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Mismatch repair deficient (dMMR) colorectal cancer (CRC) despite its association with poor histologic grade often has improved prognosis compared with MMR proficient CRC. Tumor budding and poorly differentiated clusters (PDCs) may predict metastatic potential of colorectal adenocarcinoma (CRC). In addition, their assessment may be more reproducible than the evaluation of other histopathologic parameters. Therefore, we wished to determine their potential as prognostic indicators in a cohort of dMMR CRC patients relative to histologic grade. We investigated the predictive value of conventional WHO grade, budding, PDC grade and other histopathologic parameters on the presence of lymph node metastasis (LNM) and clinical outcome in 238 dMMR CRCs. MMR status was determined by immunohistochemistry for the mismatch repair proteins hMLH1, hMSH2, hMSH6, and hPMS2. Tumor budding and PDCs were highly correlated (r=0.701; P

Fecal incontinence is a common disorder, but its pathophysiology is not completely understood.The aim of this review is to present animal models that have a place in the study of fecal incontinence.A literature review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines performed in August 2016 revealed 50 articles of interest. Search terms included fecal/faecal incontinence and animal model or specific species.Articles not describing an animal model, in vitro studies, veterinary literature, reviews, and non-English articles were excluded.The articles described models in rats (n = 31), dogs (n = 8), rabbits (n = 7), and pigs (n = 4).Different fecal incontinence etiologies were modeled, including anal sphincter lesions (33 articles) ranging from a single anal sphincter cut to destruction of 50% of the anal sphincter by sharp dissection, electrocautery, or diathermy. Neuropathic fecal incontinence (12 articles) was achieved by complete or incomplete pudendal, pelvic, or inferior rectal nerve damage. Mixed fecal incontinence (5 articles) was modeled either by the inflation of pelvic balloons or an array of several lesions including nervous and muscular damage. Anal fistulas (2 articles), anal sphincter resection (3 articles), and diabetic neuropathy (2 articles) were studied to a lesser extent.Bias may have arisen from the authors' own work on fecal incontinence and the absence of blinding to the origins of articles.Validated animal models representing the main etiologies of fecal incontinence exist, but no animal model to date represents the whole pathophysiology of fecal incontinence. Therefore, the individual research questions still dictate the choice of model and species.

BACKGROUND The rat has served usefully as a model for fecal incontinence and exploration of the mechanism of action of sacral neuromodulation. However, there is a gap in knowledge concerning representation(s) on the primary sensory cortex of this anatomical region. METHODS Multi-electrode array (32 channels) and intrinsic optical signal (IOS) processing were used to map cortical activation sites following anorectal electrical stimulation in the rat. A simple method for expanding a 32-electrode array to a virtual 2700 array was refined. KEY RESULTS The IOS method identified activation of parietal cortex following anorectal or first sacral nerve root (S1) stimulation; however, the signal was poorly localized and large spontaneous vasomotion was observed in pial vessels. In contrast, the resulting high-density maps showed two anatomically distinct cortical activation sites to anorectal stimulation. CONCLUSIONS & INFERENCES There are two distinct sites of activation on the parietal cortex following anorectal stimulation in the rat. The implications for sacral neuromodulation as a therapy for fecal incontinence are discussed.

Background This manuscript summarizes consensus reached by the International Anorectal Physiology Working Group (IAPWG) for the performance, terminology used, and interpretation of anorectal function testing including anorectal manometry (focused on high‐resolution manometry), the rectal sensory test, and the balloon expulsion test. Based on these measurements, a classification system for disorders of anorectal function is proposed. Methods Twenty‐nine working group members (clinicians/academics in the field of gastroenterology, coloproctology, and gastrointestinal physiology) were invited to six face‐to‐face and three remote meetings to derive consensus between 2014 and 2018. Key recommendations The IAPWG protocol for the performance of anorectal function testing recommends a standardized sequence of maneuvers to test rectoanal reflexes, anal tone and contractility, rectoanal coordination, and rectal sensation. Major findings not seen in healthy controls defined by the classification are as follows: rectoanal areflexia, anal hypotension and hypocontractility, rectal hyposensitivity, and hypersensitivity. Minor and inconclusive findings that can be present in health and require additional information prior to diagnosis include anal hypertension and dyssynergia. Conclusions and Inferences This framework introduces the IAPWG protocol and the London classification for disorders of anorectal function based on objective physiological measurement. The use of a common language to describe results of diagnostic tests, standard operating procedures, and a consensus classification system is designed to bring much‐needed standardization to these techniques., This document summarizes consensus reached by the International Anorectal Physiology Working Group (IAPWG) for the performance of anorectal function testing and introduces a consensus classification for disorders of anorectal function based on objective, physiological measurement.

This study aimed to determine the impact of preoperative exposure to intravenous contrast for CT and the risk of developing postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery.This prospective, multicentre cohort study included adults undergoing gastrointestinal resection, stoma reversal or liver resection. Both elective and emergency procedures were included. Preoperative exposure to intravenous contrast was defined as exposure to contrast administered for the purposes of CT up to 7 days before surgery. The primary endpoint was the rate of AKI within 7 days. Propensity score-matched models were adjusted for patient, disease and operative variables. In a sensitivity analysis, a propensity score-matched model explored the association between preoperative exposure to contrast and AKI in the first 48 h after surgery.A total of 5378 patients were included across 173 centres. Overall, 1249 patients (23·2 per cent) received intravenous contrast. The overall rate of AKI within 7 days of surgery was 13·4 per cent (718 of 5378). In the propensity score-matched model, preoperative exposure to contrast was not associated with AKI within 7 days (odds ratio (OR) 0·95, 95 per cent c.i. 0·73 to 1·21; P = 0·669). The sensitivity analysis showed no association between preoperative contrast administration and AKI within 48 h after operation (OR 1·09, 0·84 to 1·41; P = 0·498).There was no association between preoperative intravenous contrast administered for CT up to 7 days before surgery and postoperative AKI. Risk of contrast-induced nephropathy should not be used as a reason to avoid contrast-enhanced CT.El objetivo de este estudio fue determinar el impacto de la exposición preoperatoria al contraste intravenoso para la tomografía computarizada (TC) y el riesgo de desarrollar insuficiencia renal aguda (IRA) postoperatoria en pacientes sometidos a cirugía gastrointestinal mayor. MÉTODOS: Este estudio de cohorte prospectivo y multicéntrico incluyó adultos sometidos a una resección gastrointestinal, cierre de estoma o resección hepática. Se incluyeron tanto procedimientos electivos como urgentes. La exposición al contraste intravenoso preoperatorio se definió como la administración de contraste para la realización de una TC durante los 7 días previos a la cirugía. El criterio de valoración principal fue la tasa de IRA a los 7 días. Se utilizaron modelos de puntuación de propensión emparejados (propensity score matched, PSM) ajustados por paciente, enfermedad y variables operatorias. Los resultados del modelo se presentan como razón de oportunidades (odds ratio, OR) e i.c. del 95%. En un análisis de sensibilidad, se examinó la asociación entre la exposición preoperatoria al contraste y la IRA en las primeras 48 horas después de la cirugía mediante un modelo de PSM.Se incluyeron un total de 5.378 pacientes de 173 centros. Globalmente, el 23,2% (n = 1.249) de los pacientes recibieron medios de contraste intravenosos. La tasa global de IRA postoperatoria a los 7 días fue del 13,4% (718/5.378). En el modelo de puntuación de propensión emparejado, la exposición preoperatoria al contraste no se asoció con IRA a los 7 días (OR 0,95; i.c. del 95%: 0,73-1,21; P = 0,669). En el análisis de sensibilidad no se observó una asociación entre la administración de contraste preoperatorio y la IRA postoperatoria a las 48 horas (OR 1,09; i.c. del 95% 0,84-1,41; P = 0,498). CONCLUSIÓN: No hubo asociación entre la administración preoperatoria de contraste intravenoso para tomografías computarizadas durante los 7 días previos a la cirugía y la IRA postoperatoria. El riesgo de nefropatía inducida por el contraste no debe usarse de manera rutinaria como una razón para evitar la práctica de un TC con contraste.

