Pentoxifylline: A first line treatment option for severe alcoholic hepatitis and hepatorenal syndrome?

World J Gastroenterol. 2009 Jul 7; 15(25): 3194-3195
Assimakopoulos SF, Thomopoulos KC, Labropoulou-Karatza C

Although favourable results of pentoxifylline (PTX) used in treatment of severe alcoholic hepatitis patients with a Maddrey discriminant function score >= 32 have been previously reported, it is not currently recommended as a first line treatment for alcoholic hepatitis owing to lack of evidence for its efficacy as compared to the standard treatment with corticosteroids. In a very recent issue of World Journal of Gastroenterology, Dr. De BK and colleagues compared for the first time the two treatment modalities head to head in a randomized controlled study, demonstrating the advantage of PTX over corticosteroids in terms of patients' survival and risk-benefit profile. The advantage of PTX over corticosteroids in survival of patients with severe alcoholic hepatitis was found to be related to the prevention of hepatorenal syndrome in their study. This study raises the question of the use of PTX as a standard treatment for severe alcoholic hepatitis. Considering the fact that PTX presented a spectacular efficiency in prevention of hepatorenal syndrome in their study as well as that previous studies have shown that this effect is possibly related to a primary renoprotective action because it is irrelevant of tumor necrosis factor-alpha synthesis inhibition or improved liver function, we tempted to speculate that PXT might be an effective option for prevention and/or treatment of hepatorenal syndrome complicating other forms of advanced liver disease. This attractive theory remains to be elucidated by pressing future studies in view of the lack of effective treatment modalities for hepatorenal syndrome.

Translation and validation of the Nepean Dyspepsia Index for functional dyspepsia in China.

World J Gastroenterol. 2009 Jul 7; 15(25): 3173-3177
Tian XP, Li Y, Liang FR, Sun GJ, Yan J, Chang XR, Ma TT, Yu SY, Yang XG

AIM: To assess the reliability and validity of the translated version of Nepean Dyspepsia Index (NDI) in Chinese patients with documented functional dyspepsia (FD). METHODS: The translation process included forward translation, back translation, pretest and cross-cultural adaptation. Reliability and validity of the translated version were examined by asking 300 subjects to complete the Chinese version of the NDI. The mean age of subjects was 39.24 years and 68.7% of the subjects were women. Internal consistency analysis with Cronbach's alpha was performed to test the reliability. Correlation analysis was used to assess the content validity. Factor analysis and structural equation models were used to assess the construct validity. RESULTS: The Cronbach's alpha coefficients ranged 0.833-0.960, well above the acceptable level of 0.70. Correlation analysis showed that each item had a strong correlation with the corresponding domain, but a weak correlation with other domains. Confirmatory factor analysis indicated that the comparative fit index was 0.94, higher than the acceptable level of 0.90. CONCLUSION: The Chinese version of the NDI is a reliable and valid scale for measuring health-related quality of life and disease severity in Chinese patients with FD.

Cardiopulmonary bypass induced microcirculatory injury of the small bowel in rats.

World J Gastroenterol. 2009 Jul 7; 15(25): 3166-3172
Dong GH, Wang CT, Li Y, Xu B, Qian JJ, Wu HW, Jing H

AIM: To investigate microvascular injury quantitatively in the small bowel with respect to cardiopulmonary bypass (CPB) and related mechanisms. METHODS: In 10 male SD rats, normothermic CPB was established and continued with a flow rate of 100-150 mL/kg per minute for 60 min, while another 10 sham-operated animals served as controls. An approximate 10-cm loop of the terminal ileum was exteriorized for observation by means of intravital fluorescence microscopy. The small bowel microcirculatory network including arterioles, capillaries, and collecting venules was observed prior to CPB, CPB 30 min, CPB 60 min, post-CPB 60 min and post-CPB 120 min. The intestinal capillary perfusion, microvascular permeability and leukocyte adherence were also measured. RESULTS: The systemic hemodynamics remained stable throughout the experiment in both groups. In CPB animals, significant arteriolar vasoconstriction, blood velocity reduction and functional capillary density diminution were found. As concomitances, exaggerated albumin extravasation and increased leukocyte accumulation were also noted. These changes were more pronounced and there were no signs of restitution at the end of the observation period. CONCLUSION: CPB induces significant microcirculatory injury of the small bowel in rats. The major underlying mechanisms are blood flow redistribution and generalized inflammatory response associated with CPB.

