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.

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.

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery. / Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindring och det är oftast förstahandsval vid behandling av patienter med PS. Flera faktorer påverkar tillgängligheten av LD, bl.a. den hastighet som magsäcken tömmer sig med och denna verkar förlångsammad hos personer med PS vilket ger sämre tillgänglighet av LD i blodet och därmed i hjärnan. LD bryts även ner i hög grad av olika enzym ute i kroppen vilket leder till mindre mängd LD som hamnar i hjärnan och till fler nedbrytningsprodukter som orsakar biverkningar. Tillägg av enzymhämmare leder till ökad mängd LD som kan nå hjärnan och omvandlas till DA. Det anses viktigt att undvika höga toppar av LD i hjärnan då dessa verkar bidra till utvecklandet av besvärliga motoriska komplikationer hos patienter med PS. Om LD ges mer kontinuerligt, exempelvis som en kontinuerlig infusion in i tarmen eller i blodet, så minskar dessa motoriska komplikationer. Inopererande av stimulatorer i vissa delar av hjärnan (DBS) har också visat sig minska dessa motoriska komplikationer och även resultera i att man kan minska LD-dosen. Huvudsyftet med den här avhandlingen är att studera LD hos patienter med PS; i blod och fettvävnad då LD ges i tablettform och se om det finns något samband med LD-upptag och hastigheten på magsäckstömningen (MT) och om kontinuerligt given LD påverkar LD-upptaget eller MT; i blod och i ryggmärgsvätska då enzymhämmarna entakapon och karbidopa tillsätts LD; i hjärna vid behandling med DBS och då LD ges både som tablett och som infusion i blodet. Sammanfattningsvis kan vi se att LD-upptaget är mer gynnsamt hos patienter med PS i tidigare skede av sjukdomens komplikationsfas. MT är förlångsammad hos patienter med PS och det är inget tydligt samband mellan LD-upptag och MT eller mellan MT och sjukdomsgrad. Kontinuerligt given LD minskar LDnivåerna. Enzymhämmaren entakapon ökar den maximala koncentrationen av LD i blod och ryggmärgsvätska och effekten är mer tydlig vid tillägg av karbidopa vilket är viktigt att ta i beaktande vid behandling av PS för att undvika höga toppar av LD i hjärnan. LD ökar i hjärnan då man behandlar med LD i tablettform och som infusion i blodet och DA-nivåerna i hjärnan följer LD väl vilket visar på att patienter med PS fortfarande kan omvandla LD till DA trots trolig uttalad brist av de DA-producerande nervcellerna i hjärnan. DBS verkar öka DA i vissa områden i hjärnan och tillsammans med LD-infusion i blodet verkar det även öka LD i hjärnan och det kan förklara varför man kan sänka LDdosen efter DBS-operation.

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.

Erosiv esofagit (EE) innebär uppkomst av inflammation och slemhinneskador i matstrupen. Den huvudsakliga orsaken till EE är gastroesofageal reflux (GERD), då det sura maginnehållet stöts upp i matstrupen. Bristande funktion av nedre esofagussfinktern (LES) och diafragmabråck kan också orsaka EE. Obehandlad EE kan leda till komplikationer såsom Barretts esofagus (BE), adenocarcinom, förträngning av matstrupen och gastrointestinala blödningar. Diagnostiken sker med hjälp av endoskopi. Behandlingen av EE går bland annat ut på att påskynda läkning av slemhinneskador i matstrupen. Den består huvudsakligen av läkemedelsterapi och livsstil- och kostförändringar, men även kirurgi kan vara en möjlig behandling. Läkemedelsterapi består av syrahämmande läkemedel som hämmar produktionen av magsyra. Protonpumpshämmare (PPI), till exempel lansoprazol (LPZ), är standardbehandlingen vid syrarelaterade sjukdomar, bland annat EE. PPI har dock begränsningar och upp till 20 % med svårare EE uppnår inte läkning. Vonoprazan (VPZ) tillhör kalium kompetitivasyrablockerare (P-CAB) och är ett nytt syrahämmande läkemedel som är godkänt i bland annat Japan och USA för behandling av EE. Syftet med detta litteraturarbete var att undersöka effekten av 20 mg VPZ jämfört med 30 mg LPZ efter åtta veckors behandling av EE, genom att ta del av publicerade kliniska studier. Fyra olika RCT-studier hämtade från databasen PubMed användes i detta litteraturarbete. Alla fyra studier resulterade i att VPZ inte var sämre än LPZ vid behandling av EE i upp till åtta veckor. Fler patienter i VPZ-gruppen uppnådde läkning av EE i samtliga studier. Dessutom visade VPZ ha bättre effekt hos patienter med svårare EE. Number Needed to Treat (NNT) för de olika studierna varierade mycket, därför kunde inte den användas för att beskriva den kliniska effekten av VPZ vid behandling av EE. Både VPZ och LPZ tolererades väl. Slutsatsen var att VPZ 20 mg en gång dagligen var inte sämre än LPZ 30 mg en gång dagligen vid behandling av EE i 8 veckor. VPZ var effektiv och visade bättre resultat än LPZ när det gäller EE-läkning. Detta gäller speciellt patienter med svårare EE. Båda läkemedlen tolererades väl.