Akkermansia muciniphila utilises colonic mucin as its substrate. Abundance is reduced in ulcerative colitis (UC), as is the relative proportion of sulphated mucin in the mucus gel layer (MGL). It is unknown if these phenomena are related, however reduced sulphated mucins could contribute to reduced abundance, owing to a lack of substrate. The aim of this study was to quantify A. muciniphila within the MGL and to relate these findings with markers of inflammation and the relative proportion of sulphomucin present. Colonic biopsies and mucus brushings were obtained from 20 patients with active UC (AC), 14 with quiescent UC (QUC) and 20 healthy controls (HC). A. muciniphila abundance was determined by RT-PCR. High iron diamine alcian-blue staining was performed for histological analysis. Patients with AC had reduced abundance of A. muciniphila compared to HC and QUC. A positive association was found between A. muciniphila abundance and higher percentage of sulphated mucin (ρ 0.546, p = 0.000). Lower abundances of A. muciniphila correlated with higher inflammatory scores (ρ = 0.294 (p = 0.001)). This study confirms an inverse relationship between A. muciniphila and inflammation and a positive association between A. muciniphila abundance and percentage of sulfated mucin in the MGL.

To ascertain whether house officers (HOs) attain a more satisfactory surgical rotation experience when they perform basic surgical learning activities. We also sought to establish how many and which learning activities HOs achieve and the effect on their surgical experience. A questionnaire listing 20 learning activities and questions regarding satisfaction with an overall experience was disseminated to HOs in the UK and Ireland who had completed ≥3 months of surgical rotations. Satisfaction with surgical experience was dichotomised in order to perform logistic regression using R Studio software v0.98. The survey was completed by 150 respondents, with 26 % completing at least 10 basic surgical learning activities during their surgical rotation. On multivariate analysis, the completion of these learning activities was significantly associated with a satisfactory rotation experience (p

Background Faecal incontinence (FI) is a substantial health problem with a prevalence of approximately 8% in community-dwelling populations. Sacral neuromodulation (SNM) is considered the first-line surgical treatment option in adults with FI in whom conservative therapies have failed. The clinical efficacy of SNM has never been rigorously determined in a trial setting and the underlying mechanism of action remains unclear. Methods/design The design encompasses a multicentre, randomised, double-blind crossover trial and cohort follow-up study. Ninety participants will be randomised to one of two groups (SNM/SHAM or SHAM/SNM) in an allocation ratio of 1:1. The main inclusion criteria will be adults aged 18–75 years meeting Rome III and ICI definitions of FI, who have failed non-surgical treatments to the UK standard, who have a minimum of eight FI episodes in a 4-week screening period, and who are clinically suitable for SNM. The primary objective is to estimate the clinical efficacy of sub-sensory SNM vs. SHAM at 32 weeks based on the primary outcome of frequency of FI episodes using a 4-week paper diary, using mixed Poisson regression analysis on the intention-to-treat principle. The study is powered (0.9) to detect a 30% reduction in frequency of FI episodes between sub-sensory SNM and SHAM stimulation over a 32-week crossover period. Secondary objectives include: measurement of established and new clinical outcomes after 1 year of therapy using new (2017 published) optimised therapy (with standardised SNM-lead placement); validation of new electronic outcome measures (events) and a device to record them, and identification of potential biological effects of SNM on underlying anorectal afferent neuronal pathophysiology (hypothesis: SNM leads to increased frequency of perceived transient anal sphincter relaxations; improved conscious sensation of defaecatory urge and cortical/subcortical changes in afferent responses to anorectal electrical stimulation (main techniques: high-resolution anorectal manometry and magnetoencephalography). Discussion This trial will determine clinical effect size for sub-sensory chronic electrical stimulation of the sacral innervation. It will provide experimental evidence of modifiable afferent neurophysiology that may aid future patient selection as well as a basic understanding of the pathophysiology of FI. Trial registration International Standard Randomised Controlled Trial Number: ISRCTN98760715. Registered on 15 September 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-2689-1) contains supplementary material, which is available to authorized users.

The peri‐operative use of angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers is thought to be associated with an increased risk of postoperative acute kidney injury. To reduce this risk, these agents are commonly withheld during the peri‐operative period. This study aimed to investigate if withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers peri‐operatively reduces the risk of acute kidney injury following major non‐cardiac surgery. Patients undergoing elective major surgery on the gastrointestinal tract and/or the liver were eligible for inclusion in this prospective study. The primary outcome was the development of acute kidney injury within seven days of operation. Adjusted multi‐level models were used to account for centre‐level effects and propensity score matching was used to reduce the effects of selection bias between treatment groups. A total of 949 patients were included from 160 centres across the UK and Republic of Ireland. From this population, 573 (60.4%) patients had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers withheld during the peri‐operative period. One hundred and seventy‐five (18.4%) patients developed acute kidney injury; there was no difference in the incidence of acute kidney injury between patients who had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers continued or withheld (107 (18.7%) vs. 68 (18.1%), respectively; p = 0.914). Following propensity matching, withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers did not demonstrate a protective effect against the development of postoperative acute kidney injury (OR (95%CI) 0.89 (0.58–1.34); p = 0.567).

