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BACKGROUND: Surveillance colonoscopy is recommended for inflammatory bowel disease (IBD) patients with longstanding extensive colitis (LEC). AIMS: To assess modalities and results of colonoscopic surveillance in a subset of CESAME cohort patients at high risk of colorectal cancer (CRC) and followed in university French hospitals. METHODS: Among 910 eligible patients with more than a 7-year history of extensive colitis at CESAME enrolment, 685 patients completed a questionnaire on surveillance colonoscopy and 102 were excluded because of prior proctocolectomy. Finally, 583 patients provided information spanning a median period of 41months (IQR 38-43) between cohort enrolment and the end of follow-up. Details of the colonoscopic procedures and histological findings were obtained for 440 colonoscopies in 270 patients. RESULTS: Only 54% (n=312) of the patients with LEC had at least one surveillance colonoscopy during the study period, with marked variations across the nine participating centres (27% to 70%, P≤0.0001). Surveillance rate was significantly lower in Crohn's colitis than in ulcerative colitis (UC) (48% vs. 69%, P≤0.0001). Independent predictors of colonoscopic surveillance were male gender, UC IBD subtype, longer disease duration, previous history of CRC and disease management in a centre with large IBD population. Random biopsies, targeted biopsies and chromoendoscopy were performed during respectively 71%, 27 and 30% of surveillance colonoscopies. Two cases of high-grade dysplasia were detected in patients undergoing colonoscopic surveillance. Two advanced-stage CRC were diagnosed in patients who did not have colonosocopic surveillance. CONCLUSIONS: Colonoscopic surveillance rate is low in IBD patients with longstanding extensive colitis.

Background & Aims Little is known about the magnitude of the risk of anal and rectal cancer in patients with anal and/or perineal Crohn's disease. We aimed to assess the risk of anal and rectal cancer in patients with Crohn's perianal disease followed up in the Cancers Et Surrisque Associe aux Maladies Inflammatoires Intestinales En France (CESAME) cohort. Methods We collected data from 19,486 patients with inflammatory bowel disease (IBD) enrolled in the observational CESAME study in France, from May 2004 through June 2005; 14.9% of participants had past or current anal and/or perianal Crohn's disease. Subjects were followed up for a median time of 35 months (interquartile range, 29–40 mo). To identify risk factors for anal cancer in the total CESAME population, we performed a case-control study in which participants were matched for age and sex. Results Among the total IBD population, 8 patients developed anal cancer and 14 patients developed rectal cancer. In the subgroup of 2911 patients with past or current anal and/or perianal Crohn's lesions at cohort entry, 2 developed anal squamous-cell carcinoma, 3 developed perianal fistula–related adenocarcinoma, and 6 developed rectal cancer. The corresponding incidence rates were 0.26 per 1000 patient-years for anal squamous-cell carcinoma, 0.38 per 1000 patient-years for perianal fistula–related adenocarcinoma, and 0.77 per 1000 patient-years for rectal cancer. Among the 16,575 patients with ulcerative colitis or Crohn's disease without anal or perianal lesions, the incidence rate of anal cancer was 0.08 per 1000 patient-years and of rectal cancer was 0.21 per 1000 patient-years. Among factors tested by univariate conditional regression (IBD subtype, disease duration, exposure to immune-suppressive therapy, presence of past or current anal and/or perianal lesions), the presence of past or current anal and/or perianal lesions at cohort entry was the only factor significantly associated with development of anal cancer (odds ratio, 11.2; 95% CI, 1.18-551.51; P = .03). Conclusions In an analysis of data from the CESAME cohort in France, patients with anal and/or perianal Crohn's disease have a high risk of anal cancer, including perianal fistula–related cancer, and a high risk of rectal cancer.

