Dissertations / Theses on the topic 'Anatomy, Pathological'

[Truncated abstract] Clinical and pathological predictors of survival for stage II and III colon cancer patients treated with or without chemotherapy: a population-based study. Aim: Using a population-based cohort of colorectal cancer (CRC), the major aims of this study were to: 1. Identify clinico-pathological markers that can be used to define a subset of stage II colon cancer patients with excellent prognosis and who therefore do not require referral for adjuvant chemotherapy; 2. Investigate whether there is a survival benefit from the use of adjuvant chemotherapy in a population-based cohort of stage II colon cancer; 3. Investigate stage III colon cancer patients for evidence of predictive markers for response to 5FU chemotherapy; 4. Investigate CRC for age-related differences in clinico-pathological and molecular features. Hypotheses to be tested: 1. A subset of good prognosis stage II colon cancers can be defined using routine pathological markers; 2. Females colon cancer patients gain more survival advantage from 5FU chemotherapy than males; 3. Tumours from young CRC patients have different molecular characteristics to those from older patients; 4. The underlying molecular characteristics of tumour can impact upon the response to 5FU chemotherapy. Methods: The study cohort consisted of 5,971 cases diagnosed between 1993 and 2003 representing over 90% of the CRCs diagnosed in the state of Western Australia. Results: The major findings of this translational research into colon cancer can be summarized as follows: The morphological features of serosal and vascular invasion allow for prognostic stratification of stage II colon cancer into

The human ankle joint is hypothesized to be a primary controller of support, propulsion and steering during locomotion. A series of experiments were initiated to understand ankle plantarflexor muscle kinematics and kinetics in normal and pathological gait, and to define the specific locomotor demands of community ambulation. Additional experiments were then conducted to quantify the effects of walking speed on plantar pressures and centre of mass motion, to illuminate the role of the ankle in acceleration and deceleration during walking, and to examine how humans alter their kinematics and kinetics to turn. The results of these experiments provide support for the hypothesis that the ankle joint is important in a wide range of locomotor movements beyond walking straight ahead at constant speed. The ankle appears instrumental in adapting to different walking speeds, altering both the pressures on specific regions the plantar surface and the motion of the centre of mass across a range of speeds. The ankle also has subtle kinetic changes that appear to modulate acceleration and deceleration during single limb stance. For turning, the ankle plays a role during slowing into the turn and accelerating after the turn, but mediolateral shears appear to alter the trajectory of the body to negotiate a corner and the external hip rotators appear to rotate the trunk toward the new direction of travel. This work extends our understanding of the ankle in functionally relevant gait activities beyond simple straight-ahead walking at constant speed. The published papers included in this supporting statement have been cited by 180 different subsequent peerreviewed publications, suggesting that this work has had some impact on the field.

Вступ. Мистецтво —це вид людської діяльності, що відбиває дійсність у конкретно-чуттєвих образах, відповідно до певних естетичних ідеалів. Мистецтво включає в себе багато стилів і напрямів і патологічна анатомія не є виключенням. Мета: Дослідити актуальність теми патологічної анатомії в мистецтві, починаючи з минулих сторіч до сучасності.

The subplate layer of the cerebral cortex is comprised of a heterogeneous population of cells and contains some of the earliest-generated neurons. Subplate plays a fundamental role in cortical development. In the embryonic brain, subplate cells contribute to the guidance and areal targeting of corticofugal and thalamic axons. At later stages, these cells are involved in the maturation and plasticity of the cortical circuitry and the establishment of functional modules. In my thesis, I aimed to further characterize the embryonic murine subplate by establishing a gene expression profile of this population at embryonic day 15.5 (E15.5) using laser capture microdissection combined with microarrays. I found over 250 transcripts with presumed higher expression in the subplate at E15.5. Using quantitative RT-PCR, in situ hybridization and immunohistochemistry, I have confirmed specific expression in the E15.5 subplate for 13 selected genes which have not been previously associated with this compartment. In the reeler mutant, the expression pattern of a majority of these genes was shifted in accordance with the altered position of subplate cells. These genes belong to several functional groups and likely contribute to the maturation and electrophysiological properties of subplate cells and to axonal growth and guidance. The roles of two selected genes - cadherin 10 (Cdh10) and Unc5 homologue c (Unc5c) - were explored in more detail. Preliminary results suggest an involvement of Cdh10 in subplate layer organization while Unc5c could mediate the waiting period of subplate corticothalamic axons in the internal capsule. Finally, I compared the expression of a selection of subplate-specific genes (subplate markers) between mouse and rat and found some surprising species differences. Confirmed subplate markers were used to monitor subplate injury in a rat model of preterm hypoxiaischemia and it appeared that deep cortical layers including subplate showed an increased vulnerability over upper layers. Further characterization of subplate-specific genes will allow us to broaden our understanding of molecular mechanisms underlying subplate properties and functions in normal and pathological development.

En croisant l'histoire médicale et l'histoire économique, notamment pour saisir et comprendre la production et la commercialisation des analyses médicales de laboratoires, cette thèse rend visible les aspects monétaires et économiques en jeu dans la recherche, l'enseignement et les pratiques médicales et scientifiques. L'émergence des analyses médicales de laboratoire en tant qu'unités économiques, dans un cadre théorique d'économie de la connaissance, est ainsi étudiée à partir d'une étude de cas, l'histoire d'un laboratoire d'anatomie pathologique à la Faculté de médecine de Strasbourg. Cet étude associe une analyse longue durée de la circulation des matériaux, des savoirs et des pratiques en anatomie pathologique à une micro-histoire d'un laboratoire dans l'entre-deux-guerres. Ce travail décrit et contextualise la diversification des activités de laboratoire quand un service commercial est associé à la recherche et à l'enseignement, comme ce fut le cas pour le diagnostic des cancers suite à la création des Centres Anticancéreux en France. Le marché des analyses de laboratoires médicaux ne correspond pas aux modèles économiques des entreprises scientifiques, médicales, ou commerciales : le laboratoire de l'Institut d'Anatomie Pathologique, entre science et service, était une entité commune à la Faculté de médecine et à l'hôpital, avec des pratiques de production et de commercialisation, des échanges académiques et commerciaux, des produits matériels et intellectuels, des rétributions sous formes d'honoraires et d'actes tarifés. Nous présentons ainsi une histoire économique d'une discipline dans laquelle l'argent n'était pas, du moins ouvertement, visible
By superposing medical history and economic history of medical lab services, this thesis reveals economic dynamics to be integral to medical and scientific research, teaching, and practice. The emergence of medical lab analyses as medical and economic entities within a theoretical framework of knowledge-based economies is achieved with a case study of Strasbourg's medical school Institut d'Anatomie Pathologique laboratories. A long duree historical analysis of material circulation, collection, and practices in pathological anatomy is intersected with a micro-history of the laboratories in the interwar period. The description and contextualization of a diversification of laboratory activities when research and teaching activities were complemented with commercial laboratory services, notably for the diagnosis of cancer, are portrayed with supply and demand dynamics and following the creation of the Centres Anticancéreux in France. The market for clinical laboratory work does not wholly fit (classic) models of scientific, medical, or commercial entreprises; the laboratory at the Institut d’Anatomie Pathologique was between science and service, institutional settings between medical school and hospital, practices between knowledge production and commercialization, exchanges between academic moral economies and commerical economies, products between material and intellectual, income between honorariums and fees. This thesis engages with and promotes an economic history of medicine in which money was not (openly) visible