Aine Balfe,1,2 Grainne Lennon,1,2 Aonghus Lavelle,1,2 Neil G Docherty,1 J Calvin Coffey,3 Kieran Sheahan,4 Desmond C Winter,2 P Ronan O’Connell1,2 1School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, 2Centre for Colorectal Disease, St Vincent’s University Hospital Dublin, Dublin, 3Graduate Entry Medical School, University Hospital Limerick, 4i Centre for Interventions in Infection, Inflammation and Immunity, University of Limerick, Limerick, 4Histopathology Department, St. Vincent’s University Hospital Dublin, Dublin, Ireland Aim: The epithelial layer within the colon represents a physical barrier between the luminal contents and its underlying mucosa. It plays a pivotal role in mucosal homeostasis, and both tolerance and anti-pathogenic immune responses. Identifying signals of inflammation initiation and responses to stimuli from within the epithelial layer is critical to understanding the molecular pathways underlying disease pathology. This study validated a method to isolate and analyze epithelial populations, enabling investigations of epithelial function and response in a variety of disease setting. Materials and methods: Epithelial cells were isolated from whole mucosal biopsies harvested from healthy controls and patients with active ulcerative colitis by calcium chelation. The purity of isolated cells was assessed by flow cytometry. The expression profiles of a panel of epithelial functional genes were investigated by reverse transcription-polymerase chain reaction (PCR) in isolated epithelial cells and corresponding mucosal biopsies. The expression profiles of isolated cells and corresponding mucosal biopsies were evaluated and compared between healthy and inflamed colonic tissue. Results: Flow cytometry identified 97% of cells isolated as intestinal epithelial cells (IECs). Comparisons of gene expression profiles between the mucosal biopsies and isolated IECs demonstrated clear differences in the gene expression signatures. Sixty percent of the examined genes showed contrasting trends of expression between sample types. Conclusion: The calcium chelation isolation method provided a reliable method for the isolation of a pure population of cells with preservation of epithelial cell-specific gene expression. This demonstrates the importance of sample choice when investigating functions directly affecting the colonic epithelial layer. Keywords: epithelial cells, ulcerative colitis, gene expression, mucosal biopsies, molecular pathways, colonic inflammation

Summary Background Percutaneous tibial nerve stimulation (PTNS) is a new ambulatory therapy for faecal incontinence. Data from case series suggest it has beneficial outcomes in 50–80% patients; however its effectiveness against sham electrical stimulation has not been investigated. We therefore aimed to assess the short-term efficacy of PTNS against sham electrical stimulation in adults with faecal incontinence. Methods We did a double-blind, multicentre, pragmatic, parallel-group, randomised controlled trial (CONtrol of Faecal Incontinence using Distal NeuromodulaTion [CONFIDeNT]) in 17 specialist hospital units in the UK that had the skills to manage patients with faecal incontinence. Eligible participants aged 18 years or older with substantial faecal incontinence for whom conservative treatments (such as dietary changes and pelvic floor exercises) had not worked, were randomly assigned (1:1) to receive either PTNS (via the Urgent PC neuromodulation system) or sham stimulation (via a transcutaneous electrical nerve stimulation machine to the lateral forefoot) once per week for 12 weeks. Randomisation was done with permuted block sizes of two, four, and six, and was stratified by sex and then by centre for women. Patients and outcome assessors were both masked to treatment allocation for the 14-week duration of the trial (but investigators giving the treatment were not masked). The primary outcome was a clinical response to treatment, which we defined as a 50% or greater reduction in episodes of faecal incontinence per week. We assessed this outcome after 12 treatment sessions, using data from patients' bowel diaries. Analysis was by intention to treat, and missing data were multiply imputed. This trial is registered with the ISRCTN registry, number 88559475, and is closed to new participants. Findings Between Jan 23, 2012, and Oct 31, 2013, we randomly assigned 227 eligible patients (of 373 screened) to receive either PTNS (n=115) or sham stimulation (n=112). 12 patients withdrew from the trial: seven from the PTNS group and five from the sham group (mainly because they could not commit to receiving treatment every week). Two patients (one in each group) withdrew because of an adverse event that was unrelated to treatment (exacerbation of fibromyalgia and rectal bleeding). 39 (38%) of 103 patients with full data from bowel diaries in the PTNS group had a 50% or greater reduction in the number of episodes of faecal incontinence per week compared with 32 (31%) of 102 patients in the sham group (adjusted odds ratio 1·28, 95% CI 0·72–2·28; p=0·396). No serious adverse events related to treatment were reported in the trial. Seven mild, related adverse events were reported in each treatment group, mainly pain at the needle site (four in PTNS, three in sham). Interpretation PTNS given for 12 weeks did not confer significant clinical benefit over sham electrical stimulation in the treatment of adults with faecal incontinence. Further studies are warranted to determine its efficacy in the long term, and in patient subgroups (ie, those with urgency). Funding National Institute for Health Research.

BackgroundFaecal incontinence (FI) is a common condition which is often under-reported. It is distressing for those suffering from it, impacting heavily on their quality of life. When conservative strategies fail, treatment options are limited. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive outpatient treatment, shown in preliminary case series to have significant effectiveness; however, no randomised controlled trial has been conducted.ObjectivesTo assess the effectiveness of PTNS compared with sham electrical stimulation in the treatment of patients with FI in whom initial conservative strategies have failed.DesignMulticentre, parallel-arm, double-blind randomised (1 : 1) controlled trial.SettingEighteen UK centres providing specialist nurse-led (or equivalent) treatment for pelvic floor disorders.ParticipantsParticipants aged > 18 years with FI who have failed conservative treatments and whose symptoms are sufficiently severe to merit further intervention.InterventionsPTNS was delivered via the Urgent®PC device (Uroplasty Limited, Manchester, UK), a hand-held pulse generator unit, with single-use leads and fine-needle electrodes. The needle was inserted near the tibial nerve on the right leg adhering to the manufacturer’s protocol (and specialist training). Treatment was for 30 minutes weekly for a duration of 12 treatments. Validated sham stimulation involved insertion of the Urgent PC needle subcutaneously at the same site with electrical stimulation delivered to the distal foot using transcutaneous electrical nerve stimulation.Main outcome measuresOutcome measures were assessed at baseline and 2 weeks following treatment. Clinical outcomes were derived from bowel diaries and validated, investigator-administered questionnaires. The primary outcome classified patients as responders or non-responders, with a responder defined as someone having achieved ≥ 50% reduction in weekly faecal incontinence episodes (FIEs).ResultsIn total, 227 patients were randomised from 373 screened: 115 received PTNS and 112 received sham stimulation. There were 12 trial withdrawals: seven from the PTNS arm and five from the sham arm. Missing data were multiply imputed. For the primary outcome, the proportion of patients achieving a ≥ 50% reduction in weekly FIEs was similar in both arms: 39 in the PTNS arm (38%) compared with 32 in the sham arm (31%) [odds ratio 1.28, 95% confidence interval (CI) 0.72 to 2.28;p = 0.396]. For the secondary outcomes, significantly greater decreases in weekly FIEs were observed in the PTNS arm than in the sham arm (beta –2.3, 95% CI –4.2 to –0.3;p = 0.02), comprising a reduction in urge FIEs (p = 0.02) rather than passive FIEs (p = 0.23). No significant differences were found in the St Mark’s Continence Score or any quality-of-life measures. No serious adverse events related to treatment were reported.ConclusionsPTNS did not show significant clinical benefit over sham electrical stimulation in the treatment of FI based on number of patients who received at least a 50% reduction in weekly FIE. It would be difficult to recommend this therapy for the patient population studied. Further research will concentrate on particular subgroups of patients, for example those with pure urge FI.Trial registrationCurrent Controlled Trials ISRCTN88559475.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 19, No. 77. See the NIHR Journals Library website for further project information.