Summary Background Lactulose and polyethylene glycol are osmotic agents used to treat idiopathic chronic constipation. Aim To compare the effects of low doses of lactulose and PEG 4000 on transit time measured by scintigraphy in normal subjects. Methods For 5 days, 10 healthy subjects received either 10 g b.d. of lactulose or PEG 4000 in a randomized, double-blind, crossover study. On the evening of day 4, they took a capsule containing Amberlite resin pellets labelled with 111In. On day 5, after a 1000 kcal test meal labelled with 99Tcm, gastric, small bowel and colonic transits were measured. Results Gastric emptying and small bowel transit time were not different. Ascending colon emptying curve was significantly accelerated with lactulose in comparison with polyethylene glycol (P = 0.001) and, respectively, 50 ± 18% vs. 35 ± 18% of the radioactivity had left the ascending colon at the end of the study (P

Background & Aims: In hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, flat and small adenomas are particularly prone to malignant transformation but might be missed by standard colonoscopy. We prospectively studied the diagnostic yield of high-resolution colonoscopy coupled with chromoendoscopy for preneoplastic and neoplastic colorectal lesions in patients with HNPCC syndrome. Methods: Thirty-six consecutive asymptomatic patients (mean age, 42 years) belonging to HNPCC families and receiving genetic counseling were enrolled in this prospective study. Colonoscopy was performed in 2 steps. Conventional colonoscopy was performed first, followed by a second colonoscopy with chromoendoscopy with indigo carmine (.4%) dye sprayed onto the entire proximal colon. Results: Conventional colonoscopy identified 25 lesions (mean size, 4 ± 3 mm) in 13 patients. Seven lesions, detected in 5 patients, were adenomas, 3 of which were located in the proximal colon. Chromoendoscopy identified additional 45 lesions (mean size, 3 ± 1 mm) in 20 patients; most of these lesions were flat and hyperplastic. Eleven additional adenomas were detected in the proximal colon of 8 patients, and 8 of these 11 lesions were flat. The use of chromoendoscopy significantly increased the detection rate of adenomas in the proximal colon, from 3 of 33 patients to 10 of 33 patients (P = .045). Conclusion: Relative to conventional colonoscopy, high-resolution colonoscopy with chromoendoscopy markedly improves the detection of adenomas in patients with HNPCC syndrome and might help to prevent colorectal carcinoma in these patients with a very high risk of colorectal cancer.

Purpose: The target enzyme for 5-fluorouracil (5-FU) is thymidylate synthase (TS). The TYMS gene encoding this enzyme is polymorphic, having either double (2R) or tri-tandem (3R) repeats of a 28-bp sequence in the promoter region and a 6-bp variation in the 3′-untranslated region (3′-UTR). TS expression predicts response to 5-FU-based chemotherapy, and the expression seems to be determined by the TYMS gene promoter. The aim of this study was to investigate the utility of determining these two TYMS gene polymorphisms to predict the toxicity and efficacy of 5-FU treatment in patients with colorectal cancer. Experimental Design: The determination of TYMS genotypes was performed in tumor and normal tissues by PCR amplification from 90 patients with colorectal cancer who were treated with adjuvant or palliative 5-FU-based chemotherapy. Associations between polymorphisms in the TYMS promoter and in the 3′-UTR gene and clinical outcome of these 90 patients treated with 5-FU based chemotherapy were evaluated individually. The linkage between TYMS promoter and TYMS 3′-UTR region polymorphisms was evaluated and a haplotype analysis was performed. Results: Individuals who were homozygous for the double repeat in the TYMS promoter region had more severe side effects to 5-FU. Patients with a 2R/2R, a 2R/3R, or a 3R/3R genotype had a grade 3 or 4 toxicity rate of 43, 18, and 3% respectively (P < 0.01). The TYMS promoter and TYMS 3′-UTR polymorphisms were in linkage disequilibrium, and the haplotype 2R/ins 6-bp was significantly associated with a high risk of severe side effects to 5-FU. The TYMS promoter and TYMS 3′-UTR polymorphisms were not associated with a response to 5-FU and survival of patients who received palliative 5-FU-based chemotherapy. Conclusions: This study demonstrated that TYMS genotyping could be of help in predicting toxicity to 5-FU-based chemotherapy. TYMS genotyping might make it possible to individualize treatment for patients with colorectal cancer.