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Neste estudo foi proposto (1) validar a assinatura genética de metástase previamente identificada pelo grupo para cinco genes candidatos (POLR1B, IKBKB, TRIP10, PGM5 e ATM), identificados como centrais em redes biológicas e correlacionar os dados de expressão com os dados clínicos e histopatológicos das pacientes; (2) confirmar o valor prognóstico do gene ATM e o seu mecanismo de regulação pelo miR-203, miR-421, miR- 576-5p, miR-664, miR-26a, miR-26b e miR-18a. Foi utilizada a metodologia de RT-qPCR em 63 amostras de carcinomas mamários (CM) e 5 de tecido mamário normal. Foram observadas correlações positivas entre os níveis de expressão dos genes detectados pela técnica de microarray e RT-qPCR, embora sem significância estatística. Não foram observadas diferenças significativas na expressão destes genes nos CM quando comparados às amostras de mama normais. Nas comparações entre os níveis de expressão e as características clínicas e histopatológicas pode-se observar que os genes IKBKB, POLR1B e PGM5 apresentaram aumento significativo de expressão em tumores ER positivos. Foram observadas diminuições significativas dos transcritos de IKBKB, TRIP10, PGM5 e ATM em tumores HER2 positivos; para os genes PGM5 e ATM houve uma diminuição significativa de expressão nos tumores grau III. A análise da expressão proteica do ATM foi realizada por imunoistoquímica em 926 amostras de CM organizadas em quatro plataformas de microarranjos de tecidos. Foi verificada a diminuição da expressão da proteína ATM nos tumores quando comparados com a amostra de tecido mamário normal e sua diminuição estava associada a tumores de alto grau e metástase à distância. Pacientes com tumores ATM-negativos apresentaram diminuição do tempo de sobrevida livre de doença e de...
The present study aimed: 1) to validate the genetic signatures of metastasis previously detected by our group for five candidate genes (POLR1B, IKBKB, TRIP10, PGM5, and ATM), identified as central in biological networks, and to correlate the findings with clinical-histopathological data; 2) to confirm the prognostic value of the ATM gene and its mechanism of regulation by miR-203, miR-421, miR-576-5p, miR-664, miR-26a, miR- 26b and miR-18a. Sixty-three breast carcinomas (BC) samples and 5 normal breast tissue samples were evaluated by RT-qPCR. Positive correlations were observed between the gene expression levels detected by microarray and RT-qPCR, although not statistically significant. There was no significant difference between BC and normal samples. Overexpression of IKBKB, POLR1B, and PGM5 genes were significantly associated with ER positive tumours. Significant downexpression of IKBKB, TRIP10, PGM5 and ATM transcripts were observed in HER2-positive tumours. PGM5 and ATM downexpression were statistically associated with grade III tumours. ATM protein expression was evaluated by immunohistochemistry in 926 BC samples organized into four tissue microarray platforms. A decreased ATM protein expression was observed in tumours when compared to normal tissue as well as with high grade tumours and distant metastasis. Patients with ATM-negative tumours showed a decrease of diseasefree survival and overall survival. After multivariate analysis, ATM revealed to be an independent prognostic marker in BC and have been associated with lower risk of metastasis and death by disease (P<0.001, HR=0.535, and P<0.001, HR=0.534, respectively). A negative correlation between the transcript levels of ATM and the miR- 664 (P=0.035, r=-0.293), and miR-421 (P=0.075 e r=-0.249, respectively) was verified. The miR-26a... (Complete abstract click electronic access below)

Para avaliar o benefício da utilização parenteral das vitaminas C e/ou E associadas ao quelante de cobre, tetratiomolibdato de amônio (TTM), na recuperação de ovinos com intoxicação cumulativa por cobre (ICC), foram analisados os parâmetros vitais; o metabolismo oxidativo, através das concentrações séricas de ácido úrico e malondialdeído, atividade sanguínea da glutationa reduzida, habilidade de redução férrica plasmática, atividade urinária de N-acetil-β-D-glucosamidase; peso vivo, hematócrito, concentração sérica de cobre, uréia, creatinina e as alterações anatomo-patológicas de 26 ovinos da raça Santa Inês, machos, com peso médio de 25 kg e distribuídos em quatro tratamentos: apenas com TTM, TTM + vitamina C (TTM+VC), TTM + vitamina E (TTM+VE) e TTM + vitaminas C e E (TTM+VCE). A associação das duas vitaminas aumentou o tempo de recuperação renal, porém reduziu a concentração sérica de cobre. A vitamina E mostrou efeito adverso ao esperado em relação à glutationa reduzida e ao malondialdeído séricos. Em algumas variáveis, como concentração sérica de creatinina e glutationa reduzida a utilização da vitamina C proporcionou tendência para melhores resultados em relação aos demais grupos, principalmente ao que possuíam vitamina E no tratamento, coincidentemente os animais deste grupo (TTM+VC) apresentaram a maior taxa de sobrevivência. Os estudos histopatológios e histoquímicos revelaram que a principal lesão hepática encontrada foi infiltrado inflamatório. Nos rins foram freqüentes o infiltrado inflamatório, glomérulonefrite e pigmentos. Constatou-se que, embora tenham ocorrido algumas variações pontuais entre os grupos, o tratamento com TTM associado às vitaminas C e/ou E não surtiu benefícios na recuperação física dos animais nem na redução do estresse oxidativo.
The efficiency of intra muscular vitamin C (VC) and/or E (VE) associated with the classical copper chelate tetrathiomolybdate (TTM) in cumulative copper poisoning treatment was evaluated. Twenty six Santa Inês male lambs weighting 25 kg were distributed in four treatment groups (TTM; TTM+VC; TTM+VE; TTM+VCE). The oxidative metabolism was analyzed through measurement of: serum concentrations of uric acid, malondialdehyde (MDA), blood reduced glutathione, ferric reducing ability of plasma and urinary activity of N-acetyl-β-D-glucosamidase. Live weight, hematocrit; copper, urea and creatinine serum concentrations and histopathological changes were determinated. Vitamins C and E association increased the time of renal recuperation, but reduced copper serum concentration. Serum MDA raised and blood reduced glutathione concentrations diminished in animals of TTM+VE group. Serum creatinine and blood reduced glutathione concentrations had tendency of better results in TTM+VC than TTM+VE and TTM+VCE. Survival index was greater in TTM+VC. Histopathology and histochemistry showed inflammatory infiltrate in liver as well as Glomerulonephritis, inflammatory infiltrate and pigments in the kidneys, in almost all animals. The association of TTM with vitamins C and/or E didnt reduce oxidative stress and had no positive effect on treatment.

