Abstract available on the publisher's website.

This thesis focused on the acute management of patients with ST-segment elevation myocardial infarction (STEMI) in an effort to provide information that may improve outcome. The aim was to evaluate the efficacy and safety of bivalirudin versus unfractionated heparin (UFH) in STEMI patients during primary PCI. Furthermore, to provide pharmacodynamic data of novel ways of ticagrelor administration compared to standard tivcagrelor. Additionally, to identify subgroups of patients, such as women who may derive greater benefit from specific antithrombotic strategies due to their risk/benefit profile. Finally, to evaluate current formulas for estimation of renal function in the acute phase of STEMI. In Paper I, all STEMI patients in Sweden between 2008 and 2014, treated with primary PCI and UFH or bivalirudin were included in our analysis. Of the total population of 23 800 patients, 8 783 (36.9%) were included in the UFH group and 15 017 (63.1%) in the bivalirudin group. Concomitant GPI administration was 68.5% in the UFH arm compared to 3.5% in the bivalirudin arm (p<0.01).The adjusted incidence of 30-day mortality was not significant different between the two groups (UFH vs bivalirudin, adjusted HR 0.94; 95% CI 0.82 -1.07). The adjusted risk for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ significantly between the two groups. In contrast, patients treated with UFH had a significantly higher incidence of major in-hospital bleeding (adjusted OR 1.62; 95%CI 1.30 -2.03). In Paper II pharmacodynamic data of chewed or crushed ticagrelor compared to standard ticagrelor loading dose (LD) was assessed in 99 patients with stable angina. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60 minutes after LD. High Residual platelet reactivity (HRPR) was defined as > 208 P2Y12 reaction units (PRU). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60 minutes. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20 minutes whereas no difference was observed at 60 minutes. At 20 minutes, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p<0.01). In Paper III we presented a pre-specified gender analysis of the ATLANTIC trial including 1 862 STEMI patients that were randomly assigned to pre-hospital versus in-hospital administration of 180mg ticagrelor. Women were older and had higher TIMI risk score. Women had a 3-fold higher risk for all-cause mortality compared to men (5.7% vs 1.9%, HR 3.13, 95% CI 1.78 – 5.51). However, after adjustment for baseline characteristics, the difference was lesser and no longer significant (HR 1.98, 95% CI 0.97 – 4.04). Female gender was not an independent predictor of risk for bleeding after multivariable adjustments (BARC type 3-5 HR 1.52, 95% CI 0.74-3.09). There was no interaction between gender and efficacy or safety of randomised treatment. In Paper IV, forty patients with PCI- treated STEMI were included between November 2011 and February 2013. We validated the performance of the Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD-IDMS), the Chronic Kidney Disease Epidemiology (CKD-EPI) and the Grubb relative cystatin C (rGCystC) equations for estimation of GFR against measured GFR (mGFR) during the index hospitalisation for STEMI. MDRD-IDMS and CKD-EPI demonstrated a good performance to estimate GFR with accuracy within 30% (P30) 82.5% vs 82.5%, respectively. CKD was best classified by CKD-EPI (Kappa 0.83). CG showed the worst performance with the lowest P30. The rG-CystC equation had a marked bias of -17.8% and significantly underestimated mGFR (p=0.03). Conclusions – In STEMI patients treated with primary PCI, bivalirudin should be preferred in patient at high risk for bleeding. With crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared with standard integral tablets. In STEMI patients, fast and potent platelet inhibition with chewed ticagrelor may reduce the risk of early stent thrombosis and patients treated with a less aggressive antithrombotic strategy, such as UFH or bivalirudin monotherapy, may derive a greater benefit. Although gender differences in adverse outcomes could mainly be explained by older age and clustering of comorbidities in women, a bleedreduction strategy in women with high risk characteristics is warranted in order to improve their outcome. Regardless the choice of antithrombotic strategy, dose adjustment of drugs cleared by kidneys based on GFR estimation is of crucial importance. MDRD and CKD-EPI should be the formulas used for estimation of GFR in STEMI patients

