As Doenças Inflamatórias Intestinais (DII) são caracterizadas por resposta inflamatória exacerbada na mucosa intestinal, com desbalanço entre mecanismos pró-inflamatórios e reguladores. Entretanto, até o momento, nenhuma terapia é curativa e vários pacientes são refratários ou intolerantes a elas, necessitando de intervenções cirúrgicas para combater as complicações da doença. Sendo assim, é evidente que novas terapias são necessárias para o controle da progressão das DII. Dessa forma, como a saliva de insetos hematófagos constitui uma fonte importante de moléculas com potencial farmacológico, o objetivo desse trabalho foi avaliar a atividade terapêutica do extrato de glândula salivar (EGS) do Aedes aegypti e suas frações na colite experimental. Para tal, camundongos C57BL/6 foram submetidos à indução de colite pela administração de água contendo 3% de dextran sulfato de sódio (DSS). Os resultados demonstraram melhora na condição clínica e no escore pós-morte dos camundongos tratados com o EGS i.v. ou i.p. Essa melhora foi acompanhada de redução de leucócitos no sangue periférico, principalmente quando os animais foram tratados i.v. Além disso, redução do infiltrado inflamatório e das citocinas patogênicas IL-12, IFN-?, TNF-?, IL- 1? e IL-5, no intestino, foi também associada ao tratamento. Ademais, houve diminuição da frequência de linfócitos TCD4+ produtores de IFN-?, IL-17 e IL-4 no baço e nos linfonodos mesentéricos (LNM) dos animais tratados com EGS. Ainda, uma menor frequência de células CD11b+ no baço e CD49b+ nos LNM também foi detectada nos animais com inflamação intestinal tratados com o EGS. De forma interessante, quando expostos por dois ciclos ao DSS, o tratamento precoce com EGS (1o ciclo) protegeu os camundongos do desenvolvimento da colite após nova indução da inflamação intestinal (2o ciclo), sugerindo que a saliva do A. aegypti possui componentes com capacidade de retardar o aparecimento e a gravidade da recidiva da doença. A melhora na condição clínica associada ao tratamento com EGS parece também estar associada à modulação de populações bacterianas no intestino com características supostamente colitogênicas (Pseudomonas monteilii) e protetoras (Ruminococus champanelensis e Turicibacter sanguinis). De fato, o transplante de microbiota de camundongos tratados com EGS para animais que sofreram indução da colite levou à aparente melhora do escore pós-morte e à redução de leucócitos circulantes. Além disso, o transplante diminuiu a expressão de RNAm das citocinas inflamatórias IFN-? e IL-1?, indicando que alterações na microbiota intestinal podem ser um dos mecanismos pelos quais o EGS modula a colite experimental. Finalmente, experimentos utilizando a cromatografia líquida de alta performance (HPLC) sugerem que uma fração (F3) do extrato bruto da saliva, pode ser a responsável pela melhora observada nos sinais clínicos da doença. De forma geral, o EGS e seus componentes parecem representar uma fonte importante de moléculas imunomoduladoras com potencial terapêutico no tratamento da inflamação intestinal induzida experimentalmente / Inflammatory Bowel Disease (IBD) is an inflammatory disorder characterized by an imbalance between inflammatory and regulatory immune responses at the gut mucosa. However, current therapies are not totally effective and a plenty of patients require repeated surgeries to control disease complications. So, it is clear that novel therapies are still needed to control IBD progression. Thereby, since saliva from bloodsucking arthropods is a rich source of pharmacologically bioactive molecules, the aim of this study was to evaluate the therapeutic activity of Aedes aegypti total (SGE) and fractionated saliva in the treatment of experimental colitis. For this purpose, C57BL/6 male mice were exposed to 3% dextran sulfate sodium (DSS) in drinking water. The results showed an improvement in clinical disease outcome and postmortem scores after SGE treatment, regardless the route of administration used (i.p. or i.v.). This amelioration was accompanied by the systemic reduction in peripheral blood lymphocytes, especially when the i.v route was used. Furthermore, a reduction in the inflammatory area together with a local diminishment of IFN- ?, TNF-?, IL-1? and IL-5 cytokines were observed in the colon of SGE-treated mice. Similarly, a reduction of the frequency of TCD4+ lymphocytes producing IFN-?, IL-17 and IL-4 was observed in spleen and mesenteric lymph nodes (MLN) of SGE-treated mice. A lower frequency of CD11b+ cells in spleen and CD49b+ in MLN was also observed after SGE treatment. Interestingly, early