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1.
  • Abdalla, Maie (författare)
  • Cancer and reconstructive surgery in Inflammatory bowel disease
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Ulcerative colitis (UC) is a chronic inflammatory disease that affects the colon. According to the literature, some thirty percent of UC patients may require a subtotal colectomy and ileostomy due to failure of medical treatment, acute toxic colitis or dysplasia/cancer diagnosis. Some patients choose to get continence restored with either an ileorectal anastomosis (IRA) or an ileal pouch-anal anastomosis (IPAA). Worldwide most surgeons prefer an IPAA to an IRA, despite reports of pouchitis, impaired fertility and fecundity. Fear of recurring proctitis and fear of rectal cancer in the remaining rectum is contributing to the choice of an IPAA. Little is known regarding the outcomes of IRA compared with IPAA in UC patients. We aimed to investigate the anorectal function, quality of life (QoL), risk of failure and rectal cancer in patients with UC restored with IRA and IPAA respectively. <strong></strong></p><p><strong>Methods</strong>: Data about all Inflammatory bowel disease (IBD) patients was obtained from the Swedish National Patient Register (NPR) between 1964-2014 and in one study from the Linköping University Hospital medical records 2006-2012. Patients who developed cancer were identified from the Swedish National Cancer Register. We investigated the risk of cancer and inflammation, functional outcome and failure as well as the quality of life for IRA and IPAA patients. Investigation of risk for cancer in IRA and IPAA compared with the background population was performed using survival analytic techniques: uni-and multivariate regression, Kaplan Meier curves and standardized incidence ratio. <strong></strong></p><p><strong>Results: </strong>Twelve percent (7,889 /63,795) of UC patients required colectomy according to the NPR. The relative risk for rectal cancer among patients with an IRA was increased (SIR 8.7). However, the absolute risk was 1.8% after a mean follow up of 8.6 years and the cumulative risk 10- and 20-years after IRA was 1.6% and 5.6%, respectively. Risk factors for rectal cancer were primary sclerosing cholangitis in patients with an IRA (hazard ratio 6.12), and severe dysplasia or cancer of the colon prior to subtotal colectomy in patients with a diverted rectum in place (hazard ratio 3.67). Regarding IPAA, the relative risk to develop rectal cancer was (SIR 0.4) compared with the background population and the absolute risk was only 0.06% after a mean of 12.2 years of follow up. Among patients operated at the Linköping University Hospital: IRA patients reported better overall continence according to the Öresland score with in median3 (IQR 2–5) for IRA (n=38) and 10 (IQR 5–15) for IPAA (n=39, p&lt;0.001). There were no major differences regarding the QoL. According to the NPR, after a median follow up of 12.4 years failure occurred in 265(32%) out of 1112 patients, of which 76 were secondarily reconstructed with an IPAA. Failure of the IPAA occurred in 103 (6%) patients with primary and in 6 (8%) patients after secondary IPAA (log-rank <em>p</em>=0.38). <strong></strong></p><p><strong>Conclusion: </strong>IRA is a safe restorative procedure for selected UC patients. Patients should be aware of the annual postoperative endoscopic evaluation with biopsies as well as the need to the use of local anti-inflammatory preparations. However, IRA should not be offered for UC patients with an associated primary sclerosing cholangitis diagnosis due to the increased risk to develop rectal cancer in their rectal mucosa. In such case, IPAA is probably the treatment of choice.  </p>
2.
