Creutzfeldt-Jakob disease (CJD) is the commonest form of human prion disease and occurs in sporadic, genetic and acquired forms. The causative agents (prions) appear to be composed entirely of a modified host protein, the prion protein, which undergoes misfolding to a disease-associated isoform closely associated with infectivity that is resistant to conventional methods of decontamination. Prions can be transmitted from one individual to another by medical and surgical procedures, resulting in iatrogenic CJD (iCJD). The commonest cause of iCJD is the inoculation of cadaveric pituitary-derived human growth hormone (hGH) to treat growth hormone deficiency in children; this form of treatment was abandoned in 1985 after the first UK case of iCJD in a hGH recipient was identified. Seventy-eight cases of iCJD have since occurred in the UK cohort of 1849 hGH recipients, including a case in 2016. This thesis describes a comprehensive tissue-based and molecular genetic analysis of the largest series (35 cases) of UK hGH-iCJD cases reported to date, including in vitro kinetic molecular modelling of genotypic factors influencing prion transmission. The results show that the polymorphism at codon 129 of the prion protein gene strongly influences the disease incubation period in hGH-iCJD (from 7.8-32.3 years in this series) and interacts with the infectious prion strain to govern the molecular and pathological characteristics of iCJD. The findings are consistent with the hypothesis that the UK hGH-iCJD epidemic resulted from transmission of the V2 human prion strain, which is found in the second most common form of sporadic CJD. The investigation also found accumulation of the amyloid beta (Aβ) protein associated with Alzheimer’s disease (AD) in the brains and cerebral blood vessels in 18/35 hGH-iCJD patients and 5/12 control patients who had been treated with hGH, but died from causes other than iCJD. In contrast, Aβ accumulation was markedly less prevalent in age-matched patients who died from sporadic CJD (1/15 cases) and variant CJD (2/33 cases). These results are consistent with the hypothesis that Aβ, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and seeded into the brains of around 50% of all hGH recipients, producing AD-like neuropathology and cerebral amyloid angiopathy (CAA). This provides further evidence of the prion-like properties of Aβ and gives insight into the potential for possible transmission of AD/CAA. It is uncertain whether any Aβ seeding within the brains of surviving patients in the UK hGH recipient cohort will ultimately result in clinical AD; however, the CAA in these patients may be complicated by intracerebral haemorrhage resulting from rupture of the blood vessels damaged by Aβ accumulation within their walls.

Doctor of Philosophy / Department of Plant Pathology / William W. Bockus / James P. Stack / Wheat blast, caused by the Triticum pathotype of Magnaporthe oryzae (MoT), is a serious disease of wheat causing yield failures and significant economic losses during epidemic years in Brazil, Paraguay, and Bolivia. Although outbreaks occur only sporadically, wheat blast is considered a major disease affecting wheat production in South America and may be a threat to the wheat crop in the United States. Wheat is a major crop in the U.S. and wheat exports from the U.S. are important to food security of several countries around the World. Thus, it is important to understand the potential for MoT entry and establishment into the U.S. and to test U.S. wheat cultivars for susceptibility to MoT. The hypotheses of this research project were a) importing wheat grain from Brazil does not pose a risk for MoT establishment in the U.S., and b) resistance to MoT head infection does not exist in U.S. hard red winter wheat elite cultivars. Quantitative pathway analysis models were used to estimate the risk of MoT entry and establishment, in the coterminous U.S. and in a more targeted area within southeast North Carolina, via the importation of wheat grain from Brazil. The pathway model predicted that significant risk for MoT entry and establishment exists in some areas of the U.S. However, in approximately 60% of the coterminous U.S. winter wheat production areas the risk of MoT establishment was estimated to be zero. With respect to winter wheat growing areas in the U.S., conditions for MoT establishment and wheat blast outbreak occur only in small, restricted geographic areas. A higher resolution pathway analysis based on a ground transportation corridor in North Carolina indicated that conditions for MoT establishment exist seven out of ten years. Among U.S. cultivars tested, a continuum in severity to head blast was observed; cultivars Everest and Karl 92 were highly susceptible with more than 90% disease severity, while cultivars PostRock, Jackpot, Overley, Jagalene, Jagger, and Santa Fe showed less than 3% infection.

