L’occlusion colique est le mode de révélation de 8 à 29% des cancers du colon. Elle révèle undiagnostic tardif associé le plus souvent à une tumeur localement avancée ou métastatique. Laprise en charge, en urgence, de ces cancers est donc cruciale et doit intégrer l’évaluation del’état général du patient (âge, comorbidités, état nutritionnel), et le stade de la maladie quiauront un impact direct sur les résultats postopératoires précoces et à distance. Les optionsthérapeutiques disponibles pour la prise en charge en urgence de ces tumeurs sontchirurgicales (colostomie de décharge, intervention de Hartmann, colectomie segmentaireavec ou sans lavage per opératoire avec anastomose colorectale, colectomie totale avecanastomose iléorectale) ou endoscopique (prothèse colique).Les objectifs de cette thèse étaient d’évaluer l’impact de la prothèse colique sur la prise encharge à visée curative des cancers coliques en occlusion, l’étude des donnéesanatomopathologiques afin d’expliquer les différences de survie en fonction de la stratégiethérapeutique et l’élaboration de recommandations françaises et européennes afin de préciserla place de la prothèse colique dans la prise en charge des cancers coliques en occlusion / The colonic obstruction is the mode of revelation of 8 to 29% of colon cancers. It reveals latediagnosis most often associated with a tumor locally advanced or metastatic disease. Themanagement, in an emergency, of these cancers is crucial and must include the evaluation ofthe patient's general condition (age, comorbidities, nutritional status), and the stage of thedisease that will have a direct impact on early and late postoperative outcomes. Treatmentoptions available totreat in emergency these tumors are surgical (colostomy, Hartmannprocedure, segmental colectomy with or without intraoperative lavage with colorectalanastomosis, total colectomy with ileorectal anastomosis) or endoscopic (colonic stent).The objectives of this thesis were to assess the impact of the colonic stent in the curativemanagement of obstructive colonic cancer, to study pathological data to explain differences insurvival according to treatment strategy and the development of French and Europeanrecommendations to clarify the role of colonic stent in the treatment of colon cancerocclusion

Background: Postprandial symptoms in irritable bowel syndrome (IBS) have been associated with increased bowel contractility. Aim: To compare ileocolonic and colonic responses to feeding in health and IBS. Methods: We prospectively analyzed data from separate research trials in 122 IBS patients and 41 healthy volunteers. Ileocolonic transit (ICT) was evaluated before (colonic filling [CF]3h) and immediately after (CF4h) a standard lunch at 3 h 45 min, and 2 h thereafter. The colonic geometric center (GC) was calculated 2 h (GC6h) after lunch ingested at 4 h (GC4h) and directly after (GC8h) a standard dinner ingested at 7 h 45 min. Results: ICT immediately after eating was higher in IBS diarrhea predominant (IBS-D) patients than in the healthy cohort (23.1 ± 2.4 vs. 17.5 ± 2.8%, P = 0.059). ICT 2 h after lunch was similar between groups (P = 0.55). There was significant overall group differences in colonic transit 2 h post-lunch (P = 0.045), particularly in the IBS constipation predominant (IBS-C; GC6-GC4, Δ0.29 ± 0.08) patients versus healthy volunteers (Δ0.56 ± 0.12 GC units). Conclusions: After feeding, ICT is increased in IBS-D, whereas colonic transit is blunted in IBS-C.

Chronic constipation is a very common problem that negatively affects the quality of life of patients, especially the elderly population. It can also lead to significant health care expenditure. Careful assessment by obtaining a thorough history and physical examination with limited indicated diagnostic testing is important to identify potential underlying etiologies and to treat effectively.

<p> Treatment of canine colonic tissue with some O-alkyl and O-benzyl hydroxylamines potentiated the response of the tissue to histamine in different experimental environments.</p> <p> Sixteen O-substituted hydroxylamine compounds were synthesized using a modification of the Gabriel synthesis. These compounds were tested for their ability to potentiate histamine in canine colonic tissue through diamine oxidase inhibition.</p> <p> Three procedures were used to determine their activity: (1) secondary rise -hydroxylamine derivatives were added to epithelial tissue preparations in Ussing chambers after an initial dose of histamine. Active compounds caused a secondary increase in the short circuit current across the tissue, (2) dose-response profiles were constructed for several hydroxylamine compounds to determine whether they caused a significant shift to the left of the normal histamine curve (potentiated response), and (3) diamine oxidase enzyme assays were performed to examine the ability of the hydroxylamine derivatives to inhibit partially purified diamine oxidase. This aided in determining if inactive compounds could not potentiate histamine due to an inability to access the enzyme in the epithelial preparation.</p> <p> The structure-activity relation observed indicates that: (1) active compounds are oxygen and not nitrogen substituted hydroxylamines, (2) branched compounds are less active than their straight chain analogues, (3) greater steric bulk of the alkyl substituent can decrease the activity of the compound, (4) the presence of a carbon-carbon double (allyl) or triple (4-pentynyl) bond does not affect the activity of the compound, (5) longer straight chain O-alkyl hydroxylamines are less active than shorter chain derivatives, (6) steric bulk of the benzyl compounds is not likely to be the cause of its inability to inhibit diamine oxidase since the cinnamyl derivative is active, and (7) meta- and para-oxygen substituents (-OH, -OCH3) on O-benzyl hydroxylamines increase their diamine oxidase inhibiting properties.</p> / Thesis / Master of Science (MSc)

