Au cours des maladies démyélinisantes du système nerveux central (SNC), les gaines de myéline qui entourent les axones et contribuent à la rapidité de la conduction nerveuse, mais aussi les oligodendrocytes qui synthétisent la myéline sont détruits. C’est le cas dans la plus commune de ces pathologies, la sclérose en plaques, qui se caractérise par des épisodes inflammatoires et démyélinisants récurrents évoluant après quelques années vers une forme progressive secondaire. A l’heure actuelle, les traitements disponibles pour les patients sont essentiellement de type immunomodulateurs. Ces molécules sont efficaces pour réduire la fréquence des épisodes démyélinisants, mais elles sont dépourvues d’activité sur la forme progressive de la maladie. Juste avant que ne débute mon travail de thèse, les voies de signalisation respectivement induites par les protéines Hedgehog et les stéroïdes de type androgènes se sont révélées être des régulateurs positifs de la réparation de la myéline vraisemblablement en utilisant des mécanismes différents. A partir de ces découvertes, nous avons émis l’hypothèse que la modulation pharmacologique simultanée des deux voies pourrait être intéressante dans une perspective thérapeutique. En utilisant des cultures de cellules gliales mixtes ou en administrant ces modulateurs à des souriceaux nouveau-nés, nous avons d’abord montré l’existence d’une interaction fonctionnelle entre les deux voies au cours du développement physiologique de la myéline à la période post-natale précoce. De façon intéressante, le blocage de la signalisation Hedgehog est requis pour que les androgènes puissent jouer leur rôle dans le processus de myélinisation. Les mécanismes moléculaires impliqués dans la communication entre les deux voies sont apparemment indépendants de la régulation de la transcription du principal effecteur de la signalisation Hedgehog (Gli1), ainsi que de celle du récepteur nucléaire des androgènes (AR). Par ailleurs, l’administration de ces mêmes modulateurs à des animaux ayant subi une démyélinisation du SNC nous a permis de mettre en évidence un effet synergique des deux voies sur la régénération de la myéline, la résolution de l’inflammation et la récupération fonctionnelle. Ces résultats seront importants à considérer dans le contexte d’une nouvelle approche thérapeutique des maladies démyélinisantes. / During demyelinating diseases of the central nervous system (CNS), the myelin sheaths that surround the axons and contribute to nervous conduction velocity, but also the oligodendrocytes that synthesize myelin are lost. This is particularly true in multiple sclerosis, the most common of those pathologies, which is characterized by recurrent inflammatory and demyelinating attacks evolving after several years into a secondary progressive form. Presently, the treatment of patients mostly relies on the use of immunomodulators, which are successful in decreasing the frequency of the attacks. However, these molecules lead to poor results in the progressive form of the disease. Just before the beginning of my PhD, the Hedgehog and androgen signaling pathways have been identified as positive regulators of myelin repair likely by using different mechanisms. On the basis of these findings, we hypothesized that a combination therapy using pharmacological modulators of each of these pathways could be interesting from a therapeutic point of view. By using primary mixed glial cell cultures and in vivo administration of the modulators to early postnatal mice, we have shown that the Hedgehog and androgen signaling pathways functionally interact during the physiological development of myelin at the early postnatal period. Importantly, the blockade of the Hedgehog signaling is required to allow androgen to play their role in the myelination process. The molecular mechanisms implicated in the pathway crosstalk do not involve the transcriptional regulation of the main effector of Hedgehog signaling (Gli1) or the nuclear androgen receptor (AR). Moreover, the same modulators administered into demyelinated animals led us to demonstrate a synergetic effect both on myelin repair, inflammation resolution and functional recovery. These results should be considered in the context of a novel therapeutic approach of demyelinating diseases.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21995号 / 医博第4509号 / 新制||医||1037(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 戸井 雅和, 教授 万代 昌紀, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