treatment with SGE led to mice protection from a late DSS rechallenging, indicating that the mosquito saliva may present components able to prevent disease relapse. Clinical improvement due to SGE therapy seems to be also related to the modulation of intestinal bacterial population with different characteristics. Thus, SGE-therapy managed to a diminishment of colitogenic (Pseudomonas monteilii) and improvement of protective (Ruminococus champanelensis e Turicibacter sanguinis) bacteria. In fact, microbiota transplantation from SGE-tretaed mice to mice exposed to DSS-colitis improved postmortem scores and induced systemic diminishment in peripheral blood lymphocytes. Additionally, a reduced mRNA levels for the inflammatory cytokines IFN-? and IL-1?, was observed in transplanted mice, pointing to the effects of SGE-therapy in the modulation of gut microbes as one of the mechanisms related to the improvement of disease outcome. Finally, high performance liquid chromatography (HPLC) experiments suggested a major SGE pool fraction (F3) able to ameliorate disease signs. In conclusion, SGE and its components might represent a source of important immunomodulatory molecules with promising therapeutic activity for experimentally induced intestinal inflammation.

Le risque d’accidents artériels aigus chez les patients atteints de maladie inflammatoire chronique intestinale (MICI) reste incertain. L’objectif de cette thèse est d’évaluer le risque d’accident artériel aigu chez les patients atteints de MICI et l’impact des traitements sur le risque à partir des bases de données médico administratives françaises PMSI et SNIIRAM. La prise en charge thérapeutique des patients atteints de MICI a été initialement étudiée afin de valider le code diagnostique dans les bases de données. L’exposition au traitement, les taux d’hospitalisation et de chirurgie sont similaires à ceux attendus et les taux d’incidence sont comparables à ceux rapportés dans d’autres populations. Les patients atteints de maladie de Crohn (MC) et rectocolite hémorragique (RCH) ont un surrisque d’accident artériel aigu comparé à la population générale. Le risque le plus élevé est observé chez les patients de moins de 55 ans. L’activité de la MICI est un facteur de risque indépendant d’accident artériel aigu, avec une magnitude d’effet similaire dans la MC et la RCH. Comparés aux patients non exposés, les patients exposés à la monothérapie thiopurines, anti-TNFs et combothérapie ont un risque moins élevé d’accident artériel aigu, mais cette différence est seulement significative chez les patients exposés à la combothérapie. La diminution du risque est la plus importante chez les hommes atteints de MC exposés à la combothérapie. La modulation du risque d’accident artériel aigu devrait être prise en compte dans la balance bénéfice-risque des traitements par thiopurines et anti-TNFs chez les patients atteints de MICI. / The risk of acute arterial events in inflammatory bowel disease (IBD) remains unclear. The objectives of this thesis are to assemble a nationwide cohort of IBD patients based on the French administrative health databases, in order to assess the risk of acute arterial events in IBD and the impact of immunosuppressive treatment on the risk. Disease course and therapeutic management of IBD were first studied, in order to validate the coding diagnosis of IBD in the databases. Treatment exposure, hospitalisation, and surgery rates are similar to current standard of care and incidence rates are in the range of those reported in other populations. Patients with Crohn’s disease (CD) and ulcerative colitis (UC) have an increased risk of acute arterial events compared with the general population. The highest risk is observed in patients under the age of 55 years. Disease activity is an independent risk factor of acute arterial events, with a similar magnitude of risk in CD and UC. Exposure to thiopurine and anti-TNF monotherapies, and combination therapy are all numerically associated with a decreased risk of acute arterial events compared to unexposed patients, although the difference is only statistically significant for patients exposed to combination therapy. The magnitude in risk reduction is highest in men with CD exposed to combination therapy. These studies support the concept that a tight control of inflammation is crucial in patients with IBD to avoid IBD-related systemic complications. Prevention of acute arterial events should be considered in the benefit-risk balance assessment of thiopurines and anti-TNFs treatment in IBD patients, according to age, sex and IBD subtype.