The colonic mucus gel layer (MGL) is a critical component of the innate immune system acting as a physical barrier to microbes, luminal insults, and toxins. Mucins are the major component of the MGL. Selected microbes have the potential to interact with, bind to, and metabolize mucins. The tolerance of the host to the presence of these microbes is critical to maintaining MGL homeostasis. In disease states such as ulcerative colitis (UC), both the mucosa associated microbes and the constituent MGL mucins have been shown to be altered. Evidence is accumulating that implicates the potential for mucin degrading bacteria to negatively impact the MGL and its stasis. These effects appear more pronounced in UC. This review is focused on the host-microbiome interactions within the setting of the MGL. Special focus is given to the mucolytic potential of microbes and their interactions in the setting of the colitic colon.

Prior international datasets have demonstrated equivocal results in the rate of surgical procedures for the treatment of Crohn’s disease (CD) following the introduction of biologic medications. The first biologic medication licensed for use in the Republic of Ireland (ROI) was infliximab in 1999. The current study examined national trends in intestinal resection for CD in the ROI following the introduction of biologic medications. The Irish Hospital In-Patient Enquiry database was examined for the period 2000–2010. Cases of CD and relevant surgical interventions were identified using International Classification of Diseases, ninth and tenth editions. Using Irish census data to establish population denominators, trends in population-based procedure rates were examined. Trends were tested for significance with Spearman rank tests. From 2000 to 2010, there were 11,796 patient admissions with a principal diagnosis of CD. The rates of admission for CD overall (r 2 = −0.191, P = 0.574) and for emergencies (r 2 = 0.055, P = 0.873) did not change; however, elective admissions reduced (r 2 = −0.636, P = 0.035). The mean length of stay reduced (r 2 = −0.783, P = 0.004). The rates of small bowel/right colon procedures (r 2 = 0.282, P = 0.401) and proctectomy (r 2 = −0.209, P = 0.537) did not change. Left colon procedures reduced (r 2 = −0.800, P = 0.003) while the rate of total colectomy increased (r 2 = 0.718, P = 0.013). During the decade following the introduction of biologic medications in the ROI, the rate of elective hospitalization and length of stay reduced. However, there has not been a dramatic reduction in the rate of intestinal resection for Crohn’s disease at a population level.

The relevance of biogeography to the distal gut microbiota has been investigated in both health and inflammatory bowel disease (IBD), however multiple factors, including sample type and methodology, microbiota characterization and interpersonal variability make the construction of a core model of colonic biogeography challenging. In addition, how phylogenetic classification relates to immunogenicity and whether consistent alterations in the microbiota are associated with ulcerative colitis (UC) remain open questions. This addendum seeks to review the human colonic microbiota in health and UC as currently understood, in the broader context of the human microbiome.

T cell infiltration into colorectal tumors has been shown to correlate with improved patient outcomes. However, more detailed information on the makeup and relationships between the infiltrating T cell subsets is lacking. We therefore correlated the extent of immune infiltration into colorectal tumors with the frequencies of various T cell subsets. We prospectively recruited 22 patients at the time of surgical resection for colorectal cancer. The Klintrup-Mäkinen (KM) score was used to estimate the extent of immune infiltration into colorectal tumors. The frequencies of CD4 and CD8 T cells that produced cytokines or expressed the inhibitory molecule programed cell death 1 (PD-1) were determined by flow cytometry in colorectal tumor and matched uninvolved colonic tissue. In addition, the frequency of CD4 regulatory T cell (Treg) subsets was determined. An increased frequency of CD4 T cells producing IL-17 (Th17 cells) was observed in colorectal tumor tissue compared with adjacent uninvolved tissue. These Th17 cells mostly coproduced TNF-α, but not IFN-γ. IL-17 expression correlated positively with TNF-α and IL-10. Increased expression of the immune checkpoint molecule PD-1 was found in colorectal tumors compared with adjacent uninvolved tissue. There was a negative correlation between expression of PD-1 and IFN-γ, but not IL-17, for both CD4(+) and CD8(+) T cells. CD4(+)CD25(+)CD127(lo) and CD4(+)CD25(+)CD127(lo)FoxP3(+)CD39(+) Treg cells were enriched in colorectal tumors. A positive correlation between KM score and percentage CD4(+)CD25(+)CD127(lo) Treg cells was observed in tumors, suggesting that increased immune infiltration is associated with an increased proportion of Treg cells. In addition, there was a negative correlation between the frequency of CD4(+)CD25(+)CD127(lo) Treg cells and the expression of IFN-γ and IL-2, but not IL-17, in tumors. Taken together, these data suggest that both PD-1 expressing T cells and Treg cells within the tumor may have a suppressive effect on T cells secreting IFN-γ, IL-2, or TNF-α, but not Th17 cells.

Local excision is an alternative to anterior or abdomino-perineal resection in patients with early rectal cancer. In more advanced disease, neo-adjuvant therapy (CRXT) can result in significant disease regression such that local excision may be considered. The primary aim was to assess oncological outcome in patients with T3 rectal cancer treated with CRXT and local excision due to unsuitability for or aversion to anterior resection and stoma. The secondary aim was to examine oncological outcomes in patients treated in a similar way in the published literature. Between July 2006 and July 2009, patients with rectal cancer staged T3, N0/N1, M0 who were deemed unfit for or who refused anterior resection were offered long-course CRXT. Patients were restaged 8 weeks following completion. If there was a good response (regression grade 2 or 3 clinically and radiologically), full thickness transanal excision was performed. All patients were followed regularly (monthly CT abdomen/pelvis and annual endoscopy) to assess for recurrence of disease. A literature search of PubMed was performed to identify all prospective data available of T3 rectal cancers managed with CRXT and local excision. Ten patients were treated over 3 years. Six patients had complete pathological response, while four patients had a partial response. The resection margins following local excision were clear in all. There was no local recurrence (median follow-up 24 months, range 9–42 months). Neo-adjuvant chemoradiotherapy and local excision is an option in patients unfit for or averse to major surgical resection if there is a good response to CRXT.