Is percutaneous endoscopic gastrostomy tube placement safe in patients with ventriculoperitoneal shunts?

World J Gastroenterol. 2009 Jul 7; 15(25): 3148-3152
Kim JS, Park YW, Kim HK, Cho YS, Kim SS, Youn NR, Chae HS

AIM: To investigate whether percutaneous endoscopic gastrostomy (PEG) tube placement is safe in patients with ventriculoperitoneal (VP) shunts. METHODS: This was a retrospective study of all patients undergoing PEG insertion at our institution between June 1999 and June 2006. Post-PEG complications were compared between two groups according to the presence or absence of VP shunts. VP shunt infection rates, the interval between PEG placement and VP shunt catheter insertion, and long-term follow-up were also investigated. RESULTS: Fifty-five patients qualified for the study. Seven patients (12.7%) had pre-existing VP shunts. All patients received prophylactic antibiotics. The complication rate did not differ between VP shunt patients undergoing PEG (PEG/VP group) and non-VP shunt patients undergoing PEG (control group) [1 (14.3%) vs 6 (12.5%), P = 1.000]. All patients in the PEG/VP group had undergone VP shunt insertion prior to PEG placement. The mean interval between VP shunt insertion and PEG placement was 308.7 d (range, 65-831 d). The mean follow-up duration in the PEG/VP group was 6.4 mo (range, 1-15 mo). There were no VP shunt infections, although one patient in the PEG/VP group developed a minor peristomal infection during follow-up. CONCLUSION: Complications following PEG placement in patients with VP shunts were infrequent in this study.

Serum bile acid profiling reflects enterohepatic detoxification state and intestinal barrier function in inflammatory bowel disease.

World J Gastroenterol. 2009 Jul 7; 15(25): 3134-3141
Gnewuch C, Liebisch G, Langmann T, Dieplinger B, Mueller T, Haltmayer M, Dieplinger H, Zahn A, Stremmel W, Rogler G, Schmitz G

AIM: To determine free and conjugated serum bile acid (BA) levels in inflammatory bowel disease (IBD) subgroups with defined clinical manifestations. METHODS: Comprehensive serum BA profiling was performed in 358 IBD patients and 310 healthy controls by liquid chromatography coupled to electrospray ionization tandem mass spectrometry. RESULTS: Serum levels of hyodeoxycholic acid, the CYP3A4-mediated detoxification product of the secondary BA lithocholic acid (LCA), was increased significantly in Crohn's disease (CD) and ulcerative colitis (UC), while most other serum BA species were decreased significantly. Total BA, total BA conjugate, and total BA glycoconjugate levels were decreased only in CD, whereas total unconjugated BA levels were decreased only in UC. In UC patients with hepatobiliary manifestations, the conjugated primary BAs glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were as significantly increased as the secondary BAs LCA, ursodeoxycholic acid, and tauroursodeoxycholic acid compared to UC patients without hepatobiliary manifestations. Finally, we found that in ileocecal resected CD patients, the unconjugated primary BAs, cholic acid and chenodeoxycholic acid, were increased significantly compared to controls and patients without surgical interventions. CONCLUSION: Serum BA profiling in IBD patients that indicates impaired intestinal barrier function and increased detoxification is suitable for advanced diagnostic characterization and differentiation of IBD subgroups with defined clinical manifestations.

Portal hypertension secondary to myelofibrosis with myeloid metaplasia: A study of 13 cases.

