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Bile duct ligation in rats: A reliable model of hepatorenal syndrome?

World Journal of Gastroenterology 2009年第1期15卷 121-123页

作者： Stelios F Assimakopoulos constantine e vagianos Department of Internal Medicine University Hospital of PatrasPatras 26504 Greece First Surgical Department "Saint Panteleimon" General Hospital of NikaiaPiraeus 18454Greece

The two most widely used experimental models of advanced liver disease are the administration of carbon tetrachloride, and common bile duct ligation (BDL), however, neither has been systematically evaluated as a model of hepatorenal syndrome (HRS). The BDL model in rats, studied at diverse time points, induced a progressive renal dysfunction without structural changes in the kidney. The authors concluded that BDL is a good model for further studies of HRS and its treatment. However, the renal impairment observed at the acute phase of the BDL model is based on a different pathophysiology than that of HRS. Specifi cally, in acute obstructive jaundice, cholemia predominates over parenchymal liver disease (reversible at this stage without portal hypertension or cirrhosis) and independently induces negative inotropic and chronotropic effects on the heart, impaired sympathetic vasoconstriction response and profound natriuresis and diuresis that might lead to volume depletion. In addition, systemic endotoxemia contributes to the prerenal etiology of renal impairment and promotes direct nephrotoxicity and acute tubular necrosis. On the other hand, the renal failure observed in the chronic BDL model (with development of biliary cirrhosis, portal hypertension and ascites) shares pathophysiological similarities with HRS, but the accordance of the chronic BDL model to the diagnostic criteria of HRS (e.g. absence of spontaneous bacterial peritonitis, no renal function improvement after plasma volume expansion) should have been confirmed. In conclusion, we think that the BDL model is not suitable for the study of the natural history of HRS, but the chronic BDL model might be valid for the study of established HRS and its potential therapies.

关键词： Obstructive jaundice Rats Bile ductligation Hepatorenal syndrome Renal failure

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Pleiotropic effects of bombesin and neurotensin on intestinal mucosa: Not just trefoil peptides

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World Journal of Gastroenterology 2008年第22期14卷 3602-3603页

作者： Stelios F Assimakopoulos Chrisoula D Scopa Vassiliki N Nikolopoulou constantine e vagianos Department of Internal Medicine School of Medicine University of Patras Patras 26110 Greece Department of Pathology School of Medicine University of Patras Patras 26110 Greece Division of Gastroenterology Department of Internal Medicine School of Medicine University of Patras Patras 26110 Greece First Surgical Department "Saint Panteleimon" General Hospital of Nikaia Piraeus 18454 Greece

Bombesin and neurotensin are neuropeptides which exert a wide spectrum of biological actions on gastrointestinal tissues influencing intestinal growth and adaptation, intestinal motility, blood flow, secretion, nutrient absorption and immune response. Based mainly on their well-established potent enterotrophic effect, numerous experimental studies investigated their potential positive effect on the atrophic or injured intestinal mucosa. These peptides proved to be effective mucosa-healing factors, but the potential molecular and cellular mechanisms for this action remained unresolved. In a recently published study (World J Gastroenterol 2008; 14(8): 1222-1230), it was shown that their protective effect on the intestine in experimentally induced inflammatory bowel disease was related to anti-inflammatory, antioxidant and antiapoptotic actions. These results are in close agreement with our previous studies on jaundiced and hepatectomized rats that showed a regulatory effect of bombesin and neurotensin on critical cellular processes such as enterocyte' proliferation and death, oxidative stress and redox equilibrium, tight junctions' formation and function, and inflammatory response. The pleiotropic effects of bombesin and neurotensin on diverse types of intestinal injury may justify their consideration for clinical trials.

关键词： Bombesin Neurotensin Pleiotropic Neuropeptides Regulatory peptides

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Intestinal failure in obstructive jaundice

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World Journal of Gastroenterology 2005年第24期11卷 3806-3807页

作者： Stelios F.Assimakopoulos constantine e.vagianos Aristides Charonis Vassiliki N.Nikolopoulou Chrisoula D.Scopa Department of Internal Medicine Department of Surgery Laboratory of Cell Biology Department of Pathology

TO THe eDITORWe read with great interest the article by Ding LA and LiJS, which aimed to review the current knowledge on the physiology of normal intestinal barrier function and highlight the role of intestinal failure after various injurious insults in the development of septic complications or multiple organ failure with subsequent rapid clinical deterioration or even death.