Background: Intestinal fibroblasts mediate stricture formation in Crohn's disease (CD). Transforming growth factor-β1 (TGF-β1) is important in fibroblast activation, while cell attachment and migration is regulated by the adhesion molecule N-cadherin. The aim of this study was to investigate the expression and function of N-cadherin in intestinal fibroblasts in patients with fibrostenosing CD. Methods: Intestinal fibroblasts were cultured from seromuscular biopsies from patients undergoing resection for terminal ileal fibrostenosing CD (n = 14) or controls patients (n = 8). N-cadherin expression was assessed using Western blot and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Fibroblasts were stimulated with TGF-β1 and selective pathway inhibitors Y27632, PD98050, and LY294002 were used to examine the Rho/ROCK, ERK-1/2, and Akt signaling pathways, respectively. Cell migration was assessed using a scratch wound assay. N-cadherin was selectively overexpressed using a plasmid. Results: Fibroblasts from fibrostenosing CD express increased constitutive N-cadherin mRNA and protein and exhibit enhanced basal cell migration relative to those from directly adjacent normal bowel. Control fibroblasts treated with TGF-β1 induced N-cadherin in a dose-dependent manner which was inhibited by Rho/ROCK and Akt pathway modulation. Control fibroblasts exhibited enhanced cell migration in response to treatment with TGF-β1 or transfection with an N-cadherin plasmid. Conclusions: Fibroblasts from strictures in CD express increased constitutive N-cadherin and exhibit enhanced basal cell migration. TGF-β1 is a potent inducer of N-cadherin in intestinal fibroblasts resulting in enhanced cell migration. The TGF-β1-mediated induction of N-cadherin may potentiate Crohn's stricture formation. (Inflamm Bowel Dis 2011;)

A pressing need exists to identify factors that predispose to recurrence after terminal ileal resection for Crohn's disease (CD) and to determine effective prophylactic strategies. This review presents an up-to-date summary of the literature in the field and points to a role for bacterial overproliferation in recurrence.The literature (Medline, Embase, and the Cochrane Library, 1971-2009) on ileal CD and postoperative recurrence was searched, and 528 relevant articles were identified and reviewed.Smoking is a key independent risk factor for recurrence. NOD2/CARD15 polymorphisms and penetrating phenotype are associated with aggressive disease and higher reoperation rates. Age at diagnosis, disease duration, gender, and family history are inconsistent predictors of recurrence. Prophylactic 5-aminosalicylic acid therapy and nitromidazole antibiotics are beneficial. Combination therapies with immunosuppressants are also effective. Anti-TNFalpha-based regimens show benefit but the evidence base is small. Corticosteroid, interleukin-10, and probiotic therapies are not effective. Wider, stapled anastomotic configurations are associated with reduced recurrence rates. Strictureplasty and laparoscopic approaches have similar long-term recurrence rates to open resection techniques. Length of resection and presence of microscopic disease at resection margins do not influence recurrence. A lack of consensus exists regarding whether the presence of granulomas or plexitis affects outcome.Current evidence points to defects in mucosal immunity and intestinal dysbiosis of either innate (NOD2/CARD15) or induced (smoking) origin in postoperative CD recurrence. Prophylactic strategies should aim to limit dysbiosis (antibiotics, side-to-side anastomoses) or prevent downstream chronic inflammatory sequelae (anti-inflammatory, immunosuppressive, and immunomodulatory therapy).

Obstetric injury to the pudendal nerve contributes significantly to fecal incontinence. The inferior rectal nerve, a terminal branch of the motor division of the pudendal nerve, innervates the external anal sphincter. Animal models have been developed to establish the scientific basis of sacral neuromodulation. The aims of this study were to determine the spinal location of inferior rectal nerve motoneurons projecting to the external anal sphincter and whether the inferior rectal nerve carries sensory fibers.Ten female virgin Wistar rats were used; 7 underwent bilateral inferior rectal nerve section and application of the neuronal tracer fluorogold. Five days later dorsal root ganglia L5 to S2 and the lumbosacral spinal cord were harvested and stained for activating transcription factor 3, a molecular marker of nerve injury. Three animals were used to confirm the specificity of activating transcription factor 3 nuclear labeling as a marker of axotomy.Fluorogold-labeled motoneurons were found exclusively at L6 in the dorsomedial sections of Onuf's nuclei (left and right), which contained 30 +/- 9 motoneurons with a median diameter of 28.3 microm (24.4-31.0) (25th-75th centiles). Double-labeled sensory neurons (fluorogold-labeled cytoplasm and activating transcription factor 3-labeled nuclei) were found in dorsal root ganglia L6 to S2 and were smaller in diameter (20.5 microm (17.8-26.7); median (25th-75th centiles)) than motoneurons (P.0,001).The external anal sphincter receives both motor and sensory innervation from the inferior rectal nerve. Activating transcription factor 3 nuclear staining may prove useful for quantifying the degree of nerve injury in animal models of fecal incontinence.

The study was designed to determine the effect of further vaginal delivery on anal sphincter function in women after apparently uncomplicated primiparous forceps delivery.Fifty-two secundigravid women whose first child was forceps-assisted were compared with a control group of 20 women who had undergone spontaneous first vaginal delivery. Both groups were studied antenatally and again at 12 weeks after second delivery using a standardized bowel function questionnaire, endoanal ultrasound, and anal manometry. The primary outcome was fecal incontinence score after second delivery.Before second delivery, 20 of 52 (39 percent) of the forceps group and 3 of 20 (15 percent) control subjects (P = 0.103) reported minor alteration in fecal incontinence. Endoanal ultrasound was more frequently abnormal (38/52 (73 percent) vs. 6/20 (30 percent); P = 0.002), and median anal canal squeeze (71 vs. 104 mmHg; P = 0.004) and resting pressures (43 vs. 58 mmHg; P = 0.004) were lower in the forceps group. There was no difference in continence score between first and second delivery for the forceps group (P = 0.19) group or control subjects (P = 0.18). However, 10 of 38 (26 percent) women with an abnormal endoanal ultrasound after first forceps delivery developed new or worsening symptoms after second delivery.One-quarter of women with occult anal sphincter injury after first forceps delivery experienced some minor alteration in fecal continence after the second delivery.

Background: Glucocorticoids and monoclonal antibodies to tumor necrosis factor reduce inflammation in Crohn's disease (CD). Rapid luminal healing, however, may promote intestinal stricture formation. The aim of this study was to examine fibrosis-associated gene expression in the intestine of patients with CD and correlate expression levels with prior medical therapies. Methods: In all, 37 patients with stricturing CD and 18 non-CD controls underwent a transmural biopsy at the time of elective intestinal resection. Quantitative real-time polymerase chain reaction (PCR) was conducted to determine differential mRNA expression of TGF-β1, Smad-7, CTGF, collagen-1α, fibronectin, BMP-7, and MIF. Intestinal fibroblasts were treated in vitro with dexamethasone. Results: Relative to control, strictured CD intestinal tissue expressed increased TGF-β1, CTGF, collagen-1α, and BMP-7 (all P < 0.05). TGF-β1 gene expression positively correlated with the expression of its downstream targets (all P < 0.001). Preoperative infliximab exposure was not associated with increased expression in any of the target genes nor did the number of infliximab infusions correlate with gene expression. The number of cycles of corticosteroid treatment preoperatively was positively associated with CTGF (r = 0.486, P = 0.016) and MIF (r = 0.524, P = 0.009) expression. Intestinal fibroblasts treated in vitro with dexamethasone upregulated CTGF expression (P = 0.023). Conclusions: Exposure to infliximab does not appear to induce a profibrotic transcriptional response in the CD intestine. Previous corticosteroid treatment is associated with increased expression of CTGF and MIF. Treating intestinal fibroblasts in vitro with steroids upregulates CTGF expression. (Inflamm Bowel Dis 2008)

