In cirrhosis, increased RhoA/Rho-kinase signaling and decreased nitric oxide (NO) availability contribute to increased intrahepatic resistance and portal hypertension. Hepatic stellate cells (HSCs) regulate intrahepatic resistance. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) inhibit synthesis of isoprenoids, which are necessary for membrane translocation and activation of small GTPases like RhoA and Ras. Activated RhoA leads to Rho-kinase activation and NO synthase inhibition. We therefore investigated the effects of atorvastatin in cirrhotic rats and isolated HSCs. Rats with secondary biliary cirrhosis (bile duct ligation, BDL) were treated with atorvastatin (15 mg/kg per day for 7 days) or remained untreated. Hemodynamic parameters were determined in vivo (colored microspheres). Intrahepatic resistance was investigated in in situ perfused livers. Expression and phosphorylation of proteins were analyzed by RT-PCR and immunoblots. Three-dimensional stress-relaxed collagen lattice contractions of HSCs were performed after incubation with atorvastatin. Atorvastatin reduced portal pressure without affecting mean arterial pressure in vivo. This was associated with a reduction in intrahepatic resistance and reduced responsiveness of in situ-perfused cirrhotic livers to methoxamine. Furthermore, atorvastatin reduced the contraction of activated HSCs in a 3-dimensional stress-relaxed collagen lattice. In cirrhotic livers, atorvastatin significantly decreased Rho-kinase activity (moesin phosphorylation) without affecting expression of RhoA, Rho-kinase and Ras. In activated HSCs, atorvastatin inhibited the membrane association of RhoA and Ras. Furthermore, in BDL rats, atorvastatin significantly increased hepatic endothelial nitric oxide synthase (eNOS) mRNA and protein levels, phospho-eNOS, nitrite/nitrate, and the activity of the NO effector protein kinase G (PKG). Conclusion: In cirrhotic rats, atorvastatin inhibits hepatic RhoA/Rhokinase signaling and activates the NO/PKG-pathway. This lowers intrahepatic resistance, resulting in decreased portal pressure. Statins might represent a therapeutic option for portal hypertension in cirrhosis. (HEPATOLOGY 2007;46:242-253.)
In this randomized controlled multicenter trial, we compared endoscopic variceal banding ligation (VBL) with propranolol (PPL) for primary prophylaxis of variceal bleeding. One hundred fifty-two cirrhotic patients with 2 or more esophageal varices (diameter >5 mm) without prior bleeding were randomized to VBL (n ؍ 75) or PPL (n ؍ 77). The groups were well matched with respect to baseline characteristics (age 56 ؎ 10 years, alcoholic etiology 51%, Child-Pugh score 7.2 ؎ 1.8). The mean follow-up was 34 ؎ 19 months. Data were analyzed on an intention-to-treat basis. Neither bleeding incidence nor mortality differed significantly between the 2 groups. Variceal bleeding occurred in 25% of the VBL group and in 29% of the PPL group. The actuarial risks of bleeding after 2 years were 20% (VBL) and 18% (PPL). Fatal bleeding was observed in 12% (VBL) and 10% (PPL). It was associated with the ligation procedure in 2 patients (2.6%). Overall mortality was 45% (VBL) and 43% (PPL) with the 2-year actuarial risks being 28% (VBL) and 22% (PPL). 25% of patients withdrew from PPL treatment, 16% due to side effects. In conclusion, VBL and PPL were similarly effective for primary prophylaxis of variceal bleeding. VBL should be offered to patients who are not candidates for longterm PPL treatment. (HEPATOLOGY 2004;40:65-72.) U pper intestinal hemorrhage is a common and often fatal complication of portal hypertension. It occurs in 30% of patients with cirrhosis, with each bleeding episode bearing a mortality risk of 30% to 50%. 1-3 Thus, prophylactic treatment prior to the first bleeding (i.e., primary prophylaxis) is mandatory in highrisk patients. 4,5 Nonselective -blockers (i.e., propranolol, nadolol)-the current standard prophylaxis-reduce bleeding incidence and bleeding-related mortality. 6 -9 However, pharmacotherapy with -blockers is not optimal: 30% to 40% of patients will not achieve a sufficient reduction of portal pressure to prevent bleeding. 10 -12 Furthermore, contraindications and side effects are common 13,14 and may require withdrawal, which reincreases the risk of bleeding. 15 Therefore, therapeutic alternatives to -blockers are warranted. Due to heterogeneous results, prophylactic endoscopic sclerotherapy is not recommended for the primary prevention of variceal bleeding. 5,7 Compared to injection sclerotherapy, 16 variceal banding ligation (VBL) allows a more rapid and more effective eradication of varices with fewer side effects. 17 To date, only 2 trials comparing VBL with standard treatment (-blockers) have been fully published. 13,18 The results of these studies are controversial and partly inconclusive. In the present article, we report on the results of a prospective randomized multicenter trial comparing propranolol (PPL) and banding ligation for the primary prophylaxis of variceal bleeding in patients with cirrhosis.