关键词： Intestinal failure Obstructive jaundice

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Unilateral leg edema in a cirrhotic patient with tense ascites

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World Journal of Gastroenterology 2006年第35期12卷 5746-5747页

作者： Stelios F Assimakopoulos Konstantinos C Thomopoulos Christine Kalogeropoulou Ioannis Maroulis Alexandra Lekkou Christos Papakonstantinou constantine e vagianos Charalambos Gogos Department of Internal Mcdicine School of MedieineUniversity of PatrasPatrasgreece Department of Radiology School of MedicineUniversity of Patraspatrasgreece Department of surgery School of MedicineUniversity of palrasPatrasGreece

TO THe eDITOR　　A 61 year old man with cirrhosis and hepatocellular carcinoma developed on the background of chronic hepatitis B was admitted because of acute and gradually intensified right thigh pain and swelling, which, within a few hours, was expanded to his right foot. The patient,due to ascites refractory to diuretics, was almost weekly subjected to large volume paracentesis of ascitic fluid for the last six months; meanwhile he has developed a left inguinal, a right femoral and an umbilical hernia. It should be noted that 48 h before admission, the patient was referred to the emergency room because of dyspnoea and 5 L of ascitic fluid were removed.

关键词： Leg edema Tense ascites CirrhosisAssimakopoulos SF, Thomopoulos KC, Kalogeropoulou

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Pathophysiology of increased intestinal permeability in obstructive jaundice

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World Journal of Gastroenterology 2007年第48期13卷 6458-6464页

作者： Stelios F Assimakopoulos Chrisoula D Scopa constantine e vagianos Department of Internal Medicine School of Medicine University of Patras Department of Pathology School of Medicine University of Patras 1~(st) Surgical Department "Saint Panteleimon" General Hospital of Nikaia

Despite advances in preoperative evaluation and postoperative care, intervention, especially surgery, for relief of obstructive jaundice still carries high morbidity and mortality rates, mainly due to sepsis and renal dysfunction. The key event in the pathophysiology of obstructive jaundice-associated complications is endotoxemia of gut origin because of intestinal barrier failure. This breakage of the gut barrier in obstructive jaundice is multi-factorial, involving disruption of the immunologic, biological and mechanical barrier. experimental and clinical studies have shown that obstructive jaundice results in increased intestinal permeability. The mechanisms implicated in this phenomenon remain unresolved, but growing research interest during the last decade has shed light in our knowledge in the field. This review summarizes the current concepts in the pathophysiology of obstructive jaundice-induced gut barrier dysfunction, analyzing pivotal factors, such as altered intestinal tight junctions expression, oxidative stress and imbalance of enterocyte proliferation and apoptosis. Clinicians handling patients with obstructive jaundice should not neglect protecting the intestinal barrier function before, during and after intervention for the relief of this condition, which may improve their patients’ outcome.

关键词： Obstructive jaundice Intestinal barrier Intestinal permeability endotoxemia Bacterial translocation Tight junctions Occludin Claudin-4 Apoptosis Oxidative stress

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Acute upper gastrointestinal bleeding in operated stomach: Outcome of 105 cases

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World Journal of Gastroenterology 2005年第29期11卷 4570-4573页

作者： Vassiliki N Nikolopoulou Konstantinos C Thomopoulos George I Theocharis Vassiliki A Arvaniti constantine e vagianos Division of Gastroenterology Department of Internal Medicine University Hospital Patras Greece Department of Surgery University Hospital Patras Greece

AIM: To compare the causes and clinical outcome of patients with acute upper gastrointestinal bleeding (AUGB) and a history of gastric surgery to those with AUGB but without a history of gastric surgery in the ***: The causes and clinical outcome were compared between 105 patients with AUGB and a history of gastric surgery, and 608 patients with AUGB but without a history of gastric ***: Patients who underwent gastric surgery in the past were older (mean age: 68.1±11.7 years vs 62.8±17.8 years, P= 0.001), and the most common cause of bleeding was marginal ulcer in 63 patients (60%). No identifiable source of bleeding could be found in 22 patients (20.9%) compared to 42/608 (6.9%) in patients without a history of gastric surgery (P = 0.003). endoscopic hemostasis was permanently successful in 26 out of 35 patients (74.3%) with peptic ulcers and active bleeding or non-bleeding visible vessel. Nine patients (8.6%) were operated due to continuing or recurrent bleeding,compared to 23/608 (3.8%) in the group of patients without gastric surgery in the past (P= 0.028). especially in peptic ulcer bleeding patients, emergency surgery was more common in the group of patients with gastric surgery in the past [9/73 (12.3%) vs 19/360 (5.3%), P = 0.025].Moreover surgically treated patients in the past required more blood transfusion (3.3±4.0 vs 1.5±1.7, P = 0.0001) and longer hospitalization time (8.6±4.0 vs 6.9±4.9 d,P = 0.001) than patients without a history of gastric surgery. Mortality was not different between the two groups [4/105 (3.8%) vs 19/608 (3.1%)].CONCLUSION: Upper gastrointestinal bleeding seems to be more severe in surgically treated patients than in non-operated patients.