Splenic flexure mobilization is widely considered to be an essential component of anterior resection for rectal cancer. It was our hypothesis that selective splenic flexure mobilization would reduce operative times without increasing morbidity or affecting cure. A total of 100 consecutive patients with rectal cancer (mean 8 (range, 4–15) cm from anal verge) who underwent anterior resection for cure between 1996 and 2002 had splenic flexure mobilization only as required to achieve a tension-free anastomosis. Operative time, postoperative morbidity, pathologic findings, and recurrence rates were recorded. There were no clinicopathologic differences between those who had splenic flexure mobilization (n = 26) and those who did not (n = 74). Mean operative time in the splenic flexure mobilization group was longer, 167 (range, 130–200) minutes vs. 120 (range, 95–180) minutes in the nonmobilized group (P = 0.023). Mean length of specimen resected was longer in the splenic flexure mobilization group: 36 vs. 18 cm (P = 0.008). Anastomotic complications (4 percent), local recurrence (7 percent, median follow-up, 38 months), perioperative morbidity (32 percent) and mortality (2 percent), and survival did not differ between the two groups. Routine splenic flexure mobilization is not required for safe anterior resection in patients with rectal cancer. Avoiding splenic flexure mobilization results in shorter operative times and does not increase postoperative morbidity, anastomotic leakage, or local recurrence.

Electrogenic ion transport in human colon is a surrogate marker for colonic mucosal function, and may be manipulated by a variety of hormonal, neural, immune and paracrine mediators. Polyamines are present in vast quantities in the colonic lumen and appear to be integral to cellular function. This study explores some of the mechanisms of polyamine action on colonic tissue through study of their effects on differential secretory pathways, as well as examining their actions on intracellular cAMP and Ca(2+) accumulation. Human colonic mucosa was mounted in Ussing chambers and treated with polyamines (spermine, spermidine and putrescine) with changes in ion transport recorded. In separate experiments colonic crypts were treated with polyamines and intracellular cAMP levels determined by ELISA and intracellular calcium concentrations were quantified by fluorescent imaging. Polyamines at physiological concentrations (1mM) exert no effects on basal mucosal chloride secretion or transepithelial electrical resistance. Polyamines inhibit electrogenic ion secretion as stimulated by forskolin (cAMP-mediated), but not carbachol (Ach-mediated). All the polyamines used in this study inhibited intracellular cAMP accumulation, according to potency (spermine>spermidine>putrescine). Spermine increased intracellular Ca(2+) in a PKC-dependent manner, likely due to its effects on the extracellular calcium-sensing receptor (CaSR). Polyamines act to prevent cAMP-mediated Cl(-) hypersecretion in the colon, acting through CaSR to inhibit PKC-mediated [Ca(2+)]i release from intracellular stores.

Background Akkermansia muciniphila and Desulfovibrio spp. are commensal microbes colonising the mucus gel layer of the colon. Both species have the capacity to utilise colonic mucin as a substrate. A. muciniphila degrades colonic mucin, while Desulfovibrio spp. metabolise the sulfate moiety of sulfated mucins. Altered abundances of these microorganisms have been reported in ulcerative colitis (UC). However their capacity to bind to human colonic mucin, and whether this binding capacity is affected by changes in mucin associated with UC, remain to be defined. Methods Mucin was isolated from resected colon from control patients undergoing resection for colonic cancer (n = 7) and patients undergoing resection for UC (n = 5). Isolated mucin was purified and printed onto mucin microarrays. Binding of reference strains and three clinical isolates of A. muciniphila and Desulfovibrio spp. to purified mucin was investigated. Results Both A. muciniphila and Desulfovibro spp. bound to mucin. The reference strain and all clinical isolates of A. muciniphila showed increased binding capacity for UC mucin (p < .005). The Desulfovibrio reference strain showed increased affinity for UC mucin. The mucin binding profiles of clinical isolates of Desulfovibrio spp. were specific to each isolate. Two isolates showed no difference in binding. One UC isolate bound with increased affinity to UC mucin (p < .005). Conclusion These preliminary data suggest that differences exist in the mucin binding capacity of isolates of A. muciniphila and Desulfovibrio spp. This study highlights the mucin microarray platform as a means of studying the ability of bacteria to interact with colonic mucin in health and disease.

The goal of this consensus initiated by the European Crohn's and Colitis Organisation (ECCO) was to establish European consensus guidelines for the surgical treatment of ulcerative colitis. The strategy to reach the consensus involved several steps and follows the standard operating procedures for consensus guidelines of ECCO. An open call for chairs and participants for this consensus was made (see acknowledgements and www.ecco-ibd). Participants were selected by the Guidelines' Committee of ECCO (GuiCom) on the basis of their publication record and a personal statement. Four working groups (WGs) were formed: WG 1 on the preoperative phase, WG 2 on the intraoperative phase, WG 3 on the postoperative phase and WG 4 on special situations. Participants were asked to answer relevant questions on current practice and areas of controversy related to the surgical treatment of ulcerative colitis based on their experience as well as evidence from the literature (Delphi procedure).1 In parallel, the WG members performed a systematic literature search of their topic with the appropriate key words using Medline/PubMed/ISI/Scopus and the Cochrane database, as well as their own files. Provisional guideline statements (with supporting text) were then written by the WG chairs based upon answers to the questionnaire and were circulated among the WG members, prompting discussions and exchange of literature evidence. The proposed statements and the supporting text were submitted to an online platform for online discussion and two online voting procedures among all Consensus participants for the first voting procedure and also for all national representatives of ECCO for the second voting procedure. The WGs finally met in Belgrade on September 25th 2013 for a final face-to-face discussion and to vote and consent on the statements. Technically this was done by projecting the statements and revising them on screen until a consensus was reached. Consensus was defined …

Background Stricture formation in Crohn's disease occurs as a result of persistent fibroblast activation. Chronic inflammation seen in patients with Crohn's disease leads to enhanced adhesion molecule expression in fibroblasts. Stress-activated mitogen-activated protein kinases are critical signaling pathways that control expression of intracellular adhesion molecule-1 (ICAM-1) in inflammation. The purpose of this study was to investigate the involvement of stress-activated mitogen-activated protein kinases in the regulation of ICAM-1 expression by tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in serosal fibroblasts isolated from patients with Crohn's disease. Study design Fibroblasts were isolated from serosal biopsies of strictures in patients with Crohn's disease and normal colon in patients with colorectal carcinoma. Cell surface and whole cell ICAM-1 expression were evaluated by flow cytometry and Western blot analysis, respectively. Cells were stimulated with TNF-α and IL-1β. To determine the mitogen-activated protein kinase signaling pathway required for ICAM-1 induction, cells were pretreated with inhibitors to Jun N-terminal kinase, p38 kinase, and p42/44 kinase. Results Baseline ICAM-1 expression was higher (p Conclusions Serosal fibroblasts isolated from strictures of patients with Crohn's disease demonstrate enhanced expression of ICAM-1. TNF-α and IL-1β upregulate ICAM-1 expression in serosal fibroblasts through a Jun N-terminal kinase signaling pathway. Specific inhibition of inflammatory signaling pathways could provide novel therapeutic targets for treatment of Crohn's disease.

