Search

Crohn's disease (CD) is a debilitating inflammatory bowel condition of unknown aetiology that is growing in prevalence globally. Large-scale studies have determined associations between female obesity or low body mass index (BMI) with risk of CD at all ages or 8- < 40 years, respectively. For males, low BMI entering adult life is associated with increased incidence of CD or ulcerative colitis up to 40 years later. Body composition analysis has shown that combinations of lean tissue loss and high visceral fat predict poor CD outcomes. Here, we assessed dietary intake, physical activity and whole or regional body composition of patients with CD relapse or remission. This anthropometric approach found people with CD, irrespective of relapse or remission, differed from a large representative healthy population sample in exhibiting elevated gynoid fat and reduced android fat. CD is associated with mesenteric adipose tissue, or "creeping fat", that envelops affected intestine exclusive of other tissue; that fat is localised to the android region of the body. In this context, CD mesenteric adiposity represents a stark juxtaposition of organ-specific and regional adiposity. Although our study population was relatively small, we suggest tentatively that there is a rationale to refer to Crohn's disease as a fatty intestine condition, akin to fatty liver conditions. We suggest that our data provide early insight into a subject that potentially warrants further investigation across a larger patient cohort., (© 2021. The Author(s).)

The purpose of this systematic review is to ascertain the risk profile of allografts in primary anterior cruciate ligament reconstruction (ACLR) of skeletally immature patients. Three databases (PubMed, EMBASE, and MEDLINE) were searched for articles addressing primary ACLR in skeletally immature patients (i.e., open femoral and tibial physes). Inclusion criteria encompassed the use of allograft tissue with available postoperative outcomes data. The methodological index for non-randomized studies (MINORS) was used to assess all studies. Descriptive statistics such as means, 95% confidence intervals and standard deviations are presented where applicable. A total of 3,852 studies were screened, with 9 studies of a total of 406 skeletally immature patients (mean age 14.9 ± 1.2 years) satisfying inclusion criteria. The majority (98%) of included patients underwent complete transphyseal ACLR. Where specified, allograft options included Achilles tendon (AT) (66.5%), tibialis anterior tendon (7.6%), bone-patellar tendon (2.5%), and fascia lata (1.0%). The use of a bone block for the AT was reported in one patient (0.2%). Postoperatively, and where specified, patients achieved full range of motion (12.1%), had good Lysholm scores of 94 to 100 (8.1%), and a return to preinjury level athletic participation of 82.9% (8.4%). Complications (13.3%) included graft failures (7.9%), nonrevision reoperation (4.7%), and a combined leg length discrepancy and angular (valgus and extension) deformity (0.2%). There were no reported incidences of disease transmission. Although failure rates of primary allograft ACL reconstruction are acceptable compared with other studies of mainly autograft use in this young, high-risk population, there was a very low rate of clinically significant physeal damage. However, the relatively low quality of the included studies limits the ability to recommend routine use of allograft for ACLR in the skeletally immature patient. More robust studies with long-term follow-up data are necessary to better ascertain the influence of allograft choice on postoperative outcomes for these young patients. This is a Level IV study, systematic review of Levels III and IV studies., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Internuclear ophthalmoparesis (INO) in multiple sclerosis (MS) is due to demyelination of the medial longitudinal fasciculus (MLF). INO is typically modeled as an increased peak-velocity and peak-acceleration ratio of abducting to adducting eye (pulse-size ratio, PSR). PSR can be affected by fatigue during prolonged ocular-motor tasks (ocular-motor fatigue). We propose that an important component of horizontal disconjugacy in INO is due to a delayed delivery of the saccadic pulse to the adducting eye (pulse-time delay, PTD). We expanded a control-system model to account for both abnormal PSR and PTD reflecting faulty axonal transmission in INO and to provide a better understanding of possible changes induced by fatigue. Saccades were measured in 19 MS patients with INO and 10 controls, using a 10-min saccadic "fatigue test" consisting of repetitive back-to-back 20° saccades. In the horizontal saccades model the unitary MLF connection was partitioned into parallel sub-tracts representing progressive degrees of disease effect. INO patients showed baseline abnormal PSR and PTD with some changes during the fatigue test. Manipulations of gain and transmission delay in the model provided simulated saccades that closely resembled those of INO. Ocular-motor fatigue may be a heterogeneous phenomenon that involves inter-saccadic fluctuation of PSR and PTD and adaptation during demanding ocular-motor tasks. INO as a model of abnormal axonal conduction has a potential role in assessing efficacy of reparative therapies in MS., (© 2019 Elsevier B.V. All rights reserved.)