Background We have assessed the long-term efficacy and safety of a combination therapy of interferon alpha-2b (IFN) and ribavirin (RBV) for the treatment of severe chronic hepatitis C in co-infected HIV-seropositive patients in an open prospective study. Methods Fifty-one patients were treated for 12 months. Mean baseline CD4 cell count, alanine aminotransferase and aspartate aminotransferase were 412 +/- 232 x 106/l, 113 +/- 75 IU/l and 111 +/- 84 IU/l respectively. The mean Knodell score was 11.5 +/- 2.1 with 28 patients (55%) exhibiting histological evidence of active cirrhosis. Results Fifteen (29%) patients discontinued the treatment prematurely because of adverse events. An end of treatment response (ETR) as defined by the lack of detectable hepatitis C virus (HCV) RNA in plasma at the end of treatment was achieved in 15 patients (29%). A sustained virological response (SVR), defined by the lack of detectable HCV RNA in plasma 6 months after completion of combination therapy, was achieved in 11 patients (21%). The HCV genotype 3a was associated with ETR and SVR (P = 0.002 and P = 0.003, respectively). HCV viraemia at baseline was lower in patients who achieved SVR and ETR than in those who did not (6.7 +/- 7.8 versus 24 +/- 26.7 x 10(6) genome equivalents/ml, P = 0.03 and 14.3 +/- 28.7 versus 22.5 +/- 23, P = 0.05, respectively). Conclusion Our results indicate that combination therapy with IFN and RBV is effective in approximately 20% of co-infected patients with severe liver disease.

The aim of this study was to assess in nine healthy subjects the effects of CCK octapeptide (CCK-8) on colonic tonic activity, measured by a barostat, and phasic activity, measured by manometry. On 2 consecutive days, recordings were performed in the unprepared proximal and distal colons during intravenous infusion of saline and CCK-8 at 5, 20, and 40 ng ⋅ kg−1⋅ h−1. In the proximal colon CCK-8 induced, at the 20 and 40 ng ⋅ kg−1⋅ h−1doses, a tonic relaxation with an increase in barostat bag volume to 156 ± 25 and 157 ± 19% of basal ( P < 0.01) and a decrease in phasic activity to 72 ± 7 and 76 ± 7% of basal ( P < 0.01). In the distal colon, CCK-8 induced, at the 20 and 40 ng ⋅ kg−1⋅ h−1doses, a tonic relaxation (increase in intrabag volume to 133 ± 12 and 149 ± 15%, respectively; P< 0.01), whereas phasic activity increased (128 ± 8 and 132 ± 6%, respectively; P < 0.01). Effects of CCK-8 on tonic and phasic activities are different according to the colonic segment. Because meals induce colonic tonic contraction, our results suggest that CCK, as a hormone, is not an important mediator of the response of the colon to feeding in humans.

A 67-year-old woman with end-stage renal disease (ESRD) was referred with chronic diarrhoea, severe hypokalaemia and recurrent colonic pseudo-obstructions following haemorrhagic shock. The cause of secretory diarrhoea was uncertain, but an ileostomy identified the colon as the source of the watery diarrhoea and potassium (K(+)) losses, and symptoms only resolved after colectomy. Immunohistochemistry of the colon revealed over-expression of high conductance K(+) (BK) channel protein in surface colonocytes and crypt cells compared with controls and other patients with ESRD. We hypothesize that colonic ischaemia during haemorrhagic shock led to increased BK channel expression and thus enhanced colonic K(+) and water secretion, resulting in severe hypokalaemia and colonic pseudo-obstruction.

We previously showed that gastric distension inhibits the somatic nociceptive flexion RIII reflex. To explore further the viscerosomatic interactions, we tested in the present study the effects of rectal distensions on RIII reflexes. Rapid and slow-ramp rectal distensions were performed in 10 healthy volunteers with an electronic barostat. The RIII reflex was continuously recorded from the lower limb during both types of distension and from the upper limb during rapid distensions. The visceral sensations were scored on a graded questionnaire. Rapid distensions facilitated the RIII reflex recorded from the lower limb, but at the highest distension level, facilitation was followed by inhibition. Slow-ramp distension induced gradual inhibition of the RIII reflex, which correlated with both distension volume and visceral sensation. RIII reflex recorded from the upper limb was also inhibited by rapid rectal distensions. Reflex inhibitions were probably related to the activation of pain modulation systems. One plausible explanation for the facilitatory effects, observed only at the lower limb, is the convergence of rectal and reflex afferents at the same levels of the spinal cord. The differential effects of rapid and slow-ramp distensions suggest the activation of two distinct populations of mechanoreceptors by these two modes of distension.