The aim of the thesis – to investigate the role of the inflammatory bowel disease associated genetic variants in a subset of Crohn’s disease and ulcerative colitis patients from Lithuania and Latvia and to test the relation of genetic markers to disease phenotype. The following objectives were accomplished: the associations of the inflammatory bowel disease associated single nucleotide polymorphisms in the subset of Crohn’s disease and ulcerative colitis patients were determined; the associations of the single nucleotide polymorphisms with the phenotype of the inflammatory bowel disease were evaluated; the interactions of single nucleotide polymorphisms (SNP-SNP) and their association with inflammatory bowel disease were determined; the significance of the combinations of disease associated single nucleotide polymorphisms for diagnosis of inflammatory bowel disease was evaluated. TaqMan and SNPlex genotyping methods were used in this work. The statistical data analysis consisted of: statistical study power and data quality evaluations; single marker case-control association analysis using χ2 or Fisher's exact tests, Breslow-Day test, Cochran-Mantel-Haenzsel test and post-hoc Bonferroni correction; genotype–phenotype association analysis using χ2 test and post-hoc Bonferroni correction; SNP-SNP epistasis for case-control sample using logistic regression test and post-hoc Bonferroni correction; In sicilo prediction of gene interactive network; genetic risk profile construction... [to full text] / Disertacijos tikslas – ištirti su uždegiminėmis žarnyno ligomis siejamų ge¬netinių žymenų reikšmę Krono liga bei opiniu kolitu sergantiems Lietuvos ir Latvijos ligoniams bei nustatyti žymenų ryšį su ligos fenotipu. Tikslui pasiekti, įgyvendinti šie uždaviniai: ištirta su uždegiminėmis žarnyno ligomis siejamų vieno nukleotido polimorfizmų sąsaja su Krono liga bei opiniu kolitu; nustatyta vieno nukleotido polimorfizmų sąsaja su uždegiminių žarny¬no ligų fenotipu; ištirtos vieno nukleotido polimorfizmų tarpusavio epistazinės sąvei¬kos (VNP-VNP) bei jų ryšys su uždegiminėmis žarnyno ligomis; nustatytas su liga siejamų vieno nukleotido polimorfizmų derinių reikšmingumas uždegiminių žarnyno ligų diagnostikai. Darbe taikyti SNPlex ir TaqMan genotipavimo metodai. Statistinę duomenų analizę sudarė: studijos galios bei duomenų kokybės įvertinimas; atvejo-kontrolės genų sąsajos tyrimas, taikant χ2 arba Fišerio kriterijus, Breslow-Day testą, Cochran-Mantel-Haenzsel testą bei post-hoc Bonferroni kriterijų; genų sąsajų su Krono ligos ir opinio kolito fenotipu tyrimai, naudojant χ2 bei post-hoc Bonferroni kriterijų; VNP-VNP epistazinės sąveikos įvertinimas, taikant logistinės regresijos testą bei post-hoc Bonferroni kriterijų; genų tarpusavio sąveikos tinklo in silico tyrimas; genetinės rizikos profilio sudarymas, naudojant logistinę regresinę analizę.

La maladie de Crohn (MC) a une incidence élevée dans la population pédiatrique en Amérique du Nord et cette incidence est en augmentation. L’évolution naturelle de la MC est mal comprise. L'évolution du délai à la rémission au fil des ans et les causes influençant le délai à la rémission sont très limitées dans la littérature. Peu de facteurs de risque sont identifiés dans la littérature pour prédire les rechutes de la maladie chez les enfants. Le premier objectif de cette étude était de décrire les variations du phénotype clinique, des caractéristiques endoscopiques, histologiques et de laboratoire de la MC pédiatrique au cours de la dernière décennie et de décrire les variations saisonnières de la présentation de la maladie au moment du diagnostic. Le deuxième objectif était de décrire le délai à la rémission chez les enfants atteints de MC ainsi que son évolution au cours de la dernière décennie et de déterminer les facteurs associés au délai à la rémission. Le troisième objectif de l’étude était de décrire le taux de rechutes chez les enfants atteints de la MC, son évolution au cours de la dernière décennie et de déterminer les facteurs de risque associés à la rechute de la maladie. Les patients éligibles étaient âgés de 4 à 18 ans et diagnostiqués entre 2009 et 2019. Toutes les caractéristiques cliniques, endoscopiques, histologiques et de laboratoire des patients, ainsi que leurs traitements, ont été recueillis à partir de leurs dossiers médicaux. Des analyses de survie et des modèles de régression linéaire ont été utilisés pour évaluer l'impact de ces facteurs sur le délai à la rémission et des analyses de survie et des modèles de régression de Cox ont été utilisés pour évaluer l'impact de ces facteurs sur le risque de rechute. 