Trigger finger is one of the most common hand conditions, with a prevalence of almost 3%. The aetiology remains unclear even though many causes have been suggested. The prevailing paradigm is that the pathogenesis of trigger finger is ascribed to primary changes in the first fibrous condensation of the tendon sheath (A1-pulley). Several studies have investigated pathology in the pulley, but few have investigated the tendon. The general aim of this thesis was to find out if there is pathology in the trigger finger tendon and to define it. We first looked at trigger finger tendon biopsies in a light microscope, and found that they were histologically different from healthy tendons. They showed signs of micro-ruptures, collagen degradation, increased amounts of ground substance, both hyper- and hypo-cellular areas, round active cell nuclei and absence of inflammatory cells, all similar to tendinosis. The histological picture was further assessed by using a scoring system for Achilles tendinosis. The trigger finger tendons scored high, suggesting a similar histopathology. Next, we performed a quantitative real-time polymerase chain reaction (qPCR) on trigger finger tendons. We assessed the mRNA expression of 10 genes, which have been described to be differently expressed in Achilles tendinosis (collagen 1 and 3, versican, decorin, biglycan, aggrecan, MMP-2, MMP-3, ADAMTS-5, and TIMP-3). The overall expression pattern agreed with previous studies on Achilles tendinosis, suggesting that the cellular function in trigger finger tendons is disturbed in a similar way as in Achilles tendinosis. Recent experimental and observational research has suggested potential side effects of statin treatment on tendons, but firm evidence was lacking. We performed an epidemiological study on two large population-based cohorts. Statin use was found to increase the risk of both trigger finger and tendinosis in the shoulder and Achilles tendons, especially among men. This suggests a similar pathology in trigger finger and tendinosis. We have also studied the time to treatment effect after a single injection of glucocorticoid in trigger finger. Our results suggest that 60-80% of patients can expect resolution of the triggering within 14 days, and half of them within seven days. This result allows correct information to be given to the patient and proper planning of follow-ups. In conclusion, the pathology in trigger finger tendons is similar to tendinosis in other tendons.

Crohn’s disease (CD) affects about 780,000 people in the United States alone, and it is estimated that 6-15 per 100,000 persons will receive a diagnosis of this disease each year. There currently is no cure for Crohn’s disease, and available medical therapies simply serve to alleviate the inflammation. This does not help treat fibrostenosis that Crohn’s disease patients may develop, which can only be treated surgically. Finding alternatives to treat CD requires an understanding of mechanisms at the biochemical level. In this thesis, we attempted to gain a better understanding of certain pathways found to be active in Crohn’s disease-affected ileal smooth muscle cells. We found an upregulation of the ER stress pathway via expression of its surrogate, the GRP78 protein. We also showed evidence that the phosphoinositide 3-kinase (PI3K) pathway, a key proliferative pathway, is linked to ER stress in these cells, and is an upstream driving force of the ER stress response. Further research on the link between the PI3K and ER stress pathways needs to be conducted, and can potentially serve as a target for therapeutics to help reduce proliferation in fibrostenotic Crohn’s disease-affected ileal smooth muscle cells.