PURPOSE: Third-degree tears are generally managed by primary anal sphincter repair. Postoperatively, some physicians recommend laxative use, whereas others favor bowel confinement after anorectal reconstructive surgery. This randomized trial was designed to compare a laxative regimen with a constipating regimen in early postoperative management after primary obstetric anal sphincter repair. METHODS: A total of 105 females were randomized after primary repair of a third-degree tear to receive lactulose (laxative group) or codeine phosphate (constipated group) for three days postoperatively. Patients were reviewed at three days and at three months postpartum. Recorded outcome measures were symptomatic and functional outcome and early postoperative morbidity. RESULTS: Forty-nine patients were randomly assigned to the constipated group and 56 patients to the laxative group. The first postoperative bowel motion occurred at a median of four (mean, 4.5 (range, 1–9)) days in the constipated group and at two (mean, 2.5 (range, 1–7)) days in the laxative group (P < 0.001). Patients in the constipated group had a significantly more painful first evacuation compared with the laxative group (P < 0.001). The mean duration of hospital stay was 3.7 (range, 2–6) days in the constipated group and 3.05 days in the laxative group (range, 2–5; P = 0.001). Nine patients in the constipated group complained of troublesome postoperative constipation compared with three in the laxative group (P = 0.033). Continence scores, anal manometry, and endoanal ultrasound findings were similar in the two groups at three months postpartum. CONCLUSIONS: Patients in the laxative group had a significantly earlier and less painful bowel motion and earlier postnatal discharge. There was no difference in the symptomatic or functional outcome of repair between the two regimens.

Objective The purpose of this study was to assess patterns of abnormal pudendal nerve function in women who complain of postpartum fecal incontinence. Study design During a 12-month period, a cohort of 83 women underwent neurophysiologic assessment as part of an evaluation of fecal incontinence after vaginal delivery. Pudendal nerve assessment consisted of the measurement of the clitoral-anal reflex and quantitative electromyography of the external anal sphincter. Endoanal ultrasound examination and anal manometry were also performed in each patient. Results Thirty of 83 women (38%) with fecal incontinence were found to have abnormal neurophysiologic condition, among whom four identifiable patterns of abnormality emerged. Five women (17%) had evidence of pudendal nerve demylenation with a prolonged sensory threshold of the clitoral-anal reflex (>5.2 mA), although electromyography studies were normal. Eight women (27%) had abnormal electromyography results that were consistent with axonal neuropathy with or without reinervation, in whom the clitoral-anal reflex was normal. Thirteen women (43%) demonstrated a mixed demyelinating and axonal pudendal neuropathy, with evidence of reinervation. Four women (13%) had abnormal patterns of neurophysiologic condition that was not attributable directly to past obstetric trauma but to coincident medical problems. Conclusion Four abnormal patterns of pudendal nerve function may be identified, three of which (demyelinating, axonal, and mixed demyelinating/axonal) can be attributed to specific past obstetric events, although a fourth radicular pattern is due to coincident medical or orthopedic problems. Assessment of pudendal nerve function is important in women with postpartum fecal incontinence because particular patterns of abnormality correlate with different symptoms and can influence treatment options.

PURPOSE: Involvement of the urinary tract by colorectal cancer is sufficiently rare to be encountered by an individual surgeon on an infrequent basis. The aim of this review is to highlight technical and oncologic issues that should be considered when dealing with complex colorectal cancer that involves the urinary tract. METHODS: The relevant literature from 1975 to 2001 was identified using the MEDLINE database of the U.S. National Library of Medicine and reviewed. Because of the diversity of forms of presentation of urologic involvement, few randomized, controlled trials are available, with most evidence derived from retrospective studies. RESULTS: Three distinct clinical situations in which the urinary tract may be affected by colorectal cancer were identified: involvement by primary colorectal cancer, involvement by recurrent cancer, and unexpected intraoperative findings of urinary tract involvement. Management strategies to identify and treat locally advanced primary or recurrent colorectal cancer involving the urinary tract improve survival with acceptable morbidity and mortality. Careful preoperative assessment of all patients with colorectal cancer will reduce unexpected identification of urinary tract invasion at the time of surgery. In patients in whom cure is not possible, endourologic techniques combined with judicious surgical resection can provide high-quality palliation. Optimal care of many of these conditions is facilitated by specialist urologic advice. CONCLUSIONS: The wide spectrum of possible urinary tract involvement by colorectal cancer requires individual patient-specific and disease-specific consideration. The literature offers important guidelines that aid decision making and improve management of these challenging problems.

Objective To assess the effects of delayed vs immediate pushing in second stage of labour with epidural analgesia on delivery outcome, postpartum faecal continence and postpartum anal sphincter and pudendal nerve function. Design Prospective, randomised, controlled trial. Setting Tertiary referral maternity teaching hospital. Population One hundred and seventy nulliparous women randomised at full dilatation to immediate or delayed pushing. Methods A total of 178 nulliparous women, all with continuous epidural analgesia, were randomised at full cervical dilatation, but before the fetal head had reached the pelvic floor, to either immediate pushing or 1 hour delayed pushing. Labour outcome was analysed and all women underwent postpartum assessment of anal sphincter function, including anal manometry. Those women who had a normal delivery underwent neurophysiology studies, while those women who had an instrumental delivery underwent endoanal ultrasound. Main outcome measures Mode of delivery; altered faecal continence. Results Ninety women were randomised to immediate pushing and 88 to delayed pushing. The spontaneous delivery rate was 56% (50/90) in the immediate pushing group and 52% (46/88) in the delayed pushing group. Mean duration of labour for the immediate pushing group was 427 minutes compared with 480 minutes for the delayed pushing group (P = 0.005). Eighty-four percent (76/90) of women in the immediate pushing group received oxytocin to augment labour, 21/76 (28%) in the second stage only. Eighty-one percent (71/88) of women in the delayed pushing group received oxytocin to augment labour, 22/71 (31%) in the second stage only. Fetal outcome did not differ between the two groups. Episiotomy rates were 73% and 69% in the immediate pushing and delayed pushing groups, respectively. 26% (23/90) of the immediate pushing group and 38% (33/88) of the delayed pushing group complained of altered faecal continence after delivery (NS). Manometry, ultrasound and neurophysiology studies did not differ significantly between the two groups. Overall, 55% of women after instrumental delivery had endosonographic evidence of damage to the external anal sphincter, while 36% of women after spontaneous delivery had abnormal neurophysiology studies. Conclusions Rates of instrumental delivery were similar following immediate and delayed pushing, in association with epidural analgesia. Delayed pushing prolonged labour by 1 hour but did not result in significantly higher rates of altered continence or anal sphincter injury, when compared with immediate pushing.

