Inflammatory cell distribution in colon mucosa as a new tool for diagnosis of irritable bowel syndrome: A promising pilot study.

BACKGROUND: Currently, there are no histological criteria to diagnose irritable bowel syndrome (IBS). Our aims were (i) to examine the distribution of inflammatory cells in the colon of healthy and IBS subjects and (ii) to find histological diagnosis criteria for IBS. METHODS: Colonic biopsies were taken from four distinct regions of the colon from 20 controls (HC) and 11 patients with IBS (4 with constipation (IBS-C) and 7 with diarrhea (IBS-D) and embedded in paraffin. Macrophages, mast cells, eosinophils, and T lymphocytes were immunostained and positive cells counted. KEY RESULTS: In both HC and IBS patients, global cellularity decreased from the cecum to the rectum (P < .01) which is attributed to reduced number of macrophages (P < .05) and eosinophils (P < .001) but not T cells. Mast cells were reduced in IBS (P < .05) but not in HC, particularly in IBS-D (P < .05). Results showed higher number of macrophages in the left colon of IBS subjects than HC (P < .05). CONCLUSION & INFERENCES: Here we report a decreasing gradient of immune cells from the cecum to the rectum of the human colon. Although global cellularity cannot be used to distinguish between IBS and HC, closer analysis of macrophages and mast cells may be useful markers to confirm IBS histologically and to differentiate between IBS-C and IBS-D when clinical presentation alternates between constipation and diarrhoea. This pilot study remains to be confirmed with greater number of patients.

ER stress induces NLRP3 inflammasome activation and hepatocyte death.

The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1ß secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1ß secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

Osteopontin deficiency aggravates hepatic injury induced by ischemia-reperfusion in mice.

Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia-reperfusion (I-R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn(-/-) mice compared with wild-type (Wt) mice after I-R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn(-/-) mice versus Wt mice after I-R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen-glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn(-/-) mice versus Wt mice livers after I-R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I-R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.

Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation.

OBJECTIVE: To determine the role of colonic barrier defects and low-grade inflammation in irritable bowel syndrome (IBS)-like symptoms in quiescent inflammatory bowel disease (IBD). DESIGN: Caecal biopsies were collected from 51 IBS, 49 quiescent IBD (31 Crohn's disease (CD) and 18 ulcerative colitis (UC)) patients and 27 controls. IBS was assessed using the Rome III criteria and the IBS severity score. Epithelial barrier integrity was evaluated by determining the paracellular permeability of biopsies mounted in Ussing chambers and the mRNA expression of tight junction proteins (ZO-1, α-catenin and occludin). Low-grade inflammation was evaluated by counting cells, including intraepithelial lymphocytes (IELs), eosinophils and mast cells, and by determining the mRNA and protein expression of tumour necrosis factor (TNF)-α in biopsies and culture supernatants. RESULTS: IBS-like symptoms were present in 35.4 and 38% of CD and UC patients, respectively. Paracellular permeability was significantly increased in both quiescent IBD with IBS-like symptoms and IBS compared with quiescent IBD without IBS-like symptoms (p<0.01, respectively) or controls (p<0.01, respectively). Significantly lower expression of ZO-1 and α-catenin was detected in IBS and quiescent IBD with IBS-like symptoms. IELs and TNF-α were significantly increased in quiescent IBD with IBS-like symptoms, but not in IBS. CONCLUSIONS: In quiescent IBD, IBS-like symptoms related to persistent subclinical inflammation associated with increased colonic paracellular permeability. A persistent increase in TNF-α in colonic mucosa may contribute to the epithelial barrier defects associated with abdominal pain in quiescent IBD, but not in IBS. Optimisation of anti-inflammatory therapy may be considered in quiescent IBD with IBS-like symptoms.

Combination of allergic factors can worsen diarrheic irritable bowel syndrome: role of barrier defects and mast cells.

