in plasma catecholamine, prostaglandin, or thromboxane levels (p greater than 0.05), whereas the atrial natriuretic factor decreased (by 15%), probably because of unloading of the atria during exercise. We concluded that enoximone induces beneficial hemodynamic effects in coronary artery disease without causing ischemia, probably by enhancing myocardial contractility, vasodilation, and improved diastolic properties.     

Nd:YAG laser bronchoscopy. Rigid or fiberoptic mode?

One hundred twenty four Nd:YAG laser procedures were performed on 79 patients (age range, 25 to 89 years) over a five-year period at our institution. Over 90 percent of patients had malignant tumors. The fiberoptic bronchoscope (FOB group) was used exclusively during the first two years (61 cases, 32 patients). All except four of these cases utilized conscious sedation and local anesthesia. Subsequent to this, the rigid bronchoscope (RB group) was used as the primary instrument under general anesthesia (51 cases, 42 patients). Twelve cases combined both bronchoscopic modalities (combined group, 12 patients). The percentage improvement in proximal airway lumen diameter post-Nd:YAG laser therapy was significantly greater using the RB (p less than 0.05). For distal lesions, the FOB was superior (p less than 0.05). There was no difference in the complication or survival rates between the groups. Our data suggest that whenever possible, the RB should be used to treat proximal lesions, and the FOB should be used for distal lesions. Both bronchoscopes are often used together. Hence, laser bronchoscopists should be proficient in both bronchoscopic techniques.     

Critical role of RAGE and HMGB1 in inflammatory heart disease

Autoimmune response to cardiac troponin I (TnI) induces inflammation and fibrosis in the myocardium. High-mobility group box 1 (HMGB1) is a multifunctional protein that exerts proinflammatory activity by mainly binding to receptor for advanced glycation end products (RAGE). The involvement of the HMGB1–RAGE axis in the pathogenesis of inflammatory cardiomyopathy is yet not fully understood. Using the well-established model of TnI-induced experimental autoimmune myocarditis (EAM), we demonstrated that both local and systemic HMGB1 protein expression was elevated in wild-type (wt) mice after TnI immunization. Additionally, pharmacological inhibition of HMGB1 using glycyrrhizin or anti-HMGB1 antibody reduced inflammation in hearts of TnI-immunized wt mice. Furthermore, RAGE knockout (RAGE-ko) mice immunized with TnI showed no structural or physiological signs of cardiac impairment. Moreover, cardiac overexpression of HMGB1 using adeno-associated virus (AAV) vectors induced inflammation in the hearts of both wt and RAGE-ko mice. Finally, patients with myocarditis displayed increased local and systemic HMGB1 and soluble RAGE (sRAGE) expression. Together, our study highlights that HMGB1 and its main receptor, RAGE, appear to be crucial factors in the pathogenesis of TnI-induced EAM, because inhibition of HMGB1 and ablation of RAGE suppressed inflammation in the heart. Moreover, the proinflammatory effect of HMGB1 is not necessarily dependent on RAGE only. Other receptors of HMGB1 such as Toll-like receptors (TLRs) may also be involved in disease pathogenesis. These findings could be confirmed by the clinical relevance of HMGB1 and sRAGE. Therefore, blockage of one of these molecules might represent a novel therapeutic strategy in the treatment of autoimmune myocarditis and inflammatory cardiomyopathy.Inflammatory cardiomyopathy is a relatively common cause of acute heart failure in the young, for which an efficient and specific therapy is lacking. Although most patients recover completely, some present a deteriorating course. Recent work from our laboratory and others has focused on the dysregulation of the immune system as an essential modulator of disease induction and progression in heart failure (1, 2). In this context, release of cardiac troponin I (TnI) from damaged cardiomyocytes into the circulation is believed to trigger an autoimmune response to TnI (3, 4).Our group has established an animal model in which immunization with murine cardiac TnI induces severe myocardial inflammation and fibrosis, followed by severe heart failure (1). However, the exact pathomechanism and immune modulators involved in this inflammatory process are not yet fully elucidated.Extensive work has cast light on the role of high-mobility group box 1 (HMGB1) in the pathogenesis of infectious and noninfectious inflammatory diseases. HMGB1, first described as a DNA binding protein, has subsequently been associated with various pathological conditions such as cardiovascular disease (5, 6), cancer (7), and ischemia/reperfusion (I/R) injury (5). It is a key modulator of innate immune responses and regulates in part adaptive immunity (8). In response to cellular stress, HMGB1 acts as a damage-associated molecular pattern (DAMP) signal after passive release into the extracellular milieu during cell death or active secretion by mononuclear and other cell types (7). It binds to receptors such as receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) such as TLR-2 and -4, leading to the expression of inflammatory cytokines, chemokines, and corresponding receptors (9).Some studies describe differential effects of HMGB1- or RAGE-dependent signaling with regard to their concentration and release in a particular model or mode of application (10, 11). In a rodent model of myocardial infarction, exogenously administered HMGB1 had a beneficial effect on postinfarct myocardial remodeling (10). Kitahara and colleagues demonstrated reduced necrosis and smaller infarct size after myocardial infarction in transgenic mice overexpressing HMGB1 (12). However, in a murine model of I/R injury, our group recently showed that treatment of wild-type (wt) mice with recombinant HMGB1 increased the infarct size (6). In the same model of I/R injury, RAGE-deficient mice demonstrated significantly reduced myocardial damage compared with wt mice (6).The effect of HMGB1 and RAGE on the pathogenesis of cardiac disorders is not only described in preclinical animal models but is also investigated in human cardiac disorders. Different studies have revealed an elevated HMGB1 level in patients with heart failure correlating with disease severity (13–17). In addition to this, some studies have identified RAGE as a prognostic factor in human heart failure (16, 18, 19).In the present study, we aimed to clarify the role of HMGB1 and RAGE in an experimental model of murine autoimmune myocarditis. This experimental approach enables a reproducible sterile cardiac inflammation, as described previously (1, 20). Furthermore, the clinical relevance of both proteins should be investigated.Hence, we first studied the expression kinetics of HMGB1 in the inflamed myocardium and serum of wt mice. Then, inhibition of HMGB1 by glycyrrhizin (GL) was performed and heart tissue was analyzed in TnI-induced experimental autoimmune myocarditis (EAM) of wt mice. Additionally, RAGE knockout (RAGE-ko) mice were immunized with TnI to further study the role of RAGE signaling in this EAM model. Finally, the role of the HMGB1–RAGE axis in our model was analyzed by an adeno-associated virus (AAV)9-mediated cardiac overexpression of HMGB1. In a last step, we studied the clinical relevance of HMGB1 and RAGE in patients with myocarditis.     