付記する学位プログラム名: 充実した健康長寿社会を築く総合医療開発リーダー育成プログラム / 京都大学 / 新制・課程博士 / 博士(医学) / 甲第23090号 / 医博第4717号 / 新制||医||1050(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 篠原 隆司, 教授 小川 修, 教授 溝脇 尚志 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

INTRODUCTION: Polycystic Ovary Syndrome (PCOS) is the most common endocrinopathy causing infertility in women of reproductive age. According to the Rotterdam criteria, a PCOS diagnosis should be given if at least two of the following are met: 1) hyperandrogenism; 2) oligo-anovulation; and 3) polycystic ovarian morphology. Previous studies analyzing the prevalence of PCOS have done so in unselected and clinical populations but few studies have attempted to characterize the syndrome and its long-term outcomes within Electronic Health Records using International Classification of Disease (ICD) codes. OBJECTIVES: With a hospital-based electronic health record dataset, this thesis seeks to: (1) characterize PCOS in reproductively aged women (18-34) using the diagnostic codes (ICD-9 and ICD-10) versus the Rotterdam criteria, (2) determine the prevalence of metabolic syndrome (MetS), Type 2 Diabetes, and cardiac events in women above age 35, (3) determine age of diagnosis for MetS and time to diagnosis of MetS. METHODS: The following 3 cohorts were queried on the Research Patient Data Registry (RPDR): 1) patients aged 18-34 with classic PCOS (phenotype A and B) but without an ICD diagnosis for PCOS, 2) patients aged 18-34 with a PCOS ICD-9/10 diagnosis and 3) patients above age 35 with a history or current diagnosis of PCOS. Their electronic health records (between January 1 , 2003 and December 31 , 2020) were ascertained from 9 Mass General Brigham institutions after IRB approval and analyzed on Software for Statistics and Data Science (STATA). RESULTS: Overall, RPDR identified 12,669 patients aged 18-34 who fit the Rotterdam criteria (under multiple phenotypes), 4646 of which had classic PCOS but lacked an ICD- 9/10 code for PCOS. RPDR also identified 9341 women aged 35 and above with a past or current diagnosis of PCOS. Hispanics/Latinas (18-34) were two times more likely to be undiagnosed when compared to Non-Hispanic Whites (OR: 2.25, 95% CI: 1.98-2.56). The prevalence of MetS, specified by a diagnostic code (277.7 or E88.81), and other cardiac conditions in women above age 35 were considerably lower than those found in the current literature. CONCLUSION: Databases such as RPDR allow for a detailed analysis of patient demographics, labs, procedures and diagnoses. Additionally, it allows for larger cohorts of patients matching more specific criteria to be ascertained. Future studies should compare the prevalence of individual features of MetS by ICD codes and analyze the cardiology reports to determine if the events are being reported but not codified. / 2023-11-30