Aim: To study the mechanisms by which Campylobacter jejuni (C. jejuni) causes inflammation and diarrhea. In particular, direct interactions with intestinal epithelial cells and effects on barrier function are poorly under-stood., Methods: To model the initial pathogenic effects of C. jejuni on intestinal epithelium, polarized human colonic HCA-7 monolayers were grown on permeabilized filters and infected apically with clinical isolates of C. jejuni. Integrity of the monolayer was monitored by changes in monolayer resistance, release of lactate dehydrogenase, mannitol fluxes and electron microscopy. Invasion of HCA-7 cells was assessed by a modified gentamicin protection assay, translocation by counting colony forming units in the basal chamber, stimulation of mediator release by immunoassays and secretory responses in monolayers stimulated by bradykinin in an Ussing chamber., Results: All strains translocated across monolayers but only a minority invaded HCA-7 cells. Strains that invaded HCA-7 cells destroyed monolayer resistance over 6 h, accompanied by increased release of lactate dehydrogenase, a four-fold increase in permeability to [(3)H] mannitol, and ultrastructural disruption of tight junctions, with rounding and lifting of cells off the filter membrane. Synthesis of interleukin (IL)-8 and prostaglandin E(2) was increased with strains that invaded the monolayer but not with those that did not., Conclusion: These data demonstrate two distinct effects of C. jejuni on colonic epithelial cells and provide an informative model for further investigation of initial host cell responses to C. jejuni.

Background and Purpose: Kinins are acknowledged as important regulators of intestinal function during inflammation; however, their effects on human intestinal ion transport have not been reported. Here, we used muscle-stripped human colonic tissue and cultured T(84)-cell monolayers to study bradykinin (BK) actions on human intestinal ion transport., Experimental Approach: Ion transport was measured as changes in short-circuit current (I(sc)) across colonic epithelia mounted in Ussing chambers., Key Results: In intact tissue, there was a distinct polarity to BK-elicited I(sc) responses. Whereas basolateral BK stimulated sustained responses (EC(50)=0.5+/-0.1 microM), those to apical BK were more rapid and transient (EC(50)=4.1+/-1.2 nM). In T(84) cells, responses to both apical and basolateral BK were similar to those seen upon apical addition to intact tissues. Cross-desensitization between apical and basolateral domains was not observed. BK-induced responses were largely due to Cl(-) secretion as shown by their sensitivity to bumetanide and removal of Cl(-) from the bathing solution. Studies using selective agonists and antagonists indicate responses to BK are mediated by B(2) receptors. Finally, responses to basolateral BK in intact tissues were inhibited by tetrodotoxin (1 microM), atropine (1 microM), capsaicin (100 microM) and piroxicam (10 microM). BK-stimulated prostaglandin (PG)E(2) release from colonic tissue., Conclusions: BK stimulates human colonic Cl(-) secretion by activation of apical and basolateral B(2) receptors. Responses to apical BK reflect a direct action on epithelial cells, whereas those to basolateral BK are amplified by stimulation of enteric nerves and PG synthesis.