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

This thesis focuses on the characterization of rhythmic activity in the colon of healthy subjects and patients diagnosed with refractory constipation; this activity is mediated by pacemaker cells in the gastrointestinal system, the Interstitial cells of Cajal (ICC). The myogenic activity described are the cyclic motor patterns (CMP) and haustral activity; characterization of these motor patterns in healthy subjects provided control values for the subsequent comparison in patients. Frequency analysis of CMP revealed a novel high-frequency activity (7-15cpm) unrelated to the breathing artefact. Three categories of cyclic motor patterns were observed: (1) CMP following mass peristaltic events (HAPW); (2) those that occur in isolation of other colonic motor patterns (HAPW) in the colon; and (3) low-frequency (2-6cpm), prominently retrograde rhythmic activity in the rectum. CMP were scarcely present in majority of the patients; however, elevated retrograde CMP in the distal colon and rectum in some patients plays a role in retarding flow of colonic content. A detailed characterization of haustral activity (comprised of 2 boundaries and the activity within a haustrum) is reported for the first time using high-resolution colonic manometry. Furthermore, we find that over expression of haustral boundary activity in patients serves as a disproportionate hindrance in colonic transit. An in-depth methodology is developed for the identification and subsequent analysis of haustral activity and CMP; this provides transparency in the data acquisition and analysis. Lastly, a sphincter at the rectosigmoid junction, sphincter of O’Beirne is presented in a patient case report. The persistent presence and paradoxical contractions of this sphincter served to impede flow colonic content, an important factor contributing to the pathophysiology of severe refractory constipation. / Thesis / Master of Science (MSc) / Colonic manometry tests and measures strength and coordination of colonic muscles contractions. This tool was used to understand the rhythmic colonic motor patterns and their contribution to motility in healthy subjects and patients with constipation. Rhythmic activity in the gut is mediated by pacemaker cells, Interstitial cells of Cajal (ICC). We present a detailed characterization of ICC-mediated rhythmic activity that (1) occurs in the small pouches making up the colon (haustra) and (2) is greater than 5cm along the length of the colon (cyclic motor patterns-CMP).CMP possess high-frequency activity (7-15cpm), in addition to activity observed in the low-frequency range (2-6cpm). Activity in the haustra, or haustral activity, is comprised of 2 boundaries with activity within these bounds (intra-haustral activity); the overexpression in patients serves to retard flow of colonic content. Sphincter of O’Beirne is the last haustral boundary at the rectosigmoid junction; its persistent presence was characterized in a patient with refractory constipation.

Introduction: Functional motility disorders of the colon are poorly defined. Hence, patients with chronic colonic motor dysfunction are treated or undergo surgery without proper diagnosis. Most colonic motility assessment centers around the largest propagating motor pattern in the colon- the High Amplitude Propagating Pressure Wave (HAPW). However, there is no consensus regarding a definition of this important motor pattern. Additionally, no consideration is given to other aspects of colonic motility such as colo-ano-rectal coordination and control by the autonomic nervous system (ANS). The aim of this thesis was to improve understanding of HAPWs and other features of colonic motility in health and constipation, understand how autonomic dysfunction is related to observations in patients, and evaluate the effect of neuromodulation of the ANS. Methods: Motility was assessed in healthy volunteers and patients using water-perfused High Resolution Colonic Manometry (HRCM). To assess the association between ANS and colonic motor activity Heart Rate Variability (HRV) was measured in patients. Spatiotemporal maps were created using HRCM to analyse and quantify colonic motor activity following baseline, and interventions which included proximal balloon distention, meal, and rectal bisacodyl. Low-Level Light Therapy (LLLT) was also applied during HRCM as a method of neuromodulation, to observe its effect on colonic motility. Results: Normal HAPWs are those which have an amplitude of more than 50 mmHg and belong to one of 3 categories: proximally originating, proximal continuing, and transverse/descending. The best intervention sequence to generate these during HRCM assessment is baseline, proximal balloon distention, meal, rectal bisacodyl. Based on their responses to these interventions and the type of HAPWs present, patients could be classified into strong responder, weak responder and non-responder groups. Overall, patients in the strong responder group were most similar to healthy volunteers both with regard to motility and ANS control. Conversely, the weak and non-responders had showed decreased or no motility with decreased parasympathetic input and occasionally sympathetic inhibition. Additionally, other features of motility such as the sphincter of O'Beirne, and lack of colo-ano-rectal coordination were found to lead to constipation even in presence of normal HAPWs. LLLT shows promise in initiating colonic motor activity through neuromodulation of the sacral defecation center. Conclusions: HAPWs can be defined into one of three categories and used to categorize patients based on their HAPW response to different interventions. However, other aspects of colonic motility such as the colo-ano-rectal coordination and autonomic nervous system control of colonic motility should be taken into consideration in diagnosis of constipation, as they can point towards more non-invasive treatment methods such as neuromodulation using LLLT. / Thesis / Master of Science in Medical Sciences (MSMS)