654 patients ont été inclus dans cette étude de cohorte rétrospective. Le nombre de nouveaux diagnostics annuels de MC a augmenté au fil des ans et les patients diagnostiqués entre 2015 et 2019 avaient un âge au diagnostic plus bas (OR 2.53, IC à 95% [1.29; 4.98]), plus de maladies périanales (OR: 2.30, IC à 95% [ 1.52; 3.48]), plus de granulomes (OR: 1.61, IC à 95% [1.17; 2.22]), mais moins d’éosinophiles (OR: 0.35, IC à 95% [0.25; 0.48]) et moins d’infiltrat lympho-plasmocytaire chronique (OR: 0.56, IC à 95% [0.36; 0.86]) comparé aux patients diagnostiqués entre 2009 et 2014. Il y avait moins de diagnostics de MC chez les enfants en hiver. Les patients diagnostiqués à l'automne avaient une activité de la maladie plus faible (score PCDAI), moins de retard de croissance et des maladies digestives moins diffuses. Les MC diagnostiquées au printemps et à l’été avaient des taux d'hémoglobine plus faibles et des taux de vitesse de sédimentation plus élevés associées à plus d’atteintes articulaires et plus d'érythème noueux. La localisation colique était significativement plus fréquente l’été et l’automne. Il n'y a pas eu de changement dans le délai à la rémission au cours de la dernière décennie. Le sexe féminin chez les adolescents (coefficient de regression bêta ajusté (aβ) = 31.8 jours, p=0.02), l'atteinte du tube digestif supérieur (aβ= 46.4 jours, p=0.04), la maladie périanale (aβ= 32.2 jours, p=0.04), les signes d'inflammation active sur les biopsies (aβ= 46.7 jours, p=0.01) et l’exposition aux 5-ASA oraux lors de la phase d'induction (aβ= 56.6 jours, p=0.002) étaient associés à un délai à la rémission plus long. À l’inverse, l'utilisation d'antibiotiques (aβ= -29.3 jours, p=0.04), l’augmentation des éosinophiles sur les biopsies (aβ= -29.6 jours, p=0.008) et l'utilisation de la nutrition entérale exclusive comme traitement d'induction avec les anti TNF-alpha (aβ= -36.8 jours, p=0.04) étaient associés à un délai à la rémission plus court. Il y a eu une diminution du taux de rechute au cours de la dernière décennie : 69.59% chez les patients diagnostiqués entre 2009 et 2014 et 47.76% chez les patients diagnostiqués entre 2015 et 2019 (p<0.0001). Le sexe féminin (hazard ratio ajusté (aHR) = 1.51, p=0.0009), les scores PCDAI (aHR= 1.02, p=0.04) et SES-CD élevés (aHR= 1.03, p=0.03) au diagnostic, l'atteinte du tube digestif supérieur (aHR= 1.59, p=0.0003), l’utilisation des 5-ASA oraux (aHR= 1.91, p=0.0003), l’usage d'agents immunomodulateurs par rapport aux biologiques (methotrexate aHR= 1.91, p=0.0006; thiopurines aHR= 2.06, p<0.0001), la présence de granulomes (aHR= 1.27, p=0.04) et l’augmentation des éosinophiles sur les biopsies (aHR= 1.34, p=0.02), des niveaux élevés de protéine C-réactive (aHR= 1.01, p<0.0001) et de calprotectine fécale (aHR=1.09, p<0.0001) pendant la rémission clinique et de faibles taux sériques d'infliximab en post-induction (aHR pour les niveau moyen d’infliximab inférieur à 7ug/mL = 2.48, p=0.005) étaient indépendamment associés à la rechute. Le phénotype de la maladie a changé au fil des ans et des tendances saisonnières dans la fréquence et la gravité des diagnostics existent, suggérant des hypothèses étiologiques telles que la carence en vitamine D en hiver, les colites bactériennes saisonnières, les processus de réactivation virale et les changements dans la composition du microbiote. Plusieurs résultats de l'étude sont originaux et ceux-ci ont apporté de nouvelles connaissances et certains pourraient être intégrés dans les lignes directrices de prise en charge de la MC pédiatrique afin d’améliorer la qualité de vie des patients, soit obtenir une rémission rapide et durable. / Crohn's disease (CD) has a high incidence in the pediatric population in North America. The etiology of CD remains unknown and the disease incidence has been increasing. The natural evolution of CD is misunderstood, especially in the pediatric population. The trends of time-to-remission over the years and the influencing factors are very limited in the literature. Few risk factors are identified in the literature to predict