La maladie de Crohn (Crohn’s disease; CD) et la colite ulcéreuse (Ulcerative colitis ;CU) représentent deux formes distinctes de maladies inflammatoires chroniques de l’intestin (MICI), qui sont associées à une réponse immunitaire aberrante des tissus intestinaux à la flore intestinale. Les phagocytes mononucléés (MNPs) qui dialoguent, via les cytokines qu'ils produisent, avec les cellules immunitaires innées et adaptatives sont impliqués dans l’induction, la perpétuation et le maintien de la réponse inflammatoire des MICI. Chez la souris, les MNPs sont stratifiées en cellules dendritiques conventionnelles (cDCs), macrophages (M) et cellules dérivées de monocytes, une entité qui regroupe dans le tissu des cellules dendritiques dérivées de monocytes (Mo-DC), des M dérivés de monocytes et des « monocyte-like ». Toutefois, la diversité phénotypique, moléculaire et fonctionnelle des monocytes et des MNPs ainsi que la plasticité des monocytes restent à élucider dans les MICI. Les anticorps bloquant les cytokines IL12 et IL23 contrôlent la pathogénicité et la plasticité des cellules Th17, réduisant l'inflammation intestinale chez les patients atteints de MII. Cependant, il n’existe à ce jour aucun traitement curatif. L’étude approfondie de la plasticité des cellules T et du site tissulaire où elle pourrait se produire ne sont toujours pas clarifiés. Dans le premier chapitre, nous avons révélé l’existence de deux sous-populations distinctes de CD14+MNPs dans le colon de patients atteints de CU. Les cellules de type « inflammatory monocyte-like » CD14+CD163-CD64+ (P3) à l’opposé des CD14+CD163+CD64+ M (P4) s'accumulent dans le côlon inflammatoire. Nos résultats ont de plus établi un lien entre les P3 MNPs, l’IL12, l’IL1β et la détection de cellules Th17 mémoires produisant de l'IFN et de l'IL8, qui contribueraient collectivement à la pathogenèse de la CU. De plus, deux sous-populations CD14+ MNPs similaires sur le plan fonctionnel et moléculaire a ceux trouvés en CU, ont été détectées dans le côlon de patients atteints de CD. En revanche, dans le deuxième chapitre, nous fournissons des évidences que la sous-population monocytaire Slan+ pourrait contribuer à l’immunopathogenèse de la CD, mais pas à celle de la CU. La fréquence, le phénotype et la fonction des cellules Slan+ ont été examinés dans le sang, les ganglions mésentériques (MLN) et le côlon de patients atteints de MICI. Nous proposons que les cellules pro-inflammatoires CD14hiCD172α+Slan+ discriminent les tissus de CD et CU. En effet, elles ne s'accumulent que dans les MLNs et la muqueuse colique des patients atteints de CD. Dans le troisième chapitre, nous avons montré que les MLNs de CD et de CU, qui sont des tissus difficiles d'accès pour leur étude fonctionnelle en recherche, peuvent également être distingués par la distribution et le profil moléculaire des cellules T mémoire effectrices CXCR3-CCR6+ (Th17TEM). Nos données suggèrent également que la plasticité de Th17 se produit dans les MLNs avant leur migration vers l'intestin. Cette étude pourrait avoir des implications pour améliorer notre compréhension de la maladie. Enfin, il a été démontré qu’à l’homéostasie chez la souris, les monocytes sont continuellement recrutés dans la muqueuse intestinale où ils se différencient progressivement en M anti-inflammatoires. Ce processus de maturation est interrompu dans le contexte d'une inflammation. Les signaux environnementaux qui régulent la « cascade » de maturation d’un monocyte classique tissulaire demeurent inconnus chez l'homme. Dans le quatrième chapitre, nous avons récapitulé in vitro la cascade de différenciation des monocytes humains de «CD163- P3-like» en «CD163+P4-like» et avons montré leurs similitudes moléculaires avec les CD14+ MNP tissulaires. La manipulation de cette voie de différentiation pourrait ouvrir des pistes thérapeutiques pour restaurer l'homéostasie intestinale dans les MICI. En conclusion, une meilleure compréhension des sous-populations de MNPs, leurs fonction et plasticité dans la pathogenèse des MICI aidera à identifier des nouvelles cibles thérapeutiques et contribuera à augmenter les connaissances pour la mise au point de traitements personnalisés. / Crohn’s disease (CD) and ulcerative colitis (UC), the two forms of inflammatory bowel diseases (IBD), are associated with dysregulated immune response in the intestinal tissue. It is mediated by mononuclear phagocytes (MNPs) that dialogue via the cytokine they produce with innate and adaptive immune cells. In mice, MNPs are stratified into conventional dendritic cells (DCs), macrophages (M) and monocyte-derived cells that regroup tissue monocyte-derived DCs, monocyte-derived M and monocytes-like cells. However, the