The alpha(v)beta(6) integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of alpha(v)beta(6) expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of alpha(v)beta(6) in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent alpha(v)beta(6) expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate alpha(v)beta(6) expression. Detroit 562 cells showed alpha(v)beta(6)-dependent adhesion and activation of transforming growth factor-beta (TGF-beta) that was inhibited >90% with an alpha(v)beta(6) blocking antibody, 6.3G9. Although both recombinant soluble TGF-beta receptor type-II (rsTGF-beta RII-Fc) and 6.3G9 inhibited TGF-beta-mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-beta RII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by alpha(v)beta(6) antibodies, our findings support a role for alpha(v)beta(6) in human cancer and underscore the therapeutic potential of function blocking alpha(v)beta(6) antibodies.

Aims: Selective cyclooxygenase (COX)-2 inhibitors have recently been implicated as enhancing risk of myocardial infarction (MI). Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are also effective COX-2 inhibitors, so we investigated the hypothesis that they too increase risk of MI., Methods: We conducted a case-control study with direct structured interview of cases and controls. Cases were all subjects (N = 205) with a first nonfatal MI who had no previously recognized cardiovascular disease. Community controls (N = 258) were randomly selected from the same practice as the index case. Hospital controls (N = 205) were those admitted at the same time as index cases for nonmyocardial conditions not influenced by NSAID use. The effects of aspirin, NSAIDs and previously recognized influences on MI were investigated by unconditional logistic regression analysis., Results: NSAID use was associated with an increase risk of MI with an odds ratio of 1.77 (1.03, 3.03) vs. community controls and 2.61 (1.38, 4.95) vs. hospital controls. These values were 5.00 (1.18, 21.28) and 7.66 (0.87, 67.48), respectively, in aspirin users. Results were similar when naproxen was grouped with aspirin. Odds ratios for smoking and for use of antidiabetic medication were 3.91 (2.52, 6.04) and 3.92 (1.25, 12,33), respectively, vs. community controls., Conclusions: Like selective COX-2 inhibitors, non-selective NSAIDs [corrected] are associated with an increased risk of MI. The extent to which this reflects interference with aspirin warrants further investigation.

Background: Aspirin is valuable for preventing vascular events, but information about ulcer frequency is necessary to inform risk-benefit decisions in individual patients., Aim: To determine ulcer prevalence and incidence in a population representative of those given aspirin therapy and evaluate risk predictors., Methods: Patients taking aspirin 75-325 mg daily were recruited from four countries. Exclusions included use of gastroprotectant drugs or other non-steroidal anti-inflammatory drugs. We measured point prevalence of endoscopic ulcers, after quantitating dyspeptic symptoms. Incidence was assessed 3 months later in those eligible to continue (no baseline ulcer or reason for gastroprotectants)., Results: In 187 patients, ulcer prevalence was 11% [95% confidence interval (CI) 6.3-15.1%]. Only 20% had dyspeptic symptoms, not significantly different from patients without ulcer. Ulcer incidence in 113 patients followed for 3 months was 7% (95% CI 2.4-11.8%). Helicobacter pylori infection increased the risk of a duodenal ulcer [odds ratio (OR) 18.5, 95% CI 2.3-149.4], as did age >70 for ulcers in stomach and duodenum combined (OR 3.3, 95% CI 1.3-8.7)., Conclusions: Gastroduodenal ulcers are found in one in 10 patients taking low-dose aspirin, and most are asymptomatic; this needs considering when discussing risks/benefits with patients. Risk factors include older age and H. pylori (for duodenal ulcer).