World J Gastroenterol. 2009 Jul 7; 15(25): 3128-3133
Abu-Hilal M, Tawaker J

AIM: To describe the clinical presentation and complications of portal hypertension (PH) secondary to myelofibrosis with myeloid metaplasia (MMM). METHODS: Medical records for 123 patients with MMM were reviewed. RESULTS: Thirteen patients with PH secondary to MMM were identified. Median ages at time of MMM and PH diagnosis were 61 and 66 years, respectively. The interval from MMM diagnosis to presentation with one of the PH features ranged from 1 to 11 years. Variceal bleeding and ascites were the most common presentations. Of the eight patients who presented with variceal bleeding, six patients underwent endoscopic variceal ligation (EVL) with no variceal recurrence or hematological worsening during a 12-mo follow up period. CONCLUSION: Patients with MMM might develop PH. Exact mechanisms leading to PH in MMM are still controversial. As in other etiologies, variceal bleeding and ascites are the most common presentations. Anemia may correlate with, and/or predict, the severity of the PH presentation in these patients. EVL can successfully control variceal bleeding in MMM. Further clinical studies are required.

Constructive thinking, rational intelligence and irritable bowel syndrome.

World J Gastroenterol. 2009 Jul 7; 15(25): 3106-3113
Rey E, Moreno Ortega M, Garcia Alonso MO, Diaz-Rubio M

AIM: To evaluate rational and experiential intelligence in irritable bowel syndrome (IBS) sufferers. METHODS: We recruited 100 subjects with IBS as per Rome II criteria (50 consulters and 50 non-consulters) and 100 healthy controls, matched by age, sex and educational level. Cases and controls completed a clinical questionnaire (including symptom characteristics and medical consultation) and the following tests: rational-intelligence (Wechsler Adult Intelligence Scale, 3rd edition); experiential-intelligence (Constructive Thinking Inventory); personality (NEO personality inventory); psychopathology (MMPI-2), anxiety (state-trait anxiety inventory) and life events (social readjustment rating scale). Analysis of variance was used to compare the test results of IBS-sufferers and controls, and a logistic regression model was then constructed and adjusted for age, sex and educational level to evaluate any possible association with IBS. RESULTS: No differences were found between IBS cases and controls in terms of IQ (102.0 +/- 10.8 vs 102.8 +/- 12.6), but IBS sufferers scored significantly lower in global constructive thinking (43.7 +/- 9.4 vs 49.6 +/- 9.7). In the logistic regression model, global constructive thinking score was independently linked to suffering from IBS [OR 0.92 (0.87-0.97)], without significant OR for total IQ. CONCLUSION: IBS subjects do not show lower rational intelligence than controls, but lower experiential intelligence is nevertheless associated with IBS.

An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure.

World J Gastroenterol. 2009 Jul 7; 15(25): 3086-3098
Tuñón MJ, Alvarez M, Culebras JM, González-Gallego J

Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by means of the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.

A systematic review of the efficacy and safety of herbal medicines used in the treatment of obesity.

World J Gastroenterol. 2009 Jul 7; 15(25): 3073-3085
Hasani-Ranjbar S, Nayebi N, Larijani B, Abdollahi M

This review focuses on the efficacy and safety of effective herbal medicines in the management of obesity in humans and animals. PubMed, Scopus, Google Scholar, Web of Science, and IranMedex databases were searched up to December 30, 2008. The search terms were "obesity" and ("herbal medicine" or "plant", "plant medicinal" or "medicine traditional") without narrowing or limiting search elements. All of the human and animal studies on the effects of herbs with the key outcome of change in anthropometric measures such as body weight and waist-hip circumference, body fat, amount of food intake, and appetite were included. In vitro studies, reviews, and letters to editors were excluded. Of the publications identified in the initial database, 915 results were identified and reviewed, and a total of 77 studies were included (19 human and 58 animal studies). Studies with Cissus quadrangularis (CQ), Sambucus nigra, Asparagus officinalis, Garcinia atroviridis, ephedra and caffeine, Slimax (extract of several plants including Zingiber officinale and Bofutsushosan) showed a significant decrease in body weight. In 41 animal studies, significant weight loss or inhibition of weight gain was found. No significant adverse effects or mortality were observed except in studies with supplements containing ephedra, caffeine and Bofutsushosan. In conclusion, compounds containing ephedra, CQ, ginseng, bitter melon, and zingiber were found to be effective in the management of obesity. Attention to these natural compounds would open a new approach for novel therapeutic and more effective agents.

Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase.

