Abstract: Stress is known to be one of the risk factors of stroke but only a few experimental studies have examined the possible mechanisms by which prior stress may affect stroke outcome. In stroke patients, infections impede neurological recovery and increase morbidity as well as mortality. We previously reported that stress induces a bacterial translocation and that prior immobilization stress worsens experimental stroke outcome through mechanisms that involve inflammatory mediators such as release of pro-inflammatory cytokines and enzyme activation. We now investigate whether bacterial translocation from the intestinal flora of rats with stress prior to experimental ischemia is involved in stroke outcome. We used an experimental paradigm consisting of exposure of Fischer rats to repeated immobilization sessions before permanent middle cerebral artery occlusion (MCAO). The presence of bacteria and the levels and expression of different mediators involved in the bacterial translocation were analyzed. Our results indicate that stress prior to stroke is related to the presence of bacteria in different organs (mesenteric nodes, spleen, liver and lung) after MCAO and increases inflammatory colonic parameters (such as COX-2, iNOS and MPO), but decreases colonic immunoglobulin A (IgA), and these results are related with colonic inflammation and bacterial translocation. Understanding the implication of bacterial translocation during stress-induced stroke worsening is of great potential clinical relevance, given the high incidence of infections after severe stroke and their main role in mortality and morbidity in stroke patients. Key words: stress,, stroke,, bacterial translocation,, intestinal barrier.
Abstract: BACKGROUND: Pancreatitis is a potentially severe condition. Patients with inflammatory bowel disease (IBD) seem to be at increased risk for acute pancreatitis. AIM: To describe the incidence, main causes and possible predictive factors of acute pancreatitis in inflammatory bowel disease. METHODS: Information was retrospectively extracted from the clinical records of patients followed in the IBD Units of nine hospitals in Madrid (n = 5073). RESULTS: A total of 82 acute pancreatitis episodes were diagnosed (cumulative incidence, 1.6%); 98% of them were mild. Recurrent acute pancreatitis developed in 13% of patients. Most cases of acute pancreatitis (63.4%) were attributed to drug exposure [azathioprine/mercaptopurine (AZA/MP) n = 46, mesalazine (mesalamine) n = 6]; 20.7% were idiopathic, and 12.2% were biliary. Incidence of acute pancreatitis in patients treated with AZA/MP was 3.1%. In patients with acute pancreatitis, female gender (OR 3.4 95% CI: 1.3-9.3; P = 0.012) and Crohn's disease (CD) (OR 5.8 95% CI: 1.6-20.6; P = 0.007) were risk factors for AZA/MP-associated acute pancreatitis, the latter also when analysed only in patients treated with AZA/MP (n = 1477) (OR 5.2 95% CI: 1.8-14; P = 0.002). CONCLUSIONS: The incidence of acute pancreatitis in our IBD patients (1.6%) is similar to that previously described. Drugs, mainly AZA/MP, are the leading cause. AZA-induced acute pancreatitis is always mild. Patients with CD are at a higher risk for AZA/MP-associated acute pancreatitis. The frequency of idiopathic acute pancreatitis is higher than expected, suggesting that part of these cases could be extraintestinal manifestations of IBD.
Abstract: Physical and psychological stresses are widely accepted as triggers and / or modifiers of the clinical course of diverse gastrointestinal disorders such as peptic ulcer, irritable bowel syndrome or inflammatory bowel disease. Growing experimental evidence from a variety of models such as immobilization, thermal injury or early maternal deprivation in laboratory animals uniformly supports the ability of stress to induce the development of gastric ulcers, altered gastrointestinal motility and ion secretion, and increased intestinal permeability leading to the passage of antigens to the lamina propria and bacterial translocation. Stress can also synergize with other pathogenic factors such as Helicobacter pylori, non-steroidal anti-inflammatory drugs or colitis-inducing chemicals to produce gastrointestinal disease. The brain-gut axis provides the anatomical basis through emotions and environmental influences modulate the gastrointestinal function through the regulation of gastrointestinal immune system and mucosal inflammation; in this sense, mucosal mast cells - at cellular level - and corticotropin releasing factor (CRF) - at molecular level - seem to play a crucial role. On the other hand, an array of adaptive responses have been evolved in order to maintain the homeostasis and to ensure the survival of the individual. In the gut mucosa anti-inflammatory pathways counteract the deleterious effect of the stressful stimuli on the gastrointestinal homeostasis. In the present review we discuss the several experimental approaches used to mimic human stressful events or chronic stress in laboratory animals, the evidence of stress-induced gastrointestinal inflammation and dysfunction derived from them, and the involved cellular and molecular mechanisms that are being discovered during the last years.