Orientador: Silvia Regina Rogato
Coorientador: Sandra Drigo Linde
Banca: Patrícia Pintor dos Reis
Banca: Maria Isabel Alves de Souza Waddington Achatz
Resumo: Neste estudo foi proposto (1) validar a assinatura genética de metástase previamente identificada pelo grupo para cinco genes candidatos (POLR1B, IKBKB, TRIP10, PGM5 e ATM), identificados como centrais em redes biológicas e correlacionar os dados de expressão com os dados clínicos e histopatológicos das pacientes; (2) confirmar o valor prognóstico do gene ATM e o seu mecanismo de regulação pelo miR-203, miR-421, miR- 576-5p, miR-664, miR-26a, miR-26b e miR-18a. Foi utilizada a metodologia de RT-qPCR em 63 amostras de carcinomas mamários (CM) e 5 de tecido mamário normal. Foram observadas correlações positivas entre os níveis de expressão dos genes detectados pela técnica de microarray e RT-qPCR, embora sem significância estatística. Não foram observadas diferenças significativas na expressão destes genes nos CM quando comparados às amostras de mama normais. Nas comparações entre os níveis de expressão e as características clínicas e histopatológicas pode-se observar que os genes IKBKB, POLR1B e PGM5 apresentaram aumento significativo de expressão em tumores ER positivos. Foram observadas diminuições significativas dos transcritos de IKBKB, TRIP10, PGM5 e ATM em tumores HER2 positivos; para os genes PGM5 e ATM houve uma diminuição significativa de expressão nos tumores grau III. A análise da expressão proteica do ATM foi realizada por imunoistoquímica em 926 amostras de CM organizadas em quatro plataformas de microarranjos de tecidos. Foi verificada a diminuição da expressão da proteína ATM nos tumores quando comparados com a amostra de tecido mamário normal e sua diminuição estava associada a tumores de alto grau e metástase à distância. Pacientes com tumores ATM-negativos apresentaram diminuição do tempo de sobrevida livre de doença e de... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The present study aimed: 1) to validate the genetic signatures of metastasis previously detected by our group for five candidate genes (POLR1B, IKBKB, TRIP10, PGM5, and ATM), identified as central in biological networks, and to correlate the findings with clinical-histopathological data; 2) to confirm the prognostic value of the ATM gene and its mechanism of regulation by miR-203, miR-421, miR-576-5p, miR-664, miR-26a, miR- 26b and miR-18a. Sixty-three breast carcinomas (BC) samples and 5 normal breast tissue samples were evaluated by RT-qPCR. Positive correlations were observed between the gene expression levels detected by microarray and RT-qPCR, although not statistically significant. There was no significant difference between BC and normal samples. Overexpression of IKBKB, POLR1B, and PGM5 genes were significantly associated with ER positive tumours. Significant downexpression of IKBKB, TRIP10, PGM5 and ATM transcripts were observed in HER2-positive tumours. PGM5 and ATM downexpression were statistically associated with grade III tumours. ATM protein expression was evaluated by immunohistochemistry in 926 BC samples organized into four tissue microarray platforms. A decreased ATM protein expression was observed in tumours when compared to normal tissue as well as with high grade tumours and distant metastasis. Patients with ATM-negative tumours showed a decrease of diseasefree survival and overall survival. After multivariate analysis, ATM revealed to be an independent prognostic marker in BC and have been associated with lower risk of metastasis and death by disease (P<0.001, HR=0.535, and P<0.001, HR=0.534, respectively). A negative correlation between the transcript levels of ATM and the miR- 664 (P=0.035, r=-0.293), and miR-421 (P=0.075 e r=-0.249, respectively) was verified. The miR-26a... (Complete abstract click electronic access below)
Mestre

Актуальність. Проблема підготовки висококваліфікованих лікарів-спеціалістів є актуальним питанням сьогодення. Традиційні методичні підходи до вищої медичної освіти не завжди відповідають загальноєвропейським вимогам та не створюють умов для всебічного професійного навчання студентів-медиків. Бурхливий розвиток онлайн та мультимедійних технологій створює підґрунтя для ремоделювання процесу навчання у вищих медичних закладах України. Модернізація системи вищої медичної освіти України сприяє підвищенню рівня самостійності студентів, скороченню аудиторних годин. У зв’язку з цим гостро постає проблема засвоєння навчального матеріалу та контролю рівня знань студентів.

Вступ. З історії медицини відомо, що вчені вже на початку ХІХст. вказували на важливість поєднання клініки з патологічною анатомією. Вони підкреслювали, що патологічна анатомія залишається мертвою, «якщо буде обмежуватись тільки мертвим тілом»( Патологічна анатомія важливих частин людини», 1826р., Костомаров І.). Основним завданням патологічної анатомії є визначення відносин між змінами встановленими при житті і виявленими під час розтину. Необхідність вміння проведення порівнянь повинно бути віднесеним до обов'язкових елементів лікарської діяльності.

Вступ. З історії медицини відомо, що вчені вже на початку ХІХ ст. вказували на важливість поєднання клініки з патологічною анатомією. Вони підкреслювали, що патологічна анатомія залишається мертвою, «якщо буде обмежуватись тільки мертвим тілом»( Патологічна анатомія важливих частин людини», 1826р., Костомаров І.). Основним завданням патологічної анатомії є визначення відносин між змінами встановленими при житті і виявленими під час розтину. Необхідність вміння проведення порівнянь повинно бути віднесеним до обов`язкових елементів лікарської діяльності.

Les anatomopathologistes disposent d’outils permettant d’assister leurs décisions cliniques et d’évaluer les risques de récidive des patientes atteintes d’un cancer du sein. Parmi ceux-ci, le grade histologique du cancer du sein divise les patientes en trois sous-groupes pour lesquels le grade histologique 1 et 3 sont respectivement associés à de bons et mauvais pronostics. Cependant, cet outil est loin d’être parfait, dû au manque de reproductibilité de ce système et du risque de récurrence intermédiaire, peu informatif, des patients classés dans la catégorie « grade 2 ».

Afin de mieux caractériser ces tumeurs de risque intermédiaire, notre laboratoire a introduit un score appelé « Gene expression Grade Index (GGI) », basé sur l’expression de 97 gènes définis par microarrays. De façon intéressante, ce GGI permet de diviser les patientes de grade histologique 2, sur base de leur profil d’expression, en 2 groupes correspondant aux tumeurs de grade 1 ou aux tumeurs de grade 3. Cependant, bien que le GGI apporte une information importante, son applicabilité clinique est limitée par son prix et la nécessité d’utiliser du matériel congelé.

Durant ce travail de thèse, nous avons transposé la signature microarrays en un test RT-PCR, appelé PCR-GGI, basé sur l’expression de 8 gènes qui permet de reproduire les performances du GGI à partir de tissus congelés ou conservés dans de la paraffine. Cette amélioration permet de faciliter son utilisation en routine clinique.

De plus, nous avons approfondi notre connaissance du grade histologique, au niveau génomique et transcriptomique, et montré que les tumeurs mammaires (ER-positives) peuvent être divisées en deux groupes :un premier groupe de faible instabilité génomique, exprimant faiblement les gènes de prolifération et présentant un faible risque de récurrence ;et un deuxième groupe de haute instabilité génomique (impliquant principalement des amplifications localisées dans les régions 8q et 20q), une expression importante de gènes de prolifération et un mauvais pronostic.