OBJECTIVES: Recent evidence suggests a role for increased colonic permeability and mucosal mast cell (MC) mediators on symptoms related to the irritable bowel syndrome (IBS). Whether allergic factors (AFs) are involved in the pathophysiology of IBS is unclear. We addressed the question of the possible influence of an allergic background on IBS symptoms. METHODS: We assessed paracellular permeability, mucosal MCs counts, and spontaneous release of tryptase of colonic biopsy specimens in 34 IBS patients and 15 healthy subjects. The severity of IBS was assessed through self-reported questionnaires. All individuals were tested for the presence of AF, including self-perception of adverse reaction to food, personal and familial history of atopic disease, elevated total or specific immunoglobulin E against food/inhalant antigens, blood eosinophilia, and skin tests. RESULTS: IBS patients had significant enhanced colonic permeability, higher number of MCs, and spontaneous release of tryptase than healthy subjects. The severity of IBS was significantly correlated with colonic permeability (r=0.48, P=0.004), MCs counts (r=0.36, P=0.03), and tryptase (r=0.48, P=0.01). In 13 IBS patients (38.2%) having at least three AFs, symptoms scores, colonic permeability, MCs counts, and tryptase release by colonic biopsies were significantly higher than in those with less than three AFs. IBS patients with at least three AFs were more prone to diarrhea or alternating symptoms. None AF was found to be predictive of IBS severity. CONCLUSIONS: In IBS patients, the presence of an allergic background correlates with a more severe disease and diarrhea predominance, possibly by enhancing mucosal MC activation and paracellular permeability.

Epstein-Barr virus-associated hepatic leiomyosarcoma after renal transplantation: case report.

The incidence of neoplastic complications after solid organ transplantation is increasing tremendously probably as the consequence of long term immunosuppression. Beside usual risk factors, the oncogenic role of some viruses like Epstein-Barr virus is well established. We report a case of a primitive EBV-induced liver leiomyosarcoma after renal transplantation.

A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients.

BACKGROUND: Non-invasive approaches are useful to differentiate simple steatosis from non-alcoholic steatohepatitis (NASH) in obese and morbidly obese patients. AIM: To develop a new scoring system to diagnose definitive NASH. METHODS: Preoperative clinical and biological data including serum caspase 3-generated cytokeratin-18 fragments (CK18) and surgical liver biopsies were obtained from 464 morbidly obese patients who had undergone bariatric surgery. The cohort was divided into two groups: training group (n = 310) and validation group (n = 154). Definitive NASH was defined according to Kleiner's classification with a Non-alcoholic fatty liver disease Activity Score (NAS) ≥5. RESULTS: Alanine aminotransferase (ALT), CK18 fragments and the presence of metabolic syndrome were independent predictors for discriminating patients with NAS ≥5 in the training group. These three parameters were used to carry out a scoring system for the prediction of NAS ≥5. Whereas serum CK18 fragment alone had an area under the receiver operating characteristic (AUROC) curve = 0.74, AUROC curves of the scoring system were 0.88 and 0.83 in the training group and the validation group, respectively. CONCLUSION: A simple and non-invasive composite model (the Nice Model) including metabolic syndrome, ALT and CK18 fragments is able to predict accurately a non-alcoholic fatty liver disease activity score ≥5 in morbidly obese subjects.

Outcome of exfoliative rejection after isolated intestinal transplantation in an adult: case report.

A 34-year-old-man with short-bowel syndrome received an isolated small bowel graft. On postoperative day (POD) 11, ileal biopsy specimen demonstrated mild to moderate rejection that did not respond to corticosteroid bolus therapy. On POD 14, endoscopy and histologic examination revealed exfoliative rejection that was not controlled after 14 days of therapy with thymoglobulin. On POD 95, the patient underwent surgery again because of intestinal obstruction. The graft was removed 6 months after transplantation because of continuous severe abdominal pain with weight loss. After enterectomy, the patient developed multiple-organ failure and died on POD day 8. This case underlines the severity of exfoliative rejection and suggests that early enterectomy be performed when the diagnosis is made, before deterioration of clinical status and development of infectious and nutritional complications.

Esophageal varices in chronic intestinal insufficiency in absence of portal hypertension or liver cirrhosis: case report.

We report the case of a 62-year-old man with short-bowel syndrome, referred for intestinal transplantation, who had esophageal varices (EV) due to superior vena cava (SVC) thrombosis. Pretransplantation work-up revealed protein S deficiency. Results of liver function tests were normal. Upper endoscopy showed grade II to III EV in the upper and middle segments of the esophagus. Computed tomography demonstrated thrombosis of the jugular, subclavian, and SVC veins and marked collateral vessels in the chest. Transient elastography yielded normal findings. A liver biopsy specimen showed a normal aspect of the liver, without fibrosis or liver cirrhosis. Presence of EV in a patient with chronic intestinal insufficiency may be related to collateral venous circulation associated with SVC thrombosis in the absence of portal hypertension. In this situation, an isolated intestinal graft is indicated.

Bone metastasis from endometrioid ovarian carcinoma: a case study and literature review.