The liver is one of the largest organs within the human body and it handles many vital tasks such as nutrient processing, toxin removal, and synthesis of important proteins. The number of people suffering from chronic liver disease is on the rise, likely due to the present ‘western’ lifestyle. As disease develops in the liver there are pathophysiological manifestations within the liver parenchyma that are both common and important to monitor. These manifestations include inflammation, fatty infiltration (steatosis), excessive scar tissue formation (fibrosis and cirrhosis), and iron loading. Importantly, as the disease progresses there is concurrent loss of liver function. Furthermore, postoperative liver function insufficiency is an important concern when planning surgical treatment of the liver, because it is associated with both morbidity and mortality. Liver function can also be hampered due to drug-induced injuries, an important aspect to consider in drug-development. Currently, an invasive liver needle biopsy is required to determine the aetiology and to stage or grade the pathophysiological manifestations. There are important limitations with the biopsy, which include, risk of serious complications, mortality, morbidity, inter- and intra-observer variability, sampling error, and sampling variability. Cleary, it would be beneficial to be able investigate the pathophysiological manifestations accurately, non-invasively, and on regional level. Current available laboratory liver function blood panels are typically insufficient and often only indicate damage at a late stage. Thus, it would be beneficial to have access to biomarkers that are both sensitive and responds to early changes in liver function in both clinical settings and for the pharmaceutical industry and regulatory agencies. The main aim of this thesis was to develop and evaluate methods that can be used for a ‘non-invasive liver biopsy’ using magnetic resonance (MR). We also aimed to develop sensitive methods for measure liver function based on gadoxetate-enhanced MR imaging (MRI). The presented work is primarily based on a prospective study on c. 100 patients suffering from chronic liver disease of varying aetiologies recruited due to elevated liver enzyme levels, without clear signs of decompensated cirrhosis. Our results show that the commonly used liver fat cut-off for diagnosing steatosis should be lowered from 5% to 3% when using MR proton-density fat fraction (PDFF). We also show that MR elastography (MRE) is superior in staging fibrosis. Finally we presented a framework for quantifying liver function based on gadoxetate-enhanced MRI. The method is based on clinical images and a clinical approved contrast agent (gadoxetate). The framework consists of; state-of the-art image reconstruction and correction methods, a mathematical model, and a precise model parametrization method. The model was developed and validated on healthy subjects. Thereafter the model was found applicable on the chronic liver disease cohort as well as validated using gadoxetate levels in biopsy samples and blood samples. The liver function parameters correlated with clinical markers for liver function and liver fibrosis (used as a surrogate marker for liver function). In summary, it should be possible to perform a non-invasive liver biopsy using: MRI-PDFF for liver fat and iron loading, MRE for liver fibrosis and possibly also inflammation, and measure liver function using the presented framework for analysing gadoxetate-enhanced MRI. With the exception of an MREtransducer no additional hardware is required on the MR scanner. The liver function method is likely to be useful both in a clinical setting and in pharmaceutical trials.

Aim To determine that carbon dioxide (CO2), instead of air, insufflated during colonoscopy reduces pain experienced by patients post colonoscopy. Method A randomised, double blinded, controlled trial with 205 consecutive consented patients referred for elective colonoscopy was undertaken at MidCentral Health Gastroenterology Department between July 2008 and January 2009. Patients were randomised to colonic insufflation with either air or CO2. A comparison of reported pain was undertaken using a 0 -10 point numeric rating scale at several time periods; intra procedure, 10, 30, and 60 minutes post procedure. Results The results were analysed using the SPSS programme. CO2 insufflation was used in 108 patients and air in 97 patients. Pain scores 10 minutes after were 0.43 ± 1.20 for CO2 and 1.61 ± 2.40 for air (P < .0001). 30 minutes after the procedure 90% of patients in the CO2 group reported no pain, compared to 61% of the air group. CO2 significantly reduced the amount of discomfort post colonoscopy at 10, 30 and 60 minutes. Conclusion Those receiving CO2 during colonoscopy experienced less post colonoscopy pain than those who received air insufflation. Carbon dioxide should be considered as the insufflating gas during colonoscopy.