Chez les mammifères, le développement du système immunitaire intestinal est initié in utero par un programme déterminé génétiquement. Cependant, le développement complet de ce système immunitaire et sa maturation finale n'ont lieu qu'après la naissance, sous l'influence des très nombreuses bactéries qui colonisent alors l'intestin et qui composent le microbiote intestinal. L'utilisation de modèles in vivo originaux de souris axéniques, sans germe, et gnotoxéniques, colonisées avec des bactéries individuelles ou des groupes de bactéries plus ou moins complexes, nous a permis d'identifier le rôle particulier de la bactérie segmentée filamenteuse (ou SFB) dans la maturation des réponses immunes intestinales adaptatives, IgA et lymphocytaires T. Sa capacité singulière à adhérer à l'épithélium des plaques de Peyer suggère un rôle important de ces formations lymphoïdes dans l'initiation des réponses immunes induites par la SFB. Nos résultats renforcent l'idée du rôle majeur des plaques de Peyer dans l'initiation des réponses IgA intestinales par le microbiote. De façon inattendue, en l'absence de ces structures, la SFB induit dans le chorion des souris, la néogenèse de structures lymphoïdes tertiaires capables d'initier des réponses IgA associées à une forte réponse IL-17 spécifique de la SFB. Ces résultats suggèrent que les puissantes propriétés immunostimulantes de la SFB sont soutenues par de multiples voies d'induction des réponses immunes qui pourraient être liées à son adhésion à la muqueuse intestinale

Celiac disease is a lifelong disorder characterised by permanent intolerance to gluten and typical inflammatory changes in the small intestine. These changes lead to malabsorption of all nutrients, minerals, vitamins and water. The first attack of this disorder mostly occurs in childhood because the small intestine is greatly stressed by other nutrition supply. The only effective treatment is a lifelong gluten-free diet. This thesis, called Primary, secondary and tertiary prevention in children with celiac disease, consists of two parts; a theory part for which both professional publications and internet have been used and an empirical part, that comprises research itself with its results. The research target of this thesis was the sector of celiac disease occurring in children. Within the research, there were determined four objectives. The first objective was about to find out how primary, secondary and tertiary prevention is provided to children with celiac disease in GP ambulances for children and teenagers. Another task was to trace what profits the regime education brings to parents of children having celiac disease. We also dealt with the impact of the disease on the life of the child, his/her family and surrounding society. Then we investigated whether respondents take the help from outside, state support, institutions and in-kind assistance. In the empirical part of the thesis we used a method of qualitative research. For this research we chose a method of questionings through individual semi-structured interviews with two groups of respondents. The first group was made of nine nurses working in GP ambulances for children and teenagers having celiac disease. The second group was formed by nine children with celiac disease and their parents. The outcome of the research indicates that for quality health care supply it is important to obtain family anamnesis, carry out regular physicals in stated intervals within growth measurement monitoring and breastfeeding education and add other nutrition to diet. Monitoring suspicious symptoms, such as failure to thrive, inexplicable weight loss, growth retardation, abdominal pain, recurrent diarrhoea, digestive discomfort, dermatitis, stomatitis, anaemia, can soon detect celiac disorder. The secondary prevention is expressed by the work of nurses, such as biological material analysis, education, advice, help and support. Great urgency is given to risk factor monitoring, such as diabetes mellitus, Down syndrome, thyroid disorder, or genetic predispositions. The tertiary prevention is focused on the adaptation support of the child and his/her family to this chronic disorder, normal growth, and whole constitution examining and complication prevention. The outcomes indicate that the biggest problem of celiac people is financial burden of gluten-free food and also frequent limits in out-of- home eating. The financial burden of the diet influences, for example, vacation planning. It is necessary for the society to respect their disease, for example, canteens and teachers should have knowledge of the diet restrictions and provide suitable feeding. Furthermore, our findings show that only few families use financial support, because they are afraid of negative allowance examination because of their comfortable income. They mainly use allowance from Health Insurance Companies. On the grounds of the acquired information has been created an informative handout for the parents of the children with the celiac disease. The results of our research will be provided to the nurses who work in general practitioner ambulances.