D’autre part, les carcinomes canalaires in situ (DCIS) présentant des similarités avec les tumeurs invasives, nous avons voulu mieux comprendre le comportement du grade tumoral parmi ces tumeurs pré-invasives. Nous avons donc intégré le PCR-GGI au VNPI et défini le VNPI-GGI. Comparé au VNPI classique, le VNPI-GGI identifie mieux les patientes qui vont récidiver tôt dans les groupes de risque intermédiaire et haut, et permet donc d’éviter le sur-traitement.

Cependant, le calcul du VNPI est un travail fastidieux et le PCR-GGI seul ne permet pas de prédire les risques de récidives des DCIS. Nous avons donc cherché un nouveau marqueur pronostique. Alors, qu’il existe des preuves de plus en plus nombreuses supportant l’importance du rôle anti-tumoral des cellules myoépithéliales, nous avons montré qu’une diminution de l’expression de CD10 – un marqueur des cellules myoépithéliale – était hautement corrélée au risque de récidive. Ces résultats soulignent l’importance tant de l’agressivité de la tumeur que de son environnement directe, dans la progression tumorale.

En terme d’applications, les résultats obtenus durant ce travail de thèse nous ont permis de développer des outils utilisables par les cliniciens afin d’améliorer la prise en charge des patientes.

Traditional histopathological tools routinely used to evaluate breast cancer prognosis are designed to assist physicians in their evaluation of clinical outcome. The histological grade of invasive breast cancer, that assigns patients to one of 3 groups for which histological grade 1 and 3 tumors are respectively associated with lower and higher rate of recurrence, has long provided clinically important prognostic information. However, this tool is far from perfect due to concern over reproducibility and intermediate risk of recurrence of the histological grade 2 that is not informative for clinical decision.

To better characterize tumors classified as histological grade 2, our group has introduced a score called Gene expression Grade Index (GGI) based on a cassette of 97 genes defined by Microarrays. Interestingly, the GGI was able to reclassify patients with histological grade 2 tumors into 2 groups with distinct clinical outcomes similar to those of histological grade 1 and 3, respectively. However, its clinical applicability still remains expensive and often requires frozen tissue.

During this thesis work, we have transposed the GGI onto a qRT-PCR assay, called PCR-GGI, based on a set of 8 genes that could recapitulate in an accurate and reproducible manner the prognostic performance of GGI using both frozen and paraffin-embedded (FFPE) tumor samples, to facilitate its use in clinical practice.

Moreover, we have explored histological grade of invasive breast cancer at genomic and transcriptomic level and we have shown that two classes of ER-positive invasive breast cancer are observed: a first of low genomic instability, low proliferation gene expression and low risk of recurrence; and a second of high genomic instability (implying a major role for amplification of region located on chromosome arms 8q and 20q), high proliferation gene expression and worse prognosis.

In addition, since Ductal Carcinoma in situ (DCIS) and invasive breast cancer show concordant biologic behavior, we attempted to better understand the molecular basis of grade in pre-invasive breast cancer. We have then incorporated the PCR-GGI in the VNPI and defined the VNPI-GGI to improve its prognostic value. Compared to the classic VNPI, the VNPI-GGI had a better potential to identify early relapsing patients in the intermediate and high score group, and avoid under treatment in high-risk DCIS patients.

However, VNPI scoring is a tedious work and PCR-GGI alone can’t predict recurrence in pre-invasive breast cancer. We aimed then to find news prognosis marker in the field of DCIS. As there is now growing body of evidence supporting the role of myoepithelial cells (MECs) as natural tumor suppressors, we have showed that a decrease of CD10 expression- a surface biomarker of MECs – was significantly associated with an increased risk of relapse.

These results highlight the importance of assessing intrinsic DCIS properties as well as juxta-tumoral stroma, both seems to have a major role in DCIS progression.

In terms of applications, from these results obtained during this thesis work, we developed methods applicable into clinical practice to improve patients management.

Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

Els nòduls limfàtics(NLs) són estructures importants en el diagnòstic i pronòstic de malalties tant neoplàsiques com infeccioses. Estudis previs han associat els canvis observats per ecografia respecte a la grandària (augment del ratio eix-curt-eix llarg (S/L) a > 0,5), la forma (de allargada a arrodonida) i l'estructura interna dels NLs en éssers humans i gossos amb limfadenopatia. No obstant això, hi ha molt pocs estudis en gats en els quals es descriguin aquests paràmetres amb TC o US. Els objectius d’aquesta tesi van ser: (i)avaluar la capacitat de la tomografia computeritzada(TC) i l’ecografia(US) per identificar els NLs de gats sans i comparar els mesuraments d'imatge amb els valors anatòmics obtinguts; (ii)caracteritzar els NLs en gats malalts utilitzant TC i US; i (iii)avaluar la capacitat de cada tècnica de d'imatge (TC i US) per discriminar entre canvis neoplàsics i inflamatòries en els NLs. El nombre dels NLs identificats amb TC va ser més gran que amb US i l'anatomia. Els mesuraments obtinguts amb TC eren en general més alts que els obtinguts en l'anatomia i US. A més, les comparacions van mostrar diferències significatives entre les tècniques en els mesuraments, especialment l'altura. L’ús de reconstrucció multiplanar en TC va evitar la sobreestimació de la longitud i la altura detectada en els talls transversals. Els NLs identificats amb TC van mostrar una aparença similar a la descrita en el gos, essent freqüentment isoatenuats o lleugerament hipoatenuats a la musculatura que els envolta i amb realç de homogeni de contrast. En US,la majoria dels NLs van ser isoecoics o hipoecoics respecte el greix i amb forma allargada o arrodonida. Alguns NLs es van observar amb perifèria hipoecoica/isoecoica i centre hiperecoic en comparació amb la musculatura, a causa de la presència de greix en l’hil. La longitud, l'alçada i la ratio S/L, obtinguts amb TC i US, a més de les unitats Hounsfiel (HU) abans de l'administració de contrast, van ser estadísticament significatives entre els grups control i de casos per a les regions del tòrax, abdomen i extremitats anterior i posterior. A la regió del cap i el coll, les diferències estadístiques entre els grups de control i de casos es van observar només per a l'HU abans i després de l'administració de contrast i de la longitud i l'altura obtinguda per US. El ratio S/L obtingut per ambdues tècniques no va mostrar diferències entre les categories inflamatòries i neoplàsiques per a la regió de l'abdomen i les extremitats posteriors, però si en la regió del tòrax i les extremitats anteriors únicament amb TC. Els NLs neoplàsics vans ser frecuentment hipoatenuats i heterogenis. Mentre que, els inflamatoris van presentar distribució d’atenuacions amb freqüències similars al grup control. L'aspecte heterogeni i hipoatenuat freqüent en els NLs neoplàsics i alguns inflamatoris abans i després de l'administració de contrast podria suggerir canvis severs en l'estructura interna i la vascularització del NL, tot i que no va ser possible determinar un cert grau de malignitat amb TC. En US, els NLs neoplàsics van ser freqüentment hipoecoics o heterogenis. Els NLs inflamatoris van ser freqüentment hipoecoics. A la regió del cap i el coll, els NLs neoplàsics van ser més heterogenis i els NLs inflamatoris més hipoecoics. Els NLs neoplàsics van ser freqüentment arrodonits i amb marges irregulars a diferència dels inflamatoris i del grup control, en els quals sovint eren allargats i de marges llises. En conclusió, els NLs del gat és poden identificar amb les dues tècniques. La tomografia computaritzada va ser més precisa en la detecció i realització de mesuraments dels LNs que US. No obstant això, la superposició de les característiques d'ambdues tècniques en les categories del grup cas impedeix una distinció precisa entre els gats amb inflamació o neoplàsia.
Los nódulos linfáticos(NLs) son estructuras importantes en el diagnóstico y pronóstico de enfermedades tanto neoplásicas como infecciosas. Estudios previos han asociado los cambios observados por ecografía respecto al tamaño (aumento del ratio eje-corto-eje-largo(S/L) a >0,5), la forma (de alargada a redondeada) y la estructura interna de los NLs en humanos y perros con linfadenopatía. Sin embargo, existen muy pocos estudios en gatos en los que se describan estos parámetros con TC o US. Los objetivos de esta tesis fueron: (i) evaluar la capacidad de la tomografía computarizada(TC) y la ecografía(US) para identificar NLs de gatos sanos y comparar las mediciones de imagen con valores anatómicos obtenidos; (ii) caracterizar los NLs de gatos enfermos utilizando TC y US; y (iii) evaluar la capacidad de cada técnica de imagen (TC y US) para discriminar entre cambios neoplásicos e inflamatorios de los NLs. El número de NLs identificados fue mayor con TC que con US y anatomía. Las mediciones obtenidas con TC generalmente fueron más altas que las obtenidas en anatomía y US. Además, las comparaciones mostraron diferencias significativas entre las técnicas en las mediciones, especialmente la altura. El uso de la reconstrucción multiplanar en TC evitó la sobreestimación de la longitud y la altura detectada en los cortes transversales. Los LNs identificados con TC mostraron una apariencia similar a la descrita en el perro, siendo frecuentemente isoatenuados o ligeramente hipoatenuados a la musculatura alrededor y con realce homogéneo de contraste. En US, la mayoría de los NLs fueron isoecoicos o hipoecoicos respecto a la grasa y con forma alargada o redondeada. Algunos LNs se observaron con periferia hipo/isoecoica y centro hiperecoico en comparación con la musculatura, debido a la presencia de grasa en el hilio. La longitud, la altura y el ratio S/L obtenidos con TC y US, además de las unidades Hounsfield(HU) antes de la administración de contraste, fueron estadísticamente significativas entre los grupos control y caso para las regiones del tórax, abdomen y miembros anterior y posterior. En la región de la cabeza y el cuello, las diferencias estadísticas entre los grupos control y caso fueron observadas solamente para el HU antes y después de la administración de contraste y para la longitud y la altura obtenidas por US. El ratio S/L obtenido con ambas técnicas no mostró diferencias entre las categorías inflamatorias y neoplásicas para la región del abdomen y las extremidades posteriores, pero si en la región del tórax y las extremidades anteriores únicamente con TC. Los NLs neoplásicos fueron frecuentemente hipoatenuados y heterogéneos. Mientras que, los inflamatorios presentaron distribución de atenuaciones con frecuencias similares al grupo control. La apariencia heterogénea e hipoatenuado en los NLs neoplásicos y algunos inflamatorios antes y después del contraste podría sugerir cambios importantes en la estructura interna y la vascularización del NL, aunque un determinado grado de malignidad no fue posible de identificar con TC. En US, los NLs neoplásicos fueron frecuentemente hipoecoicos o heterogéneos. Los NLs inflamatorios fueron frecuentemente hipoecoicos. Para la región de la cabeza y el cuello, los NLs neoplásicos fueron más heterogéneos y los NLs inflamatorios más hipoecoicos. Los NLs neoplásicos fueron frecuentemente redondeados y con márgenes irregulares a diferencia de los inflamatorios y del grupo control, los cuales a menudo fueron alargados y de márgenes lisas. En conclusión, los NLs del gato se pueden identificar con ambas técnicas. La tomografía computarizada fue más precisa en la detección y realización de mediciones de los NLs que US. Sin embargo, la superposición de las características de ambas técnicas en las categorías del grupo caso no permitió una distinción precisa entre la gatos con inflamación o neoplasia.
The lymph nodes (LNs) are structures that play an important role in the diagnosis and prognosis of neoplastic and infectious diseases. Descriptions about the changes in size (increase of a short-to-long-axis ratio (S/L)>0.5), the shape (from elongated to rounded) and the internal structure of LNs assessed with ultrasound are associated with lymphadenopathy in humans and dogs. However, there are few studies assessing these parameters in cats. The aims of the studies described in this thesis were (i) to assess the ability to identify the LNs of healthy cats with computed tomography (CT) and ultrasonography (US) and to compare the imaging measurements with measurements from normal anatomic values; (ii) to characterize the LNs in diseased cats using CT and US; and (iii) to assess the ability of each imaging technique (CT and US) to discriminate between neoplastic and inflammatory changes in the LNs. The number of LNs identified with CT was higher than with US and anatomy. The measurements obtained with CT were in general higher than those obtained in anatomy and with US. Additionally, the comparisons showed that there were statistically significant differences in the measurements, specially the height, among techniques. With CT-reconstructed images, the overestimation of the length and height is prevented in comparison with the transverse slices. The LNs identified with CT showed a similar appearance than previously described being most frequently isoattenuating or slightly hypoattenuating to the surrounding musculature, with homogeneous contrast enhancement. Most LNs were isoechoic or hypoechoic to the surrounding fat tissue on US images. The majority of LNs were fusiform or rounded. Some LNs presented a hypoechoic/isoechoic periphery with a hyperechoic center when compared with the musculature, due to the presence of a fatty hilus. The length, height, and S/L ratio, obtained with CT and US, and the HU before contrast administration were significantly different between the control and the case group for the thorax and forelimb, and the abdomen and hindlimb regions. In the region of the head and neck, statistical differences between the control and case groups were only observed for the HU before and after contrast administration and for the length and height obtained with US. The S/L ratios were no significant different between the inflammatory and neoplastic categories in both techniques for the region of the abdomen and hindlimb, and only for the CT in the region of the thorax and forelimb. The neoplastic category presented high frequencies of heterogeneous attenuating and hypoattenuating LNs. Meanwhile, the inflammatory category presented a similar frequency of attenuations to the control group. The heterogeneous and hypoattenuating appearance of the most neoplastic and some inflammatory LNs before and after contrast administration could suggest severe changes in the internal structure and vascularization but a certain degree of malignancy was not possible to determined with CT. On US, the neoplastic LNs were most frequently hypoechoic or heterogeneous, meanwhile inflammatory LNs were more frequently hypoechoic. In the region of the head and neck, results suggest that neoplastic LNs are more heterogeneous and inflammatory are more frequently hypoechoic. The neoplastic LNs in our study presented a rounded shape more frequently than inflammatory LNs and the control group, in which they were often fusiform. The inflammatory LNs often presented regular margins. However, irregular margins were seen in markedly enlarged lymph nodes, especially in neoplastic LNs. In conclusion, identification of the LNs of the cat is possible with both techniques. Computed tomography was more accurate in the detection and performance of measurements of the LNs than US. However, overlapping in the features of both techniques in the categories of the case group prevents an accurate distinction between inflammation and neoplasia.