Abstract: BACKGROUND: Efficacy of infliximab in Crohn's disease (CD) showed by randomized controlled trials must be confirmed in clinical practice. We aimed to evaluate efficacy and safety of infliximab in CD patients of the Madrid area, looking for clinical predictors of response. METHODS: Multicenter retrospective survey of all CD patients treated with infliximab in 8 University hospitals of the Madrid area (Spain) with a minimum follow up of 14 wks. RESULTS: 169 patients included (48%males, mean age 39 +/- 12 yrs). 64% of them had perianal disease. 82% were under immunosuppressants. 1,355 infliximab infusions administered (mean 8, range 1-30). 90% response rate and 48% remission rate were obtained with induction therapy. 73% followed maintenance treatment, and 78% of them maintained or improved the response after a mean follow up of 28 months (range 3.5-86). 24 patients lost response during the follow up, after a mean of 41 wks (range 6-248). Only the prescription of maintenance therapy was predictive factor for favourable response (p < 0.01). 17 infusion reactions were reported (10% of the patients, 1.2% of the infusions; only one case was severe) and were the cause of treatment withdrawal in 7 patients. Co-treatment with immunosuppressive drugs and maintenance infliximab therapy were protective factors for infusion reactions (p < 0.05). Other adverse events occurred in 26% of the patients, and were cause of treatment withdrawal in 7 patients. CONCLUSIONS: Infliximab is effective and safe for CD management but concomitant immunosuppressive drugs and maintenance treatment should be prescribed to obtain the best outcome. That confirms in a real life clinical setting the favourable results obtained in randomized clinical trials.
Abstract: BACKGROUND: Crohn's disease patients have an increased risk for systemic thromboembolism. Their platelets are hyperactive and possess elevated endogenous content of CD40 ligand, a TNF-alpha family protein member. Under basal conditions and after stimulation, these platelets express more CD40L in their surface and release higher amounts of soluble (s)CD40L than control ones, through a mechanism that might be mediated by matrix metalloproteinases. OBJECTIVE: The aim of this work is to study whether enhanced sCD40L release secondary to changes in the platelet content of matrix metalloproteinases contributes to the higher state of activation of platelets from Crohn's disease patients. METHODS: State of activation, CD40L and metalloproteinases content of platelets isolated from patients with Crohn's disease and age- and sex-matched control individuals were analysed, respectively, by flow cytometry, western blot and gelatin zymography. RESULTS: Hyperactive state of platelets from Crohn's disease patients might rely on their enhanced sCD40L release, since its inhibition by a broad-range inhibitor of metalloproteinases (GM6001) reduced fibrinogen binding induced by platelets stimulation. Analysis of matrix metalloproteinases content in platelets from Crohn's disease patients showed an exclusive increase in MMP-9 activity. Moreover, MMP-9 inhibition diminished sCD40L release and fibrinogen binding to activated platelets. CONCLUSIONS: Our results suggest that platelets from Crohn's disease patients release more sCD40L than controls as consequence of their higher endogenous content of CD40L and of MMP-9, which is involved in CD40L shedding. The increased levels of released sCD40L might be responsible, at least in part, for the high state of activation of platelets from Crohn's disease patients.