In healthy humans, meals stimulate phasic and tonic motor activity in the unprepared distal colon. The response of the proximal colon remains unknown. In this study, we assessed the effect of a liquid meal on proximal and distal colonic motor activity. In 12 healthy volunteers, colonic tone and phasic motility were simultaneously recorded by using an electronic barostat and perfused catheters in the fasting state and in response to a 1,000-kcal meal. The meal significantly increased the phasic activity in the distal colon (230 ± 46% of the basal value; P = 0.02) but not in the proximal colon (138 ± 25% of the basal value; P = 0.2). The intrabag volume of the barostat was significantly more reduced in the distal than in the proximal colon (74 ± 11 vs. 50 ± 9% of the basal values, respectively; P = 0.04). We conclude that the postprandial response of the unprepared proximal colon is an immediate tonic contraction that is less pronounced than in the distal colon.

A 24-year-old woman (53 kg) with a 5-year history of steroid-dependent ulcerative colitis with mild and extensive ulcerations presented to the gastroenterology clinic for symptom recurrence. She was given 100 mg/day (1.9 mg · kg−1 · day−1) azathioprine (AZA)5 for 1 month, after which the dose was increased to 125 mg/day (2.3 mg · kg−1 · day−1). Four months later, the patient was tapered off steroid therapy. Her symptoms persisted after 7 months of AZA therapy, however, and she experienced gastrointestinal side effects. The patient was switched to another thiopurine drug, 6-mercaptopurine (6-MP), at 75 mg/day (1.4 mg · kg−1 · day−1), which was well tolerated but similarly ineffective (8 stools daily). A brief course of steroid therapy rapidly produced a substantial but short-lived clinical improvement. To understand this patient's unresponsiveness to 2 thiopurine agents, we quantified thiopurine metabolites (1) 1 year after initiating AZA therapy. Intraerythrocyte concentrations of 6-thioguanine nucleotides (6-TGNs) were low (132 pmol/8 · 108 erythrocytes; therapeutic interval, 230–400 pmol/8 · 108 erythrocytes), and 6-methylmercaptopurine ribonucleotides (6-MMPRs) were very high (11 666 pmol/8 · 108 erythrocytes; therapeutic interval

BACKGROUND: Somatostatin analogues effectively control flushing and diarrhoea in patients with the carcinoid syndrome. The octapeptide lanreotide is available in slow release form, which could eliminate the necessity of twice a day injections as with octreotide. PATIENTS AND METHODS: 39 patients with carcinoid syndrome were included in a prospective multicentre study. Patients received lanreotide 30 mg intramuscularly every 14 days for six months. The number and intensity of flushing episodes and bowel movements, urinary 5 hydroxy-indolacetic acid (5 HIAA) concentrations, and variations of tumour mass were recorded. RESULTS: After one month of treatment, flushing episodes (median (range)) decreased significantly (3 (0.3-24) episodes per day v 1 (0-15), p = 0.04) and completely resolved in 39% of the patients. A significant decrease was seen in the number of bowel movements and discomfort related to diarrhoea. Urinary 5 HIAA concentrations were unchanged in 57% of the patients and decreased in 18%. After six months of treatment, the actuarial proportions of patients with at least a 50% decrease in the number of flushing episodes and bowel movements were 54% and 56%, respectively. Forty two per cent of the patients who were treated for six months had at least a 50% reduction in 5 HIAA values. No clear signs of regression of tumours were seen in any of the patients. Lanreotide was well tolerated despite transient mild pain or erythema at the injection site in 25% of the patients. Biliary lithiasis appeared in two patients after six months of lanreotide. CONCLUSION: Lanreotide, 30 mg intramuscularly every other week, is an effective and convenient treatment in patients with the carcinoid syndrome.

