SIBO (Small Intestinal Bacterial Overgrowth) är ett tillstånd där tunntarmen koloniseras av bakterier som normalt finns i tjocktarmen. SIBO utvecklas när de normala homeostatiska mekanismerna som kontrollerar enteriska bakteriepopulationen störs. I tunntarmen ska det finnas väldigt liten mängd bakterier medan i tjocktarmen bör det finnas mycket större mängder bakterier. När bakterierna tar sig in i tunntarmen, resulterar det i SIBO. Denna bakteriella obalans i tunntarmen kan orsaka bland annat uppblåsthet, diarré och magsmärta, förstoppning och försämrat upptag av vitaminer och näringsämnen. Att behandla den underliggande orsaken bakom SIBO är det första steget i behandlingen och om detta inte räcker till, är antibiotikabehandlingen nästa steg. Syftet med denna litteraturstudie var att undersöka hur effektiv Rifaximin är vid behandling av bakteriell överväxt i tunntarmen (SIBO). Arbetet är en litteraturstudie och de vetenskapliga artiklarna är hämtade från databasen Pubmed. I detta arbete har fem studier analyserats. Studie I visade att högdosbehandling med rifaximin gav signifikant ökad behandlingseffekt jämfört med lågdosbehandling hos IBS-patienter. Studie II visade att kombination av amoxicillin och rifaximin kan vara en effektiv förstahandsbehandling för patienter som har både SIBO och H. pylori infektion. Studie III bekräftade att SIBO är underdiagnoserat hos Cystisk fibros patienter och är relaterad till en dålig näringsstatus. Rifaximin är en effektiv behandling av SIBO hos patienter som har Cystisk fibros. Studie IV visade att kombinationen av rifaximin tillsammans med hydrolyserat guargummi verkar vara mer effektivt vid utrotning av SIBO jämfört med enbart rifaximin hos SIBO patienter. Studie V studerade  rifaximinbehandlade IBS-patienter och fann att rifaximinbehandling var associerad med acceleration av kolontransitering samt hade svag påverkan på förändringar i mikrobiell artrikedom i feces. Baserat på de fem studierna föreligger det skäliga bevis att behandling med rifaxamin är en effektiv behandling vid SIBO. Mer forskning och studier behövs för att kunna bestämma den bästa dosen samt utvärdera rifaximin i kombination med andra läkemedel. / SIBO (Small Intestinal Bacterial Overgrowth) is a condition where the small intestine is colonized by bacteria normally found in the large intestine. SIBO develops when the normal homeostatic mechanisms controlling the enteric bacterial population are disrupted. In the small intestine, there should be very small number of bacteria while in the large intestine there should be much larger number of bacteria. When the bacteria colonizes the small intestine, it results in SIBO. This bacterial imbalance in the small intestine can cause bloating, diarrhea and stomach pain, constipation and impaired absorption of vitamins and nutrients. Treating the underlying cause of SIBO is the first step in the treatment and if this is not enough, antibiotic treatment is the next step. The purpose of this literature study was to investigate the effectiveness of Rifaximin in treatment of bacterial overgrowth in the small intestine (SIBO). The study is a literature study where the scientific articles were obtained from the database Pubmed. In this literature study, five studies have been analyzed. Study I showed that high-dose treatment with rifaximin significantly increased treatment efficacy compared to low-dose treatment. Study II showed that a combination of amoxicillin and rifaximin can be an effective first-line treatment for patients who have both SIBO and H. pylori infection. Study III confirmed that SIBO is underdiagnosed in CF patients, related to poor nutritional status. Rifaximin is an effective treatment for SIBO in patients who have CF. Study IV also showed a combination treatment where rifaximin together with hydrolyzed guar gum appears to be more effective in eradicating SIBO compared to rifaximin alone. Study V studied rifaximin-treated IBS patients, rifaximin treatment was associated with acceleration of colon transit, and a weak influence on changes in microbial species richness in faeces. Based on the five studies, there is reasonable evidence that a treatment with rifaximin is an effective treatment for SIBO. However, more research and studies are needed to determine the best dose and also rifaximin in combination with other drugs.