<p>Vitamin E is a natural lipophilic antioxidant contains eight structurally related forms, i.e., α-, β-, γ-, δ-tocopherols (αT, βT, γT, and δT) and corresponding tocotrienols. Recent research indicates that vitamin E forms are differentially metabolized to various carboxychromanols. Some these vitamin E metabolites have been shown to exhibit strong anti-inflammatory and anticancer effects, yet little is known about their bioavailability. Without this knowledge, it is impossible to assess the role of vitamin E metabolism in biological functions of vitamin E forms and their protective effects on chronic diseases. While αT and γT appear to improved gut health, the underlying mechanisms are not well understood. Furthermore, specific forms of vitamin E such as γT have been reported to have cancer-preventing effects, but their anticancer efficacy is relatively modest. For these reasons, this dissertation focused on the characterization of the pharmacokinetic formation of vitamin E metabolites after supplementation, and the investigation of the underlying mechanisms of the protective effect of vitamin E forms, αT and γT, on gut health, as well as anticancer efficacy of the combination of aspirin and γT on carcinogen-induced colon tumorigenesis.</p><p><br></p><p>The first project focuses on characterizing the pharmacokinetic formation of vitamin E metabolites after single dose supplementation of γ-tocopherol-rich mixed tocopherol (γTmT) and δ-tocotrienol (δTE). With our recently developed LC/MS/MS assay for quantifying vitamin E metabolites, we can simultaneously quantify the level of short-chain, long-chain, and sulfated carboxychromanols in plasma, urine, and fecal samples of supplemented animals. In this study, we investigated the pharmacokinetics including excretion of vitamin E forms and the formation of their metabolites after a single dose intragastric administration of tocopherols and tocotrienols in rats. We also measured vitamin E metabolites in the serum obtained from healthy humans after gT supplementation. In the plasma of rat, the pharmacokinetic profiles of γT and δTE are described as the following: γT, Cmax = 25.6 ± 9.1 μM, Tmax = 4 h; δTE, Cmax = 16.0 ± 2.3 μM, Tmax = 2 h. Sulfated CEHCs and sulfated 11’-COOHs were the predominant metabolites in the plasma of rat with Cmax of 0.4-0.5 μM (Tmax ~ 5-7 h) or ~0.3 μM (Tmax at 4.7 h), respectively. In 24-h urine, 2.7% of γT and 0.7% of dTE were excreted as conjugated CEHCs, the major identified urinary metabolites. In the feces, 17-45% of supplemented vitamers were excreted as un-metabolized forms and 4.9-9.2% as metabolites. The majority of metabolites excreted in feces were unconjugated carboxychromanols, among which 13’-COOHs constituted ~50% of total metabolites. Interestingly, 13’-COOHs derived from δTE were 2-fold higher than 13’-COOH from γT. Unlike rats, γ-CEHC is the predominant metabolites found in human plasma, although 11’-COOHs and 13’-COOHs (sulfated and unconjugated) were elevated by >20 folds responding to γT supplement. In this study, we found that tocopherols and tocotrienols, when taken as supplements, are mainly excreted as un-metabolized forms and long-chain carboxychromanols in feces. High fecal availability of 13’-COOHs may contribute to modulating effects on gut health.</p><p><br></p><p>The second project of my dissertation investigated the effect of vitamin E forms, αT and γT, on intestinal barrier function in a cellular model and a mouse colitis model. Inflammatory bowel diseases (IBD) are chronic idiopathic inflammatory conditions characterized by disruption of intestinal barrier integrity. Previous studies by others and us had demonstrated that vitamin E forms, αT and γT, can protect against chemical-induced colitis in animal models. However, the role of these vitamin E forms on intestinal barrier function has not been studied. Herein, we investigated the potential protective effects of vitamin E forms, αT and γT, on intestinal barrier function in a Caco-2 colon epithelial cell model and a dextran sodium sulfate (DSS)-induced colitis mouse model. In Caco-2 cells, pretreatment with 25mM αT and γT attenuated Caco-2 monolayer barrier dysfunction induced by 10 ng/mL TNF-α/IFN-γ, suggesting that these vitamin E forms protect intestinal barrier integrity in this cellular model. In male BALB/c mice, the supplementation of αT (0.05%) or γTmT (0.05%) when given 3 weeks before DSS treatment or at the same time as DSS treatment alleviated DSS-induced fecal bleeding and diarrhea symptoms in mice, and attenuated colon inflammation and colitis-associated damages. Additionally, αT and γTmT supplementation attenuated DSS-induced intestinal barrier dysfunction, as indicated by improving the level of occludin, a tight junction protein, in the colon and reducing lipopolysaccharide-binding protein (LBP) in the plasma. Furthermore, gut microbiota analysis demonstrated that αT and γTmT supplementation could modulate intestinal microbiome composition in mice with DSS treatment. DSS treatment reduced the relative abundance of Lachnospiraceae compared to healthy mice, and supplementation of αT and γT partially reversed this effect. Interestingly, the family Lachnospiraceae has been reported to decrease in IBD patients. Our study demonstrated the protective effects of vitamin E forms on intestinal barrier integrity in a cell-based model and a colitis model in mice. Furthermore, we demonstrated that these vitamin E forms caused favorable changes in the intestinal microbial population under colitis condition.</p><p><br></p><p>The third project of my dissertation evaluated the anticancer efficacy of the combination of aspirin and γT using an azoxymethane (AOM)-induced and colitis-promoted colon tumorigenesis mouse model. Extensive inflammation in the colon promotes the development of colorectal cancer (CRC). Eicosanoid production by pro-inflammatory enzymes, cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) play a critical role in the initiation, progression, and invasion of CRC. Thus, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, have been recommended for chemoprevention of CRC. However, long-term use of aspirin can cause many side effects, and the anticancer activity of aspirin is very modest. Previously, we have demonstrated that the combination of γT with aspirin prolonged the anti-inflammatory activity of aspirin and alleviated aspirin-associated adverse effects in a carrageenan-induced inflammation model in rats. Additionally, we found that the combination of γT and aspirin has stronger anticancer activity than aspirin or γT alone against HCT-116 human colorectal carcinoma cells. Therefore, we examined the anticancer effect of the combination of 0.025% aspirin and 0.05% γT against AOM-induced and DSS-promoted tumorigenesis in mice. In this study, we have found that the combination of aspirin and γT, but not aspirin or γT alone, suppressed colon tumorigenesis in mice, as indicated by 40% and 50% reduction in the multiplicity of total polyps (P < 0.05) and large adenomatous polyps (>2mm2, P < 0.05), respectively. More strikingly, the combination of aspirin and γT reduced the overall tumor area by 60% (P < 0.05). Noteworthy, the supplementation of γT also alleviated aspirin-induced stomach lesion and appeared to modulate intestinal microbial composition. Our study demonstrated that the combination of aspirin and γT has stronger anticancer activity than aspirin or γT alone while alleviates aspirin-associated adverse effect, suggesting that the combination of γT and aspirin is a more effective and safer chemopreventive agent for CRC than aspirin alone.</p>