Introduction Prognosis of enteropathy-associated T cell lymphoma is poor but predictors of survival remain ill-defined. How clinical presentation, pathological features and therapies influence outcome was evaluated in 37 thoroughly characterized patients with celiac disease and T-cell lymphoma. Patients and methods Medical files were studied retrospectively. Lymphoma and intestinal mucosa were analysed by histopathology, multiplex PCR and intestinal intraepithelial lymphocytes phenotyping. Survival and prognostic factors were analysed using Kaplan–Meier curves with Logrank test and Cox Model. Results Lymphoma complicated non clonal enteropathy, celiac disease (n = 15) and type I refractory celiac disease (n = 2) in 17 patients and clonal type II refractory celiac disease in 20 patients. Twenty-five patients underwent surgery with resection of the main tumour mass in 22 cases. In univariate analysis, non clonal celiac disease, serum albumin level > 21.6 g/L at diagnosis, chemotherapy and surgical resection predicted good survival (p = 0.0007, p 21.6 g/L, chemotherapy and reductive surgery were all significantly associated with increased survival (p

Background & Aims It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohn's disease who have undergone a period of prolonged remission. We assessed the risk of relapse after infliximab therapy was discontinued in patients on combined maintenance therapy with antimetabolites and identified factors associated with relapse. Methods We performed a prospective study of 115 patients with Crohn's disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months. Infliximab was stopped, and patients were followed up for at least 1 year. We associated demographic, clinical, and biologic factors with time to relapse using a Cox model. Results After a median follow-up period of 28 months, 52 of the 115 patients experienced a relapse; the 1-year relapse rate was 43.9% ± 5.0%. Based on multivariable analysis, risk factors for relapse included male sex, the absence of surgical resection, leukocyte counts >6.0 × 10 9 /L, and levels of hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g. Patients with no more than 2 of these risk factors (approximately 29% of the study population) had a 15% risk of relapse within 1 year. Re-treatment with infliximab was effective and well tolerated in 88% of patients who experienced a relapse. Conclusions Approximately 50% of patients with Crohn's disease who were treated for at least 1 year with infliximab and an antimetabolite agent experienced a relapse within 1 year after discontinuation of infliximab. However, patients with a low risk of relapse can be identified using a combination of clinical and biologic markers.

Background & Aims: The position of capsule endoscopy (CE) relative to push enteroscopy (PE) in the diagnostic algorithm of obscure gastrointestinal bleeding is unclear, as previous studies involved the use of both techniques in all patients. We therefore conducted a trial in which patients were randomized to undergo one or other exploration. Methods: All consecutive patients referred for obscure gastrointestinal bleeding were randomized between CE and PE as the first-line exploration. The alternative method was only used if the first-line method revealed no definite bleeding source, or if required for clinical reasons during follow-up. Results: CE and PE, used as the first-line exploration, identified a bleeding source in 20 of 40 patients and 9 of 38 patients, respectively (50% vs 24%; P = .02). CE missed lesions in 8% of patients, and all these lesions were located in sites accessible to standard endoscopy. PE missed lesions in 26% of patients. At the end of the 12-month follow-up period, the strategy based on CE as first-line exploration followed by PE if necessary only was similar to PE followed by CE in terms of diagnostic yield, clinical outcome, and therapeutic impact, but reduced the percentage of patients needing the alternative exploration (25% vs 79%; P Conclusions: CE has a higher diagnostic yield than PE in obscure gastrointestinal bleeding, and a strategy based on CE as first-line exploration avoids unnecessary explorations.

Many trials on probiotics are now published that use established methods to demonstrate their clinical efficacy. Convincing progress has been made in the field of inflammatory bowel disease and allergy prevention in infants. Experimental studies show clear differences (and even sometimes opposite effects) between apparently closely related probiotics and suggest new mechanisms for the observed effects, such as immunostimulation by bacterial DNA and interaction with Toll-like receptors and dendritic cells in the gastrointestinal tract.

Conscious sensations in response to gut distensions may be modulated by temporospatial interactions among different stimuli. This study investigated whether symptoms induced by gastric distension may be modified by hydrochloric acid (HCl) gastric infusion and meal ingestion. In nine healthy subjects, fixed pressure (isobaric) and fixed volume (isovolumetric) distensions were performed during continuous (4 ml/min) intragastric saline or HCl infusion, during fasting and after meal ingestion, until the maximal distension step defined as discomfort or a predefined maximal volume. During fasting isobaric distensions, the maximal distension step was significantly decreased during HCl compared with saline. The intragastric volumes were not significantly different, but the wall tension was significantly lower during HCl than saline. HCl increased gastric compliance. Meal ingestion relaxed the stomach and decreased the pressure at the maximal distension step during saline, but HCl did not further decrease it compared with fasting. During isovolumetric distensions, HCl also increased gastric compliance, but in both fasted and fed states it did not modify the maximal distension steps. In conclusion, sensations in response to gastric isobaric distensions, but not to isovolumetric distensions, are influenced by gastric acid infusion and meal ingestion. The effects of HCl might be related to a sensitization of mucosal mechanoreceptors.