La maladie d’Alzheimer (MA) est caractérisée au niveau histopathologique par la présence de plaques amyloides dans le cerveau. Ces plaques sont formées par l’accumulation de peptides amyloides (A) issus du clivage de la Protéine Précurseur Amyloide (APP). Les fonctions physiologiques précises de cette protéine ubiquitaire restent à ce jour peu connues. Le but de cette thèse a consisté à étudier les rôles physiologiques et pathologiques joués par APP in vivo, en utilisant une approche d’interférence de l’ARN. La première phase de ce travail a consisté à identifier des petits ARN interférents efficaces dirigés contre la forme murine (mAPP-siRNA) et la forme humaine (hAPP-siRNA) de APP. Les effets comportementaux de l’injection dans le cerveau de ces siRNAs ont ensuite été observés dans des souris sauvages et transgéniques. Tout d’abord, l’administration de mAPP-siRNAs dans le cerveau de souris sauvages a provoqué une diminution de 30% de l’expression de APP dans l’hippocampe, et a induit des déficits dans un test d’alternance spontanée, ce qui suggère une implication de APP dans la mémoire de travail spatiale. En revanche, des souris APP knockout n’ont pas présenté de déficits dans ce même test, ce qui suggère la mise en place probable de phénomènes compensatoires. Enfin, l’application de la technologie siRNA au modèle murin APP23 de la MA a révélé la réversibilité de l’hyperactivité locomotrice, suggèrant une implication directe de la surexpression de APP/A dans l’hyperactivité locomotrice de ces souris. Il est probable que des applications thérapeutiques des siRNAs seront développées dans les prochaines années, y compris pour certaines maladies neurodégénératives
Alzheimer’s Disease (AD) is characterized at the histopathological level by the presence of amyloid plaques in the brain. Amyloid plaques are formed by the accumulation of Abeta peptides (A), which are derived from the proteolytic processing of Amyloid Precursor Protein (APP). The precise physiological functions of this ubiquitous protein remain elusive. The aim of the present thesis was to study the physiological and pathological roles of APP in vivo by using a RNA interference approach. In the first in vitro phase of the thesis, effective small interfering RNAs were identified for mouse APP (mAPP-siRNAs) and human APP (hAPP-siRNAs). Then, the behavioral effects of the infusion of these active APP-siRNAs in the brain were examined in wild type and transgenic mice. In a first study, the infusion of mAPP-siRNAs in the brain of wild type mice resulted in a 30% knockdown of APP expression in the hippocampus accompanied by spontaneous alternation deficits at the behavioral level. This finding suggests that APP could play a role in spatial working memory. In contrast, APP KO mice were not impaired in spontaneous alternation behavior, suggesting the probable occurrence of compensatory mechanisms. Finally, the siRNA-technology was applied to the APP23 AD mouse model and revealed the reversibility of the locomotor hyperactivity phenotype. This last result suggests a direct implication of APP/A overexpression in the locomotor hyperactivity phenotype displayed by these mice. Therapeutic applications of siRNAs will likely be developed in the next years, maybe even for the treatment of certain neurodegenerative disorders

L'hippocampe est une région du cerveau importante pour la formation de mémoire. Des études récentes ont montré que la zone CA2 de l'hippocampe, longtemps ignorée, joue un rôle clef dans certaines formes de mémoire et notamment dans la mémoire sociale. De plus, des études post-mortem ont révélé des altérations spécifiques à la région CA2 chez les patients schizophrènes. Cependant, l’implication des neurones de CA2 dans les circuits de l'hippocampe reste peu connu, tant dans des conditions physiologiques que pathologiques. En combinant pharmacologie, génétique et électrophysiologie sur tranches d’hippocampe de souris, nous avons étudié comment les neurones pyramidaux (NP) CA2 sont recrutés dans les circuits hippocampiques après des changements d’inhibition et comment le recrutement des NP CA2 pourrait moduler l’information sortant de l'hippocampe. D’autre part, nous avons examiné les altérations fonctionnelles de la zone CA2 dans le modèle murin Df(16)A+/- de la microdélétion 22q11.2, le facteur génétique de risque de schizophrénie le plus élevé. Dans la région CA2 de l’hippocampe, les synapses inhibitrices contrôle les afférences des collatérales de Schaeffer (CS) et expriment une dépression à long-terme (DLTi) unique qui dépendant des récepteurs delta-opioïdes (RDO). Contrairement aux synapses CS-CA1, les synapses excitatrices CS-CA2 n’expriment pas de potentialisation à long-terme après application des protocoles d'induction. Cependant, nous avons constaté que différents types d'activités induisent une augmentation durable de l’amplitude des potentiels post-synaptiques (PPS) évoqués aussi bien par une stimulation des CS que des afférences distales des NP CA2, et ceci via une modulation de la balance excitation/inhibition. Nous avons démontré que ces augmentations du rapport excitation/inhibition sont les conséquences directes de la DLTi RDO-dépendante. De plus, la DLTi permet le recrutement des NP CA2 par les NP CA3 alors qu’une inhibition intacte empêche complètement leur activation en réponse aux stimulations des CS. Par ailleurs, le recrutement des pyramides de CA2 par les CS après disinhibition activité-dépendante ajoute une composante polysynaptique (SC-CA2-CA1) au PPS monosynaptique (SC-CA1) dans les NP CA1 et augmente leur activité. De plus, l’inactivation des interneurones exprimant la parvalbumine à l’aide d’outils pharmacogénétiques, a montré que ces cellules inhibitrices contrôlent fortement l'amplitude du PPS et l’activité des NP CA2 en réponse à la stimulation des CS et qu’elles sont nécessaires à l'augmentation RDO-dépendante du rapport excitation/inhibition entre CA3 et CA2. Enfin, l'étude de la zone CA2 chez les souris Df(16)A+/- a révélé plusieurs modifications dépendantes de l'âge dont une réduction de l'inhibition, une altération de la plasticité du rapport excitation/inhibition entre CA3 et CA2 et une hyperpolarisation NP CA2. Ces modifications cellulaires peuvent expliquer les déficiences de mémoire sociale que nous observons chez les souris Df(16)A+/- adultes. L’ensemble de nos études a permis de mettre en évidence le rôle des neurones CA2 dans les circuits de l'hippocampe. Enfin pour conclure, nous postulons que le recrutement des neurones CA2 dans les réseaux neuronaux sous-tend des aspects particuliers de la fonction de l'hippocampe
The hippocampus is a region of critical importance for memory formation. Recent studies have shown that the long-overlooked hippocampal region CA2 plays a role in certain forms of memory, including social recognition. Furthermore, post-mortem studies of schizophrenic patients have revealed specific changes in area CA2. As yet, the role of CA2 neurons in the hippocampal circuitry remains poorly understood under both normal physiological and pathological conditions. By combining pharmacology, mouse genetics and electrophysiology, we investigated how CA2 pyramidal neurons (PNs) could be recruited in hippocampal circuits in mice hippocampal slices following an activity-dependent change in the strength of their inhibitory inputs. We further investigated how subsequent recruitment of CA2 PNs could modulate hippocampal output. Moreover, we examined the functional alterations of area CA2 in the Df(16)A+/- mouse model of the 22q11.2 microdeletion, a spontaneous chromosomal deletion that is the highest known genetic risk factor for developing schizophrenia. In area CA2, inhibitory synapses exert a powerful control of Schaffer collateral (SC) inputs and undergo a unique long-term depression (iLTD) mediated by delta-opioid receptor (DOR) activation. Unlike SC-CA1 synapses, SC-CA2 excitatory synapses fail to express long-term potentiation after classical induction protocols. However, we found that different patterns of activity persistently increase both the SC and the distal input net excitatory drive onto CA2 PNs via a modulation of the balance between excitation and inhibition. We demonstrated that increases in the excitatory/inhibitory ratio are direct consequences of the DOR-mediated iLTD. Interestingly, we found that the inhibition in area CA2 completely preventing CA3 PNs to activate CA2 PNs, and following iLTD, SC stimulation allows CA2 PNs to fire action potentials. Moreover, the recruitment of CA2 PNs by SC intra-hippocampal inputs after their activity-dependent disinhibition adds a delayed SC-CA2-CA1 response to the SC-CA1 monosynaptic post-synaptic potential (PSP) in CA1 and increases CA1 PN activity. Furthermore, pharmaco-genetic silencing of parvalbumin-expressing interneurons revealed that these inhibitory cells control the PSP amplitude and the firing of CA2 PNs in response to SC stimulation and are necessary for the DOR-mediated increase in excitatory/inhibitory balance between CA3 and CA2. Finally, we found several age-dependent alterations in area CA2 in Df(16)A+/- mouse model of the 22q11.2 microdeletion. These included a reduction in inhibition, an impaired activity-dependent modulation of the excitatory drive between CA3 and CA2 and a more hyperpolarized CA2 PN resting potential. These cellular disruptions may provide a potential mechanism for the social memory impairment that we observe in Df(16)A+/- adult mice. Altogether, our studies highlight the role of CA2 neurons in hippocampal circuitry. To conclude, we postulate that the recruitment of CA2 neurons in neuronal networks underlies key aspects of hippocampal function