phenotypic, molecular and functional diversity of MNPs and their plasticity remain to be elucidated in IBD patients. Therapies in IBD employ antibodies that block IL12 and IL23, thus control Th17 pathogenicity and plasticity and decrease intestinal inflammation. However, no cure exist nowadays for the treatment of IBD. In-depth study of T cell plasticity and the tissue where it occurs remain to be investigated. In the first chapter, we revealed the existence of two distinct CD14+ MNP subsets in colon of UC patients. Only, CD163-CD64+ inflammatory monocyte-like cells (P3) but not anti-inflammatory CD163+CD64+ M (P4) accumulate in inflamed UC colon. Our findings further established a link between monocyte-like CD14hiCD172α+ CD163- MNPs, IL12, IL1β and the detection of colonic memory Th17 cells that produce IFN and IL8, which might all contribute to UC pathogenesis. Two CD14+ MNP subsets, resembling their counterparts in UC mucosa at the functional and molecular level, were also detected in CD colon. In contrast, in the second chapter, we provide evidence that Slan+ monocyte subset may contribute to CD but not UC immunopathogenesis. Frequency, phenotype, and function of Slan+ cells were examined in blood, colon, and mesenteric lymph nodes (MLN) of patients with IBD. We showed that pro-inflammatory CD14hiCD172α+Slan+ cells are a distinguishing feature between CD and UC, as they only accumulate in MLNs and colonic mucosa of CD patients. In the third chapter, we showed that MLNs of CD and UC, tissues that were hard to access for research use, can also be distinguished by frequencies of CXCR3−CCR6+ Th17 effector memory T cells (TEM) and their molecular profile. Our data further suggested that Th17 plasticity is taking place in MLN, before T cell homing to gut tissues. This investigation has clear implications in furthering our understanding of the disease. Finally, it has been demonstrated that monocytes are continuously recruited into murine gut mucosa and progressively differentiate into macrophages under homeostatic conditions, a maturation process interrupted in the context of inflammation. However, the environmental cues that regulate tissue inflammatory monocyte “waterfall” remain to be investigated in humans. In the fourth chapter we recapitulated in vitro human monocyte differentiation cascade, from CD163- inflammatory monocyte-like cells (P3) towards anti-inflammatory CD163+ macrophages (P4) and showed their molecular similarities to tissue CD14+ MNPs. Manipulating this pathway might open therapeutic avenues to restore tissue homeostasis. In conclusion, a better understanding of MNP subsets, function and plasticity in IBD pathogenesis would help identify novel therapeutic targets and shed light for the development of personalized treatments.

Bakgrund: Inflammatorisk mag-tarmsjukdom är ett samlingsnamn för Ulcerös kolit och Crohns sjukdom. Gemensamt för sjukdomarna är att de är kroniska och att de går i skov, vilket innebär att sjukdomen är mer aktiv i vissa perioder och mindre aktiv under andra. Inflammatorisk mag-tarmsjukdom påverkar patienterna fysiskt, psykiskt och socialt, vilket påverkar deras livskvalitet. Inflammatoriska mag-tarmsjukdomar kan resultera i psykiska besvär, därför har patienterna ett behov av goda copingstrategier och en god anpassning till livet med sjukdomen. Genom evidensbaserad och personcentrerad vård har sjuksköterskan en stödjande funktion i vården av dessa patienter.  Syfte: Syftet med litteraturstudien var att undersöka patienternas upplevelser av att leva med inflammatorisk mag-tarmsjukdom för att kunna belysa deras behov av stöd. Metod: En litteraturstudie med boolesk sökteknik gjordes i databaserna Cinahl, PubMed och PsycINFO där tio artiklar valdes ut genom granskning med SBU:s granskningsmall.    Resultat: När resultatet av tio artiklar sammanställts framkom fyra teman; patienters upplevelser av att leva med inflammatorisk mag-tarmsjukdom, patienternas behov av stöd, stöd i att acceptera och leva med sjukdomen samt stöd i form av utbildning. Slutsats: Patienter med inflammatorisk mag-tarmsjukdom har behov av stöd både fysiskt, psykiskt och socialt, från både sjukvårdspersonal och anhöriga. Patienterna har ett behov av stöd i form av information, undervisning samt psykiskt och emotionellt stöd. Sjuksköterskans stöd genom personcentrerad och empatisk kommunikation hjälper patienterna att acceptera sjukdomen och deras “nya normala”, vilket främjar deras självständighet, självkännedom och eget ansvar i sjukdomshanteringen. Patientutbildning bidrar till bättre egenvårdsstrategier, ökad följsamhet till behandling och livsstils anpassningar, vilket även bidrar till ökat självförtroende och välmående.