We previously showed that slow-ramp rectal distensions induce graded inhibitions of the somatic nociceptive RIII reflex recorded from the lower limb, which correlated with both distension volume and visceral sensation. In contrast, rapid phasic rectal distensions induced facilitatory or biphasic effects (i.e., facilitations followed by inhibitions) depending on the level of distension. To examine the role of mucosal and serosal rectal mechanoreceptors in these viscerosomatic interactions, we analyzed, in six healthy volunteers, the effects of both types of rectal distension on the RIII reflex after topical application of lidocaine or placebo administered in a double-blind and crossover fashion. Inhibitions of the RIII reflex induced by both slow-ramp and rapid distensions were strongly reduced after administration of lidocaine but not after placebo. In contrast, facilitations of the RIII reflex observed during the initial phase of rapid distensions were not modified after lidocaine or placebo applications. These results suggest that inhibitions, but not facilitations, of the nociceptive RIII reflex triggered by rectal distensions depend preferentially on the activation of superficial mucosal receptors. This reflexologic technique might thus represent an interesting tool for studying the role of the different rectal mechanoreceptors involved in visceral sensations.

Background & Aims: Celiac disease is a gluten-induced enteropathy characterized by the presence of gliadin-specific CD4 + T cells in the lamina propria and by a prominent intraepithelial T-cell infiltration of unknown mechanism. The aim of this study was to characterize the subset(s) of intraepithelial lymphocytes (IELs) expanding during active celiac disease to provide insights into the mechanisms involved in their expansion. Methods: Flow-cytometric analysis of isolated IELs and/or immunohistochemical staining of frozen sections were performed in 51 celiac patients and 50 controls with a panel of monoclonal antibodies against T-cell and natural killer (NK) receptors. In addition, in vitro studies were performed to identify candidate stimuli for NK receptor expression. Results: In normal intestine, different proportions of IELs, which were mainly T cells, expressed the NK receptors CD94/NKG2, NKR-P1A, KIR2D/3D, NKp46, Pen5, or CD56. During the active phase of celiac disease, the frequency of CD94 + IELs, which were mostly αβ T cells, was conspicuously increased over controls. In contrast, the expression of other NK markers was not modified. Furthermore, expression of CD94 could be selectively induced in vitro by T-cell receptor activation and/or interleukin 15, a cytokine produced by intestinal epithelial cells. Conclusions: The gut epithelium favors the development of T cells that express NK receptors. In active celiac disease, there is a specific and selective increase of IELs expressing CD94, the HLA-E–specific NK receptor that may be related to T-cell receptor activation and/or interleukin 15 secretion. GASTROENTEROLOGY 2000;118:867-879

Background Idiopathic oesophageal ulcers have only been described in patients with acquired immunodeficiency syndrome (AIDS). We report the first case occurring in an immunocompetent patient. ##### Case history A 52 year old man presented with a one year history of odynophagia, retrosternal chest pain, dysphagia, and a 10 kg weight loss. He had no history of gastrointestinal disease and had not taken drugs. An upper endoscopy, performed shortly after symptom onset, showed a 3 cm solitary oesophageal ulcer with smooth and irregular margins 3 cm above the gastro–oesophageal junction. Biopsy samples showed acute and chronic inflammation without any fungal or viral particles. Despite three months on a proton pump inhibitor, symptoms and endoscopic findings did not change. Oesophageal manometry and pH metry were normal, and endoscopic …