Bakgrund: För att barn inte ska behöva känna oro vid tumörterapi blir de nedsövda med anestetikum. Vid behandling av tumörer används joniserande strålning. Dock har tidigare studier funnit att exponering av joniserande strålning hos barn kan vara en bidragande faktor till kognitiva dysfunktioner. Man har också sett en synergistisk effekt mellan anestetikum och joniserande strålning. Syfte: Syftet med denna studie är att undersöka samverkanseffekten mellan olika anestetika och joniserande strålning. Metod: NMRI möss exponerades på postnatal dag 10. Totalt var det 6 exponeringsgrupper. Mössen exponerades antingen med ketamin (7,5 mg/kg) eller propofol (20 mg/kg). Individerna som exponerades för strålning (200 mGy) fick detta 1 timme efter administration av singeldos anestetikum. Provtagningen skedde 24 timmar efter exponering. Metoden qPCR användes för att undersöka uppregleringen och nedregleringen av gener. Resultat: En korrelation kunde observeras för generna Keap1 & Nrf2, BDNF & Grin2b och Jagged-1 & Hes5 genom att studera Spearmans korrelationskonstant. Inga signifikanta resultat erhölls för generna som studerades (p <0,05). Medelvärdena visade ingen signifikant förändring i relativ FC. Slutsats: Kombinationsbehandling med anestetikum + joniserande strålning visade inga större skillnader mellan exponeringsgrupperna i motsats till tidigare genomförda studier. Detta kan bero på tiden mellan exponering och provtagning. Det finns en korrelation mellan gener som har en teoretisk sammankoppling.

Dagens läkemedelsbehandlingar med indikation AD har dålig effekt på sjukdomsprogressionenoch behovet av nya läkemedelskandidater är stort. Aducanumab och lecanemab är tvåantikroppsläkemedel som har fått ett snabbgodkännande i USA för användning vid AD.Snabbgodkända läkemedel garanterar dock inte patientens säkerhet eller den kliniska nyttan.Syftet med denna litteraturöversikt är således att utvärdera om det finns en statistisktsignifikant effekt på minskad kognitiv försämring under behandling med lecanemab elleraducanumab jämfört med placebo och om frekvensen av antikroppsspecifika biverkningar(ARIA) är högre för dessa läkemedel jämfört med placebo. Metoden utformades med hjälp avstatens beredning för medicinsk och social utvärdering (SBU) metodhandbok och baseras påPICO formatet. Endast en av fyra kliniska studier visar att lecanemab ger signifikant minskadkognitiv försämring i samtliga skattningsskalor (p<0.01). Biverkningsfrekvensen ARIA var högreför lecanemab jämfört med placebo i två studier och var lika stor som placebo i en studie. Enfas 3 studie visade motsägelsefulla resultat för aducanumab, där signifikant minskad kognitivförsämring sågs i delstudien EMERGE men inte i ENGAGE. Biverkningsfrekvensen var högre föraducanumab än placebo i samtliga studier. Majoriteten av de kliniska studierna som granskatsi denna litteraturöversikt saknar således statistisk signifikans. Vilken påverkan detta har påpatienter och anhöriga är svår att uppskatta och därför är resultat från kommande studierviktiga för att styrka eller motbevisa den kliniska nyttan och säkerheten.