Background: Cyclooxygenase inhibiting nitric oxide donators (CINODs) are a new class of anti-inflammatory and analgesic drugs that may minimise gastrointestinal toxicity compared with standard non-steroidal anti-inflammatory drugs (NSAIDs) by virtue of nitric oxide donation., Methods: A proof of concept study of the gastrointestinal safety of AZD3582, the first CINOD available for human testing, was conducted. Thirty one subjects were randomised to receive placebo, naproxen 500 mg twice daily, or its nitroxybutyl derivative AZD3582 in an equimolar dose (750 mg twice daily) for 12 days in a double blind three period crossover volunteer study. At the start and end of each dosing period, gastroduodenal injury was assessed by endoscopy and small bowel permeability by differential urinary excretion of lactulose and L-rhamnose. Pharmacokinetic profiles were assessed at steady state., Results: On naproxen, the mean total number of gastroduodenal erosions was 11.5 (and one subject developed an acute ulcer) versus 4.1 on AZD3582 (p<0.0001). More than half of the subjects had no erosions on AZD3582. Differences were seen for both the stomach and duodenum. Naproxen increased intestinal permeability (lactulose:L-rhamnose ratio 0.030 before v 0.040 after treatment) whereas AZD3582 (0.029 before, 0.029 after; p=0.006 v naproxen) and placebo (0.030 before, 0.028 after; p<0.001 v naproxen) did not. The steady state bioavailability of naproxen metabolised from AZD3582 was 95% (95% confidence interval 87-101%) of that after naproxen administration., Conclusions: This human study supports animal data showing reduced gastrointestinal toxicity with the CINOD AZD3582. The potential combination of effective pain relief and gastrointestinal protection offered by AZD3582 warrants further evaluation in human clinical studies.

Safe and effective drug treatment is an important objective of all doctors. In the treatment of arthritis, non-steroidal anti-inflammatory drugs offer effective treatment but safety is significantly limited, largely due to gastrointestinal toxicity. Attention has recently focused on exploiting increased knowledge of metabolism of arachidonic acid to allow the development of safer anti-inflammatory drugs. Dual inhibitors of cyclo-oxygenase and lipoxygenase are planned. These drugs may inhibit formation of both prostaglandins and leukotrienes. This review outlines the salient features of cyclo-oxygenase and lipoxygenase metabolism of arachidonic acid. The role of the eicosanoids in mediating inflammation and gastrointestinal integrity is delineated. Evidence is presented regarding action of licofelone, one COX/LOX inhibitor that is currently in advanced stages of clinical trials. This review examines the hypothesis that licofelone is an effective anti-inflammatory agent that does not cause peptic damage.

Aspirin and non-aspirin NSAIDs injure the gastrointestinal tract principally as a result of their inhibition of prostaglandin synthesis. This is mediated via abrogation of the secretion of mucus and bicarbonate and by reduction in mucosal blood flow. Topical injury and inhibition of platelet thromboxane may also contribute respectively to damage and ulcer bleeding. Recognition of a second cyclooxygenase, COX-2, enabled drugs to be developed that selectively target this enzyme which is expressed in inflamed joints. These have proved to be effective treatments whilst causing little or no acute gastroduodenal injury and reduced ulcers and their complications. Future strategies may capitalise upon the phenomenon of substrate diversion of lipoxygenase products. Balanced cyclooxygenase/lipoxygenase inhibition maybe less harmful than cyclooxygenase inhibition. Also, nitric oxide can subserve many of the protective effects of prostaglandins and NO-donating NSAIDs are under evaluation.

Trials of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) suggest that it may be useful in patients intolerant of azathioprine. We examined the safety and efficacy of MMF in IBD patients intolerant of or unresponsive to azathioprine. Twelve patients [seven with Crohn's disease (CD); seven women; mean age 40 years, range 14-76 years] were treated with MMF 500 mg b.i.d. for a mean of 12.5 weeks. Intolerance was defined as the development of side effects that resolved on discontinuing MMF. Improvement was described as symptomatic improvement, decreased steroid use, or disease entering endoscopic remission. Four patients responded with symptomatic improvement and reduced steroids or mesalazine requirement. Three patients developed headache, nausea, or arthralgia. Three patients developed profuse bloody diarrhea, and in two cases with previously quiescent ulcerative colitis (UC), the source was shown to be ulcers in a drug-induced colitis with histologic features similar to those previously reported in four renal transplant patients on MMF. There is no clear evidence of efficacy of MMF in the treatment of IBD, and its use in this condition should be confined to a randomized controlled trial. Moreover, as patients with UC may be unduly prone to colonic injury, MMF may not be a suitable drug for its treatment.