Bc. Klára Horáčková DIPLOMA THESIS Mechanisms of immune dysregulation leading to inflammatory bowel disease Abstract Inflammatory bowel disease (IBD) is a complex disorder characterized by chronic inflammation of the gastrointestinal tract. Classical IBD is a multifactorial disease with adulthood or later-childhood onset. However, children with very early onset IBD (VEO-IBD, before 6 years of age) are a specific cohort, whose pathology can be caused by severe genetic defects in genes connected to immune homeostasis in the gut. We aimed to identify the causal genetic variants in 20 pediatric patients diagnosed with IBD (age of onset from 3 to 154 months) using whole exome sequencing (WES). We evaluated several bioinformatical approaches for WES data analysis. This included a comparison of two methods of variant identification using VarScan2 or GATK4-based tools. Furthermore, we compared 4 gene lists ("virtual panels") for variant filtering, one of which was compiled purposefully for this thesis. We identified and validated via segregation analysis 5 causal variants in 4 genes (DUOX2 compound heterozygote, FOXP3, NLRP3 and NOD2) accounting for 20 % of the cohort. NOD2 (p.A755V) variant has already been reported in IBD cases, while DUOX2 (p.R1216W + p.A1131T), FOXP3 (p.H400L) and NLRP3 (p.V200M) were newly...

This diploma thesis is focused on patients who are undergoing surgery - intestinal resection. In a surgical patient, malnutrition is a frequent and significant negative factor that affects postoperative morbidity and lethality. Proper nutritional care has an irreplaceable role in the prevention and treatment of malnutrition. Nutritional elements are part of the perioperative care of the modern ERAS concept, which leads to reduction in the frequency of postoperative complications and a shortening of the hospitalization duration. The concept emphasizes early physical rehabilitation and shortening of the fasting period around the time of the operation, which leads to a significant saving of body protein. The theoretical part describes particular diseases that lead to surgical treatment. Special attention is paid to idiopathic intestinal inflammations and colorectal cancer. It also includes current recommendations of professional companies. The primary objective of the practical part is to compare two groups of patients who underwent intestinal resection. To find out whether targeted nutritional intervention (before, during and after surgery) has an impact on postoperative convalescence, the frequency of complications and the overall length of hospitalization. The aim was also to improve the quality of...

Background: Inflammatory Bowel Disease (IBD) is a chronic, relapsing, autoimmune disease, affecting one in every 150 Canadians. Failure to induce remission of IBD with pharmacotherapy can necessitate surgical interventions, such as the creation of an ostomy. Ostomy surgery can help manage severe IBD and thus improve quality of life; however, individuals living with IBD report the possibility of ostomy surgery as a top concern, which can lead them to refuse or delay this decision until the disease becomes life threatening. Research Objective: The aim of this study is to understand what factors influence the decision to have ostomy surgery in young women with IBD, how the perception of the surgery compares to the reality of living with an ostomy, and the role healthcare professionals play in this decision. Methods: Nine participants who (1) identify as female, (2) are between the ages of 19 and 30, and (3) are currently living with an ostomy to treat IBD were recruited for this study. Additionally, seven healthcare professionals who work with IBD patients were recruited. Participants were invited for an individual, semi-structured interview. Findings: Young adult women living with an ostomy to treat their IBD reflected on their initial fears and concerns about undergoing surgery. Due to the severity of their illness, the majority of participants had requested surgery after having some time to adjust to the idea. This request, however, was often met with resistance or obstacles in the healthcare system. Healthcare professionals share mixed perceptions of ostomy surgery, with some viewing it as a last resort and others perceiving it as a treatment option. Once surgery had been performed, young adult women describe some challenges adjusting to life with an ostomy; but the majority report experiencing an overall improvement in quality of life. Conclusion: Understanding the perceptions that influence how young women perceive ostomies prior to versus after surgery will help identify the factors that influence the decision-making process for ostomy surgery, such as gender, age and stigma. Challenging current beliefs and assumptions may allow more supportive conversations between healthcare professionals and patients and provide insight on the actual lived experience of young women living with an ostomy. / Graduate / 2023-01-13