Bakgrund: Det har visat sig under de senaste 20 åren att användning av aripiprazol ökar risken för spel- och impulskontrollstörningar. Aripiprazol är ett första generationens antipsykotiska läkemedel och fungerar som en partiell serotonin 5-HT1A-receptoragonist, en 5-HT2A-receptorantagonist och en specifik partiell dopamin D2/D3-agonist.  Syfte: Syftet är att studera hur förekomsten av spel- och impulskontrollstörningar skiljer sig mellan neurologiska patienter som får Aripiprazol respektive andra antipsykotiska läkemedel som komplement till behandling med Parkinsons sjukdom eller Restless Legs Syndrome.  Metoder: Detta är en retrospektiv registerstudie som analyserar läkemedelsdata som täcker åren 2005 till 2022 och patientdata som innehåller diagnoser för Parkinsons sjukdom och Restless Legs Syndrome samt spel- och impulskontrollstörningar. Data analyserades genom att mäta frekvensen av recept för att analysera antalet händelser av spelstörningar, impulskontrollstörningar och kontrollgrupper hos personer med Parkinsons sjukdom och Restless Legs Syndrome.  Resultat: Det finns en tydlig skillnad mellan de antipsykotiska läkemedlen. Första och andra generationens antipsykotika, inklusive litium, olanzapin, levomepromazin och aripiprazol, har visats vara associerade med störningar i spel och impulskontroll hos patienter med Parkinsons sjukdom och Restless Legs Syndrome. Aripiprazol visade sig ha det starkaste sambandet med störningar i impulskontroll och litium hade det starkaste sambandet med spelstörningar hos personer med Restless Legs Syndrome. Dessutom hade Levomepromazin det starkaste sambandet med störningar i impulskontroll och Olanzapin hade det starkaste sambandet med spelstörningar hos personer med Parkinsons sjukdom.  Slutsatser: Denna studie har konsekvenser för framtiden då den hjälper till att veta om det finns risk för spel- och impulskontrollstörningar vid användning av antipsykotiska läkemedel. Så det hjälper till att skapa maximal säkerhet för antipsykotiska läkemedel och hantera risken för spel- och impulskontrollstörningar på bästa möjliga sätt.

Despite recent advances, prognosis in metastatic prostate cancer remains poor. As with other cancers, tumor heterogeneity is an increasingly evident contributor in prostate tumorigenesis and developed resistance. Using in vitro and in vivo model systems, we examined novel diagnostic and therapeutic strategies in prostate cancer. In these studies, combination treatment with amuvatinib, a receptor tyrosine kinase inhibitor, and erlotinib, an epidermal growth factor inhibitor, was assessed for its ability to differentially modulate growth signaling in pathway diverse LNCaP (PTEN⁻) and DU-145 (PTEN⁺) human prostate cancer cell and mouse xenograft models. Our results suggest both individual mechanistic signaling activities, as well as benefits of the combination therapy though modulations of MAPK (pERK) and 4EBP1/cyclin D1 in growth signaling divergent PTEN+ and PTEN- prostate cancer cells. Additionally, despite the importance preanalytical tissue preservation on downstream diagnostic assays, exact protocols are not well defined and highly variable clinically and, as such, critical diagnostic information is lost. We show that a novel 2+2 fixation method induces target- and cell-specific alterations in immunostain intensity and efficacy. Importantly, cyclin D1 is increasingly utilized for as a clinical prognostic/diagnostic marker and demonstrated improved immunohistochemical staining efficacy with 2+2 fixation compared with treatment-matched xenograft protein alterations as assessed by western analysis. Finally, pentoxifylline (PTX) is a clinically utilized and well tolerated PDE inhibitor that has shown promise as a radio-/chemo-sensitization and anti-cancer agent against a variety of cancers. In these studies, we demonstrate that PTX induces cell and tumor growth inhibition in LNCaP prostate cancer cells. Mechanistically, PTX induces transient cellular signaling modulations of both the AMPK metabolic and AKT/mTOR growth pathways, while inducing autophagy. Also, PTX sensitizes LNCaP prostate cancer to cytotoxicity induced by first line chemotherapy docetaxel, inducing significant cellular apoptosis and reducing effective docetaxel concentrations by >10 fold for equivalent toxicity in viability assays. These findings nominate PTX as an adjunct therapy for the treatment of prostate cancer. In summary, these studies characterize the targeted signaling modulation by combination erlotinib and amuvatinib therapy, as well as pentoxifylline, for their use as therapies for prostate cancer. A novel fixation protocol was also assessed for improved diagnostic tissue preservation of critical signaling proteins. Further understanding in these areas will aid and expand the development of effective diagnostics, as well as emphasize the benefits of these and similar therapeutics for the treatment of prostate cancer.