Introduction: According to the literature, low serum testosterone levels are associated with diabetes mellitus. Minimal data exist for its prevalence or predictors in South Africa. Erectile dysfunction is a common condition in diabetic patients. The prevalence and predictors in our patient population is unknown. Methods: An observational, cross-sectional study was performed in 150 consecutive male diabetic patients over the age of 50 years in the Diabetic clinic of Steve Biko Academic Hospital. These patients were evaluated for diabetes control and complications, the presence of erectile dysfunction and for hypogonadism symptoms. Morning serum testosterone levels were done. Subjects with low testosterone levels were compared to those with normal levels. Results: The mean age of the patients was 62 years (standard deviation (SD) 7.87), 91.3% had type 2 diabetes, and 84.7% were on insulin. The mean duration of diabetes was 15 years (SD 8.65). The mean body mass index was 30.7 (SD 5.37), the mean waist circumference was 112.4cm (SD 16.42), the median creatinine was 96μmol/L (interquartile range (IQR) 79-133) and the median HbA1C was 7.85% (IQR 6.80-9.30). Ischaemic heart disease was previously diagnosed in 40.7% of patients. Some degree of erectile dysfunction was reported in 95.3% of the patients with 51.3% reporting serious dysfunction. The prevalence of androgen deficiency symptoms was 94.7%. Fifty percent of the men had low total testosterone levels; 40.7% had low modified calculated bioavailable testosterone levels, and in 27.3% both were low. With multivariate logistic regression the significant factors associated with low total testosterone were waist circumference and known cardiovascular disease. For a low modified calculated bioavailable testosterone level significant variables were age, diabetes duration and body mass index and for an outcome defined as both the above the significant factors were diabetes duration, body mass index, and known cardiovascular disease. With multivariate logistic regression the significant factors associated with erectile dysfunction were age, body mass index, peripheral neuropathy score, and diuretic therapy. The prevalence of symptoms of androgen deficiency was very high with 94.7% of all patients reporting a significant amount of symptoms on the Androgen Deficiency in Adult Males (ADAM) questionnaire. If only the total serum testosterone level was evaluated instead of the modified calculated bioavailable testosterone, the sensitivity was 69%, the specificity was 63%, with a poor positive predictive value of only 56%. The negative predictive value was better at 75%. Differences in quality of life scores were only seen for some erectile dysfunction subgroups but not for low testosterone levels. Conclusion: This study confirms the high prevalence of low testosterone levels and of erectile dysfunction in diabetic male patients in a tertiary setting, and argues in favour of universal screening of this population group. Multiple predictors of low testosterone levels and of erectile dysfunction were identified. The ADAM questionnaire was not useful in identifying subjects with a low testosterone level. Total testosterone testing alone performed poorly in comparison with modified calculated bioavailable testosterone and is not the recommended test of choice. Erectile dysfunction negatively affected the quality of life. / Dissertation (MSc)--University of Pretoria, 2014. / gm2015 / Clinical Epidemiology / MSc / Unrestricted

We report a de novo dup(X)(q23→q26) in a 3-year-old girl with growth retardation, developmental delay, and minor anomalies. X-inactivation in lymphocytes by BRDU labeling showed the abnormal X was late replicating. The androgen receptor assay (HAR) demonstrated a skewed methylation (88.8%) of the paternal allele and a 11.2% methylation of the maternal allele. These data, which suggest the duplication was paternally inherited, are the first parental-origin identification of a duplication Xq. The mild phenotype of the patient may be related to the size and region of the duplication, the low percentage of a dup(X) active detected by the HAR assay, or a combination of these mechanisms. .

OBJECTIVE. To determine if the levels of circulating myeloid-derived suppressor cells increase with progression of prostate cancer (PCa); to determine if such cells could contribute to the relative inefficiency of PCa immunotherapy. MATERIALS AND METHODS. We analyzed peripheral blood mononuclear cells isolated from untreated PCa patients (uPCa; N=18; mean age±SD: 72.1± 6.9 years), tPCa (N = 22; 72.8 ± 9.8 years) and age matched controls (AMC; N = 12; 68.8 ± 7.5 years). We quantified surface marker phenotype, differentiation potential, effects on T cell proliferation and intracellular cytokines. RESULTS. We observed an unexpectedly high percentage of a type of myeloid-derived suppressor cells, CD14+HLA-DR low/- monocytes, in tPCa (30.7±15.0% of CD14+ cells) relative to AMC (4.1+6.5%, P<0.0001) and uPCa (10.6 ± 14.3%, P = 0.0001). The levels of CD14+ HLA-DR low/- cells were significantly correlated with circulating PSA levels and treatment with LHRH-agonist leuprolide in combination with either an antiandrogen or dexamethasone. Monocytes from tPCa inhibited autologous T cell proliferation statistically significantly more effectively than AMC monocytes and were defective in their ability to differentiate into phenotypically mature dendritic cells. Isolated CD14+HLA-DRlow/- cells expressed higher levels of intracellular interleukin-10 and suppressed T cell proliferation more effectively than isolated CD14+HLA-DR+ cells. CONCLUSIONS. This is the first report of CD14+ cells exhibiting reduced expression of HLADRmolecules in PCa patients. These cells suppress immune cell function in vitro and, plausibly, in vivo, a finding that must be factored into the design of immunotherapy protocols for PCa patients.