Background: Recent national trends and distribution of ileal pouch-anal anastomosis (IPAA) procedures for patients with ulcerative colitis (UC) are unknown. We examined the frequency of use of elective IPAA procedures among patients with UC and the distribution of IPAA procedures across more than 140 U.S. academic medical centers and their affiliates. Methods: Data were obtained from the University HealthSystem Consortium for patients with a primary diagnosis of UC admitted electively between 2012 and 2015. Results: The mean age of the study population (n=6,875) was 43 years and 57% were men. Among these, one-third (n=2,307) underwent an IPAA, while two-thirds (n=4,568) underwent colectomy, proctectomy, proctocolectomy or other procedures. The proportion of IPAA cases among all elective admissions was relatively stable at 33-35% during the years under study. A total of 131 hospitals, out of 279 hospitals participating in the UHC, performed IPAA. The median number of IPAA cases performed annually was 1.9 [IQR 0.8 – 4.3]. Nearly one half (48%) of these cases were performed by the top ten hospitals. Overall, only a total of 30 centers performed ³ five elective IPAA cases annually. Conclusions: Although the frequency of elective IPAA surgery in recent years has been stable, nearly one half of all IPAA cases was performed at ten hospitals. The concentration of IPAA cases at high-volume centers, and the steady number of cases performed annually, have potential implications for fellowship training, patient clinical outcomes and access to care.

Tesis por compendio / [ES] La presente tesis doctoral titulada "Sistemas de liberacio'n controlada de fa'rmacos diseñados para mejorar el tratamiento de Enfermedad Inflamatoria Intestinal" se centra en el diseño, preparación, caracterización y evaluación in vivo de distintos sistemas de liberación controlada de fármacos en colon (CDDS, por sus siglas en inglés) utilizando como soporte micropartículas de silice mesoporosa, funcionalizadas con puertas moleculares. En conclusión, los estudios realizados demuestran que los materiales de silice mesoporosa, en combinación con puertas moleculares sensibles a estímulos específicos, tienen un gran potencial para el desarrollo de nuevos sistemas de liberación controlada de fármacos en el colon, dirigidos a mejorar el arsenal terapéutico disponible para el tratamiento de EII. La posibilidad de adaptar o personalizar la carga y las puertas moleculares hace que estos soportes de sílice mesoporosa sean una opción interesante para el desarrollo de nuevos sistemas de liberación controlada de fármacos en diferentes aplicaciones biomédicas. Finalmente, esperamos que los resultados obtenidos en esta tesis doctoral sirvan de inspiración para el desarrollo de sistemas de liberación controlada de fármacos innovadores y cada vez más inteligentes, para su aplicación tanto en medicina como en otras áreas. / [CA] La present tesi doctoral titulada "Sistemes d'alliberament controlat de farmacs dissenyats per a millorar el tractament de Malaltia Inflamatoria Intestinal" se centra en el disseny, preparacio, caracteritzacio i avaluacio in vivo de diferents sistemes d'alliberament controlat de farmacs en colon (*CDDS, per les seues sigles en angles) utilitzant com a suport microparticules de si'lice mesoporosa, funcionalitzades amb portes moleculars. En conclusio, els estudis realitzats demostren que els materials de si'lice mesoporosa, en combinacio amb portes moleculars sensibles a estimuls especifics, tenen un gran potencial per al desenvolupament de nous sistemes d'alliberament controlat de farmacs en el colon, dirigits a millorar l'arsenal terapeutic disponible per al tractament de MII. La possibilitat d'adaptar o personalitzar la carrega i les portes moleculars, fa que aquests suports de silice mesoporosa siguen una opcio interessant per al desenvolupament de nous sistemes d'alliberacio controlada de farmacs en diferents aplicacions biomediques. Finalment, esperem que els resultats obtinguts en aquesta tesi doctoral servisquen d'inspiracio per al desenvolupament de sistemes d'alliberament controlat de farmacs innovadors i cada vegada mes intel·ligents, per a la seua aplicacio tant en medicina com en altres arees. / [EN] This PhD thesis entitled "Smart drug delivery systems designed to improve Inflammatory Bowel Disease therapy" is focused on the design, synthesis, characterization and in vivo evaluation of several Colon Drug Delivery Systems (CDDS) using hybrid mesoporous silica microparticles as scaffolds containing molecular gates. In conclusion, the studies shown in this Thesis demonstrate that mesoporous silica materials in combination with responsive molecular gates have great potential in the design and preparation of new CDDS to improve the therapeutic options available for IBD. The possibility to adapt the cargo and the molecular gate makes mesoporous silica support especially appealing for similar controlled drug delivery applications in the biomedical field. We hope that the obtained results could inspire the development of new innovative smart drug delivery systems in this or other fields. / We thank the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R (MINECO/FEDER)) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. AHT thanks to the Spanish MEC for his FPU grant. We thank the Generalitat Valenciana (Project PROMETEO2018/024) / Hernández Teruel, A. (2019). Smart drug delivery systems designed to improve Inflammatory Bowel Disease therapy [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/129863 / TESIS / Compendio

No description available.