Synucleinopathies are a family of neurodegenerative diseases, with the distinctive pathological feature of Lewy bodies, which include Parkinson’s disease. Lewy bodies are intracellular inclusions filled with α-synuclein, a small neuronal protein with prion-like properties. The main function of α-synuclein is not fully understood, however, it plays a major role in disease progression. Dopamine interactions with α-synuclein have also been implicated in the progression of Parkinson’s disease. Dopamine crosslinks α-synuclein and causes generation of toxic oligomeric species of the protein. Little is known about dopamine-α-synuclein adducts, and one section of the current dissertation focuses on dopamine, levodopa, and α-synuclein interactions. Studies detailed herein demonstrated that lysine residues on α-synuclein have an essential role in the dopamine-induced oligomer formation. Evidence is also presented showing that removal of one of the reactive sites on dopamine by N-acetylcysteine and/or glutathione inhibits dopamine-induced oligomer formation, although the dopamine thiol-conjugates still bind to α-synuclein. In contrast, thiol-conjugates of the dopamine precursor levodopa, significantly increase α-synuclein oligomer formation. The data demonstrate the importance of the scavenging of dopamine and levodopa quinones by N-acetylcysteine and glutathione, and the subsequent changes in the interaction with α-synuclein and its oligomeric states. Environmental factors are key players in the development of synucleinopathies. Although arsenic pesticide exposure has been linked to elevated risk of Parkinson’s disease, there is a paucity of information on arsenic-induced pathological changes, which may be attributed to the onset of neurodegenerative processes. SH-SY5Y cells exposed to environmentally relevant levels of arsenic for 72 hours, develop α-synuclein oligomers and exhibitaugmented expression of stress markers. Thus, there is an increase in autophagy markers and other stress markers, including the accumulation and co-localization of LC3, major autophagy marker, and α-synuclein. Animals transiently exposed to arsenic through drinking water for 2 or 5 weeks, exhibited pathological features resembling synucleinopathies. Although animals were exposed at two-months of age and remained exposure free up to geriatric age (18 months), they still exhibited accumulation of α-synuclein and elevations in autophagy markers. The results demonstrated how even a short period of exposure to a toxicant can have detrimental neurological effects, which may contribute to the development of neurodegenerative disease years after exposure.

Sources of arsenic exposure include air, water, and food from both natural and anthropogenic sources. Arsenic is categorized as a human carcinogen, and is associated with pleiotropic toxicities including cancers of the skin, lung, and bladder. Despite arsenic's long recognition as a human carcinogen, the exact mechanisms of arsenical-induced carcinogenesis are unknown. Arsenic exposure has been shown to cause DNA damage. However, because arsenic does not directly react with DNA, genotoxicity is generally considered to result from indirect mechanisms. The generation of arsenical-induced reactive oxygen species and the inhibition of critical DNA repair systems are believed to contribute to arsenical-induced carcinogenicity. The DNA damaging effects of arsenical exposure and alterations in DNA repair processes were examined within the human bladder urothelial cell line, UROtsa, following continuous exposure to the arsenic metabolite, monomethylarsonous acid [MMA(III)]. Chronic, low-level MMA(III) exposure results in the induction of DNA damage that remains elevated following the removal of MMA(III). Furthermore, data presented herein, defines the critical period in which continuous low-level MMA(III) exposure causes the malignant transformation of the UROtsa cell line. Results indicate that malignant transformation of UROtsa cells is irreversible following 12 wk of low-level MMA(III) exposure. Assessment of the MMA(III)-induced biological alterations leading to the malignant transformation of UROtsa cells following 12 wk of exposure suggest two potential interdependent mechanisms in which MMA(III) may increase the susceptibility of UROtsa cells to genotoxic insult and/or malignant transformation. These mechanisms include MMA(III)-induced DNA damage via the production of reactive oxygen species and the MMA(III)-induced inhibition of poly(ADP-ribose) polymerase-1 as a result of the direct MMA(III)-mediated displacement of zinc.