Abstract: BACKGROUND & AIMS: Psychological stress has been implicated in the clinical course of several gastrointestinal diseases, but the mechanisms implicated and the effects of stress on the normal colon are not yet fully understood. METHODS: Male Wistar rats were exposed to various immobilization periods as a stress paradigm. Colon was processed to assess myeloperoxidase activity, nitric oxide synthase 2, cyclooxygenase 2, and peroxisome proliferator-activated receptor gamma (PPARgamma) expression and production of prostaglandins. Colonic permeability, bacterial translocation, tight junctions ultrastructure, and immunoglobulin (Ig) A levels were also evaluated. RESULTS: Exposure to acute (6 hours) immobilization stress produced an increase in myeloperoxidase activity and nitric oxide synthase 2 and cyclooxygenase 2 expression. All these parameters remained increased after 5 days of repeated stress exposure, showing a trend to normalize after 10 days. Levels of the anti-inflammatory eicosanoid 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and expression of PPARgamma run parallel with these changes. Colonic epithelial barrier was altered after stress exposure, and a significant decrease in colonic IgA levels after acute stress exposure was observed. Pretreatment with PPARgamma agonists 15d-PGJ(2) and rosiglitazone prevented colonic inflammation and barrier dysfunction as well as the decrease of IgA production induced after acute stress; PPARgamma specific antagonist T0070907 reverted these effects. CONCLUSIONS: Activation of PPARgamma in rat colon in vivo seems to counteract colonic inflammation and dysfunction induced by stress. On the other hand, PPARgamma ligands may be therapeutically useful in conditions in which inflammation and barrier dysfunction takes place in colon after exposure to stress.
Abstract: There are important individual differences in susceptibility to stress-induced diseases, most of them associated to the hypothalamic-pituitary and sympatho-medullo-adrenal axis functioning. Characterization of individual differences in animals may help to find the origin of this susceptibility. In order to study differences in oxidative and neuroinflammatory consequences in brain after stress exposure, we used an adult, male, outbred (Wistar:Hannover) population of 60 rats. Animals were subjected to 6h of immobilisation stress. Basal (1 week before stress) and post-stress (immediately after stress) plasma corticosterone (CC) was measured for each animal from the tail vein (basal: 239.74+/-19.44 ng/ml at 1500 h). Group H was assigned to animals with 33% higher levels of CC (>279.53 ng/ml) and group L to animals with 33% lower levels of CC (<199.09 ng/ml). After stress, animals with higher plasma CC levels in basal conditions showed higher adrenal response (higher post-stress CC levels) than rats with lower levels of basal CC. Furthermore, rats from H group are more vulnerable to accumulation of oxidative/nitrosative mediators in brain (higher calcium-independent nitric oxide activity and higher lipid peroxidation, by malondialdehyde determination, MDA) and also to the accumulation of proinflammatory mediators (higher PGE(2) levels) whereas showing less antiinflammatory protection (less 15-deoxy-PGJ(2) levels). Statistical analysis, by using ROC curves revealed cut-off values of basal plasma CC predicting animals with higher post-stress MDA and PGE(2) and lower PGJ(2) levels in brain. These data indicate that plasma basal levels of CC are an easily detectable and reproducible parameter for predicting the response of the individuals after an acute stress, providing further support for studies on individual differences.
Abstract: Intestinal epithelial cells (IECs) are a first line of defense against microbial pathogens that enter the host through the intestinal tract. Moreover, viral pathogens that infect the host via the intestinal epithelium are an important cause of morbidity and mortality. However, the mechanisms by which viral pathogens activate antiviral defense mechanisms in IECs are largely unknown. The synthetic dsRNA analog polyinosinic-polycytidylic acid and infection with live virus were used to probe the molecules that are activated and the mechanisms of signaling in virus-infected human IECs. Polyinosinic-polycytidylic acid activated IFN regulatory factor 3 dimerization and phosphorylation, increased activity of the IFN-stimulated response element, induced a significant increase in IFN-beta mRNA transcripts and IFN-beta secretion, and up-regulated the expression of IFN-regulated genes in IECs. Those responses were dependent upon activation of the dsRNA binding protein retinoic acid inducible gene I (RIG-I) and the RIG-I interacting protein IFN promoter stimulator-1, but not on dsRNA-activated protein kinase or TLR3, which also were expressed by IECs. Virus replication and virus-induced cell death increased in IECs in which RIG-I was silenced, consistent with the importance of the RIG-I signaling pathway in IEC antiviral innate immune defense mechanisms.