Drug repositioning can save considerable time and resources and significantly speed up the drug development process. The increasing availability of drug action and disease-associated transcriptome data makes it an attractive source for repositioning studies. Here, we have developed a transcriptome-guided approach for drug/biologics repositioning based on multi-layer self-organizing maps (ml-SOM). It allows for analyzing multiple transcriptome datasets by segmenting them into layers of drug action- and disease-associated transcriptome data. A comparison of expression changes in clusters of functionally related genes across the layers identifies “drug target” spots in disease layers and evaluates the repositioning possibility of a drug. The repositioning potential for two approved biologics drugs (infliximab and brodalumab) confirmed the drugs’ action for approved diseases (ulcerative colitis and Crohn’s disease for infliximab and psoriasis for brodalumab). We showed the potential efficacy of infliximab for the treatment of sarcoidosis, but not chronic obstructive pulmonary disease (COPD). Brodalumab failed to affect dysregulated functional gene clusters in Crohn’s disease (CD) and systemic juvenile idiopathic arthritis (SJIA), clearly indicating that it may not be effective in the treatment of these diseases. In conclusion, ml-SOM offers a novel approach for transcriptome-guided drug repositioning that could be particularly useful for biologics drugs.

Bakgrund: Inflammatorisk tarmsjukdom innefattar både ulcerös kolit och Crohns sjukdom, vilka är kroniska inflammatoriska tarmsjukdomar. De båda sjukdomarna löper i skov med plötsliga försämringsperioder och långa perioder utan besvär. Det är viktigt att sjuksköterskan vidtar specifika omvårdnadsåtgärder samt förhåller sig personcentrerat där värden som värdighet bevaras för att stödja personen. Syfte: Att beskriva personers erfarenheter av att leva med inflammatorisk tarmsjukdom. Metod: Till metod valdes en litteraturöversikt och de databaser som användes var PubMed samt Cinahl Complete. Inklusionskriterier var vetenskapliga originalartiklar, genomgått peer-review, engelskt språk samt publicerade från år 2014 till 2024. Genom ett systematiskt urval arbetades tio artiklar fram, varav nio med kvalitativ design och en med mixad metod. Resultat: I litteraturöversiktens resultat framkom det att personer med inflammatorisk tarmsjukdom hade erfarenheten av att sjukdomen påverkade deras dagliga liv, både i det sociala livet och yrkeskarriären. Personer med inflammatorisk tarmsjukdom hade även erfarenheter att sjukdomen påverkade det emotionella välbefinnandet. Det lyftes även fram hur personer hanterade sjukdomen, vilka strategier som användes och stödets betydelse beskrevs. Slutsats: Litteraturöversikten visade att personer med inflammatorisk tarmsjukdom möter utmaningar inom många områden i livet. På grund av de anpassningar som individen måste genomgå är det viktigt att sjuksköterskan bidrar med stöd för att möjliggöra effektiv sjukdomshantering. Roys adaptionsteori kan ge sjuksköterskan en bättre förståelse för personernas anpassningsförmåga och kompensera med stöd för att hälsa och livskvalité ska upprätthållas. / Background: Inflammatory bowel disease encompasses both ulcerative colitis and Crohn's Disease, which are chronic inflammatory bowel diseases. Both diseases are characterized by periods of flare-ups with sudden exacerbations and long periods of remission. It is important for nurses to implement specific nursing interventions and to maintain a person-centered approach where values like dignity are preserved to support the person. Aim: To describe people's experiences of living with inflammatory bowel disease. Method: The chosen method was a literature review, with PubMed and CINAHL Complete as the selected databases. Inclusion criteria were scientific original articles that had undergone peer review, were in English, and were published from 2014 onwards. Through a systematic selection process, ten articles were identified, of which nine had a qualitative design and one used mixed methods. Results: In the results of the literature review, it was found that individuals with inflammatory bowel disease experienced the impact of the disease on their daily lives, including their social life and professional careers. They also reported that the disease affected their emotional well-being. Additionally, the review highlighted how individuals managed the disease, the strategies they used, and the significance of support. Conclusion: The literature review showed that individuals with inflammatory bowel disease face challenges in many areas of life. Due to the adaptations that the individual must undergo, it is important for nurses to provide support to enable effective disease management. Roy`s adaption theory can provide the nurse with a better understanding of individual`s adaptability and compensate with support to maintain health and quality of life.