  • Agnafors, Sara, 1981- (författare)
  • A Biopsychosocial and Long Term Perspective on Child Behavioral Problems Impact of Risk and Resilience
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Mental health has become a prominent issue in society. Yet, much remains unknown about the etiology of psychiatric disorders. The aim of the present thesis was to investigate the association between biological, psychological and social factors of risk and resilience and behavioral problems in a birth cohort of Swedish children. 1723 mothers and their children were followed from birth to the age of 12 as part of the South East Sweden Birth Cohort Study (the SESBiC study). Information was gathered through register data, standardized questionnaires and DNA samples.</p><p>In study I, stability of maternal symptoms of depression and the impact on child behavior at age 12 were investigated. The prevalence of depressive symptoms was found to be 12.0 % postpartum. Symptoms of postpartum depression significantly increased the risk for subsequent depressive symptoms 12 years later in women. Children whose mothers reported concurrent symptoms of depression and anxiety had an increased risk for both internalizing and externalizing problems at age 12, but no long term effect on child behavior was seen for postpartum depressive symptoms. The greatest risk was seen for children whose mothers reported symptoms of depression on both occasions. In study II, the impact of gene-environment interaction of 5-HTTLPR and BDNF Val66Met and experience of life events together with symptoms of maternal depression and anxiety on child behavior at age 12 was studied. A main effect of 5-HTTLPR was noticed, but no geneenvironment effects were shown. Similarly to study I, concurrent symptoms of maternal depression and anxiety were an important predictor of child behavioral problems. A high degree of psychosocial stress around childbirth was found to have long lasting detrimental effects on child behavior, increasing the risk for internalizing problems at age 12. Study III investigated the impact of geneenvironment interactions of 5-HTTLPR and BDNF Val66Met and life events together with symptoms of maternal depression and birth characteristics on behavioral problems at age 3. Symptoms of postpartum depression were found to predict internalizing as well as externalizing problems in children three years later. Child experience of life events was a stable predictor of behavioral problems across the scales similar to sociodemographic factors such as parental immigration status and unemployment. No gene-environment interaction effects of 5-HTTLPR or BDNF Val66Met were shown. Study IV used the risk factors identified in studies I-III to investigate factors of resilience to behavioral problems at age 12. The l/l genotype of 5-HTTLPR was associated with a lower risk for behavioral problems at age 12, especially for children facing low adversity. Good social functioning was found to be a general resource factor, independent of the level of risk, while an easy temperament was associated with resilience for children with a high degree of adversity. However, effect sizes were small.</p><p>In summary, the results from the present thesis emphasize the importance of maternal mental health and sociodemographic factors for child mental health at ages 3 and 12, which must be taken into account in clinical settings. Moreover, it adds to the null-findings of the gene-environment effect of 5-HTTLPR and BDNF Val66Met on behavioral problems in children, but indicates a main effect of 5-HTTLPR on internalizing symptoms at age 12.</p>
3.
  • Ahlander, Britt-Marie, 1954- (författare)
  • Magnetic Resonance Imaging of the Heart Image quality, measurement accuracy and patient experience
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background:</strong> Non-invasive diagnostic imaging of atherosclerotic coronary artery disease (CAD) is frequently carried out with cardiovascular magnetic resonance imaging (CMR) or myocardial perfusion single photon emission computed tomography (MPS). CMR is the gold standard for the evaluation of scar after myocardial infarction and MPS the clinical gold standard for ischemia. Magnetic Resonance Imaging (MRI) is at times difficult for patients and may induce anxiety while patient experience of MPS is largely unknown.</p><p><strong>Aims:</strong> To evaluate image quality in CMR with respect to the sequences employed, the influence of atrial fibrillation, myocardial perfusion and the impact of patient information. Further, to study patient experience in relation to MRI with the goal of improving the care of these patients.</p><p><strong>Method:</strong> Four study designs have been used. In paper I, experimental cross-over, paper (II) experimental controlled clinical trial, paper (III) psychometric crosssectional study and paper (IV) prospective intervention study. A total of 475 patients ≥ 18 years with primarily cardiac problems (I-IV) except for those referred for MRI of the spine (III) were included in the four studies.</p><p><strong>Result:</strong> In patients (n=20) with atrial fibrillation, a single shot steady state free precession (SS-SSFP) sequence showed significantly better image quality than the standard segmented inversion recovery fast gradient echo (IR-FGRE) sequence (I). In first-pass perfusion imaging the gradient echo-echo planar imaging sequence (GREEPI) (n=30) had lower signal-to-noise and contrast–to-noise ratios than the steady state free precession sequence (SSFP) (n=30) but displayed a higher correlation with the MPS results, evaluated both qualitatively and quantitatively (II). The MRIAnxiety Questionnaire (MRI-AQ) was validated on patients, referred for MRI of either the spine (n=193) or the heart (n=54). The final instrument had 15 items divided in two factors regarding Anxiety and Relaxation. The instrument was found to have satisfactory psychometric properties (III). Patients who prior CMR viewed an information video scored significantly (lower) better in the factor Relaxation, than those who received standard information. Patients who underwent MPS scored lower on both factors, Anxiety and Relaxation. The extra video information had no effect on CMR image quality (IV).</p><p><strong>Conclusion:</strong> Single shot imaging in atrial fibrillation produced images with less artefact than a segmented sequence. In first-pass perfusion imaging, the sequence GRE-EPI was superior to SSFP. A questionnaire depicting anxiety during MRI showed that video information prior to imaging helped patients relax but did not result in an improvement in image quality.</p>
4.