Theoretical foundation Crohn's disease is a chronical autoimmune disease categorized, together with ulcerative colitis, in the group of idiopatic intestinal inflammations. But in spite of this categorization, Crohn's disease may not be found only in the intestines but anywhere in the gastrointestinal tract. However, the intestinal localization is most frequent and is related with numerous manifestations like stomachake, diarrhoea, bloating, flatulence, belching, loss of weight, etc. The pathogenetic cause of those discomforts consists in disorder of autoimmunity, when the body starts producing antibodies against its own tissues. But the cause of start of that pathogenetic mechanism has not been clarified so far. Experts speak about influence of infections, food, psychosomatics, smoking, genetic perceptiveness, etc. The hope of the patients is pinned on the continuously improving treatment, culminating by biological preparations that have most influenced the health condition of those persons so far. But in spite of the modern therapy, all characteristics of the disease can have negative impact on the quality of life of the patients. Goal of the thesis The goal of this thesis consists in ascertaining the quality of life of Crohn's disease patients. Hypotheses H1: Crohn's disease patients have problems in physical area. H2: Crohn's disease patients have problems in psychic area. H3: Crohn's disease patients have problems in social area. Methodology The practical part of the thesis was implemented based on quantitative inquiry within the grant Project No. 120/2012/S ?Reflection of life quality in nursing?. Two standardized questionnaires were used for the inquiry: the WHOQOL-100 general questionnaire and the IBDQ specific questionnaire, distributed among Crohn's disease patients. Valid licence was bought for both questionnaires. The size of the research set was determined at 100 Crohn's disease patients, the Crohn's disease diagnosis being the only criterion for selection of the respondents. The distribution of the questionnaires among the respondents took place with the help of gastroenterological centres. Results All data obtained were statistically processed in the SASD (Statistical Analysis of Social Data) program. The results of the processing can be divided into three areas, by the three main hypotheses verified. The first area of results provided information on the problems confronted by Crohn's disease patients in physical area. Only one problem was confirmed here: the Crohn's disease patients feel fatigue. All the remaining problems under verification in this area were refused. The second area brought information on psychical problems of the patients. Similarly to the preceding case, only one problem troubling the Crohn's disease patients was found here: feeling of irritation. The occurrence of the remaining psychical problems under verification was not confirmed. The last area of results found out the problems of the patients in social area. The results were the most positive in this case, as none of the problems under verification in this area was confirmed. Based on all results stated above, the hypotheses were evaluated as follows: H1 Crohn's disease patients have problems in physical area - refused; H2 Crohn's disease patients have problems in psychic area - refused and H3 Crohn's disease patients have problems in social area - refused. Conclusion The thesis provides comprehensive view on the issue of quality of life of Crohn's disease patients. The results may be used particularly in the work of so called IBD nurses, endoscopic nurses, but also general nurses working with the patients. The thesis can be also used as study material or as foundation for further research.

Made available in DSpace on 2015-03-26T13:47:07Z (GMT). No. of bitstreams: 1 texto completo.pdf: 487807 bytes, checksum: 3b38b9ece555d67e478d2c80b4328f96 (MD5) Previous issue date: 2006-09-25 / There is much debate over the possible causes of the behavioral problems of horses; stable stress is among the most significant. Nevertheless, given the large number of variables related to these abnormal behaviors, all conclusions reached until today remain questionable. Furthermore, it is also possible that the real determining factor of these behavioral problems is simply the incapacity of horses to adapt to the environment to which they are submitted today. The unceasing search for the etiology of these disorders aims to prevent and treat diseases that are possibly related to these behavioral problems, such as tympanic colic, compaction colic, dental wear and decreased performance; in addition to addressing problems related to aesthetical and economical factors. The present experiment aims to show the correlation between