relapses of the disease in children. The first part of this study was to describe the trends in the clinical phenotype, endoscopic, histological, and laboratory characteristics of pediatric CD during the last decade and to describe the seasonal variation of disease presentation at diagnosis. The secondary part of this study was to describe the time to remission in children with CD as well as its evolution over the past decade and to determine factors associated with time to remission. The third part of the study was to describe the rate of relapses in children with CD, its evolution over the past decade and to determine risk factors associated with relapse of the disease. Eligible patients were aged from 4 to 18 years and diagnosed between 2009 and 2019. All clinical, endoscopic, histological, laboratory and treatment data were collected from their medical records. Survival analyses and linear regression models were used to assess the impact of those factors on time to remission. Likewise, survival analyses and Cox regression models were applied to assess the impact of those risk factors on relapse. A total of 654 patients were included in this retrospective cohort study. The number of new diagnoses per year increased over the decade. Patients diagnosed between 2015 and 2019 had a lower age at diagnosis (OR 2.53, 95% CI [1.29; 4.98]), more perianal diseases (OR: 2.30, 95% CI [1.52; 3.48]), more granulomas (OR: 1.61, 95% CI [1.17; 2.22]), but less eosinophils (OR: 0.35, 95% CI [0.25; 0.48]) and less chronic lympho-plasma cells infiltrate (OR: 0.56, 95% CI [0.36; 0.86]) on ileo-colonic biopsies compared to patients diagnosed in 2015-2019. There were fewer diagnoses of CD in children in winter. Patients diagnosed in fall had lower PCDAIs and less failure to thrive. CD diagnosed in spring and summer had lower hemoglobin levels and higher erythrocyte sedimentation rate levels. In addition, arthritis and erythema nodosum were more frequent in spring and summer. Colonic location was significantly more frequent in summer and fall. There was no change in the time to clinical remission over the past decade. Female sex in adolescents (adjusted bêta regression coefficient (aβ)= 31.8 days, p=0.02), upper digestive tract involvement (aβ= 46.4 days, p=0.04) perianal disease (aβ= 32.2 days, p=0.04), presence of active inflammation on biopsies (aβ= 46.7 days, p=0.01) and oral 5-ASA exposure (aβ= 56.6 days, p=0.002) were all associated with longer time to clinical remission. However, antibiotic exposure (aβ= -29.3 days, p=0.04), increased eosinophils on biopsies (aβ= -29.6 days, p=0.008) and combination of exclusive enteral nutrition and TNF-alpha inhibitors as induction therapy (aβ= -36.8 days, p=0.04) were associated with shorter time to clinical remission. There has been a decrease in the relapse rate over the past decade : 69.6% in patients diagnosed between 2009 and 2014 and 47.8% in patients diagnosed between 2015 and 2019 (p<0.0001). Female sex (adjusted hazard ratio (aHR) = 1.51, p=0.0009), high PCDAI (aHR= 1.02, p=0.04) and SES-CD (aHR= 1.03, p=0.03) scores at diagnosis, upper digestive tract involvement (aHR= 1.59, p=0.0003), exposure to oral 5-ASA (aHR= 1.91, p=0.0003), use of immunomodulatory agents compared to TNF-alpha inhibitors (methotrexate aHR= 1.91, p=0.0006; thiopurines aHR= 2.06, p<0.0001), presence of granulomas (aHR= 1.27, p=0.04) and increased eosinophils on biopsies (aHR= 1.34, p=0.02), high levels of C-reactive protein (aHR= 1.01, p<0.0001) and fecal calprotectin (aHR=1.09, p<0.0001) during clinical remission and low serum infliximab levels during maintenance (aHR for mean serum infliximab level under 7ug/mL = 2.48, p=0.005) were all significantly associated with relapse in patients. The disease phenotype has changed over the years and important trends in the frequency and severity of diagnoses exist according to the diagnosis period within a year, suggesting etiological hypotheses such as vitamin D deficiency in winter, seasonal bacterial and viral colitis and academic stress. Many of the results of the study are original and brought new knowledge while confirming certain statements which had not obtained consensus in recent studies of expert opinions and some could be incorporated into management guidelines of pediatric CD to short time to remission and avoid relapse in patients.