Human papillomaviruses (HPV) are double-stranded, DNA, epitheliotropic viruses that infect skin and mucosal membranes. Over 200 types of HPV have been identified and classified into alpha (α), beta (β), gamma (γ), mu (µ), and nu (ν) genera. HPV in the genus α mainly infect mucosal membranes, cause the majority of the ano-genital cancers, and are widely studied. However, epidemiology of HPV in the other genera, which mainly infect skin, is poorly understood. Few studies have reported the seroprevalence of cutaneous HPV among healthy individuals, and to date, no study has prospectively examined the association between cutaneous HPV seropositivity and development of external genital lesions (EGLs) in men. The objectives of this study were to estimate the seroprevalence of cutaneous HPV types and investigate factors associated with the seropositivity, and evaluate the association between seropositivity to cutaneous HPV types and the risk of development of EGLs. Several studies have reported the seroprevalence of mucosal HPV types (6, 11, 16 and 18) in the 4-valent HPV vaccine among men. However, few studies have reported the seroprevalence of the five additional HPV types (31, 33, 45, 52 and 58) in the recently approved 9-valent HPV (9vHPV) vaccine specifically among men across a broad age range. Baseline data on seroprevalence prior to vaccine introduction and dissemination are needed to establish the effectiveness of vaccines over time. Also, this study estimated the seroprevalence of 9vHPV vaccine types and investigated factors associated with the seropositivity among men residing in Brazil, Mexico, and the United States (U.S.). To estimate the seroprevalence of cutaneous HPV types and 9vHPV vaccine types, 600 men were randomly selected from the HPV Infection in Men (HIM) Study. To examine the association between seropositivity to cutaneous HPV types and development of EGLs, a case-control study of 163 incident EGL cases and 352 EGL-free controls nested in the HIM cohort was conducted. Cases were ascertained through visual inspection at each of up to 10 biannual clinical visits, confirmed through biopsy, and categorized into condyloma, suggestive of condyloma, penile intraepithelial neoplasia (PeIN) and other EGLs. Archived serum specimens were tested for antibodies against 14 cutaneous HPV types, β types (5, 8, 12, 14, 17, 22, 23, 24, 38 and 47), α type 27, γ type 4, µ type1 and ν type 41, and 9vHP types (6, 11, 16, 18, 31, 33, 45, 52 and 58) using a glutathione S-transferase (GST) L1-based multiplex serology assay. Socio-demographic and sexual behavior data were collected through a questionnaire. Binomial proportions were used to estimate seroprevalence, and logistic regression was used to examine factors associated with seropositivity. Overall, seroprevalence of ≥1 cutaneous HPV types was 65.4%, 1≥ β-HPV types was 39.0%, α-HPV 27 was 8.9%, γ-HPV 4 was 30.9%, µ-HPV 1 was 28.6%, and ν-HPV 41was 9.4%. Higher educational attainment was significantly associated with seropositivity to ≥1 cutaneous HPV types (adjusted odds ratio [AOR] 1.75 for ≥16 years of education vs. ≤12 years of education, 95% confidence interval [CI] 1.08-2.83), and seropositivity of ≥1 β-HPV types was significantly associated with increasing age (AOR 1.72 for men aged 31-44 years vs. men aged 18-30 years, 95% CI: 1.12–2.63,). Country of residence, circumcision status, and lifetime number of male anal sex partners were other factors significantly associated with various type-specific cutaneous HPV seropositivity. No statistically significant association was observed between grouped or individual cutaneous HPV seropositivity and the risk of development of EGLs across all pathological diagnoses. The seroprevalence of grouped and individual cutaneous HPV types was similar across different EGL categories and controls, with the most frequent types being ɤ-HPV 4, µ-HPV 1, and β-HPV 8. The seroprevalence of ≥1 9vHPV vaccine types was 28.3%, ≥1 high-risk types was 14.0%, five additional high-risk types was 11.2%, and low-risk types (6/11) was 17.4%. Compared to men with no male anal sex partners, men with ≥2 partners were two times more likely to be seropositive for grouped 9vHPV vaccine types, ≥1 high-risk types and ≥1 low-risk types, in addition to individual HPV types 6, 16, 33, and 58, with AORs ranging from 2.19 to 7.36. Older age, current smoking, and being single were other factors significantly positively associated with different grouped and type-specific seropositivity. In conclusion, our data show that exposure to cutaneous HPV was common in men although different risk factors were independently associated with grouped and type-specific cutaneous HPV seropositivity. It appears that exposure to cutaneous HPV is not likely to increase the risk of EGLs among men. Similarly, exposure to 9vHPV vaccine types was also common in men and seropositivity to 9vHPV vaccine types was positively associated with older age and lifetime number male anal sex partners.