Hepatology. 2009 May 6;
Apte U, Gkretsi V, Bowen WC, Mars WM, Luo JH, Donthamsetty S, Orr A, Monga SP, Wu C, Michalopoulos GK

Following liver regeneration after partial hepatectomy, liver grows back precisely to its original mass and does not exceed it. The mechanism regulating this "hepatostat" is not clear and no exceptions have been found to date. Although pathways initiating liver regeneration have been well studied, mechanisms involved in the termination of liver regeneration are unclear. Here, we report that integrin-linked kinase (ILK) (involved in transmission of the extracellular matrix [ECM] signaling by way of integrin receptors) and/or hepatic adaptations that ensue following ILK hepatocyte-targeted removal are critical for proper termination of liver regeneration. Following partial hepatectomy (PHx), mice with a liver-specific ILK ablation (ILK-KO-Liver) demonstrate a termination defect resulting in 58% larger liver than their original pre-PHx mass. This increase in post-PHx liver mass is due to sustained cell proliferation driven in part by increased signaling through hepatocyte growth factor (HGF), and the beta-catenin pathway and Hippo kinase pathways. Conclusion: The data indicate that ECM-mediated signaling by way of ILK is essential in proper termination of liver regeneration. This is the first evidence of a defect leading to impaired termination of regeneration and excessive accumulation of liver weight following partial hepatectomy. (HEPATOLOGY 2009.).

Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver.

Hepatology. 2009 Apr 24;
Breous E, Somanathan S, Vandenberghe LH, Wilson JM

The mechanisms of tolerance in the liver that limit susceptibility to food allergy and that mediate the acceptance of liver transplants, even with a complete major histocompatibility complex (MHC) mismatch, remain poorly defined. Here we report that in a model of liver-directed gene transfer, cytotoxic T lymphocyte (CTL) responses to non-self antigens are controlled by hepatic regulatory T cells (Tregs) that secrete the immunosuppressive cytokine interleukin (IL)-10 in response to the antigen. In addition, Kupffer cells (KCs), normally thought to initiate immune responses, are rendered tolerogenic in this context. The depletion of KCs results in a complete abrogation of IL-10 production by hepatic Tregs, indicating an interaction between Tregs and KCs in the induction of tolerance. Conclusion: Our study suggests that hepatic Tregs together with KCs create a local suppressive microenvironment that prevents the establishment of the CTL response. These mechanisms provide pivotal insights and may prove instrumental in the tolerization toward non-self therapeutic proteins delivered to the liver. (HEPATOLOGY 2009.).

Thymus cell antigen-1-expressing cells in the oval cell compartment.

Hepatology. 2009 Apr 6;
Yovchev MI, Zhang J, Neufeld DS, Grozdanov PN, Dabeva MD

Thymus cell antigen-1 (Thy-1)-expressing cells proliferate in the liver during oval cell (OC)-mediated liver regeneration. We characterized these cells in normal liver, in carbon tetrachloride-injured liver, and in several models of OC activation. The gene expression analyses were performed using reverse-transcriptase polymerase chain reaction (RT-PCR), quantitative RT-PCR (Q-RT-PCR) of cells isolated by fluorescence-activated cell sorting (FACS), and by immunofluorescent microscopy of tissue sections and isolated cells. In normal liver, Thy-1(+) cells are a heterogeneous population: those located in the periportal region do not coexpress desmin or alpha smooth muscle actin (alpha-SMA). The majority of Thy-1(+) cells located at the lobular interface and in the parenchyma coexpress desmin but not alpha-SMA, i.e., they are not resident myofibroblasts. Although Thy-1(+) cells proliferate moderately after carbon tetrachloride injury, in all models of OC-mediated liver regeneration they proliferate quickly and expand significantly and disappear from the liver when the OC response subsides. Activated Thy-1(+) cells do not express OC genes but they express genes known to be expressed in mesenchymal stem cells (CD105, CD73, CD29), genes considered specific for activated stellate cells (desmin, collagen I-a2, Mmp2, Mmp14) and myofibroblasts (alpha-SMA, fibulin-2), as well as growth factors and cytokines (Hgf, Tweak, IL-1b, IL-6, IL-15) that can affect OC growth. Activated in vitro stellate cells do not express Thy-1. Subcloning of Thy-1(+) cells from OC-activated livers yield Thy-1(+) fibroblastic cells and a population of E-cadherin(+) mesenchymal cells that gradually discontinue expression of Thy-1 and begin to express cytokeratins. However, upon transplantation these cells do not differentiate into hepatocytes or cholangiocytes. Activated Thy-1(+) cells produce predominantly latent transforming growth factor beta. Conclusion: Thy-1(+) cells in the OC niche are activated mesenchymal-epithelial cells that are distinct from resident stellate cells, myofibroblasts, and oval cells. (HEPATOLOGY 2009.).