Bakgrund: Inflammatorisk tarmsjukdom (IBD) inkluderar Ulcerös kolit och Crohns sjukdom som kännetecknas av återkommande inflammation i tarmen. Etiologin för sjukdomarna är fortfarande okänd och forskning visar en ökning, framför allt i Europa. För att främja hälsa trots en livslång sjukdom behöver individen ta ansvar för att anpassa sin sjukdom genom egenvård, detta för att förebygga exacerbation. Syfte: Syftet med studien var att sammanställa personers upplevelser av att anpassa sitt liv utifrån sin kroniska inflammatoriska tarmsjukdom.  Metod: En beskrivande litteraturstudie baserat på 12 kvalitativa studier. Databaserna som användes vid artikelsökningarna var PubMed och CINAHL. Sökbegränsningarna var engelska, människor och 10 år.  Resultat: En återkommande upplevelse bland personerna med IBD var att livet blev begränsat både gällde skola- och arbetsliv, det sociala livet och kosten. För att anpassa sitt liv med en IBD-sjukdom upplevde personerna att kunskap och stöd från andra var betydande. För att hålla sjukdomen i remission upplevdes behandlingar och kostanpassningar vara en viktig fördel. Upplevelsen av sig själv förändrades där en känsla av att inte vara normal var vanligt, att acceptera och hitta mening i livet var en viktig anpassning och resulterade i ett bättre mentalt välbefinnande. Slutsats: Sjukdomen upplevdes skapa begränsningar i det dagliga livet och ändrade självbilden hos personerna. Att acceptera sitt liv med IBD ansågs vara en viktig anpassning för att skapa möjlighet till att leva sitt liv utan dessa upplevda begränsningar. Enligt författarna kommer resultatet ge sjuksköterskor en ökad förståelse gällande omvårdnaden för personer med en IBD-sjukdom samt möjliggöra en fungerande egenvård för dessa personer. / Background: Inflammatory bowel disease (IBD) include Ulcerative Colitis and Crohn’s disease who are characterized by recurrent inflammation in the bowel. The etiology of the diseases is still unknown, and research shows that it’s increasing, especially in Europe. To promote health despite a lifelong illness, the individual needs to take responsibility for their self-care to keep the disease in check. Aim: The aim of this study was to describe persons experience of adapting their life with their inflammatory bowel disease. Method: A descriptive literature study based on 12 qualitative studies. The databases used were PubMed and CINAHL. The study's limitations were English, humans, and 10 years.  Results: A recurring experience among people with IBD was that life was limited in school, work, social life and diet. Knowledge and support from others were important to adapt to a life with IBD. To keep the disease in remission, treatments and dietary adjustments were perceived as an important advantage. The experience of yourself changed, where a feeling of not being normal was common. Patients who were able to accept their disease, and who also transcended to find a higher purpose, ultimately improved their mental health.   Conclusion: The disease creates limitations in daily life and changes the self-image of people. Accepting a life with IBD was an important adjustment to create the opportunity to live one's life without these perceived limitations. According to the authors, the results will give nurses an increased understanding of caregiving and improved self-care for people with IBD.

Cancer treatments including chemotherapy and radiotherapy treat cancer by targeting rapidly dividing cells. Although these forms of treatment damage rapidly dividing cancer cells, they are also toxic to the cells of the gastrointestinal tract, leading to inflammation of the mucosal layer (mucositis) and causing nausea, vomiting, diarrhea, and abdominal pain. Improvement in symptoms may allow patients to have better performance status permitting ongoing treatment and possibly a better prognosis. This article describes the pathophysiology of chemotherapy-induced mucositis and includes 3 case reports of treatment of mucositis with serum bovine immunoglobulin.