Abstract: Celiac disease (CD) is an important cause of serum aminotransferase elevation: between 5 and 10% of patients with persistent and cryptogenetic transaminase elevation may have CD. In fact, a wide spectrum of liver injuries in children and adults may be related to CD, particularly: a) mild parenchymal damage characterized by absence of any clinical signs or symptoms suggesting chronic liver disease, and by non-specific histological changes reversible on a gluten-free diet; b) chronic liver damage with autoimmune etiology, including autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis, which may be associated with CD but are generally unaffected by gluten withdrawal; and c) severe liver failure and decompensated cryptogenetic liver cirrhosis, potentially treatable with a gluten-free diet. Such different types of liver injuries may represent one same disorder where individual factors, such as genetic predisposition, precocity, and duration of exposure to gluten may influence reversibility of liver damage. A rigorous cross-checking for asymptomatic liver damage in CD individuals and, conversely, for CD in any cryptogenic liver disorder, including end-stage liver failure, is recommended.
Abstract: OBJECTIVES: To estimate the prevalence of portal hypertensive duodenopathy (PHD) in patients with cirrhosis and portal hypertension, and to evaluate its relationship with clinical and haemodynamic parameters. PATIENTS AND METHODS: Endoscopy reports and clinical history of 549 consecutive patients with cirrhosis and portal hypertension were evaluated retrospectively. A diagnosis of PHD was obtained in those patients with a congestive vascular pattern of the duodenum. RESULTS: PHD was found in 46 patients (8.4%). Previous endoscopic band ligation and coexistence of severe gastropathy were significantly more frequent in PHD group. Systemic and hepatic haemodynamic evaluations were performed in 20 patients with PHD and 160 without PHD: the mean hepatic venous pressure gradient was higher in those cases with PHD (22.5 (5.4) vs. 19.8 (5.5) mmHg, P=0.045). Hypertensive colopathy was found in seven out of the 10 patients with PHD and a colonoscopic evaluation. In five of six patients PHD disappeared after liver transplant. CONCLUSIONS: PHD is an uncommon finding of portal hypertension in cirrhotic patients. It is associated with previous endoscopic band ligation, to manifestations of portal hypertension in other sites of the gastrointestinal tract and to greater values of hepatic venous pressure gradient. The clinical relevance of this syndrome remains to be determined.
Abstract: Inflammatory bowel disease is a chronic disease with an unknown ethiology although multiple factors intervene such as individual, genetic and immunologic susceptibility, as well as different environmental factors. Like other multisystemic diseases, its clinical manifestations are diverse and it may affect other organs besides the gastrointestinal tract. In the last few years there is a growing interest for one of these extraintestinal manifestations, osteoporosis and osteopenia that may affect up to 42% of patients and can condition an important increase in morbility. Inactivity, prolonged corticosteroid treatment, nutritional deficiencies and the disease per se have an important role in the development of this complication. This article reviews clinical and ethiological aspects of inflammatory bowel disease associated osteoporosis and offers a strategy for diagnosis and treatment.
Abstract: INTRODUCTION: argon-plasma coagulation (APC) has been used safely and efficaciously in multiple settings including colon polyp treatment. The aim of this study was to evaluate APC efficacy and safety in the treatment of flat colorectal adenomas. MATERIALS AND METHODS: APC ablation was prospectively performed and evaluated in 22 consecutive patients with colorectal adenomas, 11 of which had large sessile adenomas that were treated with piecemeal polypectomy and APC ablation of residual adenomatous tissue, whereas the remaining eleven patients with flat or carpet-like adenomas were only treated with APC. The mean initial longitudinal extension of adenomas to be treated with APC was 22 mm (range, 20 to 40 mm). RESULTS: the mean age of patients was 70 years. Adenomas were found most frequently in the rectum (50%) and cecum (23%). Complete ablation was achieved in 90.9% of adenomas. Recurrence was observed in 20% of patients, all of them in the rectum, after a mean follow-up period of 16.3 months (range, 8 to 35). All recurrences were managed satisfactorily. No major complications were seen. CONCLUSIONS: argon plasma coagulator ablation of flat colorectal adenomas is an efficacious and safe technique, specially in the right colon, but results must be confirmed in controlled trials with a higher number of patients.