In zahlreichen Studien konnte an Mausmodellen gezeigt werden, dass dendritische Zellen eine wichtige Rolle im Rahmen der mukosalen Immunabwehr spielen. Eine unkontrollierte Aktivierung immunologischer Effektorzellen durch antigenpräsentierende Zellen ist die Folge, welche die Antigene der luminalen Flora folglich falsch erkennen und damit zu einer Schädigung des Gewebes führen. In der Arbeit wurden humane CD1c+CD11c+CD14-CD19- myeloide dendritische Zellen (mDCs) aus dem peripheren Blut und der intestinalen Mukosa von CED Patienten sowie von gesunden Probanden phänotypisch und funktionell näher charakterisiert. mDCs von Patienten reagieren auf LPS im Gegensatz zu DCs von Gesunden mit der Ausbildung eines aktivierten Phänotyps und der Sekretion pro-inflammatorischer Zytokine. Die Daten lassen vermuten, dass ihre tolerogene Rolle gestört ist und die Zellen so möglicherweise aktiv zum Entzündungsgeschehen durch eine Fehlreaktion auf die kommensale Flora beitragen. Es konnte gezeigt werden, dass zirkulierende mDCs von Erkrankten mehr LPS aufnehmen. Des Weiteren ist die Häufigkeit von mukosalen und aktivierten mDCs bei CED Patienten signifikant erhöht. Die vermehrte Häufigkeit von aktivierten mDCs in der entzündeten Mukosa ist ein Hinweis auf intestinales „homing“, also ein Wiedereinwandern der gereiften Lymphozyten in die Darmwand. Es ist bekannt, dass die Hefe Saccharomyces boulardii (Sb) eine Wirksamkeit bei entzündlichen sowie infektiösen Erkrankungen des Gastrointestinaltraktes hat. Kulturexperimente von mDCs mit Zellkulturüberständen von Sb (SbS) und LPS zeigten eine deutliche Reduzierung in der Expression von CD40 und CD80 sowie des Reifemarkers CD197. SbS reduzierte die Sekretion von TNF- und IL-6. Während es die Sekretion von IL-10 bei gesunden Probanden erhöhte, konnte bei CED Patienten eine leichte Abnahme verzeichnet werden. SbS vermindert die Proliferation von naïven T-Zellen in einer gemischten Lymphozytenreaktion mit gesunden mDCs signifikant. / Various animal studies have provided insights that mucosal dendritic cells play a key role in this process. However, the specific function of certain dendritic cells in IBD is still unknown. Primary CD1c+CD11c+CD14-CD19- myeloid blood (mDCs) and mucosal DCs from IBD patients and healthy controls were compared. More mDCs from IBD patients exhibited an activated phenotype shown by expression of co-stimulatory molecules. mDCs from patients secrete higher levels of pro- and anti-inflammatory cytokines. Circulating mDCs from IBD patients take up more LPS and the frequency of mucosal mDCs and the number of activated, i.e. CD40 and CD80 expressing mucosal mDCs, is significantly greater in CED. The increased frequency of activated mDCs in the inflamed mucosa suggests intestinal homing of mDCs in acute stages of IBD. Further, the data suggests an aberrant LPS response of mDCs in patients suffering from IBD which results in an inflammatory phenotype. The most widely accepted hypothesis for the cause of IBD is a disturbed interaction of the host immune system with commensal microflora and other luminal antigens. The well controlled balance of the intestinal immune system is disturbed and luminal antigens like LPS gain access to the underlying mucosal tissue via the leaky barrier. It was investigated whether the yeast preparation Saccharomyces boulardii (Sb) modulates dendritic cell function which has shown efficacy in inflammatory and infectious disorders of the gastrointestinal tract. Culture experiments of mDCs in the presence of Sb culture supernatant (SbS) significantly reduced the expression of CD40 and CD80 as well as the DC maturation marker CD197 (CCR7) induced by the prototypical microbial antigen LPS. SbS reduced secretion of TNF- and IL-6, while the secretion of anti-inflammatory IL-10 increased. IBD patients showed also a reduction in their secretion level of IL-10. SbS inhibited proliferation of naïve T cells in a mixed lymphocyte reaction with healthy mDCs.