Blood vessels form a migratory scaffold in the rostral migratory stream.

J Comp Neurol. 2009 May 15; 516(2): 94-104
Whitman MC, Fan W, Rela L, Rodriguez-Gil DJ, Greer CA

In adult mice, new neurons born in the subventricular zone (SVZ), lining the lateral ventricles, migrate tangentially into the olfactory bulb along a well-delineated path, the rostral migratory stream (RMS). Neuroblasts in the RMS migrate tangentially in chains, without a recognized migratory scaffold. Here we quantitatively examine the distribution of, and relationships between, cells within the RMS, throughout its rostral-caudal extent. We show that there is a higher density of blood vessels in the RMS than in other brain regions, including areas with equal cell density, and that the orientation of blood vessels parallels the RMS throughout the caudal to rostral path. Of particular interest, migratory neuroblast chains are longitudinally aligned along blood vessels within the RMS, with over 80% of vessel length in rostral areas of the RMS apposed by neuroblasts. Electron micrographs show direct contact between endothelial cells and neuroblasts, although intervening astrocytic processes are often present. Within the RMS, astrocytes arborize extensively, extending long processes that are parallel to blood vessels and the direction of neuroblast migration. Thus, the astrocytic processes establish a longitudinal alignment within the RMS, rather than a more typical stellate shape. This complementary alignment suggests that blood vessels and astrocytes may cooperatively establish a scaffold for migrating neuroblasts, as well as provide and regulate migratory cues. J. Comp. Neurol. 513:94-104, 2009. (c) 2009 Wiley-Liss, Inc.

Can you cover me now?

Pediatr Blood Cancer. 2009 Jul 2;
Chandra S

fMRI activation in late-life anxious depression: a potential biomarker.

Int J Geriatr Psychiatry. 2009 Jul 2;
Andreescu C, Butters M, Lenze EJ, Venkatraman VK, Nable M, Reynolds CF, Aizenstein HJ

OBJECTIVE AND METHODS: The neurobiology of late-life anxious depression (LLAD) is poorly characterized despite evidence that this is a common and severe subtype of late-life depression. To identify the neuroanatomical substrate of LLAD, we examined event-related fMRI data collected in eight subjects with late-life depression, half of whom had high levels of comorbid anxiety. Subjects were trained on the Preparing to Overcome Prepotency (POP) task, which is an executive control task that reliably activates the lateral prefrontal cortex-anterior cingulate cortex (ACC) cognitive control circuit. RESULTS: Time series analysis showed that, when compared with elderly depressed subjects, elderly subjects with anxious depression performing the POP task produced a significantly greater and more sustained signal in three regions: BA24 (dorsal anterior cingulate), BA31 (posterior cingulate), and BA6 (prefrontal cortex). While elderly subjects with pure depression presented a bimodal activation curve in the dorsal anterior cingulate and the posterior cingulate, elderly subjects with anxious depression presented a sustained unimodal activation pattern. CONCLUSIONS: Our preliminary results suggest specific activation patterns unique to anxious depression that may suggest greater and more sustained efforts of the ACC to carry out cognitive control tasks. Further research is needed to clarify the neuroanatomical basis of LLAD. Copyright (c) 2009 John Wiley & Sons, Ltd.

Porcine EPCs downregulate stem cell markers and upregulate endothelial maturation markers during in vitro cultivation.