关键词： Operated stomach Active bleeding endoscopic hemostasis

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experimental obstructive jaundice alters claudin-4 expression in intestinal mucosa: effect of bombesin and neurotensin

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World Journal of Gastroenterology 2006年第21期12卷 3410-3415页

作者： Stelios F Assimakopoulos constantine e vagianos Aristides S Charonis Ilias H Alexandris Iris Spiliopoulou Konstantinos C Thomopoulos Vassiliki N Nikolopoulou Chrisoula D Scopa Department of Internal Medicine School of Medicine University of PatrasPatrasGreece Department of Surgery School of Medicine University of PatrasPatrasGreece Section of Histology Center for Basic Research Foundation of Biomedical Research of the Academy of AthensAthensGreece Department of Microbiology School of Medicine University of PatrasPatrasGreece Department of Internal Medicine Division of Gastroenterology School of MedicineUniversity of PatrasPatrasGreece Department of Pathology School of Medicine University of PatrasPatrasGreece

AIM： To investigate the influence of experimental obstructive jaundice and exogenous bombesin （BBS） and neurotensin （NT） administration on the expression of the tight junction （TJ）-protein claudin-4 in intestinal epithelium of rats. MeTHODS： Forty male Wistar rats were randomly divided into five groups： Ⅰ = controls, Ⅱ = sham operated,Ⅲ = bile duct ligation （BDL）,Ⅳ = BDL＋BBS （30μg/kg per d）, V = BDL＋NT （300μg/kg per d）. At the end of the experiment on d 10, endotoxin was measured in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically and immunohistochemically for evaluation of claudin-4 expression in intestinal epithelium. ReSULTS： Obstructive jaundice led to intestinal barrier failure demonstrated by significant portal and aortic endotoxemia. Claudin-4 expression was significantly increased in the upper third of the villi in jaundiced rats and an upregulation of its lateral distribution was noted. Administration of BBS or NT restored claudin-4 expression to the control state and significantly reduced portal and aortic endotoxemia. CONCLUSION： experimental obstructive jaundice increases claudin-4 expression in intestinal epithelium,which may be a key factor contributing to the disruption of the mucosal barrier. Gut regulatory peptides BBS and NT can prevent this alteration and reduce portal and systemic endotoxemia.

关键词： Obstructive jaundice Tight junctions Claudin-4 Intestinal permeability Intestinal barrier Regulatory peptides Bombesin Neurotensin

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effect of bombesin and neurotensin on gut barrier function in partially hepatectomized rats

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World Journal of Gastroenterology 2005年第43期11卷 6757-6764页

作者： Stelios F Assimakopoulos Ilias H Alexandris Chrisoula D Scopa Panagiotis G Mylonas Konstantinos C Thomopoulos Christos D Georgiou Vassiliki N Nikolopoulou constantine e vagianos Department of Internal Medicine Department of Surgery Department of Pathology Department of Internal edicine Department of Biology