INTRODUCTION: Bone metastases from epithelial ovarian carcinoma are rare, usually discovered postmortem. The survival of these patients is poor. Furthermore, only two cases of endometrioid ovarian carcinoma with metastasis to the skeletal structures have been described in the literature. CASE REPORT: We present the case of a 58-year-old woman with a lytic metastasis in the left iliac ramus from endometrioid ovarian carcinoma that occurred seven years after the initial diagnosis. DISCUSSION: A review of the literature since 1966 on bone metastasis of ovarian cancer is also presented. In patients suffering from a neoplasm that rarely metastasises to bone, histological proof should be obtained to diagnose uncommon sites of disease relapse.

Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome.

BACKGROUND: A subset of patients with irritable bowel syndrome (IBS) have an increased number of mast cells (MCs) in the colonic mucosa. Psychological factors are believed to contribute to the course of IBS. AIMS: To examine associations between fatigue, depression and MCs of the colonic mucosa in IBS. METHODS: Colonic biopsies were taken from 50 Rome II IBS patients, 21 healthy controls and 11 depressed/fatigued patients without IBS. The cellularity of the lamina propria was determined as the number of inflammatory cells per high power field (hpf) through a 400x microscope. The Fatigue Impact Scale (FIS) and the short form Beck Depression Inventory (BDI) evaluated the severity of fatigue and depression. RESULTS: IBS patients had a significant increase in the cellularity of the lamina propria compared with controls or with depressed patients (mean (SD) 94.5 (48-110) vs 68 (58-82) and 78 (87-90) cells per hpf, p = 0.005 and p = 0.05, respectively), in particular of MCs (9.3 (5.6-11.7) vs 4.0 (2.7-6.8) and 4.3 (2.8-7.8) cells per hpf, p = 0.001 and p = 0.005, respectively). Both the FIS and BDI scores were significantly higher in IBS or in depressed patients than in controls (p<0.001). In IBS, the FIS score correlated significantly with the cellularity of the lamina propria (r = 0.51, p<0.0001) and MCs (r = 0.64, p<0.0001). In IBS, the BDI score correlated significantly with MCs (r = 0.29, p = 0.03). CONCLUSIONS: Elevated MCs counts are a key feature of the low-grade inflammatory infiltrate in the caecal mucosa of IBS. Fatigue and depression are associated with mucosal cell counts, in particular MCs, suggesting that psychological factors are associated with the low-grade inflammatory infiltrate in IBS.

[Imaging of inflammatory pseudotumors of the liver]. / Imagerie des pseudo-tumeurs inflammatoires hépatiques.

PURPOSE: To describe the imaging features of inflammatory pseudotumors of the liver. INTRODUCTION: Inflammatory pseudotumors of the liver are rare benign lesions that may simulate malignancy on imaging studies. Diagnosis is most frequently confirmed after surgical resection of the lesion. MATERIALS AND METHODS: Retrospective study from 1998 to 2006 of histologically proven cases of inflammatory pseudotumors of the liver. A combination of the following imaging modalities were utilized: US, contrast enhanced US, helical CT and MRI. RESULTS: A total of seven lesions (mean diameter of 61.4 mm) were detected in 6 patients (mean age of 66 years). Clinical and laboratory results were non-specific. The following imaging studies were available: US in 5 cases, including one with contrast material, CT in 5 cases and MRI in 3 cases. All tumors were hypoechoic on US, with no enhancement after injection of Levovist. The tumors were generally hypodense on noncontrast CT and enhancement, when present, was delayed and moderate. On MRI, the tumors were iso- or slightly hyperintense on T2W images and iso- or slightly hypointense on T1W images with subtle peripheral enhancement on delayed imaging. CONCLUSION: The differential diagnosis of inflammatory pseudotumor of the liver should be known to radiologists and could be suggested in a clinical context of chronic inflammatory process in patients with non-specific liver mass showing imaging features of partial fibrosis with delayed enhancement.

[MR Features of hepatic macronodular mycobacteriosis]. / IRM des atteintes macronodulaires hépatiques à mycobactéries.

Hepatic macronodular mycobacteriosis is rare. Its diagnosis is challenging and is most often proposed on the basis of histological analysis. Final diagnosis, except for germ-proven cases, is made in conjunction with clinical, biological, and radiological arguments. We retrospectively report the MR features of ten hepatic lesions discovered on five patients. MRI is sensitive but has a low specificity in demonstrating pseudotumoral lesions most often exhibiting hypointensity on the T1-weighted sequence, hyperintensity on the T2-weighted sequence, and a slight rim enhancement after gadolinium-enhanced T1-weighted sequences.

Transjugular liver biopsy: prospective evaluation of the angle formed between the hepatic veins and the vena cava main axis and modification of a semi-automated biopsy device in cases of an unfavorable angle.

