Leptin signaling is involved in T‐cell polarization and is required for profibrotic function of hepatic stellate cells (HSCs). Leptin‐deficient ob/ob mice do not develop liver fibrosis despite the ...presence of severe long‐standing steatohepatitis. Here, we blocked leptin signaling with our recently generated mouse leptin antagonist (MLA), and examined the effects on chronic liver fibrosis in vivo using the chronic thioacetamide (TAA) fibrosis model, and in vitro using freshly‐isolated primary HSCs. In the chronic TAA fibrosis model, leptin administration was associated with significantly enhanced liver disease and a 100% 5‐week to 8‐week mortality rate, while administration or coadministration of MLA markedly improved survival, attenuated liver fibrosis, and reduced interferon γ (IFN‐γ) levels. No significant changes in weight, serum cholesterol, or triglycerides were noted. In vitro administration of rat leptin antagonist (RLA), either alone or with leptin, to rat primary HSCs reduced leptin‐stimulated effects such as increased expression of α‐smooth muscle actin (α‐SMA), and activation of α1 procollagen promoter. Conclusion: Inhibition of leptin‐enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality. (HEPATOLOGY 2009;49:278‐286.)
Background Although colonoscopy is the criterion standard for detecting colorectal adenomas and cancers, a significant percentage of adenomas are missed. Objective To compare forward-viewing with ...ultrawide-viewing colonoscopy in the detection of simulated colon polyps in an in vitro colon model. Design Prospective, multicenter. Setting Six endoscopy units (3 in the United States and 3 in Israel). Patients In vitro colon model with simulated colon polyps (n = 21 metallic beads). Interventions Detection of simulated colon polyps on colonoscope withdrawal. Main Outcome Measurements Incremental detection of simulated colon polyps and endoscopist evaluation of the usability, visibility, and maneuverability of ultrawide-viewing colonoscopy. Results On forward-viewing colonoscopy, the number of simulated polyps (mean ± standard deviation) detected per endoscopist was 11.1 ± 2.3 polyps, a 52.9% detection rate. Simulated polyp detection rates per colon segment were 3.0 ± 0.93 (60.0%) right colon, 2.4 ± 0.87 (48.0%) transverse colon, and 5.7 ± 1.5 (51.8%) left colon. On ultrawide-viewing colonoscopy, the simulated polyp detection rate per endoscopist significantly increased to 18.0 ± 1.98 polyps, an overall 85.7% polyp detection rate ( P < .001). Simulated polyp detection rates were also significantly higher by using the ultrawide-viewing mode in each colon segment, 4.5 ± 0.65 polyps (90.0%) right colon, 4.0 ± 0.87 (80.0%) polyps transverse colon, and 9.6 ± 1.28 polyps (87.3%) left colon (all comparisons, P < .001). Importantly, the ultrawide-viewing mode detected significantly more “hidden” simulated polyps (81.9% vs 31.9%, P < .0001). Limitations Nonrandomized design, use of a colon model, and “simulated” colon polyps. Conclusions Ultrawide-view colonoscopy significantly improved simulated polyp detection in a colon model. Clinical studies in human subjects should be pursued to further evaluate this new endoscopic technology.
Abstract Background The epidemic nature of type 2 diabetes mellitus (T2DM), along with the downsides of current treatments, has raised the need for therapeutic alternatives. Methods We studied ...normo-glycemic and high-fat diet (HFD), induced insulin-resistant Wistar Han rats for 2 to 3 weeks. Rats received peripheral electrical stimulation (PES) treatment (2 Hz/16 Hz bursts, 10 mA) in their hind limbs for 3 min, 3 times per week. Glucose tolerance was evaluated by using a glucose tolerance test at the beginning and again at the end of the study. The effect of an acute PES treatment on metabolic rates of glucose appearance and turnover was measured by using the hyperinsulinemic–euglycemic clamp (HEGC) test. Results Repeated PES treatment significantly inhibited the progression of glucose intolerance in normal and insulin-resistant rats and prevented HFD-induced gains in body weight and fat mass. Acute treatment induced a prolonged effect on glucose turnover, as evaluated by the HEGC test. Increased hepatic glucose output was observed during the basal state ( P < 0.005). Under hyperinsulinemic conditions, PES improved tissue sensitivity to insulin (41.1%, P < 0.01), improved suppression of hepatic glucose production (58.9 ± 4.4% vs. 87.1 ± 4.4%, P < 0.02) and significantly elevated the rate of glycogenesis ( P < 0.01), compared with controls. Conclusions The present study indicates that a noninvasive PES treatment of very short duration is sufficiently potent to stimulate glucose utilization and improve hepatic insulin sensitivity in rats. Repeated PES treatment may have a beneficial effect on HFD-induced adiposity and control of body weight.