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24478号 / 医博第4920号 / 新制||医||1062(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山本 洋介, 教授 近藤 尚己, 教授 柳田 素子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Quinolones are a group of antibiotics that have gained significant popularity on a global scale since the end of the last century. This popularity was predominantly based on their proven potency, broad coverage against a wide range of bacteria, in addition to possessing a favorable pharmacologic profile. Whereas quinolone-associated adverse reactions are generally tolerable and self-limiting, some reactions have generated heightened concerns due to their serious nature, which have resulted in label changes or even market withdrawal in some instances. This thesis investigates the association between quinolone antibiotics and two adverse reactions of an acute and serious nature: acute liver failure and retinal detachment. Each adverse reaction is investigated through integrating evidence from three studies utilizing different designs based on data from different sources, with each source offering a unique perspective on this issue. The first study type (chapter 2 for acute liver failure ‘ALF’ and Chapter 5 for retinal detachment ‘RD’) analyzes spontaneous reports submitted to the US Food & Drug Administration (FDA) adverse event reporting system database. Chapters 3 and 6 systematically identified all relevant (published and unpublished) clinical trials for occurrences of ALF and RD, respectively, among trial participants. Finally, chapters 4 (ALF) and 7 (RD) involved case-control analysis of a major US database of electronic health records for nearly 70 million inpatients admitted to more than 500 hospitals between 2000 and 2016. The FAERS analysis revealed a positive ALF signal with ciprofloxacin and a marginal signal for RD with moxifloxacin. Examination of the evidence from clinical trials revealed only two cases of ALF, one associated with gemifloxacin and one with moxifloxacin. No cases of RD were reported in any of the identified clinical trials. Primary analyses of the Health Facts® data revealed no overall association between quinolones and the risk of ALF or RD. However, elevated risk was identified in some subgroups, including African Americans (ALF, RD), Caucasians (ALF), women (ALF, RD), men (ALF), those ≤60 years of age (ALF) or 56-70 years of age (RD), and those with no or few comorbidities (ALF). Evidence from analyses of data from spontaneous reports and clinical trials provided some evidence for an elevated risk of ALF or RD following the systemic administration of quinolone antibiotics. Some evidence of elevated risk was also identified in the case-control analyses of inpatient EHR records. Findings from our six epidemiologic studies are in line with current advisories by FDA and Health Canada.

Dietary factors may affect development and progression of prostate cancer. Experimental and epidemiological studies have suggested an effect of phytoestrogens on prostate cancer. Lignans are the predominant phytoestrogen in a Western diet. The effects of a diet rich in phytoestrogens and in particular lignans, as compared to a control diet, were assessed in several prostate cancer models. In paper I, 70 athymic nude mice with transplanted subcutaneous LNCaP tumours, an androgen sensitive human prostate cancer cell line, were fed one out of six phytoestrogen rich diets or a control diet after tumour injection. The rye diet, with high lignan content, decreased tumour take and growth, decreased secretion of prostate specific antigen and increased apoptosis. Addition of fat to the rye diet decreased the beneficial effects. In paper II, transgenic mice designed to develop prostate cancer (TRAMP) were fed rye bran or a control diet from the age of four weeks. Rye bran decreased prostate epithelial cell volume by 20%, and increased cell apoptosis by 31% as compared to the control diet. In paper III, we examined the effects of 7-hydroxymatairesinol (HMR), a purified lignan, in nude mice with subcutaneous LNCaP tumours in two different concentrations as compared to a control diet. Mice on the HMR diets had a reduced tumour take rate, lower total tumour volume, increased proportion of non-growing tumours, and increased apoptosis as compared to the control diet. Paper IV was a three week intervention study exploring the effects of rye bran bread vs. a control diet in men with prostate cancer. The men in the rye group had increased levels of plasma enterolactone and in biopsies from the prostate after the intervention an increase in apoptosis was observed in comparison with biopsies obtained before the intervention. In paper V, we examined the association between plasma levels of enterolactone, and risk of prostate cancer in a nested case control study. In the Northern Sweden Health and Disease Cohort, enterolactone concentrations were measured in plasma obtained at a mean time of 5 years before diagnosis from 265 cases of prostate cancer, and from 525 matched controls. We found no significant association between plasma enterolactone and risk of prostate cancer. Men with very low enterolactone levels (bottom decile) however, had significantly higher risk of prostate cancer. Phytoestrogen rich diet including soy, rye bran, substances purified from rye, and a purified lignan (HMR) all inhibited prostate tumour growth. However, it cannot be concluded that the effects observed were due solely to lignans as other components in rye grain such as tannins, phytic acid, ferulic acid, vitamins and minerals may have contributed to the beneficial effects. Thus, additional studies are needed to further elucidate the effects of phytoestrogens on prostate cancer development and progression.