AIM： To investigate the effect of regulatory peptides bombesin （BBS） and neurotensin （NT） on intestinal barrier function in partially hepatectomized rats. MeTHODS： Ninety male Wistar rats were randomly divided into five groups： Ⅰ （n = 10）： controls, Ⅱ （n = 20）： sham operated, Ⅲ （n = 20）： partial hepatectomy 70% （PHx）, Ⅳ （n = 20）： PHx＋BBS （30 μg/kg/d）, Ⅴ （n = 20）： PHx＋NT （300 μg/kg/d）. Groups IV and V were treated for 8 days before PHx and 48 h post surgery. At the end of the experiment, on day 10, intestinal barrier function was assessed by measuring endotoxin concentrations in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically and villus density, mucosal thickness, mitotic activity and apoptosis in crypts were assessed. In addition, ileal mucosa was analyzed for DNA and protein content and microbiological analysis was performed in cecal contents. To estimate intestinal oxidative stress, lipid peroxidation was determined on tissue homogenates from terminal ileum. ReSULTS： BBS or NT administration significantly reduced portal and systemic endotoxemia observed 48 h after partial hepatectomy. In hepatectomized rats （group Ⅲ）, a trend towards induction of mucosal atrophy was observed, demonstrated by the reduction of villus density, mucosal thickness, protein content and significant reduction of DNA, while these alterations were reversed by regulatory peptides administration. This trophic effect of BBS and NT was accompanied by induction of mitoses above control levels and a significant reduction of apoptosis in intestinal crypts. Intestinal lipid peroxidation was found significantly lower in PHx group and regulatory peptides exerted an antioxidant action, further decreasing this parameter of oxidative stress. The ：bacterial population of e. coli and aerobic Gram （＋） cocci was increased in cecal content of hepatectomized rats, while this parameter was not affected by the administration of BBS or NT. CONCLUSION： Gut regulatory pep

关键词： Hepatectomy Rats Bombesin Neurotensin Intestinal barrier Apoptosis Oxidative stress

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Stimulation of oval cell and hepatocyte proliferation by exogenous bombesin and neurotensin in partially hepatectomized rats

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World Journal of Gastrointestinal Pathophysiology 2011年第6期2卷 146-154页

作者： Stelios F Assimakopoulos Athanassios C Tsamandas Ilias H Alexandris Christos Georgiou constantine e vagianos Chrisoula D Scopa Department of Internal Medicine University Hospital of PatrasPatras 26504Greece Department of Pathology University Hospital of PatrasPatras 26504Greece Department of Surgery General Hospital of AmfissaAmfissa 33100Greece Department of Biology Section of GeneticsCell Biology and DevelopmentUniversity of PatrasPatras 26100Greece 1st Department of Surgical "Saint Panteleimon"General Hospital of NikaiaPiraeus 18454Greece

AIM:To investigate the effect of the neuropeptides bombesin(BBS)and neurotensin(NT)on oval cell proliferation in partially hepatectomized rats not pretreated with a known hepatocyte ***:Seventy male Wistar rats were randomly divided into five groups:Ⅰ=controls,Ⅱ=sham operated,Ⅲ=partial hepatectomy 70%(PHx),Ⅳ=PHx+ BBS(30μg/kg per day),Ⅴ=PHx+NT(300μg/kg per day).Forty eight hours after liver resection,portal en-dotoxin levels and hepatic glutathione redox state were determined.α-fetoprotein(AFP)mRNA(in situ hybridisation),cytokeratin-19 and Ki67 antigen expression (immunohistochemistry)and apoptosis(TUNeL)were evaluated on liver tissue *** with morphological features of oval cells that were cytokeratin-19 (+)and AFP mRNA(+)were scored in morphometric analysis and their proliferation was *** addition,the proliferation and apoptotic rates of hepatocytes were ***:In the control and sham operated groups,oval cells were significantly less compared to groups Ⅲ,ⅣandⅤ(Pe neuropeptides BBS and NT significantly increased the proliferation of oval cells compared to groupⅢ(Ped a significant increase of hepatocyte proliferation(Pereas it decreased their apoptotic activity(Ped to groupⅢ.BBS and NT significantly decreased portal endotoxemia (Peased the hepatic GSH:GSSG ratio (Pespectively)compared to groupⅢ.CONCLUSION:BBS and NT stimulated oval cell proliferation in a model of liver regeneration,without use of concomitant suppression of hepatocyte proliferation as oval cell activation stimuli,and improved the hepatocyte regenerative *** peptides-induced combined stimulation of oval cell and hepatocyte proliferation might serve as a possible treatment modality for several liver diseases.

关键词： Liver regeneration Partial hepatectomy Hepatic progenitor cells Oval cells Apoptosis Proliferation Oxidative stress

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STRONG SHOCKS IN NONISeNTROPIC GAS DYNAMICS

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Acta Mathematica Scientia 2009年第4期29卷 973-979页

作者： constantine M. Dafermos Division of Applied Mathematics Brown University

In nonisentropic gas dynamics, with general equations of state, strong cornpressive shocks satisfying the Liu e-condition may violate the Second Law of thermodynamics.

关键词： gas dynamics entropy Lax e-condition Liu e-condition

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