Des études de liaison et d’association génétiques ont permis d’identifier certains des facteurs de risque génétiques aux maladies inflammatoires de l’intestin (MII) dans la région chromosomique 3p21. Dans cette région, le polymorphisme nucléotidique simple (SNP) codant non-synonyme du gène MST1, rs3197999, encodant pour la mutation R689C, a été associé et répliqué à la fois à la colite ulcéreuse (CU) et à la maladie de Crohn (MC). Un autre SNP, corrélé à des SNP codants non-synonymes du gène MST1R, a également été associé à la MC. Afin de déterminer si d’autres variantes des gènes MST1 et MST1R sont associés à la CU, nous avons testé pour association des SNP de ces gènes. Seul un proxy de R689C a montré un signal d’association significatif aux MII, ce qui suggère que R689C est la variante causale aux MII dans le gène MST1. En cherchant à déterminer si la région 3p21 contenait plusieurs signaux d’association mutuellement indépendants, trois SNP ont été identifiés comme possible facteurs de risque indépendants, et ont été génotypés dans des cas de CU et de MC et des témoins, puis nos résultats d’association ont été combinés à ceux provenant de trois autres cohortes indépendantes. Les trois SNP, R689C (MST1), rs6802890 et rs7629936 (CDHR4), sont associés aux MII, mais une étude d’association conditionnelle suggère qu’il existe en fait deux signaux d’association mutuellement indépendants dans la région 3p21. Le signal principal provient de R689C, une mutation de la protéine MSP. Cette protéine a un rôle dans l’inflammation chez les macrophages murins, et la migration, la cicatrisation et la survie chez les cellules épithéliales. Dans cette étude, le rôle de la MSP a été investigué dans des modèles de macrophages humains et de cellules épithéliales de côlon, et seule la phosphorylation d’AKT, un acteur dans la voie de signalisation de la survie cellulaire, a été modulée par la MSP dans nos modèles. Ce projet a donc permis d’apporter des connaissances sur les facteurs de risques génétiques aux MII dans la région 3p21, en identifiant 2 signaux d’association indépendants, et en nous informant sur le rôle de MST1, duquel provient le signal d’association principal, chez les cellules humaines. / Linkage studies and association studies allowed the discovery of some of the genetic risk factors of inflammatory bowel disease (IBD) in the chromosomal region 3p21. In this region, the non-synonymous coding single nucleotide polymorphism (SNP) rs3197999, situated in the gène MST1 and encoding for the mutation R689C, has been associated to UC and CD multiple times, and an other SNP, correlated to non-synonymous coding SNPs in the gene MST1R, has also been associated to CD. In order to verify if other variants of MST1 and MST1R are associatied to UC, we tested the association of some of their SNPs. Apart from R689C, only its proxy showed a significative association signal to IBD. It suggests that R689C might be the causal variant of IBD in the region 3p21. In the aim to determine if the region 3p21 has multiple independant association signals, 3 SNPs have been identified, from the results of a published meta-analysis of UC genome-wide association studies, as being possibly independant risk factors for UC based on their correlation. Their association to IBD and their independance have been tested by genotyping them in a cohort composed of controls, and UC and CD cases. The results of the association tests have been combined, in a meta-analysis, to the results of 3 other independent association studies. The 3 SNPs, R689C (MST1), rs6802890 and rs7629936 (CDHR4) are associated to IBD, but the results of the subsequent conditional association tests suggest that there is only 2 independant association signals in the region 3p21. The main signal is raising from R689C, a mutation of the protein MSP. According to published studies, this protein has a function in the inflammation in murine macrophages, and also in the scattering, wound healing and survival of epithelial cells. In this thesis, we investigated the role of MSP in human macrophage models and in human côlon epithelial cells, and it has been show that MSP modulates the phosphorylation of AKT, an actor in the pathway of cellular survival. This project brought some knowledges about the IBD genetic risk factors in the region 3p21. We identified 2 independent association signals to IBD in this region, and the main signal is coming from a SNP in MST1, a gene which has a role, based on our results, in the survival in human colon epithelial cells.

