Intragastric Nitroglycerin at a Vasodilatory Dose Attenuates Acidified Aspirin-Induced Gastric Mucosal Injury

Clinical studies reveal that aspirin intake to prevent myocardial and cerebral ischemia is associated with a significant increase in upper gastrointestinal hemorrhage requiring hospitalization and that nitroglycerin or long-acting nitrates significantly lower this risk. Nitroglycerin can increase gastric blood flow and slow gastric emptying. We hypothesized that both features contribute to its gastroprotective property. Fasted anesthetized rats (Study 1) and conscious mice (Studies 2 to 4) received intragastric nitroglycerin or vehicle. The effects of these two treatments on various parameters were assessed in Study 1, on blood pressure and gastric blood flow; Study 2, on acidified aspirin-induced gastric mucosal lesions; and Study 3, on the weight of gastric content. In Study 4, the effect of nitroglycerin, vehicle, or vehicle plus saline, on acidified aspirin-induced gastric mucosal lesion was assessed. Compared with vehicle, nitroglycerin decreased blood pressure and produced a mild but significant increase in gastric vascular conductance, blood flow, and volume of gastric content. The number and length of gastric mucosal lesions induced by acidified aspirin were significantly attenuated by intragastric nitroglycerin in a vasodilatory dose. Exogenous saline in a volume equivalent to the increase produced by nitroglycerin, however, did not attenuate the lesions. These experimental data are consistent with the clinical observation that nitrates lower the risk of aspirin-induced gastrointestinal complications. Confirmation of the efficacy of nitroglycerin and nitrates in preventing such aspirin-induced complications in controlled trials is worthy of consideration by clinical investigators.     

Etiologic Factors of Chronic Constipation—Review of the Scientific Evidence

Geriatric patient educational material and a general practice review suggest insufficient dietary fiber intake, inadequate fluid intake, decrease physical activity, side effects of drugs, hypothyroidism, sex harmones and colorectal cancer obstructin may play a role in the pathogenesis of constipation. A search of recent literature, however, reveals that there is a paucity of evidence-based publications that address the etiologic factors of chronic constipation. Much of current writings on the subject may be based primarily on myths handed down from one generation to the next. In the absence of well-designed studies, there do not appear to be sufficient evidence-based information to implicate the above as major etilogic factors in the development of chronic constipation. The etiological role of each of these factors in the development of chronic constipation deserves to be assessed by modern techniques and methodologies. Funding agencies including the government and industry sponsors should support the development of evidence-based data sets. The understanding of the etiology of chronic constipation is the foundation on which cost-effective management strategies are to be built.     

Haemodynamic effects of intravenous quinaprilat in comparison to sodium nitroprusside in patients with chronic heart failure

We compared the haemodynamic effects of intravenous boluses of the ACE inhibitor quinaprilat with an intravenous infusion of sodium nitroprusside in 23 patients with chronic heart failure (NYHA Class III or IV). At the highest drug doses, sodium nitroprusside significantly increased stroke volume index (+6.63 ml/m(2), p=0.045), whereas quinaprilat induced only a minor increase (+1.79 ml/m(2), n.s.).     

Genetic deletion of p66(Shc) adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress

Increased production of reactive oxygen species (ROS) and loss of endothelial NO bioavailability are key features of vascular disease in diabetes mellitus. The p66(Shc) adaptor protein controls cellular responses to oxidative stress. Mice lacking p66(Shc) (p66(Shc-/-)) have increased resistance to ROS and prolonged life span. The present work was designed to investigate hyperglycemia-associated changes in endothelial function in a model of insulin-dependent diabetes mellitus p66(Shc-/-) mouse. p66(Shc-/-) and wild-type (WT) mice were injected with citrate buffer (control) or made diabetic by an i.p. injection of 200 mg of streptozotocin per kg of body weight. Streptozotocin-treated p66(Shc-/-) and WT mice showed a similar increase in blood glucose. However, significant differences arose with respect to endothelial dysfunction and oxidative stress. WT diabetic mice displayed marked impairment of endothelium-dependent relaxations, increased peroxynitrite (ONOO(-)) generation, nitrotyrosine expression, and lipid peroxidation as measured in the aortic tissue. In contrast, p66(Shc-/-) diabetic mice did not develop these high-glucose-mediated abnormalities. Furthermore, protein expression of the antioxidant enzyme heme oxygenase 1 and endothelial NO synthase were up-regulated in p66(Shc-/-) but not in WT mice. We report that p66(Shc-/-) mice are resistant to hyperglycemia-induced, ROS-dependent endothelial dysfunction. These data suggest that p66(Shc) adaptor protein is part of a signal transduction pathway relevant to hyperglycemia vascular damage and, hence, may represent a novel therapeutic target against diabetic vascular complications.     