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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

La relation entre le risque de décès par cancer du poumon et l’exposition au radon est aujourd’hui établie, notamment à partir des études conduites chez les mineurs d’uranium. Mais de nombreuses interrogations persistent sur les risques de cancers extra-pulmonaires et de maladies non-cancéreuses, et sur l'impact sur la santé des autres expositions radiologiques professionnelles. L’objectif général de cette thèse est de contribuer à l’estimation des risques radio-induits aux faibles débits de dose au travers de l'analyse des risques de décès par cancer du rein et par Maladie de l'Appareil Circulatoire (MAC) chez les mineurs d’uranium.Les analyses du risque de décès par cancer du rein ont été réalisées au sein de la cohorte française des mineurs d'uranium (n=5 086 ; période de suivi : 1946-2007), la cohorte post-55 (n=3 377 ; période de suivi : 1957-2007) et la cohorte allemande de la Wismut (n=58 986; période de suivi : 1946-2003) au sein desquelles sont respectivement répertoriés 24, 11 et 174 décès par cancer du rein. L’exposition au radon et à ses descendants à vie courte (exprimée en Working Level Month WLM), aux poussières d’uranium (kBqh.m-3) et aux rayonnements gamma (mSv) a été estimée individuellement et la dose absorbée au rein a été calculée. La relation dose-réponse a été affinée par rapport à l'analyse classique en considérant deux types de réponse : le risque instantané de décès par cancer du rein (analyse classique, Cause-specific Hazard Ratio (CSHR) estimé avec le modèle de Cox) et sa probabilité d'occurrence au cours du suivi (Subdistribution Hazard Ratio (SHR) estimé avec le modèle de Fine & Gray). Un excès de mortalité par cancer du rein était observé dans la cohorte française (SMR = 1,62 IC95%[1,04; 2,41]), mais pas dans la cohorte post-55. Dans la cohorte de la Wismut, un déficit de mortalité par cancer du rein était observé (0,89 [0,78; 0,99]). Pour ces trois populations, aucune relation n'a pu être mise en évidence entre les expositions radiologiques (ou la dose au rein) et le risque de décès par cancer du rein (ex : CSHRWismut_radon/100WLM=1,023 [0,993; 1,053]), ni avec sa probabilité d'occurrence au cours du suivi (ex : SHRWismut_radon /100WLM=1,012 [0,983; 1,042]).L’étude du risque de décès par MAC dans la cohorte française a montré une augmentation significative du risque de décès par MAC (n=442, CSHR/100WLM=1,11 [1,01; 1,22]) et par Maladie CérébroVasculaire (MCeV, n=105, CSHR/100WLM=1,25 [1,09; 1,43]) avec l’exposition au radon. Une enquête cas-témoins nichée au sein de la cohorte a été mise en place pour recueillir dans les dossiers médicaux les facteurs de risque classiques de MAC (surpoids, hypertension, diabète...) pour 313 mineurs (76 décès par MAC (dont 26 par Cardiopathie Ischémique (CI) et 16 par MCeV) et 237 témoins). Pour les trois expositions radiologiques, la relation exposition-risque a été analysée au sein d'une pseudo-cohorte (obtenue en pondérant les observations par l'inverse de la probabilité de sélection, n=1 644 pseudo-individus) avec le modèle de Cox, en ajustant sur les différents facteurs de risque. L’association entre les expositions radiologiques et le risque de décès par MAC, CI ou MCeV n'était pas significative (ex : CSHRMAC_radon/100WLM=1,43 [0,71; 2,87]). La prise en compte des facteurs de risque ne modifiait pas sensiblement cette association.L'absence de relation dose-réponse significative suggère que l'excès de mortalité par cancer du rein chez les mineurs français serait induit par d'autres facteurs, non-disponibles pour cette analyse. La faible variation des coefficients avec l'ajustement sur les facteurs de risque de MAC dans l'enquête cas-témoins nichée soutient l'hypothèse de l'existence d'une augmentation du risque de MCeV dans la cohorte