behavioral problems and prevalence of colic; between wear of incisive teeth and colic. Furthermore, it analyses other variables such as age, stable, weight, body condition, heart frequency and incisive teeth size. 407 horses were examined, of various breeds, with ages between 2 and 25 years, of both sexes. All animals were kept in stalls, with standardized feeding for each group, at the Regimento de Cavalaria de Guarda (RCG), located in Brasília, Federal District, Brazil. The total incidence of behavioral problem found in this group of animals was of 28.9%, divided among the following stereotypy: cribbiting, wind sucking, crib-biting with the neck, gnawing wood, bear syndrome, aggression, stable walking and kicking. On studying crib-biting, a significant incidence of colic was found between the years 2000 and 2005. During that period, 900 colic episodes were observed, and most of them due to spasmodic colics, compaction and overfeeding, as registered by the RCG veterinary hospital. Wear of incisive teeth in those horses was 14.5%. Fisher's exact test and the regression test were used for the different correlations investigated, using a reference of p< 0.05. / Há grande discussão em torno das possíveis causas dos distúrbios de comportamento apresentados pelos eqüinos; o estresse de baia é tido como a principal delas. No entanto, o grande número de variáveis que existe acerca desses comportamentos considerados anormais faz com que todas as conclusões a que se tem chegado até hoje sejam questionáveis. Existe ainda a possibilidade de que o real fator determinante de todos estes transtornos comportamentais seja simplesmente a incapacidade do eqüino adaptar-se ao meio a que é submetido na vida moderna. A inesgotável busca da etiologia desses distúrbios visa, além de preservar fatores estéticos e econômicos, prevenir e tratar algumas doenças às quais os distúrbios estejam possivelmente relacionados tais como cólicas gasosas, cólicas por compactação, desgaste dentário e diminuição de rendimento. Este experimento tem como objetivo mostrar que há correlação entre distúrbio de comportamento e a prevalência de cólica; entre desgaste dos dentes incisivos e a cólica. Além disso, o experimento analisa outras variáveis como idade, baia, peso, escore, freqüência cardíaca e tamanho dos incisivos. Foram examinados 407 eqüinos, sem raça definida, com idade variando entre 2 e 25 anos, de ambos os sexos, todos em sistema intensivo de baia, com alimentação padronizada por cada grupo, no Regimento de Cavalaria do Exército (RCG), Brasília, Distrito Federal. A incidência de distúrbio de comportamento total encontrada nestes animais foi de 28,9%, distribuídos entre as seguintes estereotipias: aerofagia com apoio, aerofagia sem apoio, aerofagia com pescoço, roer madeira, síndrome de urso, agressividade, andar na baia e coices. Quando analisada a aerofagia com apoio houve significância quanto à incidência de cólica nos anos de 2000 a 2005. Nesse período foram identificados 900 episódios de cólica, esses em sua maioria compostos por cólicas espasmódicas, compactação e sobrecarga alimentar, conforme registrado no hospital veterinário do RCG. O desgaste dos dentes incisivos destes eqüinos foi de 14,5%. O teste exato de Fisher e de regressão foi utilizado para diferentes correlações analisadas, tomando como referência: p< 0,05.

OBJETIVOS: Determinar la proporción de trabajos presentados en el Congreso Peruano de Gastroenterología (1998-2008) que fueron publicados en revistas científicas y sus factores asociados. MATERIALES Y MÉTODOS: Se revisó todos los resúmenes presentados al Congreso Peruano de Gastroenterología y se evaluó sus características. Luego se buscó si fueron publicados a través de una estrategia de búsqueda usando Google Académico. Se evaluó la asociación entre las características de los resúmenes y su publicación usando regresión logística múltiple. RESULTADOS: Se evaluó 417 resúmenes, la media de autores fue de 4,9 ± 2,6, 17% fueron reportes de caso. Los estudios retrospectivos fueron más frecuentes (66,3%) pero disminuyeron con los años (p<0,001) al igual que los descriptivos (79,1%), solo 2,9% fueron experimentales y 12,2% longitudinales. Tuvieron una mediana de 65 personas por estudio. La proporción de publicación fue de 8,2% (34/417), la mayoría (82,4%) fue publicado en la Revista de Gastroenterología del Perú y solo uno en inglés, 16/34 tenían al menos un autor diferente al resumen. El tiempo medio de publicación fue de 10,8±10,4 meses. En el análisis multivariado se encontró asociación la publicación de los resúmenes con haber sido presentado en los congresos después del año 2004 (OR: 5,5; IC95%: 2,2-14,0) y ser analíticos (OR: 3,4; IC95%: 1,4-8,3). CONCLUSIONES: El Congreso Peruano de Gastroenterología tiene