This dissertation centers on the study of epithelial to mesenchymal cell transition (EMT) in the heart model of valve development. EMT is a process used by specific cells to invade adjacent matrix in order to differentiate into a three-dimensional structure. The first section of the project includes a study on the effects of inorganic arsenic on EMT and therefore the environmental concerns produced by deleterious effects on EMT. The second section focuses on the discovery of an intrinsic regulator of EMT, olfactomedin-1 (OLFM1). The discovery of a novel regulator of EMT in the atrioventricular canal is interesting, by itself, as it allows us to better understand the intrinsic molecular regulation of EMT in valve formation of the heart. The activity of this protein, as a regulator of cell invasion, identifies an important checkpoint in EMT. Because OFLM1 is conserved across many species, including humans, it may be a common or shared regulator of all types of EMT including cancer. Therefore, OLFM1 represents a promising new target for an anti-cancer agent as well as a potential clinical inducer of EMT to repair congenital heart disease that include valve defects.

Intimal hyperplasia (IH) is characteristic of a cell population increase within the innermost layer of the arterial wall. It is hypothesized that extracellular matrix vascular remodeling secondary vascular injury is dependent upon the Th17 subset of the CD4+ lymphocytes. Male C57BL/6J and FVB/NJ murine strains underwent complete left common carotid artery ligation for periods of 14 and 28 days. A therapeutic simvastatin model was carried out in the FVB/NJ strain and involved a daily subcutaneous injection regimen of 40 mg/kg/mouse beginning 72 hours prior to and daily following a 14 day carotid ligation period. Histological and RT-PCR analysis was carried out with harvested carotid artery samples. The FVB/NJ 14 day and 28 day histological stains of the left common carotid artery following ligation injury developed evident structured and disassembled intimal hyperplasia, respectively. A gene array demonstrated dramatic expression of immune and cytokine transcription markers particularly in the FVB/NJ strain at both ligation time points. IL-17 and IL-6 transcriptional gene expression was upregulated greater than 20-fold in the FVB/NJ 28 day injury model. IL-17 transcription was significantly expressed by a change of 50.06 ± 0.19 (p = 0.004) in this strain at 28 days versus the control. Lastly, the simvastatin treatment model was found to exacerbate the immune response to ligation injury. These results revealed that the immune system elicits a role in the vascular remodeling that potentiates intimal hyperplasia.

Metabolic syndrome affects approximately 25% of the US population and increases risk for the development of cardiovascular disease, as well as, and Type 2 diabetes. Inorganic arsenite exposure has been associated with cardiovascular disease, insulin resistance and Type 2 diabetes. The mechanisms by which arsenic increases these health risks has not been fully elucidated. In this report we show two pathways by which arsenite may contribute to metabolic syndrome. First through induction of C-Reactive Protein (CRP) and secondly through inhibition of insulin stimulated glucose uptake. CRP is a clinical marker for metabolic syndrome and a predictive clinical marker for cardiovascular disease and type 2 diabetes. Treatment of HepG2 cells with arsenite resulted in elevated CRP production and secretion. In addition, treatment of FvB mice with 100 ppb sodium arsenite via drinking water for six months starting at weaning age resulted in dramatically higher levels of CRP in both the liver and inner medullary region of the kidney. Further, mouse Inner Medullary Collecting Duct cells (mIMCD-3), a mouse kidney cell line, were stimulated with CRP, which resulted in activation of NFkappaB. Pretreatment with Y27632, a Rho kinase inhibitor, prior to CRP stimulation attenuated NFkappaB activation. Additionally, L6 myocytes, an insulin responsive cell line, exposed to arsenite for 4 or 7 days showed decreased insulin-stimulated glucose uptake but no decrease in AKT activation. In addition, we found that ERK activity decreased, while p38 MAPK activity increased, in response to prolonged arsenite treatment. These data support the epidemiological evidence that chronic exposure to low physiologically relevant levels of arsenite can contribute to insulin resistance and type 2 diabetes. These data provide a novel pathway by which arsenic can contribute to metabolic syndrome, cardiovascular disease, insulin resistance and type 2 diabetes.