Reboxetine and cytochrome P450--comparison with paroxetine treatment in humans

OBJECTIVES: The noradrenaline-selective antidepressant reboxetine in vitro is a weak inhibitor of both cytochrome P450 (CYP) 2D6 and CYP3A4. Thus, in this study the pharmacokinetics of reboxetine in relation to pharmacogenetics and the effects of reboxetine compared to paroxetine treatment on the CYP2D6 and CYP3A4 phenotype were analyzed in healthy control subjects. METHODS: Healthy male volunteers were treated with either 6 mg reboxetine (n = 26) or 30 mg paroxetine (n = 25). On Days 10/11 of treatment, serum concentrations of the antidepressants were measured and pharmacokinetic parameters calculated. Volunteers were phenotyped at the end of treatment and after at least 3 weeks washout (true phenotype) using 30 mg dextromethorphan (DM) hydrobromide given orally and measuring DM and metabolites in serum 2 h after intake. CYP2D6 and CYP2C19 genotypes were determined in parallel. RESULTS AND CONCLUSION: Reboxetine serum concentrations showed no correlation with the CYP2D6 genotype and the CYP2D6 phenotype, whereas paroxetine concentrations showed some dependence on CYP2D6. In contrast to in vitro investigations, indicating a major role of CYP3A4 in reboxetine metabolism, reboxetine concentrations in serum showed no correlation with the respective DM metabolic ratios. There was also no correlation between paroxetine concentrations and the CYP3A4 phenotype data. The CYP2C19 genotype (only heterozygosity) had no influence on reboxetine and paroxetine pharmacokinetics. There were only minor changes in the DM metabolite pattern on treatment with reboxetine and no evidence of enzyme inhibition was obtained. In contrast and as expected, paroxetine strongly inhibited CYP2D6. Thus, reboxetine treatment has no effect on the CYP2D6 genotype and no clinically relevant drug interactions involving CYP2D6 are anticipated.     

Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression

HMG-CoA-reductase inhibitors (statins) are widely used drugs to interfere with cholesterol biosynthesis. Besides this usage, evidence is increasing that statins might also be useful in therapy of viral infections or cancer. We investigated the effects of fluva-, simva-, atorva-, rosuva- and lovastatin on the viability of primary mouse and human hepatocytes as well as mouse (Hepa1-6) and human (Huh7, HepG2) hepatoma cell lines. Our results show selective cytotoxic effects of fluva-, simva- and lovastatin on hepatoma cells in comparison to primary hepatocytes. Using human hepatoma cells we found significant reduction of cell viability and induction of apoptosis in HepG2 cells, while statins did not affect Huh7 cells at concentrations not toxic for primary hepatocytes. Stable knockdown of endogenous p53, which is overexpressed in Huh7 cells, was able to restore susceptibility of Huh7 cells towards statin-induced toxicity. The anti-tumor effect of statins did not depend on a lack of cholesterol production, but was restored by supplementation of mevalonate or geranyl-geranyl pyrophosphate, prerequisites for prenylation of small G proteins. In conclusion, statins display a selective apoptotic effect on human hepatoma cells, with fluva-, simva- and lovastatin being both, most selective for tumor cells and most effective in inducing tumor cell apoptosis. Additionally, our results implicate that anti-tumor activity of statins requires cell proliferation and is reduced by p53 overexpression.     

Measurement of kinetically resolved vesicular dopamine uptake and efflux using rotating disk electrode voltammetry

The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine (DA) into vesicles for storage and subsequent release. VMAT-2 activity has traditionally been measured in small synaptic vesicles isolated from rat striatum by monitoring [3H] DA uptake and in cellular expression systems using fast scan cyclic voltammetry. This is the first report using rotating disk electrode (RDE) voltammetry to measure VMAT-2 DA uptake and efflux in small synaptic vesicles. DA uptake profiles followed mixed order kinetics with apparent zero order kinetics for the first 25 s and apparent first order kinetics thereafter. Vesicular DA uptake was temperature- and ATP-dependent and was blocked by the VMAT-2 inhibitor tetrabenazine. Initial velocities of DA uptake were kinetically resolved and displayed Michaelis-Menten kinetics with a Km and Vmax of 289 +/- 59 nM and 1.9 +/- 0.2 fmol/(s microg protein), respectively. Methamphetamine-induced DA efflux was blocked by tetrabenazine and kinetically resolved with an initial velocity of 0.54 +/- 0.08 fmol/(s microg protein). These results suggest that RDE voltammetry can be used to make kinetically resolved measurements of vesicular DA uptake and efflux and will allow the design of experiments that could reveal important information about the kinetics of VMAT-2 activity and its inhibition.