française associée à l’exposition au radon. La poursuite du suivi de la cohorte permettra d'affiner ces résultats. / The relation between lung cancer risk and radon exposure has been clearly established, especially from the studies on uranium miner cohorts. But the association between radon exposure and extrapulmonary cancers and non-cancer diseases remains not well known. Moreover, the health risks associated with the other mining-related ionizing radiation exposures are still under consideration. The aim of this thesis is to contribute to the estimation of the radio-induced health risks at low-doses through the analysis of the kidney cancer and Circulatory System Disease (CSD) mortality risks among uranium miners.Kidney cancer mortality risk analyses were performed from the French cohort of uranium miners (n=5086; follow-up period: 1946-2007), the post-55 cohort (n=3,377; follow-up period: 1957-2007) and the German cohort of the Wismut (n=58,986; follow-up period: 1946-2003) which included 24, 11 and 174 deaths from kidney cancer, respectively. The exposures to radon and its short-lived progeny (expressed in Working Level Month WLM), to uranium ore dust (kBqh.m-3) and to external gamma rays (mSv) were estimated for each miners and the equivalent kidney dose was calculated. The dose-response relation was refined considering two responses: the instantaneous risk of kidney cancer mortality (corresponding to the classical analysis, Cause-specific Hazard Ratio (CSHR) estimated with the Cox model) and its occurrence probability during the follow-up (Subdistribution Hazard Ratio (SHR) estimated with the Fine & Gray model). An excess of kidney cancer mortality was observed only in the French cohort (SMR = 1.62 CI95%[1.04; 2.41]). In the Wismut cohort, a decrease of the kidney cancer mortality was observed (0.89 [0.78; 0.99]). For these three cohorts, the occupational radiological exposures (or the equivalent kidney dose) were significantly associated neither with the risk of kidney cancer mortality (e.g. CSHRWismut_radon/100WLM=1.023 [0.993; 1.053]), nor with its occurrence probability during the follow-up (e.g. SHRWismut_radon /100WLM=1.012 [0.983; 1.042]).CSD mortality risk analyses in the French cohort showed a significant increase of the risks of mortality from CSD (n=442, CSHR/100WLM=1.11 [1.01; 1.22]) and from CerebroVascular Disease (MCeV, n=105, CSHR/100WLM=1.25 [1.09; 1.43]) with radon exposure. A case-control study nested in the French cohort was set up to collect the information related to CSD risk factors (overweight, hypertension, diabetes...) from the medical records of 313 miners (76 deaths from CSD (including 26 from Ischemic Heart Disease (IHD) and 16 from MCeV) and 237 controls). For the three radiological exposures, the exposure-risk relation was analyzed in a pseudo-cohort (n=1,644 pseudo-individuals, obtained from the weighting of the observations by their inverse selection probability) with the Cox model, adjusted for the CSD risk factors. The association between the radiological exposure and the risk of mortality from CSD, IHD or MCeV was not significant (e.g. CSHRCSD_radon/100WLM=1.43 [0.71; 2.87]). The adjustment for CSD risk factors did not substantially change the exposure-risk relation.The lack of a significant dose-response relation suggests that the excess of kidney cancer mortality among the French uranium miners may be induced by other risk factors, unavailable for this study. The small change of the coefficients observed after adjustment for CSD risk factors in the nested case-control study supports the assumption of the existence of the MCeV mortality risk increase associated with radon exposure in the French cohort of uranium miners. Future analyses based on further follow-up updates should allow to confirm or not these results.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.