This thesis studies neural computation models and neuromorphic implementations of the auditory pathway with applications to cochlear implants and artificial auditory sensory and processing systems. Very low power analogue computation is addressed through the design of micropower analogue building blocks and an auditory preprocessing module targeted at cochlear implants. The analogue building blocks have been fabricated and tested in a standard Complementary Metal Oxide Silicon (CMOS) process. The auditory pre-processing module design is based on the cochlea signal processing mechanisms and low power microelectronic design methodologies. Compared to existing preprocessing techniques used in cochlear implants, the proposed design has a wider dynamic range and lower power consumption. Furthermore, it provides the phase coding as well as the place coding information that are necessary for enhanced functionality in future cochlear implants. The thesis presents neural computation based approaches to a number of signal-processing problems encountered in cochlear implants. Techniques that can improve the performance of existing devices are also presented. Neural network based models for loudness mapping and pattern recognition based channel selection strategies are described. Compared with state—of—the—art commercial cochlear implants, the thesis results show that the proposed channel selection model produces superior speech sound qualities; and the proposed loudness mapping model consumes substantially smaller amounts of memory. Aside from the applications in cochlear implants, this thesis describes a biologically plausible computational model of the auditory pathways to the superior colliculus based on current neurophysiological findings. The model encapsulates interaural time difference, interaural spectral difference, monaural pathway and auditory space map tuning in the inferior colliculus. A biologically plausible Hebbian-like learning rule is proposed for auditory space neural map tuning, and a reinforcement learning method is used for map alignment with other sensory space maps through activity independent cues. The validity of the proposed auditory pathway model has been verified by simulation using synthetic data. Further, a complete biologically inspired auditory simulation system is implemented in software. The system incorporates models of the external ear, the cochlea, as well as the proposed auditory pathway model. The proposed implementation can mimic the biological auditory sensory system to generate an auditory space map from 3—D sounds. A large amount of real 3-D sound signals including broadband White noise, click noise and speech are used in the simulation experiments. The efiect of the auditory space map developmental plasticity is examined by simulating early auditory space map formation and auditory space map alignment with a distorted visual sensory map. Detailed simulation methods, procedures and results are presented.

Background and Aim: Gastric hypersensitivity to mechanical distension has been observed in functional dyspepsia, but no drug is available that specifically acts on gastric afferent pathways to decrease gastric nociception. The aim of this study was to assess the effect of fedotozine, a synthetic ligand for peripheral kappa receptors, on human gastric sensitivity. Methods: Twenty-seven healthy volunteers were randomized to receive either fedotozine (30 mg t.d.s.) or a placebo, for 7 days. On day 7, the effects of fedotozine were tested on discomfort threshold and gastric compliance during graded isobaric and isovolumic distensions. In 16 of these subjects, the effect of this drug was tested on somatic sensitivity. In 10 other healthy volunteers the effect of fedotozine on gastric distension-induced inhibition of the RIII reflex, a process closely related to visceral sensitivity, was also studied. Results: During isobaric distensions, the discomfort threshold was significantly higher in subjects on fedotozine than in those on placebo (14.4±0.92 vs. 12.0±1.13 mmHg; P=0.04). Compared to placebo, fedotozine did not modify gastric compliance and somatic sensitivity. Fedotozine also reduced the inhibition of the RIII reflex induced by gastric distension. Conclusion: Fedotozine decreases gastric sensitivity to distension by exerting specific action on gastric afferent pathways.

A manometric method was developed to study the motor activity in the unprepared human colon, and the results in eight healthy subjects were compared with those obtained in the same subjects after bowel cleansing with a non-absorbable solution containing polyethylene glycol 4000 (PEG). A tube assembly (4.5 m long, 12 lumen) was introduced through the nose and passed through the gastrointestinal tract. Two manometric recordings were performed one month apart, one without any preparation and the other after bowel cleansing with PEG. There was no obvious qualitative difference between the recordings performed in the uncleansed and PEG cleansed colon. Moreover, in the unprepared colon motility indices were close to those measured in the cleansed colon. The number of high amplitude propagated contractions (mean (SEM)) was, however, higher in the cleansed colon (8.6 (2.8) v 5.4 (1.8)/subject/9 h in the unprepared colon; p < 0.04). It is concluded that in healthy subjects taking a regular diet, motor activity is not different between the uncleansed and cleansed colon with PEG, except for the high amplitude propagated contractions, which occur more frequently in the cleansed colon.