<p>UVOD: Hronične inflamatorne bolesti se ispoljavaju kao Kronova bolest i ulcerozni kolitis. Njihova značajnost ogleda se u hronicitetu kao i u stepenu u kom ograničavaju rast i razvoj dece i omladine. Brojne su posledice ovih oboljenja: dugotrajno izostajanje sa nastave, ograničavanje životnih aktivnosti i pojava komplikacija koje neretko zahvataju i druge organske sisteme. Etiologija je i dalje nerazja&scaron;njenja navodeći kao značajan hronični inflamatorni proces u genetski uslovljenih pojedinaca a provociranih nekim infektivnim agensom. Početkom 21. veka genetska istraživanja su otkrila osnovu nasleđivanja hroničnih inflamatornih oboljenja povezanih sa NOD2 genom. Kako je u pitanju organskim sistem koji je ograničeno pristupačan kliničkom pregledu, osnovu dijagnostike čine radiolo&scaron;ke metode. Kako je potrebno sprečiti kontinuirano izlaganje &scaron;tetnom dejstvu rendgenskog zračenja istraživanja se usmeravaju ka UZ i magnetnoj rezonanca. Na&scaron;e istraživanje se baziralo na mogućnostima ovih dveju metoda u svakodnevnom radu za dijagnostiku i dalje praćenje hroničnih inflamatornih bolesti creva. CILJEVI: Utvrditi senzitivnost i specifičnost ultrazvučne dijagnostike i magnetne resonance kod upalnih oboljenja creva u dečjem i adolescentnom uzrastu. Definisati i uporediti prednosti i ograničenja ultrazvučne dijagnostike sa dijagnostikom magnetne rezonace kod upalnih obolenja creva u dečjem i adolescentnom uzrastu. MATERIJAL I METODE: U istraživanje je uključeno 62. dece i adolescenata u toku prvog ataka bolesti ili ponovljenim fazama bolesti ili tokom redovnog praćenja u remisiji. Obuhvaćeni uzrast je od 4. do 18. godina. Potom su razvrstani u grupe na osnovu vrste pregleda i prisustva zadebljanja crevnog zida na A i B (pregled UZ), gde je A grupa imala zabeleženo zadebljanje crevnog zida preko 3 mm, a kod dece u grupi B debljina crevnog zida je bila između 2,5-3 mm. Sa druge strane na osnovu pregleda magnetnom rezonancom podeljeni su u A1 i B1 grupe, takođe po kriterijumu zadebljanja crevnog zida većeg od 3 mm (A1), odnosno između 2,5-3 mm (B1). Istraživanje je sprovedeno na Institutu za zdravstvenu za&scaron;titutu dece i omladine Vojvodine i Institutu za radiologiju Kliničkog centra Vojvodine. Prvi pregled načinjen je UZ a potom je načinjen pregled magnetnom rezonanacom. Podaci su obrađivani retrospektivno i prospektivno. Kriterijumi za uključivanje u studiju pored uzrasta bili su radiolo&scaron;ki: zadebljanje crevnog zida &gt;3mm, postojanje naru&scaron;ene arhitektonike crevnog zida, zadebljanje pojedinih crevnih segmenata-dužina segmenta, znaci fibroze, odsustvo peristaltike, izražena hiperemija na kolor Doppleru, transmuralni znaci upale, uvećani mezenterijalni limfni nodusi kao i kontrolni pregledi kod dece sa ranije ustanovljenom dijagnozom. Načinjena je endoskopija sa biopsijom radi postavljanja definitivne dijagnoze, potom se pristupilo statističkoj obradi dobijenih podataka. Izračunate su prosečne i standardne devijacije i frekvencije kao i pripadajući procenti. Određivane su maksimalne i minimalne vrednosti, medijane i interkvartalni raspon. Dobijeni podaci prikazani su u grafikonima i tabelama. Za parametrijske varijable upotrebljavan je Man &ndash; Vitni U test. Za kategoričke vrednosti upotrebljeni su &chi;2 i Fi&scaron;erov test. Nadalje su određivane senzitivnost, specifičnost kao i pozitivne i negativne prediktivne vrednosti. Veze između dva parametra uspostavljene su pomoću Pirsonove korelacione analize i linearnim regresionim modelom. Upotrebljen je program za obradu podataka SPSS 21 Statistics,a kao statistički značajne vrednosti uzete su vrednosti p&lt;0,05. REZULTATI: Nakon statističke obrade nije zabeležena signifikantnost u pogledu zastupljenosti hroničnih inflamatornih bolesti među polovima. Statistička značajnost pronađena je u pogledu uzrasta dece u akutnoj fazi kao i remisiji bolesti. Statistička značajnost je dobijena za posmatranu debljinu crevnog zida, hiperemiju creva, prisustvo fibroze u digestivnom traktu. Primećeno je da UZ bolje razgraničava decu sa akutnim oboljenjem po pitanju zahvaćenosti segmenata. Ostala posmatrana obeležja nisu nakon statističke obrade imala statistički značaju razliku kada se procenjuju ultrazvučno ili magnetnom rezonancom. ZAKLJUČAK: Inicijalne hipoteze ovog istraživanja su nakon obrade podataka i potvrđene. Određivanjem senzitivnosti i specifičnosti UZ i MR dobijene su sledeće vrednosti: senzitivnost UZ je 88,4% naspram 92,3% koliko ima pregled magnetnom rezonancom. U pogledu specifičnosti UZ ima 88% a magnetna rezonanca 91,6%. Verifikovano je da magnetna rezonanca bolje razvrstava decu u akutnoj fazi bolesti kao i decu u remisiji. Rezultati pozitivnih i negativnih verovatnoća odnosa ne predviđaju neuspeh nijednim od ova dva pregleda.