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To evaluate the safety of single intravitreal injection of 0,1ml of sunitinib (one group with 1mg/ml and the other group with 10mg/ml), 0,1ml of a solution containing solid lipid nanoparticles and 0,1ml of a solution containing nanocapsules analyzing the possible toxic effects by the electrophysiology and histology in the albino rabbits retina. An experimental controlled study was performed with 20 eyes of albino rabbits. It were performed intravitreal injections of 0,1ml (1mg/ml) of sunitinib in 5 eyes, 0,1ml (10mg/ml) of sunitinib in 5 eyes, 0,1ml of nanocapsules solution in 5 eyes and 0,1ml of a solution containing solid lipid nanoparticles in 5 eyes. Contralateral eye did not receive any treatment and was used as control. Changes in electroretinography were not observed in groups of sunitinib (1mg/ml and 10mg/ml) and in the group of solid lipid nanoparticles. However, in the group of the nanocapsules significant changes were found. They were in the morphology and at the electroretinogram. At histological study only the group of nanocapsules degenerative changes were detected. Changes were severe edema and formation of cytoplasmic vacuoles, suggesting retinal toxicity.
O presente estudo teve por objetivo avaliar a segurança da injeção intravítrea de 0,1ml de sunitinibe (um grupo com 1mg/ml e o outro grupo com 10mg/ml), 0,1ml de solução contendo nanocápsulas e 0,1ml de solução contendo nanopartículas lipídicas sólidas analisando os possíveis efeitos tóxicos à retina de coelhos albinos detectados pela eletrofisiologia e histologia por microscopia óptica. Foi realizado estudo experimental, com 20 olhos de coelhos albinos, nos quais foram realizadas injeções intravítreas de 0,1ml (1mg/ml) de sunitinibe (5 olhos), 0,1ml (10mg/ml) de sunitinibe (5 olhos), 0,1ml de solução contendo nanocápsulas (5 olhos) e 0,1ml de solução contendo nanopartículas lipídicas sólidas (5 olhos). Os olhos adelfos não receberam injeção e foram utilizados com o controle. Não foram observadas alterações eletrorretinográficas nos grupos do sunitinibe (1mg/ml e 10mg/ml) e no grupo das nanopartículas lipídicas sólidas. No grupo das nanocápsulas houveram alterações significativas tanto na morfologia quanto na amplitude e tempo das ondas do eletrorretinograma. Ao estudo histológico, somente o grupo das nanocápsulas apresentou alterações degenerativas (núcleos tumefeitos) com acentuado edema e formação de vacúolos citoplasmáticos, sugerindo toxidade retiniana.