  • Ahlander, Britt-Marie, 1954- (författare)
  • Magnetic Resonance Imaging of the Heart Image quality, measurement accuracy and patient experience
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background:</strong> Non-invasive diagnostic imaging of atherosclerotic coronary artery disease (CAD) is frequently carried out with cardiovascular magnetic resonance imaging (CMR) or myocardial perfusion single photon emission computed tomography (MPS). CMR is the gold standard for the evaluation of scar after myocardial infarction and MPS the clinical gold standard for ischemia. Magnetic Resonance Imaging (MRI) is at times difficult for patients and may induce anxiety while patient experience of MPS is largely unknown.</p><p><strong>Aims:</strong> To evaluate image quality in CMR with respect to the sequences employed, the influence of atrial fibrillation, myocardial perfusion and the impact of patient information. Further, to study patient experience in relation to MRI with the goal of improving the care of these patients.</p><p><strong>Method:</strong> Four study designs have been used. In paper I, experimental cross-over, paper (II) experimental controlled clinical trial, paper (III) psychometric crosssectional study and paper (IV) prospective intervention study. A total of 475 patients ≥ 18 years with primarily cardiac problems (I-IV) except for those referred for MRI of the spine (III) were included in the four studies.</p><p><strong>Result:</strong> In patients (n=20) with atrial fibrillation, a single shot steady state free precession (SS-SSFP) sequence showed significantly better image quality than the standard segmented inversion recovery fast gradient echo (IR-FGRE) sequence (I). In first-pass perfusion imaging the gradient echo-echo planar imaging sequence (GREEPI) (n=30) had lower signal-to-noise and contrast–to-noise ratios than the steady state free precession sequence (SSFP) (n=30) but displayed a higher correlation with the MPS results, evaluated both qualitatively and quantitatively (II). The MRIAnxiety Questionnaire (MRI-AQ) was validated on patients, referred for MRI of either the spine (n=193) or the heart (n=54). The final instrument had 15 items divided in two factors regarding Anxiety and Relaxation. The instrument was found to have satisfactory psychometric properties (III). Patients who prior CMR viewed an information video scored significantly (lower) better in the factor Relaxation, than those who received standard information. Patients who underwent MPS scored lower on both factors, Anxiety and Relaxation. The extra video information had no effect on CMR image quality (IV).</p><p><strong>Conclusion:</strong> Single shot imaging in atrial fibrillation produced images with less artefact than a segmented sequence. In first-pass perfusion imaging, the sequence GRE-EPI was superior to SSFP. A questionnaire depicting anxiety during MRI showed that video information prior to imaging helped patients relax but did not result in an improvement in image quality.</p>
5.