In neutropenic patients the disease entities Ôfever of unknown originÕ (FUO) and ÔpneumoniaÕ have been clearly assessed in numerous prospective studies. Abdominal infections are less frequent but relevant life-threatening complications. Among these, neutropenic enterocolitis is the most important clinical entity, whereas cholecystitis, appendicitis and hepatolienal candidiasis are less common. Neutropenic enterocolitis occurs most frequently after intensive chemotherapy in acute leukaemias. The reported incidences of neutropenic enterocolitis in adults in the literature vary considerably from 0.8% to 26% (1, 2). Several authors observed mortality rates of 50% and higher (3-6).The practitioner, looking for good evidence facilitating his decisions concerning diagnosis and treatment of a neutropenic patient suffering from fever and abdominal pain has a difficult problem. A MEDLINE search produces numerous hits suggesting a broad data basis at the first look. However, the potential for costly time loss by disorganised searching within articles of a very low grade of evidence is great. The vast majority of the literature on this subject consists of case reports and smaller retrospective case series. A systematic review is not available.In guidelines dealing with infections in neutropenia (IDSA, DGHO and NCCN) (7-9) very few Abstract: Objective: Neutropenic enterocolitis is a life-threatening complication occurring most frequently after intensive chemotherapy in acute leukaemias. The literature is heterogenous and a systematic review is lacking. Methods: Following a systematic search we categorised all relevant reports according to their quality and extracted evidence to answer the questions: Which diagnostic criteria are appropriate? What is the incidence of neutropenic enterocolitis? Are there good quality studies supporting specific interventions: Which empiric antimicrobial therapy is recommendable? Is neutropenic enterocolitis without surgical emergency complications an indication for bowel resection? Results: We found and analysed 145 articles of these reports: 64 were reports of single cases, 30 papers reported of two or three cases, 13 were narrative reviews, 34 were retrospective case series of more than three cases and four were prospective diagnostic studies. There were no prospective trials or case control studies on the therapy of neutropenic enterocolitis. There was no consensus on diagnostic criteria. We discuss the difficulty to define diagnostic criteria without having a disease definition. Histology is mostly not available in the living patients. We suggest applying a combination of clinical and radiological criteria: fever, abdominal pain and any bowel wall thickening >4 mm detected by ultrasonography (US) or computed tomography. We calculated a pooled incidence rate from 21 studies of 5.3% (266/5058; 95% CI: 4.7%-5.9%) in patients hospitalised for haematological malignancies, for high-dose chemotherapy in solid tumours or for aplastic anaemia. Conclusions: This systematic review provides diagnostic...
Placement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.