Close Monitoring of CRP and Fecal Calprotectin is Able to Predict Clinical Relapse in Patients With Crohn's Disease in Remission After Infliximab Withdrawal. a Sub-Analysis of the Stori Study Nicolas de Suray, Julia Salleron, Gwenola Vernier-Massouille, Jean-Charles Grimaud, Yoram Bouhnik, David Laharie, Jean-Louis Dupas, Helene PillantLe Moult, Laurence Picon, Michel Veyrac, Mathurin Flamant, Guillaume Savoye, Raymond Jian, Martine De Vos, Eric Piver, Jean-Frederic Colombel, Edouard Louis

The spinal nociceptive RIII reflex, an exteroceptive cutaneous-muscular flexion reflex, is powerfully and specifically inhibited by painful heterotopic somatic stimuli. The aim of the present study was to evaluate the effects of nonpainful and painful visceral stimuli on this reflex.In nine healthy volunteers, the effects of five levels of gastric distention were tested on the RIII reflex, recorded from the biceps femoris, and elicited by electrical stimulation of the ipsilateral sural nerve. Distentions were performed by means of a balloon that was placed in the proximal part of the stomach and connected to an electronic barostat. The sensations evoked by gastric distention were scored using a graded (0-6) questionnaire.The 200- and 400-mL distention levels elicited no significant modifications of the RIII reflex; the 600-, 800-, and 1000-mL levels inhibited the RIII reflex by 25%, 35%, and 55%, respectively. The magnitude of this inhibition correlated significantly (P0.0001) with both the level of distention and the intensity of visceral perception.Gastric distention produces volume-dependent inhibition of the somatic RIII reflex in humans. This model may provide an interesting tool for objective and quantitative evaluation of normal and disturbed visceral sensations in humans.

Propulsion of colonic contents after eating in the whole colon was studied in 15 volunteers by scintigraphy with injection of 111In-diethylenetriamine-pentaacetic acid and 99mTc-sulfur colloid into the colon through a nasogastric tube. The radionuclide was injected into the cecoascending colon (n = 7), the hepatic flexure (n = 6), the splenic flexure (n = 9), and the descending colon (n = 4). Changes of activity in the regions distal from and proximal to the injection points were determined before and after a 1000-kcal meal. Isotopic movements were also analyzed when a simultaneous injection of the two markers in the right and left parts of the colon was achieved (n = 11). During fasting, no significant change of activity was seen. After eating, radioactivity injected into the cecoascending and the hepatic flexure was transferred distally (P less than 0.01 and P = 0.07); radioactivity injected into the splenic flexure was transferred both distally (P = 0.07) and proximally (P less than 0.02); and no significant change of activity was seen proximally from or distally to the descending colon. Both antegrade and retrograde isotopic movements increased after eating (P less than 0.01), but the number of antegrade movements was significantly greater (P less than 0.05). This study confirms the colonic propulsive effect of eating and shows that this response is different in the right and left parts of the colon.

Rectal distension studies have suggested the existence of 2 types of mechanoreceptors. Our aim was to confirm this functional duality by using a reflexologic technique, based on the recording of a nociceptive somatic reflex (the Rill reflex) which allows an objective evaluation of visceral sensitivity, during slow ramp or rapid phasic rectal distensions together with application of a local anesthetic. Methods: during a randomized double blind study, the effects of rectal distension on the amplitude of the Rill reflex recorded on the lower limb, were measured in 6 healthy volunteers after intrarectal application of 20 mL of local anesthetic, 2% lidocaine (L), or saline (S). Rectal distensions were performed with an electronic barostat on 4 days separated by a week. Each experimental day, one type of distension was performed with either L or S: rapid (900 mL/min) phasic distension (3 min duration) in a random order at 10, 20 and 30 mmHg, or slow (40 mL/min) ramp distension. The RIII reflex was continuously stimulated and the amplitude of the reflex response recorded before (control, 3 rain), during and after (3 min) each distension, and expressed as percentage of control values. Volumes, pressure and sensations were also measured. Results: (mean-+ SEM) : the RIII reflex threshold of detection was not modified by intrarectal application of L or S. During rapid distension, at 10 mmHg, the Rill response was not modified. At 20 mmHg, a facilitation of the reflex followed by a partial inhibition was obtained with S, and L abolished this inhibition (maximal inhibition : 64 _+_ 9% vs. 109 + 13%; P < 0.05). At 30 mmHg, an inhibition of the response was obtained with S that was partially abolished by L (maximal inhibition : 60 -+ 8% vs. 80 -+ 7%; P = NS). During S, slow ramp distension induced an inhibition of the RIII response that was completely abolished by L (maximal inhibition : 47-+ 8% vs. 100-+ 8%; P