  • Ahle, Margareta, 1966- (författare)
  • Necrotising Enterocolitis epidemiology and imaging
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Necrotising enterocolitis (NEC) is a potentially devastating intestinal inflammation of multifactorial aetiology in premature or otherwise vulnerable neonates. Because of the broad spectrum of presentations, diagnosis and timing of surgical intervention may be challenging, and imaging needs to be an integrated part of management.</p><p>The first four studies included in this thesis used routinely collected, nationwide register data to describe the incidence of NEC in Sweden 1987‒2009, its variation with time, seasonality, space-time clustering, and associations with maternal, gestational, and perinatal factors, and the risk of intestinal failure in the aftermath of the disease.</p><p>Early infant survival increased dramatically during the study period. The incidence rate of NEC was 0.34 per 1,000 live births, rising from 0.26 per 1,000 live births in the first six years of the study period to 0.57 in the last five. The incidence rates in the lowest birth weights were 100‒160 times those of the entire birth cohort. Seasonal variation was found, as well as space-time clustering in association with delivery hospitals but not with maternal residential municipalities.</p><p>Comparing NEC cases with matched controls, some factors, positively associated with NEC, were isoimmunisation, fetal distress, caesarean section, persistent ductus arteriosus, cardiac and gastrointestinal malformations, and chromosomal abnormalities. Negative associations included maternal pre-eclampsia, maternal urinary infection, and premature rupture of the membranes. Intestinal failure occurred in 6% of NEC cases and 0.4% of controls, with the highest incidence towards the end of the study period.</p><p>The last study investigated current practices and perceptions of imaging in the management of NEC, as reported by involved specialists. There was great consensus on most issues. Areas in need of further study seem mainly related to imaging routines, the use of ultrasound, and indications for surgery.</p><p>Developing alongside the progress of neonatal care, NEC is a complex, multifactorial disease, with shifting patterns of predisposing and precipitating causes, and potentially serious long-term complications. The findings of seasonal variation, spacetime clustering, and negative associations with antenatal exposure to infectious agents, fit into the growing understanding of the central role of bacteria and immunological processes in normal maturation of the intestinal canal as well as in the pathogenesis of NEC. Imaging in the management of NEC may be developed through future studies combining multiple diagnostic parameters in relation to clinical outcome.</p>
6.
  • Aho, Nikolas, 1970- (författare)
  • Victimization, Prevalence, Health and Peritraumatic Reactions in Swedish Adolescents
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The aim of this thesis was to expand the knowledge of victimization in children and youth in Sweden. Victimization, prevalence, health and peritraumatic reactions were explored in a cross sectional, representative sample of 5,960 second grade high school students in Sweden. A computerized survey was developed and administered in class room setting.</p><p>Lifetime victimization was found in 84.1% of the sample (m=83.0%, f=85.2%), and, in relation to the five domains, 66.4% had experienced conventional crime, 24% child maltreatment, 54.4% peer and sibling victimization, 21.8% sexual victimization, and 54% had experienced witness victimization. Females experienced significantly more child maltreatment, peer and sibling victimization, sexual victimization, and witnessed victimization, males more conventional crime (p&lt;0.001). Using logistic regression risk factors for victimization were confirmed by a significant increase OR regarding gender, environment and lack of both parents.</p><p>Symptoms (TSCC), were clearly associated with both victimizations per se and the number of victimizations. The results indicated a relatively linear increase in symptoms with an increase in number of events experienced. Mental health of the polyvictimized group was significantly worse than that of the non-polyvictimized group, with significantly elevated TSCC scores (t&lt;0.001). Hierarchical regression analysis resulted in beta value reduction when polyvictimization was introduced supporting the independent effect on symptoms. Social anxiety was found in 10.2 % (n = 605) of the total group (n = 5,960). A significant gender difference emerged, with more females than males reporting social anxiety. Elevated PTSS was found in 14.8 % (n=883). Binary logistic regression revealed the highest OR for having had contact with child and adolescent psychiatry was found for the combined group with social anxiety and elevated PTSS (OR = 4.88, 95 % CI = 3.53–6.73, p&lt;001). Significant associations were also found between use of child and adolescent psychiatry and female gender (OR = 2.05, 95 % CI = 1.70–2.45), Swedish birth origin (OR = 1.68, 95 % CI = 1.16–2.42) and living in a small municipality (OR = 1.33, 95 % CI = 1.02–1.73).</p><p>Mediation models used peritraumatic reactions (PT): total, physiological arousal (PA), peritraumatic dissociation (PD), and intervention thoughts (IT) and JVQ and TSCC. Of the n=5,332 cases, a total of n=4,483 (84.1%) reported at least one victimizing event (m = 83.0%, f = 85.2%). Of these, 74.9% (n=3,360) also experienced a PT reaction of some kind. The effect mediated by PT tot was b= 0.479, BCa CI [0.342 – 0.640], representing a relatively small effect of 7.6%, κ2=0.076, 95% BCa CI [0.054- 0.101]. The mediating effect of JVQ on TSCC was mediated by PD more for males (b=0.394 BCa CI [0.170-0.636]) than for females (b=0.247, BCa CI [0.021-0.469]). The indirect effect of the JVQ on the TSCC tot mediated by the different PT reactions was significant for PD (b=0.355, BCa CI [0.199- 0.523]. In males a mediating effect of PD could be seen in the different models, while females had a more mixed result. IT did not show any indirect effect in males, but had a mixed effect for females.</p><p>The empirical findings in this thesis lead to the conclusion that victimization is highly prevalent in children and youth and is related to health issues. The association of victimization on symptoms was mediated by peritraumatic reactions. Using a comprehensive instrument such as the JVQ provides the researcher or clinician the opportunity to acquire more complete measurement and also makes it possible to identify polyvictimization, a high-level category of events with severe impact on health.  </p>
7.