SAMMANFATTNING Livet förändras både fysiskt och emotionellt när individen får en diagnos med en kronisk sjukdom. Den sjuke tvingas att anpassa och acceptera att livet förändras. Hur livet med sjukdomen upplevs och hur personen anpassar sig, är individuellt. Även anhöriga och vänner runt den sjuke drabbas. Vården kan bli en viktig del i den sjukes livsvärld och det är viktigt att lyfta fram hur den som är sjuk upplever sin sjukdom och sin vardag. Syfte: Syftet var att beskriva personers upplevelser av att leva med kronisk inflammatorisk tarmsjukdom och hur sjukdomen inverkar på deras vardag. Metod: En litteraturöversikt valdes som metod. Resultatet består av 16 vetenskapliga artiklar, publicerade mellan 2005-2016 vilka passade till studiens syfte och frågeställning. I analysen hittade författarna meningsenheter som omvandlades till koder, koderna delades in i sub-kategorier och dessa delades in i huvudkategorier. Resultat: Tre huvudkategorier kunde utläsas efter analysarbetet; begränsningar i vardagen, emotionell påverkan och kontakter med vården. Begränsningar i vardagen beskrevs vara okontrollerad tarm, fysiska symtom, begränsning av att inte kunna medverka vid aktiviteter, arbetet och nutritionen. Emotionell påverkan var kopplad till maktlöshet, oro, skuld och bristande förståelse. Kontakter med vården beskrivs utifrån vårdens stöd och behandlingar. Slutsats: Stora delar av livet påverkas för personer som lever med kronisk inflammatorisk tarmsjukdom. Varje person upplever sin situation individuellt och har olika erfarenheter och tillgång till stöd. För att skapa kontroll av sin sjukdom krävs det att flera faktorer samspelar med varandra. Det gäller att prova sig fram till vad som fungerar bäst för varje individ. Här är det viktigt att vården är lyhörd och anpassar vården utefter varje individs individuella behov. / ABSTRACT Life changes both physically and emotionally when an individual is diagnosed with a chronical illness. The person is forced to adapt and accept that life changes. How life as ill is perceived individually and how the individual adapts to a new situation differs. Even relatives and friends around the patient suffer. The care can be an important part of the patient’s life-world and it is important to highlight how the patient experience their illness and their daily lives. Aim: The aim was to describe peoples’ experiences of living with chronic inflammatory bowel disease and how the disease affects their daily lives. Method: A literature review was chosen as method. The result consists of 16 scientific articles, published between 2005-2016 which were suited to the purpose of the study and research question. In the analysis aouther found meaning units that were converted into codes, the codes were divided into sub-categories and these were divided into major categories. Results: Three main categories could be seen after the analysis; limitations in everyday life, emotional impact and contacts with healthcare. Limitations in everyday life were described to be uncontrollable bowel, physical symptoms, and limitation of not being able to participate in activities, work and nutrition. Emotional impact was linked to powerlessness, anxiety, guilt and lack of understanding. Contacts with healthcare were based on healthcare support and treatment. Conclusion: Big parts of life is affected for people living with chronic inflammatory bowel disease. Every individual experience their situation differently and have different experiences and access to support. In order to control their illness they require several factors that interact with each other. It’s up to every individual to try and find out what works best for them. Here it’s important that the healthcare personal is responsive and adapt healthcare along each person's individual needs.