ObjectivesThe Endocuff is a device mounted on the tip of the colonoscope to help flatten the colonic folds during withdrawal. This study aimed to compare the adenoma detection rates between Endocuff-assisted (EC) colonoscopy and standard colonoscopy (SC).MethodsThis randomized prospective multicenter trial was conducted at four academic endoscopy units in Germany. Participants: 500 patients (235 males, median age 64[IQR 54–73]) for colon adenoma detection purposes were included in the study. All patients were either allocated to EC or SC. The primary outcome measure was the determination of the adenoma detection rates (ADR).ResultsThe ADR significantly increased with the use of the Endocuff compared to standard colonoscopy (35.4%[95% confidence interval{CI} 29–41%] vs. 20.7%[95%CI 15–26%], p<0.0001). Significantly more sessile polyps were detected by EC. Overall procedure time and withdrawal time did not differ. Caecal and ileum intubation rates were similar. No major adverse events occurred in both groups. In multivariate analysis, age (odds ratio [OR] 1.03; 95%[CI] 1.01–1.05), male sex (OR 1.74; 95%CI 1.10–2.73), withdrawal time (OR 1.16; 95%CI 1.05–1.30), procedure time (OR 1.07; 95%CI 1.04–1.10), colon cleanliness (OR 0.60; 95%CI 0.39–0.94) and use of Endocuff (OR 2.09; 95%CI 1.34–3.27) were independent predictors of adenoma detection rates.ConclusionsEC increases the adenoma detection rate by 14.7%(95%CI 6.9–22.5%). EC is safe, effective, easy to handle and might reduce colorectal interval carcinomas.Trial RegistrationClinicalTrials.gov NCT02034929.
The use of the EC is feasible and safe with significantly higher polyp detection rates, especially for those located in the sigmoid region. The cuff system has the potential to improve the accuracy of screening colonoscopies.
In cirrhosis, vascular hypocontractility leads to vasodilation and contributes to portal hypertension. Impaired activation of contractile pathways contributes to vascular hypocontractility. Angiotensin II type 1 receptors (AT 1 -Rs) are coupled to the contraction-mediating RhoA/Rhokinase pathway and may be desensitized by phosphorylation through G-protein-coupled receptor kinases (GRKs) and binding of -arrestin-2. In the present study, we analyzed vascular hypocontractility to angiotensin II in cirrhosis. Human hepatic arteries were obtained during liver transplantation. In rats, cirrhosis was induced by bile duct ligation (BDL). Contractility of rat aortic rings was measured myographically. Protein expression and phosphorylation were analyzed by Western blot analysis. Immunoprecipitation was performed with protein A-coupled Sepharose beads. Myosin light chain (MLC) phosphatase activity was assessed as dephosphorylation of MLCs. Aortas from BDL rats were hyporeactive to angiotensin II and extracellular Ca 2؉ . Expression of AT 1 -R and G␣ q/11,12,13 remained unchanged in hypocontractile rat and human vessels, whereas GRK-2 and -arrestin-2 were up-regulated. The binding of -arrestin-2 to the AT 1 -R was increased in hypocontractile rat and human vessels. Inhibition of angiotensin II-induced aortic contraction by the Rho-kinase inhibitor Y-27632 was pronounced in BDL rats. Basal phosphorylation of the ROK-2 substrate moesin was reduced in vessels from rats and patients with cirrhosis. Analysis of the expression and phosphorylation of Ca 2؉ -sensitizing proteins (MYPT1 and CPI-17) in vessels from rats and patients with cirrhosis suggested decreased Ca 2؉ sensitivity. Angiotensin II-stimulated moesin phosphorylation was decreased in aortas from BDL rats. MLC phosphatase activity was elevated in aortas from BDL rats. Conclusion: Vascular hypocontractility to angiotensin II in cirrhosis does not result from changes in expression of AT 1 -Rs or G-proteins. Our data suggest that in cirrhosis-induced vasodilation, the AT 1 -R is desensitized by GRK-2 and -arrestin-2 and that changed patterns of phosphorylated Ca 2؉ -sensitizing proteins decrease Ca 2؉ sensitivity. (HEPATOLOGY 2007;45:495-506.)
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