J Tissue Eng Regen Med. 2009 Jul 2;
Avci-Adali M, Nolte A, Simon P, Ziemer G, Wendel HP

In recent years, interest in endothelial progenitor cells (EPCs) in the field of tissue engineering and regenerative medicine has increased tremendously. However, each clinical stem cell application requires prior validation through animal experiments. This study investigates the isolation and characterization of porcine EPCs from peripheral blood and the change of their cell surface marker expression during in vitro cultivation. RT-PCR demonstrated that the EPCs express stem cell markers CD34 and CD133, which decrease with in vitro cultivation time. Throughout the cultivation process EPCs did not express monocytic (CD14) or haematopoietic marker (CD45). Surprisingly, the CD31 and VE-cadherin expression in EPCs was significantly higher than in endothelial cells (ECs). In contrast, the VEGFR2 and E-selectin expression was significantly lower than in ECs, but increased during the expansion process. This study clarifies the characteristic properties of porcine EPCs during cell culture and may help to improve the impact of EPC-based therapies in porcine animal studies. Copyright (c) 2009 John Wiley & Sons, Ltd.

Signalling molecules and growth factors for tissue engineering of cartilage-what can we learn from the growth plate?

J Tissue Eng Regen Med. 2009 Jul 2;
Brochhausen C, Lehmann M, Halstenberg S, Meurer A, Klaus G, Kirkpatrick CJ

Modern tissue engineering concepts integrate cells, scaffolds, signalling molecules and growth factors. For the purposes of regenerative medicine, fetal development is of great interest because it is widely accepted that regeneration recapitulates in part developmental processes. In tissue engineering of cartilage the growth plate of the long bone represents an interesting, well-organized developmental structure with a spatial distribution of chondrocytes in different proliferation and differentiation stages, embedded in a scaffold of extracellular matrix components. The proliferation and differentiation of these chondrocytes is regulated by various hormonal and paracrine factors. Thus, members of the TGFbeta superfamily, the parathyroid hormone-related peptide-Indian hedgehog loop and a number of transcription factors, such as Sox and Runx, are involved in the regulation of chondrocyte proliferation and differentiation. Furthermore, adhesion molecules, homeobox genes, metalloproteinases and prostaglandins play a role in the complex regulation mechanisms. The present paper summarizes the morphological organization of the growth plate and provides a short but not exhaustive overview of the regulation of growth plate development, giving interesting insights for tissue engineering of cartilage. Copyright (c) 2009 John Wiley & Sons, Ltd.

Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production.

Hepatology. 2009 Jul 2;
Omenetti A, Syn WK, Jung Y, Francis H, Porrello A, Witek RP, Choi SS, Yang L, Mayo MJ, Gershwin ME, Alpini G, Diehl AM

The mechanisms mediating hepatic accumulation of inflammatory cells in cholestatic liver disease remain enigmatic. Our thesis is that Hedgehog (Hh) pathway activation promotes hepatic accumulation of immune cells that interact with cholangiocytes. We believe that myofibroblastic hepatic stellate cells (MF-HSCs) release soluble Hh ligands that stimulate cholangiocytes to express chemokines that recruit mononuclear cell types with cognate receptors for these chemokines, thereby orchestrating a repair-related mechanism for liver inflammation. To address this thesis, we used three experimental systems that allow the definition of Hh-dependent mechanisms that induce phenotypic changes in cholangiocytes. First, cholangiocytes were cultured alone or in the presence of Hh-producing MF-HSCs in a transwell coculture system and/or treated with MF-HSC-conditioned medium with or without Hh-neutralizing antibodies. Changes in the cholangiocyte phenotype were then evaluated by microarray analysis, quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR), and/or enzyme-linked immunosorbent assay for chemokine (C-X-C) motif ligand 16 (Cxcl16). Bile duct ligation was chosen to model biliary fibrosis in mice with an overly active Hh pathway, control littermates, and healthy rats, and the gene profile was evaluated by QRT-PCR in whole liver tissue. Second, a transwell chemotaxis assay was used to examine natural killer T (NKT) cell migration in response to cholangiocytes and particularly cholangiocyte-derived Cxcl16. Finally, we studied liver samples from primary biliary cirrhosis patients and controls by QRT-PCR to compare differences in the Hh pathway and Cxcl16. Co-immunostaining of cytokeratin-7 and Cxcl16 was then performed to localize the phenotypic source of Cxcl16. We found that MF-HSCs release soluble Hh ligands that stimulate cholangiocytes to produce Cxcl16 and recruit NKT cells. Hh pathway activation during cholestatic liver injury also induces cholangiocyte expression of Cxcl16. Conclusion: During biliary injury, Hh pathway activation induces cholangiocyte production of chemokines that recruit NKT cells to portal tracts. (HEPATOLOGY 2009.).