Bakgrund: IBD är en kronisk inflammatorisk tarmsjukdom som innefattar sjukdomarna ulcerös kolit och Crohns sjukdom. Sjukdomen har ökat kraftigt i förekomst de senaste tre decennierna, även i Sverige. En person som har en kronisk sjukdom får en påverkad tillvaro och behöver stöd utöver bara kunskap om sjukdomen för att kunna hantera den. Professionell attityd och empati är viktiga aspekter för att skapa ömsesidigt förtroende och respektfull vård för personer med IBD. Syfte: Litteraturstudiens syfte var att belysa personers (≥18 år) upplevelser av att leva med inflammatorisk tarmsjukdom (IBD). Metod: En litteraturstudie med kvalitativ ansats, som omfattade 11 vetenskapliga artiklar med kvalitativ metodik, genomfördes. Databaserna CINAHL och PubMed användes för databassökning. Analysen genomfördes som en stegvis process inspirerad av innehållsanalys. Resultat: Personernas upplevelse av att leva med IBD sammanställdes i två kategorier; ‘Upplevelser ur ett inre perspektiv’ och ‘Upplevelser ur ett relationellt perspektiv’. Kategorierna delades därefter in i nio subkategorier; ‘Oförutsägbarhet och kontrollförlust’, ‘Oro för framtiden’, ‘Kroppsbild och stigma’, ‘Fysiska påfrestningar’, ‘Optimism’, ‘Sociala situationer’, ‘Familj och partner’, ‘Arbete samt ‘Sjukvård’. Konklusion: Personer med IBD upplever både fysiska och psykiska påfrestningar som kräver en helhetssyn i omvårdnaden. En individanpassad omvårdnad är avgörande för att upprätthålla förtroendet för vården och främja positiva resultat för personens behandling och hälsa. Sjuksköterskor bör vara lyhörda för de individuella behoven och ta hänsyn till de psykiska påfrestningar som sjukdomen kan bidra till. Det är också viktigt att skapa en trygg miljö för personerna, då sjuksköterskan kan fungera som en stödjande faktor vid sociala problem. Litteraturstudien visar därmed att omvårdnad spelar en betydande och värdefull roll i personers upplevelser av att leva med IBD. / Background: IBD is a chronic inflammatory bowel disease that includes ulcerative colitis and Crohn disease. It has significantly increased in incidence over the past three decades, in Sweden as well. A person with chronic illness experiences an impacted life and requires support beyond just knowledge of the disease in order to be able to manage it. Professional attitude and empathy are important aspects to create mutual trust and respectful care for people with IBD. Aim: The aim was to illuminate people’s (≥18 years) experiences of living with inflammatory bowel disease (IBD). Method: A literature review with a qualitative approach, which included 11 scientific articles with qualitative methodology. The databases CINAHL and PubMed were used for the database searching. The analysis was conducted as a stepwise process inspired by content analysis. Results: The people’s experience of living with IBD was compiled into two categories; ‘Experiences from an inner perspective’ & ‘Experiences from a relational perspective’. The categories were then divided into 9 subcategories; ‘Unpredictability and loss of control’, ‘Anxiety about the future’, ‘Body image and stigma’, ‘Physical stress’, ‘Optimism’, ‘Social situations’, ‘Family and partner’, ‘Work’ and ‘Healthcare’. Conclusion: People with IBD experience both physical and psychological stress, which requires a holistic view in nursing. Individualized care is crucial to maintaining trust and promoting positive outcomes for a person's treatment and health. Nurses should be attentive to individual needs and consider the psychological impacts of the disease. Additionally, creating a safe environment is important, as nurses can act as a supportive factor in case of social problems. The literature review highlights the significant and valuable role of nursing care in the experiences of individuals living with IBD.

Introduction Inflammatory bowel disease (IBD) and its complications have been well-established. The literature shows an association between IBD and decreased bone mineral density in the adult population. However, most studies have reported an association between IBD and osteoporosis, while the risk of fractures has not been well-studied. The aim of this meta-analysis is to summarize the best available evidence regarding IBS and osteoporotic fractures. Methods A review of the literature using the MEDLINE and EMBASE databases was performed during November 2017. We included cross-sectional and cohort studies that reported the relative risks, odds ratios, and hazard ratios comparing the risk of developing osteoporotic fractures among patients with IBD patients, both ulcerative colitis (UC) and Crohn's disease (CD), versus patients without IBD as controls. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using the generic inverse-variance method. Results After a review of the literature, seven studies fulfilled the eligibility criteria established during the analysis. A significant association was found between IBD and osteoporosis, with a pooled OR of 1.32 (95% CI, 1.2 - 1.4). Low heterogeneity among the studies was found, I=42.3. No publication bias was found using the Egger regression test p=0.18. Sensitivity analysis showed that the inclusion of data on children by Kappelman et al. (2007) did not change the results. Conclusion A significant association between IBD and the risk of developing osteoporotic fractures was observed in this study. There is a 32% increased risk, which is consistent with different cohort studies previously done.