  • Ali, Zaheer, 1984- (författare)
  • Investigating mechanisms of angiogenesis in health and disease using zebrafish models
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Angiogenesis, the growth of blood vessels from an existing vasculature, can occur by sprouting from preexisting vessels or by vessel splitting (intussusception). Pathological angiogenesis drives choroidal neovascularization (CNV) in age related macular degeneration (AMD) which is commonly restricted under the retinal pigment epithelium (RPE), called occult CNV, but may also involve vessels penetrating through the RPE into the sub-retinal space. Pathological vessels are poorly developed, insufficiently perfused and highly leaky, phenotypes that are considered to drive disease progression and lead to poor prognosis. Currently, a number of anti-angiogenic drugs exists, the majority of which target vascular endothelial factor (VEGF), but although they often are highly beneficial for treating eye diseases in the short-term, they are generally of limited efficacy in other diseases such as cancer, and also have poorer efficacy when used for treatment of eye diseases in the long-term. A better understanding of the mechanisms underlying pathological angiogenesis can generate new targets for treatment leading to development of better drugs for cancer and retinopathies, but perhaps also other angiogenesis-dependent diseases, in the future. In this thesis mechanisms involved in developmental angiogenesis or pathological angiogenesis in the choroid, cornea or melanoma was identified. These findings highlight the need to further elaborate our knowledge related to angiogenesis in different tissues/conditions for a more targeted, and potentially effective treatment of diseases in the future.</p><p>In paper I, we for the first time identified the choriocapillaries (CCs) in adult zebrafish and found that occult CNV could be induced by exposing the fish to severe hypoxia. Interestingly, we found that occult CNV relied on intussusception, involving not only <em>de novo </em>generation of intussusceptive pillars but also a previously poorly understood mechanism called pillar splitting. This involved HIF-VEGF-VEGFR2 signaling and evidence that this also occurred in both rats and humans suffering from AMD suggested that the mechanism was conserved and clinically relevant.</p><p>In contrast, we found in paper II that the development of CCs in the zebrafish relies on sprouting angiogenesis, involve continuous remodeling, and delayed maturation of the vasculature in 2D. The initial development was found to occur by a unique process of tissuewide synchronized vasculogenesis. As expected, VEGFA via VEGFR2 was also critical for the development of these vessels in the zebrafish embryo, but surprisingly this was independent on hypoxia-inducible factor (HIF)-1.</p><p>Inflammatory nuclear factor-kB (NF-kB) signaling is involved in the progression of angiogenesis, but this signaling pathway has mainly been studied in the inflammatory cells and the role of NF-kB in the endothelial cells during angiogenesis is poorly understood. In paper III, we found that blocking NF-kB signaling using a specific IKK2 blocker IMD0354, specifically blocks pathological as well as developmental angiogenesis by targeting endothelial cell NF-kB signaling in the endothelial cells. Using a rat model for suture-induced corneal neovascularization, IMD0354 treatment lead to reduced production of inflammatory C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 5 (CXCL5) and VEGF, and thereby reduced pathological corneal angiogenesis in this model.</p><p>Using the zebrafish tumor xenograft model in paper IV, we found an association between Microphthalmia associated transcription factor (MITF) and pigment epithelium derived factor (PEDF), which was involved in pathological tumor angiogenesis and metastasis. Similarly, in paper V we used zebrafish transplantation models to study and investigate the use of biocompatible polymers for the delivery of pro-angiogenic FGF-2 as a potential treatment strategy for ischemic diseases such as myocardial infarction (MI). Conclusively, this thesis provides new insights into diverse fields of angiogenic assays using zebrafish, and reveals new mechanisms of angiogenesis in health and disease. This work will hopefully provide a foundation for further studies into occult CNV related to AMD, a process that has not been possible to study previously in pre-clinical models. In addition, zebrafish xenograft or other transplantation models used in this work will likely be important to study cancer biology and to develop more attractive pharmaceutical preparations based on biocompatible hydrogels formulated as microspheres in the future.</p>
8.