Most patients with Crohn’s disease (CD) ultimately require surgical resection of their disease. 1 Stricture formation and intestinal obstruction is the precipitating factor in many of these patients. Despite the significant morbidity associated with this complication, the etiology of stricture formation remains unclear. Efforts to explain the stricturing process characteristic of CD have focused on identification of the cell types and the connective tissue matrix present within CD strictures. Smooth muscle cell accumulation and excessive deposition of collagen may contribute toward the stricturing process. 2,3 In addition, there are alterations in the predominant collagen subtypes found in the connective tissue matrix of gastrointestinal strictures in patients with CD. 2,3 The fibroblast plays a key role in the collagen production, rearrangement, and fibrosis that is essential in wound healing. 4 Fibroblasts are influenced by multiple cytokines 5,6 secreted both by acute inflammatory cells and neighboring fibroblasts. During wound healing, fibroblasts express cellular adhesion molecules (e.g., ICAM-1 and CD11b) that are essential for intercellular interaction 7 and part of normal fibroblast function. Extensive research in the field of rheumatology has produced new insights into the molecular mechanisms involved in fibroblast activity. 8,9 Altered fibroblast adhesion molecule expression has been described among patients with fibrotic conditions such as scleroderma. 10 It is unclear whether these findings are a primary phenomenon or secondary to the disease process, but these observations may have important implications regarding the pathophysiology of inflammatory bowel disease (IBD). Expression of cellular adhesion molecules, including ICAM-1, is controlled by gene transcription. Cytokines affect adhesion molecule expression through their effect on intracellular enzyme cascades, which culminate in the release of cellular transcription factors (e.g., NFκB). Control of gene expression by transcription factors is central to regulated cellular function. NFκB regulates the expression of genes responsible for promoting inflammation and regulating apoptosis. NFκB is a pleiotropic transcription factor with key functions in the intestinal immune system. The NFκB family controls transcriptional activity of various promoters of proinflammatory cytokines, cell surface receptors, transcription factors, and cellular adhesion molecules that are involved in intestinal inflammation. 11 NFκB can be found in the cytoplasm of most cells as an inactive complex with unprocessed precursor proteins or IκB proteins. 12 Activation of cells with various stimuli initiates a signaling cascade that induces site-specific phosphorylation of IκBα and leads to dissociation of the complex. 13 NFκB then translocates into the nucleus and binds to specific DNA gene promoter regions, thus activating or augmenting transcription. Increased production of proinflammatory cytokines in the intestinal mucosa may be important in the pathophysiology of intestinal inflammation in IBD. Many of the genes that code for these cytokines are transcriptionally regulated by NFκB binding site proteins. 14,15 The presence of nuclear transcription factors in fibroblasts and other inflammatory cells would therefore appear to be a common denominator among all cell types, including fibroblasts, in patients with IBD. This intracellular final common pathway may provide an attractive target for therapeutic strategies in patients with CD. Previous work from our laboratory has shown that fibroblasts isolated from the serosa of patients with CD exhibit an increased ability to contract a collagen matrix in vitro. 16 Whether this phenomenon represents a constitutive abnormality in patients with CD or is a secondary response to transmural inflammation is unknown and is the subject of this study.

Sacral nerve stimulation (SNS) was originally developed in the field of urinary incontinence. Without adaptation, it was subsequently applied to treat faecal incontinence. SNS has now become a first line therapy for this socially disabling condition, however the mechanism of action is unknown. This review examines the evidence for stimulation parameters currently used for SNS in humans and considers the potential electrophysiological effects of changing these parameters. However, without a proper understanding of the physiology of SNS, changing stimulation parameters remains empirical.

Whether this classic text book can still be called ‘A Short Practice of Surgery’ is debatable. It now runs to 1500 pages and 5 kg: a weighty tome indeed! Interestingly, my 20th edition, the yellow coloured book, weighs 2.5 kg. Nevertheless, this is the 25th anniversary edition so one should expect something extra special. The editors are to be congratulated on maintaining the consistently high standard, which had been developed during Chris Russell's 4-year reign as senior editor. Much of the traditional style is preserved and this is highly desirable. The historical attributes and vignettes, the hallmark of Bailey and Love since its inception, happily remain. Each of the 77 chapters is preceded by a series of learning objectives, designed to ensure that the reader is familiar with what should be understood having read the chapter. The book is beautifully illustrated with clear and descriptive colour photographs of a very high quality. Even the X-rays and scans are easy to read and interpret, and the publishers are to be congratulated for this. The chapters that particularly interested me (gastrointestinal and oncology) were easily readable and informative. There is a remarkably consistent style, which is clearly, once again, a tribute to the editors, especially since there are 102 contributors. Bailey and Love is still a major reference book from which one can both refresh and keep up to date with rapidly developing surgical concepts. At the same time, it provides a comprehensive explanation and revision of those important basic principles that remain constant. This book remains a useful reference for final-year surgical students and for first and second-year surgical trainees who are looking for a broad view of surgery prior to sitting membership examinations. There is no doubt that Bailey and Love provides exceptional background information for all of surgery in general. For these reasons, the book remains at the very forefront of surgical texts and I have no doubt that the 25th edition of Bailey and Love will prove as popular as its predecessors.

Objective: We compared, in a prospective, randomized clinical trial, the subjective and objective outcomes after primary anal sphincter overlap or approximation repair of third-degree obstetric tears. Study Design: In a prospective, randomized clinical trial at our university teaching hospital, we studied 112 primiparous women who sustained a third-degree tear during a 1-year period (July 1998–June 1999); they were randomly selected, at diagnosis, to receive either an overlap or an approximation repair. Obstetric personnel, trained in both methods, carried out the repairs immediately after delivery. Fifty-five women underwent an overlap procedure, and 57 women underwent an approximation repair. Outcome measures assessed were symptoms of fecal incontinence, abnormal findings on anal manometry, and abnormal findings on endoanal ultrasonography at 3 months post partum. Results: Obstetric factors, including mode of delivery, birth weight, duration of labor, and episiotomy incidence, did not differ significantly between the 2 groups. Experience of the operator, analgesia used, and place of repair were similar in both groups. The median incontinence scores were 0/20 after overlap repair and 2/20 after approximation repair (difference not significant). Eleven women (20%) complained of fecal urgency after overlap repair, in comparison with 17 (30%) after approximation repair (difference not significant). There were no significant differences in either anal manometry or endoanal ultrasonographic results between the 2 groups. Six women (11%) had a significant (>1 quadrant) anal sphincter defect after primary overlap repair, compared with 3 (5%) after approximation repair (difference not significant). Overall, 66% of women had ultrasonographic evidence of a residual full-thickness defect in the external anal sphincter after primary repair. Conclusion: The outcome after primary repair of third-degree obstetric tear was similar whether an approximation or an overlap technique was used. Overall symptomatic outcome was good, although two thirds of women had ultrasonographic evidence of residual anal sphincter damage irrespective of the method of repair. (Am J Obstet Gynecol 2000;183:1220-4.)