The signal environment is more important than diet or chemical specialization in the evolution of warning coloration

Aposematic coloration, or warning coloration, is a visual signal that acts to minimize contact between predator and unprofitable prey. The conditions favoring the evolution of aposematic coloration remain largely unidentified. Recent work suggests that diet specialization and resultant toxicity may play a role in facilitating the evolution and persistence of warning coloration. Using a phylogenetic approach, we investigated the evolution of larval warning coloration in the genus Papilio (Lepidoptera: Papilionidae). Our results indicate that there are at least four independent origins of aposematic larval coloration within Papilio. Controlling for phylogenetic relatedness among Papilio taxa, we found no evidence supporting the hypothesis that either diet specialization or chemical specialization facilitated the origin of aposematic larvae. However, there was a significant relationship between the signal environment and the evolution of aposematic larvae. Specifically, Papilio lineages feeding on herbaceous or narrow-leaved plants, regardless of the plants' taxonomic affiliation, were more likely to evolve aposematic larvae than were lineages feeding only on trees/shrubs or broad-leaved plants. These results demonstrate that factors other than diet specialization, such as the signal environment of predator-prey interactions, may play a large role in the initial evolution and persistence of aposematic coloration.     

Inhalation of Moli1901 in patients with cystic fibrosis

BACKGROUND: In cystic fibrosis (CF) patients, the absence or dysfunction of the chloride channel CF transmembrane conductance regulator (CFTR) results in reduced chloride ion transport in respiratory epithelial cells. Moli1901 stimulates an alternative chloride channel and may thus compensate for the CFTR deficiency in the airway epithelium of CF patients. METHODS: A phase II, placebo-controlled, double-blinded, single-center, multiple (5 consecutive days), rising-dose (daily dose, 0.5, 1.5, or 2.5 mg of Moli1901) study was conducted to investigate the safety and tolerability of multiple doses of aerosolized inhaled Moli1901 in 24 patients with CF and stable lung disease. RESULTS: Moli1901 was well tolerated in all but one CF patient, in whom a transient significant decrease in FEV(1) developed following inhalation, which resolved spontaneously, and in a second patient in whom transient throat numbness developed during drug inhalation. A significant improvement of FEV(1) was observed in the group receiving treatment with 2.5 mg/d Moli1901 compared to the group receiving placebo (p = 0.01 [Wilcoxon test]). Moli1901 was not detected in the plasma of the highest dose group. CONCLUSIONS: The inhalation of Moli1901 up to a total cumulative dose of 12.5 mg appears to be safe in adult patients with CF. In addition, Moli1901 had a sustained beneficial effect on pulmonary function, which supports further studies of its efficacy in CF patients.     

Development of a novel ERCP mechanical simulator

BACKGROUND: There is a paucity of objective methods for evaluating trainee performance and comparing ERCP accessories. OBJECTIVE: Use of a mechanical ERCP simulator to evaluate trainee performance and to compare ERCP accessories via procedure time. DESIGN: Pilot study using a mechanical simulator. SETTING: Hands-on ERCP practice workshops. SUBJECTS: Endoscopists at various levels of ERCP experience. METHOD: Validation studies are described to show that the simulator permits participants with varying ERCP experience to demonstrate their skill levels and offers novel training applications in ERCP courses. The time required for completing a simulated stent placement procedure, simulated fluoroscopy time, and participant expectations were recorded in different settings. Participants' expectations were compared before and after training to determine whether the simulator was a credible adjunct to ERCP training. RESULTS: Significantly shorter procedure times were recorded for the same accessories used by participants with more ERCP experience than those with less experience and for the same group of participants when using accessories with 1 design compared with another. The mean total credibility score showed a significant increase after simulator practice. LIMITATIONS: In vitro practice by using a mechanical simulator; results may not translate directly to the clinical setting. How the objective procedure times measured during practice can complement assessment of trainee competence or define usefulness of different accessories is unknown but deserves to be explored in future studies. CONCLUSIONS: The procedure times can categorize participants according to their ERCP experience and separate accessories according to their ease of use. An increase in credibility score validates participants' endorsement of such practice as a credible adjunct to ERCP training.     