</p> / <p>INTRODUCTION: Chronic inflammatory diseases are manifested through two clinical entities: Crohn&#39;s disease and ulcerative colitis. Their significance lies in the chronicity and the degree to which they restrict the growth and development of children and youth. There are many consenquences that come with the very nature of the disease, in addition to long-term absence from school, limiting life activities and the occurrence of complications that often affect other organ systems. The etiology of the disease has long been in favor of the theory that a chronic inflammatory process in genetically conditioned individual is provoking an inflammation due to a certain infectious agent. However, a step closer was made regarding the etiology of the disease - when the genetic basis of inheritance studies have revealed chronic inflammatory bowel diseases were associated with NOD2 gene. It is particularly important to prevent continuous exposure to the harmful effects of X-rays. Therefore, numerous studies have been made towards the validation of complementarity, accuracy and diagnostic capabilities of ultrasound and magnetic resonance imaging as noninvasive techniques. Our research was based on the capabilities of these two methods in their daily work for diagnosis and follow-up of chronic inflammatory bowel disease. OBJECTIVES: The objectives were to determine the sensitivity and specificity of ultrasound and magnetic resonance imaging in inflammatory bowel disease in children and adolescents. Furthermore, the aim was to define and compare the advantages and limitations between ultrasound diagnosis and magnetic resonance in inflammatory bowel disease in children and adolescents. MATERIAL AND METHODS: The study included 62 children and adolescents during the first attack of disease or recurrent stages of the disease, or during regular monitoring in remission. Patients included children of both sexes, aged 4-18. Then they were sorted into groups based on the type of the examination and the presence of a thickening of the intestinal wall into groups A and B - in these groups children were examined by ultrasound, A group had observed thickening of the intestinal wall &gt; 3 mm whereas children in group B had had thickening of the intestinal wall between 2,5-3 mm. Based on the review of MRI children were divided into groups A1 and B1, also according to the criterion of bowel wall thickening greater than 3mm (A1) and between 2,5-3mm (B1). The research was conducted at the Institute for Health Protection of Children and Youth and the Institute of Radiology, Clinical Center of Vojvodina. The first review was made by ultrasound, followed by the review of magnetic resonance. Data were analyzed retrospectively and prospectively. Criteria for inclusion in the study were: thickening of the intestinal wall greater than 3 mm, the existence of disturbed intestinal wall architectural structure, no clear distinction of layers, abnormal thickening of certain intestinal segments, signs of fibrosis, the absence of peristalsis, expressed hyperemia on color Doppler, transmural inflammation, increased mesenterial lymph nodes as well as check-ups for children with previously established diagnosis. Endosccopy with biopsy has made for the definitive diagnosis and then we approached statistical analysis of the data obtained. The data are presented in graphs and tables. For parametric variables we used Man - Whitney U test. For categorical values &chi;2 and Fisher&#39;s test were used. Further the sensitivity, specificity and positive and negative predictive values were determined. Relationship between these two parameters were established using Pearson correlation analysis and linear regression model. For data processing we used the program SPSS Statistics 21, statistically significant values were taken p values &lt;0.05. RESULTS: After statistical analysis there was no for the number of chronic inflammatory diseases between the sexes. Statistical significance was found in terms of age of the children during the acute phase as well as remission. Statistical significance was obtained for the observed thickness of the intestinal wall, intestinal hyperemia, the presence of fibrosis in the digestive tract. It was noted that US better demarcates children with acute disease in terms of involvement of segments. Other features are not observed as significant after the statistical analysis. CONCLUSION: The initial hypothesis of this study, after data processing were confirmed. By determining the sensitivity and specificity of ultrasound MRI results we came to the following results: sensitivity of ultrasound was 88,4% versus 92,3%, for magnetic resonance. In terms of specifics UZ has a 88% and 91,6% of magnetic resonance imaging. The classification of children in the acute phase of the disease as well as children in remission was better when MRI was used. The results of positive and negative predictions do not predict the probability of failure in neither of these methods.</p>