Abstract: OBJECTIVE: The present study analyzes inducible and neuronal nitric oxide synthase activity and expression in colonic mucosa of patients with ulcerative colitis, and correlates them with the progression of disease extent. METHODS: Thirty patients with ulcerative colitis were included. Synthases activity and expression were analyzed both in inflamed and noninflamed mucosa. After 2 yr, disease extent was determined and compared with extent at inclusion. RESULTS: Ca(2+)-independent activity, expressed as median with (interquartile range), in inflamed mucosa was higher than in noninflamed and control mucosa (102 (165-66), 24 (50-3), 1 (2.5-0.1) pmol.min(-1) mg prot(-1), respectively, p < 0.005), whereas Ca(2+)-dependent activity was significantly lower in inflamed than in noninflamed and control mucosa. Western blot analysis identified inducible and neuronal isoforms and confirmed these differences. Patients with more extended disease after 2 yr had higher levels of Ca(2+)-independent activity in noninflamed mucosa at inclusion and lower levels of Ca(2+)-dependent activity than patients with persistence of similar extent of inflammation (50 (78-29) vs 8 (30-0.1), p < 0.005; 51 (100-36) vs 150 (156-106), p < 0.05, respectively). Values of Ca(2+)-independent activity in noninflamed mucosa greater than 30 pmol. min(-1) mg prot(-1) showed 80% sensitivity and 87.5% specificity in the detection of patients with subsequent progression of disease extent, whereas values of Ca(2+)-dependent activity in noninflamed mucosa greater than 125 pmol. min(-1) mg prot(-1) showed 75% sensitivity and 80% specificity in the detection of patients with stability of disease extent. A ratio of Ca(2+)-independent/Ca(2+)-dependent activities over 0.29 showed 90% sensitivity and 87.5% specificity in the detection of patients with subsequent progression of extent. CONCLUSIONS: Our results show an up-regulation of inducible nitric oxide synthase and a down-regulation of neuronal isoform not only in inflamed mucosa but also in apparently healthy mucosa of patients with ulcerative colitis. The values of activity of both isoforms in apparently healthy mucosa could predict the disease extent after 2 yr follow-up.
Abstract: Inflammatory bowel diseases (IBDs) are multifactorial processes. Clinical and animal studies indicate that emotional stress may contribute to the onset and progress of these diseases. On the other hand, enhanced free radical production in mucosal cells has been also implicated in the pathogenesis of IBD. Using an experimental model of colitis induced by intrarectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) plus ethanol (vehicle), we sought to determine whether prior exposure to immobilization stress modifies the susceptibility to oxidative damage in colonic mucosa. Several groups of Wistar rats were used: control (C) and stressed (by immobilization of 6 hr every day during 10 days; S) groups and rats receiving a colitis-inducing dose of TNBS on day 5 (30 mg; TNBS30) and a noninflammatory dose of TNBS on day 5 (5 mg; TNBS5) with or without stress (prior exposure, days 0-5, and after, days 5-10). At the 10th day, colonic tissue was dissected and processed for biochemical studies. TNBS30 led to body weight loss, macroscopic colonic ulceration, and inflammation (determined by histological parameters and myeloperoxidase [MPO] activity) and to an increase in inducible nitric oxide synthase (NOS-2) activity and expression. TNBS5-instilled animals' body weight and biochemical inflammatory parameters were not significantly different from those in control animals. Interestingly, while stress did not modify body weight, macroscopic aspect of the mucosa, or NOS activity in animals receiving TNBS30, immobilization increased body weight loss, MPO levels, and malondialdehyde (MDA; an indicator of lipid peroxidation) levels after TNBS5. On the other hand, stress increased NOS-2 activity and immunohistochemical expression after instillation of TNBS5. Moreover, constitutive, Ca2+ -dependent NOS activity decreased in stressed animals instilled with TNBS5 compared with nonstressed animals receiving TNBS5 (-28.5 +/- 6.6%; P < 0.05). These findings indicate that previous exposure to stressful stimuli is a factor in susceptibility to oxidative damage in experimental colitis and support a possible protective effect of treatment of stress before and during the development of inflammation in the colon.