  • Aljabery, Firas (författare)
  • Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Aim: </strong>To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.</p><p><strong>Patients and Methods: </strong>We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.</p><p><strong>Results: </strong>Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.</p><p><strong>Conclusion: </strong>PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.</p>
9.
  • Alkaissi, Hammoudi, 1983- (författare)
  • Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>BACKGROUND: </strong>Autoimmune diseases require the involvement and activation of immune cells and occur when the body builds up an immune response against its own tissues. This process takes place due to the inability to distinguish self-antigen from foreign antigen. Systemic autoimmunity represents an important cause of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Genome wide association study (GWAS) is a powerful method, used to identify genetic risk factors in numerous diseases, such as systemic autoimmune diseases. The goal of GWAS is to identify these genetic risk factors in order to make predictions about who is at risk and investigate the biological process of disease susceptibility. There are several valuable mouse models to investigate the underlying mechanisms causing systemic autoimmune diseases in which mercury induced autoimmunity (HgIA) is a well- established and relevant model. HgIA in mice includes development of autoantibodies, immune complex glomerulonephritis, lymphocyte proliferation, hypergammaglobulinemia and polyclonal B cell activation. In humans, mercury exposure accumulates with considerable concentrations in kidney, liver, and brain. Toxicokinetics of Hg has been studied extensively but the key for inter-individual variation in humans are largely unclear. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic inter-strain variation regulating retention or/and excretion of Hg.</p><p><strong>OBJECTIVES: </strong>To find loci and candidate genes associated with phenotypes involved in the development of autoimmunity and find candidate genes involved in the regulation of renal Hg excretion.</p><p><strong>METHODS: </strong>MHC II (H-2<em>s</em>) mice were paired (A.SW x B10.S) to obtain F2 offspring exposed to 2.0 or 4.0 mg Hg in drinking water for 6 weeks. Mercury induced autoimmune phenotypes were studied with immunofluorescence (anti-nucleolar antibodies (ANoA)), ELISA anti-DNP/anti-ssDNA (polyclonal B cell activation), anti-chromatin antibodies (ACA) (4.0 mg Hg), and serum IgG1 concentrations. Mercury accumulation in kidney was performed previously and data was included as phenotype. F2 mice exposed to 2.0 mg Hg were genotyped with microsatellites for genome-wide scan with Ion Pair Reverse Phase High Performance Liquid Chromatography (IP RP HPLC). F2 mice exposed to 4.0 mg Hg were genotyped with single nucleotide polymorphisms for genomewide scan with SNP&amp;SEQ technology platform. Quantitative trait loci (QTL) was established with R/QTL. Denaturing HPLC, next generation sequencing, conserved region analysis and genetic mouse strain comparison were used for haplotyping and fine mapping on QTLs associated with Hg concentration in kidney, development of ANoA and serum IgG1 hypergammaglobulinemia. Candidate genes (<em>Pprc1</em>, <em>Bank1 </em>and <em>Nfkb1</em>) verified by additional QTL were further investigated by real time polymerase chain reaction. Genes involved in the intracellular signaling together with candidate genes were included for gene expression analysis.</p><p><strong>RESULTS: </strong>F2 mice exposed to 2.0 mg Hg had low or no development of autoantibodies and showed no significant difference in polyclonal B cell activation in the B10.S and F2 strains. F2 mice exposed to 4.0 mg Hg developed autoantibodies and significantly increased IgG1 concentration and polyclonal B cell activation (anti-DNP). QTL analysis showed a logarithm of odds ratio (LOD) score between 2.9 – 4.36 on all serological phenotypes exposed to 4.0 mg Hg, and a LOD score of 5.78 on renal Hg concentration. Haplotyping and fine mapping associated the development of ANoA with <em>Bank1 </em>(B-cell scaffold protein with ankyrin repeats 1) and <em>Nfkb1 </em>(nuclear factor kappa B subunit 1). The serum IgG1 concentration was associated with a locus on chromosome 3, in which <em>Rxfp4 </em>(Relaxin Family Peptide/INSL5 Receptor 4) is a potential candidate gene. The renal Hg concentration was associated with <em>Pprc1 </em>(Peroxisome Proliferator-Activated Receptor Gamma, Co-activator-Related). Gene expression analysis revealed that the more susceptible A.SW strain expresses significantly higher levels of <em>Nfkb1</em>, <em>Il6 </em>and <em>Tnf </em>than the less susceptible B10.S strain. The A.SW strain expresses significantly lower levels of <em>Pprc1 </em>and cascade proteins than the B10.S strain. Development of ACA was associated with chromosomes 3, 6, 7 and 16 (LOD 3.1, 3.2, 3.4 and 6.8 respectively). Polyclonal B cell activation was associated with chromosome 2 with a LOD score of 2.9.</p><p><strong>CONCLUSIONS: </strong>By implementing a GWAS on HgIA in mice, several QTLs were discovered to be associated with the development of autoantibodies, polyclonal B cell activation and hypergammaglobulinemia. This thesis plausibly supports <em>Bank1 </em>and <em>Nfkb1 </em>as key regulators for ANoA development and HgIA seems to be initiated by B cells rather than T cells. GWAS on renal mercury excretion plausibly supports <em>Pprc1 </em>as key regulator and it seems that this gene has a protective role against Hg.</p>
10.
  • Amirhosseini, Mehdi (författare)
  • Aseptic Loosening of Orthopedic Implants Osteoclastogenesis Regulation and Potential Therapeutics
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Aseptic loosening is the main cause of failure of orthopedic prostheses. With no pharmaceuticals to prevent or mitigate periprosthetic bone degradation, a surgery to replace the loose implant with a new one is the only choice to restore patients’ function. Most studies on mechanisms for aseptic loosening investigate wear debris particle-induced osteolysis. However, pathological loading conditions around unstable implants can also trigger osteoclast differentiation and bone loss.</p><p>In the first study, global gene expression changes induced by mechanical instability of implants, and by titanium particles were compared in a validated rat model for aseptic loosening. Microarray analysis showed that similar signaling pathways and gene expression patterns are involved in particle- and instability-induced periprosthetic osteolysis with an early onset innate immune response as a hallmark of osteolysis induced by mechanical instability.</p><p>Further, effects of potential therapeutics on restriction of excessive osteoclast differentiation were evaluated. Wnt signaling pathway is known to regulate bone remodeling. In the second study, effects of inactivation of glycogen synthase kinase 3 beta (GSK-3β), a negative regulator of canonical Wnt signaling, on instability-induced periprosthetic osteolysis were examined using our rat model for aseptic loosening. Inhibition of GSK-3β led to a decrease in osteoclast numbers in the periprosthetic bone tissue exposed to mechanical instability while osteoblast perimeter showed an increase. This was accompanied by higher bone volume fraction (BV/TV) in animals treated with the GSK-3β inhibitor.</p><p>In the third study, potential beneficial effects of two selective inhibitors of cyclindependent kinase 8/19 (CDK8/19) on bone tissue were evaluated. CDK8/19 is a Mediator complex-associated transcriptional regulator involved in several signaling pathways. CDK8/19 inhibitors, mainly under investigation as treatments for tumors, are reported to enhance osteoblast differentiation and bone formation. We show in this study, for the first time, that inhibition of CDK8/19 led to marked suppression of osteoclast differentiation from bone marrow macrophages in vitro through disruption of the RANK signaling. In mouse primary osteoblasts downregulation of osteopontin mRNA, a negative regulator of mineralization, together with increased alkaline phosphatase activity and calcium deposition indicated that osteoblast mineralization was promoted by CDK8/19 inhibition. Moreover, local administration of a CDK8/19 inhibitor promoted cancellous bone regeneration in a rat model for bone healing.</p><p>These studies contribute to better understanding of mechanisms behind mechanical instability-induced periprosthetic osteolysis and propose potential therapeutics to restrict bone loss with effects on both osteoclasts and osteoblasts.</p>
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