Electromagnetic navigation diagnostic bronchoscopy in peripheral lung lesions

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) with biopsy under fluoroscopic guidance has enhanced the yield of flexible bronchoscopy in the diagnosis of peripheral lung lesions. However, the accuracy of ENB navigation suggests that the addition of fluoroscopy is redundant. OBJECTIVES: Data were prospectively collected to determine the yield of ENB without fluoroscopy in the diagnosis of peripheral lung lesions. METHOD: ENB was performed via flexible bronchoscopy (superDimension/Bronchus system; superDimension Inc; Plymouth, MN). Biopsy specimens were obtained through the extended working channel after navigation. Fluoroscopy was not utilized, but post-transbronchial biopsy chest radiographs were obtained to exclude pneumothorax. The primary end point was diagnostic yield, and the secondary end points were navigation accuracy, procedure duration, and safety. Analysis by lobar distribution was also performed to assess performance in different lobes of the lung. RESULTS: Ninety-two peripheral lung lesions were biopsied in the 89 subjects. The diagnostic yield of ENB was 67%, which was independent of lesion size. Total procedure time ranged from 16.3 to 45.0 min (mean [+/- SD] procedure time, 26.9 +/- 6.5 min). The mean navigation error was 9 +/- 6 mm (range, 1 to 31 mm). There were two incidences of pneumothorax for which no intervention was required. When analyzed by lobar distribution, there was a trend toward a higher ENB yield in diagnosing lesions in the right middle lobe (88%). CONCLUSIONS: ENB can be used as a stand-alone bronchoscopic technique without compromising diagnostic yield or increasing the risk of pneumothorax. This may result in sizable timesaving and avoids radiation exposure.     

Vitamin C blocks vascular dysfunction and release of interleukin-6 induced by endothelin-1 in humans in vivo

OBJECTIVE: Inflammation of the vessel wall is of importance in atherosclerosis. Endothelin-1 (ET-1) exerts pro-inflammatory effects and contributes to endothelial dysfunction. The objective was to test whether ET-1 impairs vascular function by increasing oxidative stress and release of pro-inflammatory cytokines in humans. METHODS: Forearm blood flow (FBF) was determined in 12 young healthy males with venous occlusion plethysmography. RESULTS: Intra-brachial infusion of ET-1 (20 pmol/min) decreased both endothelium-dependent and -independent vasodilatation (P<0.001). ET-1 also increased venous IL-6 levels (0.96+/-0.14-1.40+/-0.15 ng/ml; P<0.001). Administration of Vitamin C (24 mg/min) following the ET-1 infusion did not restore vascular function. However, pre-treatment with Vitamin C before ET-1 prevented the decrease in endothelium-dependent and -independent vasodilatation as well as the increase in IL-6 levels (1.20+/-0.28 versus 1.29+/-0.27 ng/ml; P=0.57). Infusion of a control vasoconstrictor substance, noradrenaline (80 ng/min) for 30 min did not affect IL-6 levels. CONCLUSIONS: ET-1 impairs endothelium-dependent and -independent vasodilatation and stimulates release of IL-6 in humans in vivo. These effects are inhibited by pre-treatment with the antioxidant Vitamin C. This suggests that the mechanism by which ET-1 impairs vascular function and stimulates release of IL-6 involves increased oxidative stress.     

AT1-receptor blockade with irbesartan improves peripheral but not coronary endothelial dysfunction in patients with stable coronary artery disease

Activation of the renin-angiotensin-aldosterone system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis. Studies evaluating the effect of AT1-receptor blockers on endothelial dysfunction in patients with coronary artery disease (CAD) revealed mixed results. Studies addressing the effects of AT1-receptor blockers on the coronary and peripheral function in the same study population, are still lacking. We therefore aimed to test the effects of long-term therapy with the AT1-receptor blocker irbesartan (IRB) on both, the coronary and peripheral endothelial function in patients with CAD. Seventy-two patients with CAD were randomly assigned to double-blinded treatment for 6 months with IRB 300 mg per day or placebo, respectively. Coronary and peripheral endothelial function were measured by intracoronary infusion of acetylcholine (final intracoronary concentration 10(-7.3) to 10(-5.6)M) and by determining flow-dependent dilation (FMD) of the brachial artery, respectively. IRB significantly improved FMD, while no change of coronary endothelial function was observed. Interestingly, plasma levels of N(G),N(G)-dimethyl-arginine, and the isoprostane excretion rate were not modified. IRB treatment improves peripheral but not coronary endothelial dysfunction in patients with CAD. Since reduced FMD of the brachial artery has been shown to be associated with a high-cardiovascular event rate, improvement of FMD by IRB may lead to better prognosis of patients with CAD.