ABSTRACT
Objectives:
The aim was to present the workup of patients with acute recurrent pancreatitis (ARP) for genetic analysis and electrophysiological testing.
Methods:
Patients with ARP with ...unknown etiology were referred for genetic testing and evaluation of cystic fibrosis transmembrane conductor regulator (CFTR) function by nasal potential difference (NPD) testing.
Results:
A total of 67 patients were evaluated. The mean age was 23 ± 17 years (median 17.0 years, range 1.5–72 years); 90% were Jewish and 10% Arab. Ten (15%) patients carried PRSS1 gene mutation (K23R(7), R122H(2), and D21A(1)). One patient had K172E/− (chymotrypsin C CTRC) mutation, 1 had I42M (serine protease inhibitor Kazal type 1 SPINK1)/V235I (CTRC) together with ΔF508/5T, 1 patient had R67H (SPINK1)/V235I (CTRC), and 1 patient had V235I (CTRC)/−. Ten of 67 (15%) patients submitted for CFTR gene testing carried mutations (ΔF508/L997F, ΔF508/5T(11TG), W1282/5T(12TG), W1282X/Y1014C, ΔF508/R31C, R117H/−, R117H/Y1014C, D1152H/−, 5T(11TG)/−, and L997F/−). Fifty‐four (80%) patients underwent sweat testing. Of these, 5 had sweat chloride ≥60 mEq/L, and 22 patients had sweat chloride from 40 to 60 mEq/L. Of the 56 (83%) patients had nasal potential difference testing, 4 (6%) with abnormal results.
Conclusions:
One‐third (34%) of patients with ARP carry mutations for hereditary pancreatitis including rare mutations (K23R), and 12.5% have evidence of cftr mutations and 10% had CFTR dysfunction underscoring the importance of genetic and functional workup of these patients.
Background and Aims The advent of capsule endoscopy has revolutionized evaluation of the small bowel. Capsule endoscopy has become the criterion standard as the initial examination to diagnose ...small-bowel abnormalities, but does not allow for tissue sampling or therapeutic intervention. Deep enteroscopy can be performed by using a balloon-assisted device or a spiral overtube for both diagnostic and therapeutic interventions of the small bowel. Deep enteroscopy is time-consuming and requires special endoscopes and accessories to perform the examination. We studied a novel through-the-scope balloon catheter system used for deep enteroscopy that uses a conventional colonoscope and standard accessories. Methods We performed a 9-center, retrospective study using a novel TTS balloon system for small-bowel evaluation. The new through-the-scope device is an on-demand balloon catheter that is inserted through the instrument channel of a standard colonoscope and enables deep advancement into the small bowel in either the anterograde or retrograde approach. It consists of a balloon inflation/deflation system and a single-use balloon catheter designed for anchoring in the small bowel. The balloon is inflated to an anchoring pressure in the small intestine, and a repetitive push-pull technique is performed, with the endoscope sliding over the guiding catheter to the inflated balloon. The catheter may be removed and reinserted to allow for therapeutic intervention while maintaining the endoscope position. Results A total of 98 patients were included; 52% were male, and the mean age was 55 years old (range 15-94 years). Indications included abdominal pain, iron-deficiency anemia, occult GI bleeding, diarrhea, abnormal capsule endoscopy, weight loss, protein losing enteropathy, retained foreign body, altered anatomy ERCP, and small-bowel strictures. Anterograde enteroscopy was performed in 65 patients. The average depth of insertion was 158 cm (range 50-350 cm) from the pylorus. Retrograde enteroscopy was performed in 33 cases. The average depth of insertion was 89 cm (range 20-150 cm) beyond the ileocecal valve. Overall, diagnostic yield was 44%. The average advancement time for the anterograde and retrograde enteroscopy cases was 15.5 minutes. There were no procedural adverse outcomes reported in the 98 cases. Conclusions The TTS advancing balloon is a safe and effective way to perform deep enteroscopy by using a conventional colonoscope without the need for an overtube. Procedure time is shorter than that of other forms of deep enteroscopy. Diagnostic yield and depth of insertion are on par with other forms of deep enteroscopy. This is the largest reported study using this novel technology to diagnose and treat small-bowel disease.