Crohn's disease is associated with restless legs syndrome.

Inflamm Bowel Dis. 2009 Jul 2;
Weinstock LB, Bosworth BP, Scherl EJ, Li E, Iroku U, Munsell MA, Mullen GE, Walters AS

BACKGROUND:: Extraintestinal manifestations of Crohn's disease (CD) have not previously included the central nervous system (CNS). Restless legs syndrome (RLS) is a CNS disorder that is either idiopathic or secondary to a number of diseases. The aim of this study was to determine if RLS was associated with CD because both are associated with iron deficiency, inflammation, and bacterial overgrowth. METHODS:: Consecutive CD outpatients (N = 272) were prospectively surveyed at 4 centers for criteria for RLS. Incidence (having RLS at any point in time), prevalence (having RLS at time of survey), clinical characteristics, risk factors, and potential qualitative relationship between RLS and gastrointestinal symptoms were queried. RESULTS:: The incidence of RLS in patients with CD was 42.7%. Prevalence was 30.2% compared with 9% of spouses. CD patients with and without RLS had a mean age of 46.8 versus 42.6 years, small intestine involvement in 77.9% versus 66.7%, colon involvement in 39.7% versus 63.2%, and prior iron deficiency anemia in 49.3% versus 33.1%. There was no difference between the CD groups with respect to current iron deficiency, RLS family history, or rare prevalence of concomitant RLS disorders. In 91.8% of patients with RLS and CD, RLS started during or after the onset of CD diagnosis. Among 73 patients with RLS, 67 (44.5%) stated there was a relationship between qualitative RLS symptom improvement with overall CD symptom improvement. CONCLUSIONS:: These results demonstrate that RLS occurs frequently in CD and appears to be a possible extraintestinal manifestation. The potential relationship of RLS with CD activity warrants further investigation. (Inflamm Bowel Dis 2009;).

Comparison of several activity indices for the evaluation of endoscopic activity in UC: Inter- and intraobserver consistency.

Inflamm Bowel Dis. 2009 Jul 2;
Osada T, Ohkusa T, Yokoyama T, Shibuya T, Sakamoto N, Beppu K, Nagahara A, Otaka M, Ogihara T, Watanabe S

BACKGROUND:: This study evaluated inter- and intraobserver agreement in the assessment of ulcerative colitis (UC) activity using 4 established indices and a newly designed Modified 6-point Activity Index. METHOD:: In all, 279 endoscopic pictures of inflammatory lesions from 93 UC patients were displayed twice to 4 expert and 4 trainee endoscopists, at an interval of 1 month. Each picture was assessed for inflammatory changes using established indices (Matts, Schroeder [a.k.a. Mayo Score], Baron, and Blackstone) and our new Modified 6-point Activity Index. Weighted kappa statistics were used to estimate intra- and interobserver variation. RESULTS:: The Matts and Schroeder indices gave a "good" degree of concordance for expert endoscopists in terms of inter- and intraobserver agreements (0.74-0.78); this was not so evident with the Baron and Blackstone indices (0.61-0.73). For trainee endoscopists, all scores for inter- and intraobserver weighted kappa values using established indices (0.41-0.51) were lower than for the experts. The degree of concordance using the Modified 6-point Activity Index was rated as "good" for inter- and intraobserver agreements for expert endoscopists (0.65 and 0.79), and as "moderate" for trainee endoscopists (0.54 and 0.64). CONCLUSIONS:: Accurate assessment of UC disease activity from endoscopic findings benefited from experience. For expert endoscopists, the Matts and Schroeder indices proved the most reliable of the 4 established indices. Current endoscopic technologies may be adequate for assessing UC activity, particularly if modified to permit a finer classification of disease severity based on 6 grades, as with our newly developed Modified 6-point Activity Index. (Inflamm Bowel Dis 2009;).