It appears that selective Cox-2 inhibitors do not affect the gastro duodenal mucosa whilst having anti-inflammatory and analgesic efficacy similar to non-selective NSAIDs. Two broad categories of drugs are Cox-2 selective: coxibs and a number of pre-existing NSAIDs retrospectively found to have selectivity. Cox-2 inhibitors cause less dyspepsia than NSAIDs. They spare gastrointestinal mucosal generation of prostaglandins (PGs) and PG-dependent bicarbonate secretion. Coxibs cause no acute mucosal injury in endoscopic ulcers compared to NSAID comparators. In the VIGOR study all upper GI events were reduced from 4.5 per 100 patient years to 2.1 per 100 patient years with supra-therapeutic doses of rofecoxib compared with naproxen. In the CLASS study, over a period of 3 days to 6 months, incidence of ulcer complications was 0.76% with celecoxib and 1.45% for ibuprofen or diclofenac. The less substantial reduction in events in the CLASS study compared with the VIGOR may be due, at least in part, to the fact that 21% of the patients were also on low dose aspirin. However it is premature to say that the benefit of Cox-2 inhibitors is lost in patients taking aspirin. There is continuing debate on the role of Cox-2 inhibitors in patients who have other risk factors for complicated ulcer disease e.g. patients who are elderly, on aspirin or corticosteroids, have a previous ulcer or have H. pylori infection.

Background/aims: The significance of abnormal liver function tests in the absence of diagnostic serology is unclear. The aim of this study was to report liver biopsy findings in a large group of patients with unexplained abnormal liver biochemistry., Methods: Histological findings were examined in 354 patients who underwent liver biopsy to investigate abnormal liver function tests., Results: Six percent of patients had a normal liver biopsy while 26% were found to have some degree of fibrosis and 6% were cirrhotic. Thirty four and 32% of biopsies suggested non-alcoholic steatohepatits or fatty liver respectively. Other diagnoses included cryptogenic hepatitis, drug toxicity, primary and secondary biliary cirrhosis, autoimmune hepatits, alcohol-related liver disease, primary sclerosing cholangitis, haemochromatosis, amyloid and glycogen storage disease. Patient management was directly altered in 18% of patients due to liver biopsy findings and three families were entered into screening programmes for inheritable liver disease., Conclusions: The finding of abnormal liver function tests in the absence of diagnostic serology may indicate significant liver disease. Liver biopsy yields a range of liver diseases of diverse nature and extent. Liver diseases may be uncovered for which specific treatment is indicated.

A real-time method for the detection of gait events that occur during the electrically stimulated locomotion of paraplegic subjects is described. It consists of a two-level algorithm for the processing of sensor signals and the determination of gait event times. Sensor signals and information about the progression of the stimulator though its pre-specified stimulation "pattern" are processed by a machine intelligence (fuzzy logic) algorithm to determine an initial estimate of the patient's current phase of gait. This is then reviewed and modified by a second algorithm that removes spurious gait estimates, and determines gait event times. These gait event times are known to the system within approximately one-half of a gait cycle. The resulting gait event detection system was successfully evaluated on three subjects. Detection accuracy is not adversely affected by day-to-day gait variability. This work resolved technical and practical issues that previously limited the real time application of these methods. In particular, cosmetically acceptable insole force transducers were used. This gait event detector is designed for use in a real time controller for the automatic adjustment of the intensity and timing of stimulation while the subject is walking using functional electrical stimulation (FES).