Background Although standard colonoscopy is considered the optimal test to detect adenomas, it can have a significant adenoma miss rate. A major contributing factor to high miss rates is the ...inability to visualize adenomas behind haustral folds and at anatomic flexures. Objective To compare the diagnostic yield of balloon-assisted colonoscopy versus standard colonoscopy in the detection of simulated polyps in a colon model. Design Prospective, cohort study. Setting International gastroenterology meeting. Subject A colon model composed of elastic material, which mimics the flexible structure of haustral folds, allowing for dynamic responses to balloon inflation, with embedded simulated colon polyps (n = 12 silicone “polyps”). Interventions Fifty gastroenterologists were recruited to identify simulated colon polyps in a colon model, first using standard colonoscopy immediately followed by balloon-assisted colonoscopy. Main Outcome Measurements Detection of simulated polyps. Results The median polyp detection rate for all simulated polyps was significantly higher with balloon-assisted as compared with standard colonoscopy (91.7% vs 45.8%, respectively; P < .0001). The significantly higher simulated polyp detection rate with balloon-assisted versus standard colonoscopy was notable both for non-obscured polyps (100.0% vs 75.0%; P < .0001) and obscured polyps (88.0% vs 25.0%; P < .0001). Limitations Non-randomized design, use of a colon model, and simulated colon polyps. Conclusion As compared with standard colonoscopy, balloon-assisted colonoscopy detected significantly more obscured and non-obscured simulated polyps in a colon model. Clinical studies in human participants are being pursued to further evaluate this new colonoscopic technology.
We have previously shown that hyperthyroidism is detrimental for liver fibrosis and in this study we have investigated the mechanisms regulating triiodothyronine (T3) and L-thyroxine (T4) activation ...of hepatic stellate cells (HSC). Expression of α-smooth muscle actin (αSMA) and p75 neurotrophin receptor (p75NTR) was determined by western blot analyses and transient transfection of the promoters. Rho activation was assayed using a pull-down assay and by ELISA. Expression of thyroid hormone receptor α1 decreases, whereas T4 receptor integrin αVβ3 increases, with transdifferentiation of HSC to myofibroblasts. T3 and T4 enhance HSC activation, without affecting proliferation or phosphorylation of mitogen-activated protein kinase, signal transducer and activator of transcription 3 or Akt. Addition of 10−7 M T3 or T4 to thyroid hormone-depleted serum induces a twofold increase in activation marker αSMA, as well as upregulation of p75NTR protein levels. Both hormones enhance transcription of αSMA and p75NTR. We report a novel signaling pathway for thyroid hormones, activation of Rho. T4 induces activation of Rho acting through αvβ3 integrin, and the activation is abolished by the T4 antagonist, tetraiodothyroacetic acid, by peptide RGD and by a function-blocking antibody to integrin β3. T3 and T4 increase phosphorylation of non-muscle myosin light chain II, a downstream signal to Rho/Rho-kinase activation. T3 also induces expression of tumor necrosis factor-α. In vivo, administration of T3 or T4 together with thioacetamide (TAA) enhances fibrosis after 3 weeks, compared with the TAA-treated group, accompanied by increased αSMA in T3- and T4-treated groups, and of p75NTR in T4-treated rats. Thyroid hormones enhance activation of HSC through increased p75NTR and αSMA expression and activation of Rho, therefore accelerating development of liver fibrosis.