una baja proporción de publicación de los resúmenes presentados, lo cual puede ser tomado como indicador de calidad de estos resúmenes y del proceso de revisión. Se deben tomar medidas para estimular la publicación de los trabajos presentados. / OBJECTIVES: To determine the proportion of abstracts presented at the Congreso Peruano de Gastroenterología (the major Peruvian gastroenterological scientific meeting), that had been published in scientific journals, the date of publication and its associated factors. MATERIALS & METHODS: Longitudinal retrospective and analytic study; the publication rate of all the abstracts presented in the biennial Congreso Peruano de Gastroenterología between 1998 and 2008 was assessed. Google Scholar engine was used. The searching strategy performed included: (“Study location” AND “population studied” AND “main outcome”) AND (autor:First OR autor:Second OR autor:Last). Logistic regression was used, considering p<0.05 statistically significant. RESULTS: Publication rate was 8.2% (34/217), statistically significant differences were found among meeting years (p<0.001). There were also differences between study design, objectives (more in analytic studies) and measurement (more in longitudinal studies)(p<0.001). 82.4% were published in the Revista de Gastroenterología del Perú. The median time for publication was 10.8±10.4 months; this variable and the meeting year, study type, journal of publication or accordance between the abstract and publication characteristics showed no statistical differences. The mean authors’ number was 5.02±2.4; analytic studies have less authors than the descriptive ones (3.6 vs 6.1; p=0.012) CONCLUSION: The Congreso Peruano de Gastroenterología presents a low publication rate of the abstracts presented, which can be used as a quality indicator of the abstracts and the reviewing process.

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease. Clinically, the distinction between ongoing inflammation attributed to SLE, and organ damage due to medication or co-morbidities remains challenging. In addition, SLE is a heterogeneous disease where the various disease phenotypes complicate the search for biomarkers that adequately reflect disease activity and/or signs of increasing organ damage. The aim of the thesis was to investigate and evaluate potential new biomarkers of disease activity and/or organ damage in SLE patients. High mobility group box protein-1 (HMGB1) is a nuclear non-histone protein that can shuttle to the cytoplasm, become secreted extracellularly, and participate in systemic inflammation. Administration of monoclonal anti-HMGB1 antibodies has been reported both to attenuate and intensify disease in animal models of arthritis and lupus. In Paper I of the thesis, circulating anti-HMGB1 was found in 23% of the SLE patients and correlated with disease activity variables. The biological role of these autoantibodies remains to be elucidated. As a consequence of massive circulating levels of cellular debris and immune complexes, SLE patients have insufficient capacity to remove such material via the reticuloendothelial system. Pentraxin 3 (PTX3) may possibly protect against lupus flares due to classical complement activation, opsonization of apoptotic cells, and cytokine induction. In Paper II, circulating PTX3 was found to be inhibited or exhausted by interferon (IFN)-α, a key cytokine of SLE pathogenesis, and serum levels of PTX3 in SLE patients were inversely related to IFN-α levels. Suppressed PTX3 levels may contribute to a vicious circle resulting in impaired waste clearance, autoantigen exposure and autoantibody production, and sustained disease activity. Osteopontin (OPN), a protein known to influence cell signaling and apoptosis, has been proposed as a marker of organ damage in pediatric lupus. In a Swedish cross-sectional study, circulating OPN levels were found to be raised in SLE (Paper III). In patients with recent-onset disease, OPN reflected disease activity, while in established disease, OPN appeared to mirror damage accrual and cardiovascular damage. In Paper IV, OPN was instead analyzed in an international longitudinal multi-center study based on patients with recent-onset SLE and follow-up data. OPN turned out to be a poor predictor of organ damage, but significant associations were observed between OPN and disease activity both at disease onset, as well as over 5 years of follow-up. In conclusion, increased anti-HMGB1 antibody and decreased PTX3 levels could potentially sustain the impaired waste-disposal. Of the molecules analyzed in this thesis, OPN seems to be the best marker of disease activity. Further studies of these proteins may help to better understand SLE pathogenesis and to optimize treatment of patients.