Background/aims: Activation of cells within the lamina propria can cause electrogenic chloride secretion across intestinal epithelia by release and/or synthesis of mediator molecules, including reactive oxygen metabolites (ROMs). In this investigation we examined whether indirect (immune) stimulation of ion transport across rat colon was ROM-mediated., Methods: Paired segments of rat colon, stripped of underlying smooth muscle, were mounted on Ussing chambers in order to measure electrogenic ion transport. Changes in short circuit current (SCC) were used as a measure of net electrogenic ion transport measured in response to the bacterial tri-peptide formyl-Met-Leu-Phe (fMLP) which was used to activate lamina propria neutrophils. The effect of the established anti-oxidants catalase and diethyldithiocarbamate (DDTC) and the putative anti-oxidant taurine upon immune-stimulated ion transport was examined., Results: The anti-oxidant DDTC but not catalase significantly attenuated ion transport responses to fMLP. Taurine applied basolaterally reduced ion transport response to fMLP but not to the directly acting secretagogues forskolin. Taurine applied apically enhanced ion transport responses to fMLP., Conclusion: Anti-oxidants, including taurine, may be useful in treatment of colitis. The enhancement of effect seen when taurine was applied apically may have negative implications regarding the therapeutic usefulness of taurine administration to the lumenal compartment., (Copyright 2001 S. Karger AG, Basel)

The effects of berberine on ion transport in both human colonic mucosal epithelia and an intestinal epithelial cell line (T84) were examined. Berberine (concentration range 0-500 microM) reduced both basal and stimulated ion transport responses in human colonic mucosae in a manner which was non-specific for Ca2+ -or cAMP-mediated signals. Similarly, in cultured intestinal epithelial monolayers, berberine inhibited Ca2+ -and cAMP-mediated responses indicating an inhibitory activity directly at the level of the epithelium rather than an indirect effect through other mucosal element(s). Berberine did not alter the rate of generation of cAMP by adenylyl cyclase or the activity of protein kinase A, the effector enzyme of the cAMP pathway. Berberine inhibited carbachol-stimulated 86Rb+ efflux from T84 monolayers. Berberine also inhibited K+ conductance in apically-permeabilised re-sected mucosae. These results indicate i) that berberine exerts an anti-secretory action directly upon epithelial cells and ii) the mechanism of action may be at the level of blockade of K+ channels.

Urokinase-type plasminogen activator (u-PA) is a serine protease that has been implicated in cancer invasion and metastasis. We quantitated u-PA levels in normal colorectal mucosa, adenomatous polyps, and colorectal cancers and correlated these levels with clinicopathological features and patient survival. Detergent extracts were prepared from 133 colorectal cancers, 133 corresponding colorectal mucosal samples, and 15 synchronous adenomatous polyps. u-PA levels were determined using an ELISA, and a cancer:normal u-PA ratio was calculated for each case. u-PA levels were higher in cancers than in normal tissues, whereas adenomas had intermediate levels (P < 0.0001). u-PA levels were unrelated to clinical or pathological features. Survival was decreased in patients with a high cancer:normal u-PA ratio (P = 0.007). Multivariate survival analysis of patients undergoing curative surgery confirmed that the u-PA cancer:normal ratio was related to outcome (relative risk, 2.67; P = 0.02) and was independent of tumor stage (relative risk, 2.26; P = 0.03). Our study suggests that a high ratio of cancer to normal mucosal u-PA indicates an increased risk of colorectal cancer progression. Measurement of u-PA may provide useful prognostic information in patients undergoing curative surgery for colorectal cancer. The aggressive behavior of colorectal cancers with a high u-PA ratio suggests that the protease might be a suitable target for the development of therapeutic agents to prevent invasion and metastasis.

This study determined whether the long-term outcome of patients with obstructing colorectal cancer could be related to conventional pathological prognostic variables or to other clinical, operative or histological features. Ninety-eight patients with bowel obstruction who had undergone potentially curative surgery and survived the postoperative period were studied. Features related to poor long-term outcome after a median follow-up of 5 years included bowel perforation at initial operation (P = 0.007), advanced tumour stage (P < 0.001), poor tumour differentiation (P = 0.02), mucin production by tumour (P = 0.004) and the presence of vascular (P = 0.08) and neural (P = 0.004) invasion. Outcome was not significantly related to the seniority of the operating surgeon (P = 0.52), even when this was adjusted for potentially confounding variables (adjusted hazard rate ratio for trainee surgeons 1.4 (95 per cent confidence interval 0.9-2.4), P = 0.16). Conventional prognostic features may help to identify the majority of patients with obstructed colorectal cancer at high risk of tumour recurrence and death.