The therapy of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases despite significant improvements in our understanding of both immunological and molecular events that lead ...to loss of tolerance to the E2 component of pyruvate dehydrogenase, the immunodominant autoepitope of PBC. It is well known that Ly6C
monocytes are innate immune cells infiltrating inflammatory sites that are dependent on the expression of C-C motif chemokine receptor 2 (CCR2) for emigration from bone marrow. Importantly, humans with PBC have a circulating monocyte pro-inflammatory phenotype with macrophage accumulation in portal tracts. We have taken advantage of an inducible chemical xenobiotic model of PBC and recapitulated the massive infiltration of monocytes to portal areas. To determine the clinical significance, we immunized both CCR2-deficient mice and controls with 2OA-BSA and noted that CCR2 deficiency is protective for the development of autoimmune cholangitis. Importantly, because of the therapeutic potential, we focused on inhibiting monocyte infiltration through the use of cenicriviroc (CVC), a dual chemokine receptor CCR2/CCR5 antagonist shown to be safe in human trials. Importantly, treatment with CVC resulted in amelioration of all aspects of disease severity including serum total bile acids, histological severity score, and fibrosis stage. In conclusion, our results indicate a major role for Ly6C
monocytes and for CCR2 in PBC pathogenesis and suggest that inhibition of this axis by CVC should be explored in humans through the use of clinical trials.
Differential regulation of CXCL12 receptors is suggested as mechanism to modulate T cells function in mucosal homeostasis and inflammation.
IBDs are characterized by increased influx of immune cells ...to the mucosa of genetically susceptible persons. Cellular migration to injury sites is mediated by chemokines. CXCL12 is a ubiquitous, constitutive chemokine that participates in stem cell proliferation and migration and mediates T lymphocyte migration to inflamed tissues. We have recently reported that CXCL12 and its receptor, CXCR4, are expressed in normal and more prominently, inflamed human intestinal mucosa. However, the interactions and roles of CXCL12 and its receptors, CXCR4 and the recently discovered CXCR7, in intestinal inflammation have not been defined. In the present study, we further dissected the effects of CXCL12 on lymphocytes in intestinal homeostasis and inflammation and delineated the interplay between CXCL12 and its receptors CXCR4 and CXCR7. To that end, fresh mononuclear cells were isolated from mucosa and PB of healthy or IBD patients. Phenotypical and functional assays were conducted using flow cytometry, Transwell migration chambers, and ELISA. The data show that CXCL12‐mediated migration of T cells is CXCR4‐ but not CXCR7‐dependent. T cell activation reciprocally regulates CXCR7 and CXCR4 expression and migratory capacity. IBD PBTs expressed more CXCR7 than normal PBTs. Finally, T cells attracted by CXCL12 are mostly of a memory phenotype. In conclusion, the present study suggests that the interplay between CXCL12 and its receptors affects homeostasis and inflammation in the intestinal mucosa.
Background & Aims: Endoscopic screening of the colon with available instruments requires considerable training, is often painful, and carries a risk of perforation. New instrument platforms for ...endoscopic screening could be useful. The aim of this study was to evaluate the extent of colonic intubation by using a novel self-propelled, self-navigating endoscope (the Aer-O-Scope; GI View Ltd, Ramat Gan, Israel). Methods: Twelve young healthy volunteers underwent complete bowel preparation followed by a nonsedated examination using the novel device. Each examination was followed by a standard colonoscopy for safety evaluation. Cecal intubation was confirmed by endoscopic landmarks and fluoroscopy. Results: In 10 out of 12 subjects (83%) the cecum was successfully reached, whereas in 2 cases the Aer-O-Scope advanced to the hepatic flexure. The time to complete advancement to cecum averaged 14.0 ± 7 minutes, and the driving pressures averaged 34 ± 2.3 milibar. Two subjects requested analgesics during the procedures (in both cases the cecum was reached). Four subjects experienced sweating and a bloating sensation that resolved spontaneously. All subjects were followed up to 48 hours and then for 30 days postprocedure, and no complications were observed. Conclusions: In a preliminary pilot feasibility study of this new instrument, the Aer-O-Scope effectively intubated all or most of the colon. Further clinical studies are warranted.
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