Primary sclerosing cholangitis (PSC) is a rare inflammatory chronic liver disease that causes damage to the intra- and or extrahepatic bile ducts leading to cholestasis. As the disease proceeds the development of cirrhosis and eventually liver failure occurs. This study aims to determine the role of IgG subclasses in the prognosis of PSC and its outcome. A retrospective analysis was performed of 183 patients followed at the Department of Upper Abdominal Diseases at the Karolinska University Hospital. Factors that were analysed were sex, age at PSC diagnosis, total IgG values, IgG subclasses values and events of autoimmune hepatitis (AIH), inflammatory bowel disease (IBD), colectomy, cirrhosis, cholangitis, endoscopic retrograde cholangiopancreatography (ERCP), liver transplantation and cholangiocarcinoma. This study showed that high IgG4 levels were associated with a higher incidence of cirrhosis, liver transplantation, cholangitis and ERCP, while low IgG4 levels were associated with a prior IBD diagnosis. In conclusion, elevated IgG4 levels were associated with a higher occurrence of cirrhosis, cholangitis, ERCP and liver transplantation. It seems that IgG4 could be of importance for outcome prediction in PSC.

<p>Predictive modeling in healthcare involves the development of data-driven and computational models which can predict what will happen, be it for a single individual or for an entire system. The adoption of predictive models can guide various stakeholders’ decision-making in the healthcare sector, and consequently improve individual outcomes and the cost-effectiveness of care. With the rapid development in healthcare of big data and the Internet of Things technologies, research in healthcare decision-making has grown in both importance and complexity. One of the complexities facing those who would build predictive models is heterogeneity of patient populations, clinical practices, and intervention outcomes, as well as from diverse health systems. There are many sub-domains in healthcare for which predictive modeling is useful such as disease risk modeling, clinical intelligence, pharmacovigilance, precision medicine, hospitalization process optimization, digital health, and preventive care. In my dissertation, I focus on predictive modeling for applications that fit into three broad and important domains of healthcare, namely clinical practice, public health, and healthcare system. In this dissertation, I present three papers that present a collection of predictive modeling studies to address the challenge of modeling heterogeneity in health care. The first paper presents a decision-tree model to address clinicians’ need to decide among various liver cirrhosis diagnosis strategies. The second paper presents a micro-simulation model to assess the impact on cardiovascular disease (CVD) to help decision makers at government agencies develop cost-effective food policies to prevent cardiovascular diseases, a public-health domain application. The third paper compares a set of data-driven prediction models, the best performing of which is paired together with interpretable machine learning to facilitate the coordination of optimization for hospital-discharged patients choosing skilled nursing facilities. This collection of studies addresses important modeling challenges in specific healthcare domains, and also broadly contribute to research in medical decision-making, public health policy and healthcare systems.</p>