A doença diverticular dos cólons (DDC) é relacionada à civilização, industrialização e à dieta. Estudos fisiológicos demonstraram que uma pressão intraluminal elevada, bem como alterações estruturais adquiridas da parede intestinal parecem ser fator decisivo, que se intensificam com o envelhecimento. Estas alterações podem ser causadas por alterações no tecido muscular e tecido conjuntivo relacionados ao metabolismo do colágeno e elastina, que presumivelmente pode ser geneticamente determinada. Sabe-se que pacientes com desordens genéticas do gene da elastina (ELN), como a estenose aórtica supravalvar e a cutis laxa, podem manifestar hérnia, diverticulose e disfunção urinária. Recentemente, foi demonstrado mutação pontual no exon 20 do ELN em pacientes com hérnia inguinal. No presente estudo investigamos o polimorfismo do exon 20 do ELN em 14 pacientes com DDC e 26 controles. A presença de mutação foi verificada por eletroforese conformacional de fita simples e sequenciamento automático. Demonstramos bandas anormais em alguns pacientes, que representaram uma mutação não conservativa: substituição de um nucleotídeo (AGT->GGT) no códon 422 do gene da ELN em cinco pacientes com DDC. Nenhum indivíduo controle estudado apresentou este tipo de mutação. Observamos uma associação significante (P=0,003) desta mutação com o desenvolvimento da DDC e risco relativo 3,89 vezes maior (intervalo de confiança de 95%: 2,21-6,83) dos indivíduos com esta mutação desenvolver DDC. Esta mutação troca Serina, um aminoácido não polar, por glicina, um aminoácido neutro, alterando a estrutura hidrofóbica da elastina e secundariamente a estrutura da fibra elástica. Esta alteração pode promover perda da complacência da parede intestinal e o desenvolvimento de divertículo / Colonic diverticular disease (CDD) is related to civilization, industrialization and diet. Physiological studies demonstrated that increased intraluminal pressures as well as acquired structural changes of the intestinal wall seem to be decisive factors, which intensify during ageing. These changes may be due to alterations of the musculare and connective tissues and are related to collagen and elastin metabolism, which presumably can be genetically determined. It is known that patients with genetic disorders of elastin gene (ELN), such as supravalvular aortic stenosis and cutis laxa, may also manifest hernias, diverticulosis and bladder dysfunction. Recently, punctual mutations were demonstrated in ELN exon 20 of inguinal hernia patients. In the the present study, the polymorphism ELN exon 20 was tested in 14 patients with CDD and in 26 controls. Mutations were sought by singlestrand conformation polymorphism and by automatical sequence. An abnormal band was demonstrated in some patients, representing a missense mutation: a single nucleotide substitution (AGT->GGT) was detected in codon 422 in five patients with CDD. There is a substituion of serine, a nonpolar amino acid, by glycine, na uncharged one. No controls showed this punctual mutation(P=0,003), and the odds ratio for development of CDD was 3.33 (95% confidence interval:1,98-5,62). As a consequence of this substitution, the hydrophobic structure of elastin and of elastic fiber may promote a loss of compliance of the intestinal wall and development of diverticula

<p>Oral 111-Indium-DTPA colonic scintigraphy was used to assess segmental transit in 23 patients with slow transit constipation (STC) and 13 controls. The transit time did not differ between patients and controls in the right colon, whereas the patients had a consistent delay from the transverse colon and distally (<i>P</i><0.05–0.001). Two individual patients had a delay in the right colon.</p><p>Twenty-eight patients underwent a left- (n=26) or a right (n=2) hemicolectomy for STC, after evaluation including colonic scintigraphy. Twenty-three patients (80%) were satisfied with the outcome after a median of 50 months. The median stool frequency increased from one to seven per week (<i>P</i><0.001). The number of patients with bloating, excessive straining and painful defecation decreased (<i>P</i><0.05). The laxative use decreased (<i>P</i><0.01) and faecal continence was unchanged. A blunted rectal sensation correlated to a poor outcome.</p><p>Fifty constipated patients with slow colonic transit and 28 controls were investigated with anorectal manovolumetry. Anal resting pressure was lower (<i>P</i><0.05), and squeeze pressure tended to be lower (<i>P</i>=0.09) in patients. Rectal sensation was not different between groups, although ten patients had a threshold for filling sensation above the 95^th percentile of controls. The rectal compliance was increased in patients (<i>P</i><0.05–0.01).</p><p>Total and segmental colonic transit was assessed with radio-opaque marker study and scintigraphy in 35 constipated patients, and related to normal values. Twenty-seven of 31 female patients had a prolonged total transit time on marker study, and 26 on scintigraphy. Of those 31 patients, 29 had prolonged segmental transit only in one or two segments on marker study. The two methods gave a similar result, except in the descending colon (<i>P</i><0.05). However, the results varied considerably for individual patients.</p><p>In conclusion, patients with STC often benefit from a segmental colonic resection, following assessment including scintigraphy. Anorectal physiology testing may predict surgical results.</p>