In cases of transjugular liver biopsies, the venous angle formed between the chosen hepatic vein and the vena cava main axis in a frontal plane can be large, leading to technical difficulties. In a prospective study including 139 consecutive patients who underwent transjugular liver biopsy using the Quick-Core biopsy set, the mean venous angle was equal to 49.6 degrees. For 21.1% of the patients, two attempts at hepatic venous catheterization failed because the venous angle was too large, with a mean of 69.7 degrees. In all of these patients, manual reshaping of the distal curvature of the stiffening metallic cannula, by forming a new mean angle equal to 48 degrees , allowed successful completion of the procedure in less than 10 min.

MRI features of a pancreatic schwannoma.

A case of a pancreatic schwannoma is presented. The patient, a previously healthy woman, is hospitalized with the diagnosis of purulent pleuritis. Ultrasonography (US) of the abdomen shows a 3-cm mass in the head of the pancreas. Magnetic resonance imaging (MRI) reveals, in T1-weighted sequences, the mass to be hypointense, and an early and persistent enhanced signal is noted following the administration of gadolinium. In T2-weighted fat saturation sequences, the lesion appears markedly hyperintense. A duodenopancreatotomy is performed, and the pathologic specimen demonstrates a schwannoma of the pancreas with Antoni A pattern.

Epidermal growth factor receptor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and clinical implications.

BACKGROUND: Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of colorectal cancer (CRC). There are several potential strategies to target EGFR. However, monoclonal antibodies and low molecular weight tyrosine kinase inhibitors are the most advanced in clinical development. The majority of studies so far have merely required EGFRs to be expressed by CRC cells. The detection of EGFR expression is usually performed by immunohistochemistry (IHC) in the primary tumor. There are few data regarding the EGFR status in the corresponding distant metastases. PATIENTS AND METHODS: EGFR status was analyzed by IHC in 80 patients (31 male, 49 female) with CRC (70 colon, 10 rectum) and at least one distant metastatic lesion. Metastatic sites analyzed (n=80) were liver (79 patients) and lung (one patient). RESULTS: EGFR reactivity was similar in the primary tumor and the related metastases. Among the 80 paired primary/metastatic tumors, only five (6.3%) showed discordance in EGFR status: two cases with EGFR expression in the primary tumor but not in the metastasis, and three samples with EGFR expression in the metastasis but not in the primary tumor. CONCLUSIONS: Between the paired primary tumors and distant metastatic lesions, 94% of samples had concordant EGFR status when analyzed by IHC.

[Bilateral pulmonary nodules in an HIV-infected patient]. / Nodules pulmonaires bilatéraux chez un patient infecté par le VIH.

INTRODUCTION: Although infectious causes are the most common source of pulmonary nodules in HIV-infected patients, malignant diseases such as Kaposi sarcoma and lymphoma must also be considered. OBSERVATION: A 40 year-old man, diagnosed with HIV infection 16 years earlier and with a satisfactory viro-immunological control, was hospitalized for bilateral pulmonary nodules and a dorsal lytic mass. Bone and pleural biopsies showed a malignant epithelioid hemangioendothelioma. COMMENT: Epithelioid hemangioendothelioma is an uncommon low grade vascular tumor. We report the first case in an HIV-infected patient. Bilateral pulmonary nodules are common in this malignant disease but are not specific. In a HIV-infected patient, such clinical presentation is associated with numerous differential diagnoses and must be interpreted in relation to the immune status. CONCLUSION: In HIV-patients without immunosuppression, pulmonary nodules are often malignant. With the increased survival of these patients, these etiologies closer to those of non-infected patients.

Kaposi's sarcoma confined to the colorectum: a case report.

Reported is a new case of a Kaposi's sarcoma involving only the colorectal area in an HIV-negative patient presenting with hemorrhagic rectocolitis. The colonoscopic examination and the radiological imaging showed the presence of multiple nodular pseudopolypoid formations in the rectum, which suggested, in the differential diagnosis, primarily a malignant non-Hodgkin lymphoma.

Traumatic neuroma of the cystic duct with biliary obstruction. Report of a case.

A case of amputation neuroma of the biliary tract occurring 12 years after a cholecystectomy is reported. The patient, a 81 year-old man, presented with obstructive jaundice due to a stricture of the extrahepatic biliary tract. The stricture was resected and biliary reconstruction was achieved with a Roux-en-Y jejunal loop. The diagnosis of neuroma was obtained only at histology that showed hyperplastic nerve bundles, positive for protein S 100. The patient is well one year and six months after surgery without signs of recurrence of the stricture. Although the amputation neuroma of the biliary tract has already been reported, it seems worthwhile to emphasise this further report. This lesion is an unusual cause of benign stricture of the biliary tract that may pose difficult diagnostic problems.