Abstract: Mushroom poisoning, mainly due to the Amanita genus, is an infrequent cause of liver failure in our environment. However, because of its high morbidity and mortality, it constitutes a medical emergency. The characteristic initial symptoms of vomiting, abdominal pain, and diarrhea are nonspecific and may be confused with gastroenteritis. If correct and early treatment is not given, renal and hepatic failure can develop, sometimes requiring liver transplantation. We present three cases of mushroom poisoning, which presented a different clinical course ranging from complete recovery with traditional medical treatment to severe acute liver failure requiring transplantation in one patient and albumin dialysis (molecular absorbent recycling system [MARS]) in another with favorable outcome. Although controlled clinical studies of the treatment of mushroom poisoning are lacking, recommendations based on the experience of various authors have been established. Penicillin G and silymarin seem to be useful. The development of new techniques of extracorporeal detoxification, mainly MARS, may represent an important support system in the treatment of these patients.
Abstract: 3,4-methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, known as ecstasy. Because of its euphoric effects, the use of this substance as a drug of abuse is becoming increasingly widespread. The development of hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure, cardiac arrhythmia and neurotoxicity have been described in association with the use of this drug. Moreover, in the last few years, cases of liver involvement, associated or not with the above-mentioned entities, have been described, ranging from mild acute hepatitis to fulminant hepatic failure and death. We present four cases of ecstasy-induced hepatotoxicity. Outcome was favorable in three patients while the fourth required liver transplantation. Consequently, ecstasy ingestion should be ruled out as a cause of acute non-viral hepat
Abstract: Tumour necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine which is shed in its soluble form by a disintegrin and metalloproteinase (ADAM) called TNF-alpha convertase (TACE; ADAM17). TNF-alpha plays a role in inflammatory bowel disease (IBD) and is involved in the expression of inducible nitric oxide synthase (iNOS) which has also been implicated in IBD. The study was designed to investigate whether colitis induced by trinitrobenzene sulphonic acid (TNBS) in rats produces an increase in TACE activity and/or expression and whether its pharmacological inhibition reduces TNF-alpha levels, iNOS expression and colonic damage in this model. TNBS (30 mg in 0.4 ml of 50% ethanol) was instilled into the colon of female Wistar rats. Saline or TACE inhibitor BB1101 (10 mg/kg/day) was administered intraperitoneally 5 days after TNBS instillation. On day 10, colons were removed and assessed for pathological score, myeloperoxidase (MPO), NO synthase (NOS), TACE enzymatic activity and protein levels, colonic TNF-alpha and NOx- levels. Instillation of TNBS caused an increase in TACE activity and expression and the release of TNF-alpha. TNBS also resulted in iNOS expression and colonic damage. BB1101 blocked TNBS-induced increase in TACE activity, TNF-alpha release and iNOS expression. Concomitantly, BB1101 ameliorated TNBS-induced colonic damage and inflammation. TNBS causes TNF-alpha release by an increase in TACE activity and expression and this results in the expression of iNOS and subsequent inflammation, suggesting that TACE inhibition may prove useful as a therapeutic means in IBD.
Abstract: Gastrointestinal inflammation has been associated with an increased generation of nitric oxide (NO) and the expression of the inducible NO synthase (iNOS). Using an experimental model of colitis induced by trinitrobenzene sulphonic acid (TNBS), we sought to determine whether the administration of N-(3-(Aminomethyl)benzyl)acetamidine (1400W), a specific inhibitor of iNOS, has a beneficial action on the colonic injury. 1400W (0.4 and 2 mg/kg/day) was administered intraperitoneally from day 5 to 10 after intrarectal instillation of TNBS. TNBS led to colonic ulceration and inflammation, an increase of colonic myeloperoxidase activity and the expression of the calcium-independent NOS from days 1 to 15. 1400W reduced the macroscopic damage and the histological changes induced by TNBS as well as the calcium-independent NOS activity and myeloperoxidase activity determined over 30 min after sacrifice. These findings indicate that the expression of iNOS accounts for most of the damage caused by TNBS and that the administration of 1400W after the onset of colitis has a beneficial action on the colonic injury.