<p>U&nbsp; ovom&nbsp; radu&nbsp; ostvarene&nbsp; su&nbsp; sinteze C19-derivatizovanih&nbsp; steroidnih&nbsp; D-homo laktona.&nbsp; Takođe,&nbsp; sintetisani&nbsp; su&nbsp; i&nbsp; 5,6-halogeni derivati,&nbsp; 5,6-supstituisani&nbsp; kiseonični&nbsp; derivati,<br />kao&nbsp; i&nbsp; 6,19-epoksi&nbsp; steroidi.&nbsp; Za&nbsp; sva&nbsp; sintetisana jedinjenja&nbsp; je&nbsp; utvrđen&nbsp; antitumorski&nbsp; potencijal ispitivanjem&nbsp; njihove&nbsp; oralne&nbsp; bioraspoloživosti, antiproliferativne&nbsp; aktivnosti&nbsp; na&nbsp; &scaron;est&nbsp; ćelijskih linija&nbsp; kancera,&nbsp; vezivanja&nbsp; za&nbsp; odabrane&nbsp; steroidne receptore&nbsp; i&nbsp; inhibitorne&nbsp; aktivnosti&nbsp; na&nbsp; enzim AKR1C3.</p> / <p>In&nbsp; this&nbsp; paper,&nbsp; a&nbsp; synthesis&nbsp; of&nbsp; C19-derivatized steroidal D-homo lactones has been conducted. 5,6-Halogen derivatives, 5,6-substituted oxygen derivatives&nbsp; and&nbsp; 6,19-epoxy&nbsp; steroids&nbsp; were&nbsp; also synthesized.&nbsp; Antitumor&nbsp; potential&nbsp; was determined&nbsp; for&nbsp; all&nbsp; synthesized&nbsp; compounds&nbsp; by examining&nbsp; their&nbsp; oral&nbsp; bioavailability, antiproliferative activity on six cancer cell lines, binding&nbsp; to&nbsp; selected&nbsp; steroid&nbsp; receptors&nbsp; and inhibitor activity on the AKR1C3 enzyme.</p>

Androgen receptor (AR) gene CAG polymorphisms may be associated with body shape, and are associated with certain breast and prostate cancers. In addition, body shape is associated with risk for a variety of diseases, including heart disease, diabetes, and certain forms of cancer. The CAG repeat in exon l of the AR gene was quantified using Perkin Elmer Applied Biosystems GeneScan analysis software in 96 and 59 healthy Caucasian men and women, respectively, who were over the age of 50 years. All participants had body measurements taken and donated a blood sample. Waist measurements included circumferences at the 1) umbilicus (wstumb), 2) top of the iliac crest (wstili), and 3) midpoint between the lowest rib and the iliac crest (wstwst). Waist-hip ratio (Wl-IR) was calculated using each corresponding waist measurement, respectively (WHRUMB, WHRILI, WHRWST). Mean repeat length was significantly different (p < 0.01) between men (22 ± 0.3 repeats) and women (23 ± 0.3 repeats). There was a significant relationship (p < 0.05) between mean individual CAG repeat number and tertile of WHRUMB in women based on the mean number of CAG repeats for each woman. Waist measurements in women were significantly different for all pairwise comparisons (p < 0.05). In addition, the three measurements of WHR in women, WHRUMB, WHRILI, and WHRWST, were significantly different from each other (p < 0.05). Thus, lesser numbers of CAG repeats may indicate a more androgenic phenotype in women.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第19545号 / 理博第4205号 / 新制||理||1603(附属図書館) / 32581 / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 村山 美穂, 教授 幸島 司郎, 教授 伊谷 原一 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DFAM