Contexte: La grande majorité des mutations délétères identifiées sur le gène BRCA1 sont des mutations « privées ». Cependant, certaines d’entre elles proviennent d’un ancêtre commun, à l’origine d’un effet fondateur. Ainsi, la mutation BRCA1-3600del11 (c.3481_3491del11, p.Glu1161Phefs*3) est localisée en France pour 82% des familles porteuses et 85% d’entre elles sont originaires du quart Nord-Est. En 2006, cette mutation représentait respectivement 51,5% et 42,0% de toutes les mutations du gène BRCA1 identifiées dans les familles lorraines et alsaciennes atteintes d’un cancer du sein et/ou de l’ovaire. En 2004, parmi les 27 cas-index ayant consulté en Alsace et présentant une mutation de BRCA1, 37% sont porteurs de cette mutation, tous issus de familles originaires des Vosges, suggérant l’existence d’un effet fondateur. L’identification d’un haplotype commun est venue confirmer l’existence de cette hypothèse. Une équipe alsacienne a mentionné dans deux publications en 2000 et 2004 sur la mise en évidence de la mutation 3600del11 que les caractéristiques des cancers associés à cette mutation, ne plaidaient pas en faveur d’une relation génotype-phénotype. Or, les caractéristiques anatomo-pathologiques des cancers associés à cette mutation n’ont pas été abordées par ces deux publications. Nous nous sommes alors posés la question de caractéristiques anatomo-pathologiques particulières des cancers du sein et des cancers de l’ovaire diagnostiqués chez les femmes porteuses de cette mutation dans notre région. Nous nous sommes également posés la question de l’existence d’un phénomène d’anticipation génétique dans ces familles. L’anticipation génétique est la survenue plus précoce d’une pathologie et/ou l’aggravation de ses signes cliniques lors de la transmission d’une mutation d’une génération à la suivante au sein d’une même famille. Très peu d’études ont cherché à mettre en évidence ce phénomène d’anticipation dans des cohortes issues de familles de syndrome sein-ovaire associées à une mutation de BRCA1 ou BRCA2. Les études publiées présentaient des biais de sélection du fait de l’inclusion de patients non testés dans leur analyse. Les études publiées sur des cohortes issues de familles présentant une mutation sur le gène BRCA1/2 suggéraient que le dépistage ciblé et l’excès de surveillance pourraient avoir une influence sur l’âge au diagnostic d’un cancer du sein chez les jeunes femmes incluses.Les améliorations majeures au niveau de la mammographie et du traitement du cancer du sein, de même que le programme de dépistage organisé pour les femmes de 50 ans et plus sont apparues en France, après 1980. A notre connaissance, à ce jour, aucune étude n’a été réalisée en France visant à identifier un phénomène d’anticipation génétique dans les familles associées à une mutation sur BRCA1ou BRCA2 et à analyser ce phénomène.Objectif: Notre premier objectif est de constituer une première cohorte lorraine de patientes porteuses de la mutation 3600del11 et d’analyser les caractéristiques anatomo-pathologiques des cancers du sein et de l’ovaire liés à cette mutation. Notre deuxième objectif rechercher l’existence d’une anticipation génétique dans des familles présentant la mutation fondatrice BRCA1-3600del11.Patientes: Quatre cent quatre patientes sont porteuses d’une mutation BRCA1 à l’Institut de Cancérologie de Lorraine (ICL) sur la période s’étendant de 1994 à 2012, parmi elles, nous avons identifié les patientes porteuses de la mutation BRCA1-3600del11. Nous avons identifié à l’Institut de Cancérologie de Lorraine, 38 paires mères-filles atteintes d’un cancer du sein ou de l’ovaire issues de 37 familles présentant le syndrome sein-ovaire associé à cette mutation dont 25 paires mères-filles atteintes d’un cancer du sein et 13 paires mères-filles atteintes d’un cancer de l’ovaire [...]
Introduction: Over 1000 alterations in the BRCA1 gene have been documented. Most of these are frameshifts and ~10% are missense mutations that generate stop codons leading to a truncated and therefore inactive BRCA1 protein. In the French population, prevalence of BRCA1 mutations has been reported in few studies; In a preliminary study of 14 breast and/or ovarian cancer families, a frequent BRCA1 mutation was detected in five unrelated families; the c.3481_3491del11 mutation (BIC: 3600del11), an 11 base-pair deletion in exon 11 leading to a premature stop codon at 1165. In a second study carried out in 2004 involving 27 index cases, the c.3481_3491del11 mutation accounted for 37%. The haplotype analysis of the families carrying the mutation c.3481_3491del11, all originating from Alsace-Lorraine (North-East of France), revealed the presence of a common allele, indicating a founder effect. Purpose: To an attempt to better define the clinical and pathologic characteristics of breast and ovarian cancer related with the 3600del11 BRCA1 mutation, we report our experience with breast and ovarian cancer patients carrying the 3600del11 mutation at the Lorraine Oncology Institute in France. The aim of the current analysis is also to evaluate any differences of breast or ovarian cancer age at diagnosis between mothers and daughters carrying the c.3481_3491del11 mutation in the BRCA1 gene.Patients: Within the population who were referred between 1994 and 2012 to our oncogenetic clinic at the Lorraine oncology institute and who underwent genetic testing for BRCA1 and BRCA2, we identified 404 women carrying a BRCA1 mutation. Interestingly, 45% (180 of 404) of women with detected BRCA1 mutation had the germline 3600del11 mutation. These women were members of 89 different families with breast and or ovarian cancer cases. A study cohort of 38 women carrying the c.3481_3491del11 mutation and affected by first breast or ovarian cancer who reported a first breast or ovarian cancer in their mother carrying the c.3481_3491del11 mutation, was identified in 37 different families including members with breast and/or ovarian cancer at the Oncology Institute of Lorraine. Twelve mothers underwent genetic testing. Twenty five pairs of the 38 mothers-daughters pairs with c.3481_3491del11 mutation were affected by breast cancer and 13 pairs by ovarian cancer.Methods: Clinical and genetic data were collected from medical files and family pedigrees. Analyses were conducted for each cancer type. We investigated an early breast cancer detection effect due to early screening programs and also an increased breast tumor aggression. Since major improvements in breast cancer clinical management and imaging techniques appeared after 1980, we compared the age at breast cancer diagnosis and the age at death in mothers and daughters before and after 1980, first, in the group of women including mothers and daughters taken together and then in mothers and daughters separately. Genetic data were retrieved from familial files and clinical and pathological data from medical files. Descriptive statistics for the study population were calculated using the SPSS software (version 20.0). Results: Ninety one patients (71, 7%) were affected by first breast cancer and 31 (24,4%) by ovarian cancer. Breast tumors were identified in 37.4% of cases aged <40 years. Estrogen receptor status and progesterone receptor status were reported to 67 patients. Hormonal receptors status was positive in 31.4% of breast tumors. A triple-negative subtype was found in 21 cases, which accounts for 65.6% of the 32 patients with 3600del11 mutation for whom HER2 status was available. Ovarian tumors of the serous type, which constitute about 71 percent of all epithelial ovarian carcinomas, predominate among patients with 3600del11 mutation. Eighty six per cent of carriers were diagnosed at advanced stages III/IV [...]

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Introduction. Tumor growth and metastasis depend greatly on angiogenesis. There are several angiogenic growth factors able to induce new vessels in renal tumors, but the most important are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF). The aim of our study was to investigate expression of b-FGF and to quantify microvessel density (MVD) in oncocytomas and renal cell carcinomas (RCCs) and to relate these parameters of tumor vascularity to other clinicopathological features. Material and Methods. b-FGF and CD31 immunostaining were performed on formalin-fixed paraffin-embedded archival tissues from Larpac Laboratories files, including 36 RCCs (10 conventional, 10 papillary, 8 sarcomatoid, and 8 chromophobe) and 5 oncocytomas. Angiogenesis was quantified microscopically by two independent observers. Results. b-FGF was positive in all five oncocytomas and only in seven of 36 RCCs: 5 of conventional type, 1 papillary, and 1 chromophobe. All sarcomatoid carcinomas were negative. The expression of b-FGF was not related to tumor size, grade, stage, or short survival in either group. MVD mean value was 124.16 ± 50.1 in oncocytomas and 91.54 ± 52.4 in RCCs. The pattern of vascularization observed in oncocytomas was characterized by a fine vascular network around groups of tumor cells although in RCCs the microvessels tended to be more disorganized. When analyzing only carcinomas, patients who died within 12 months after the diagnosis had a tumoral MVD mean value significantly higher (124.12 ± 75.2) than that observed in patients who were still alive one year after diagnosis (80.34 ± 37.8). ix Conclusion. We demonstrate that b-FGF is expressed more often in oncocytomas than in RCCs but MVD is similar in both groups of tumors. The high expression of b-FGF in oncocytomas may reflect the peculiar pattern of vascularization of these tumors. High MVD in rapidly lethal RCCs is an indication that angiogenesis may be correlated with the degree of malignancy of these tumors.
O desenvolvimento dos tumores e das suas metastases dependem em grande parte da angiogenese tumoral. Existem varios fatores de crescimento capazes de induzir à neoformação vascular nas neoplasias renais, porém, os mais importantes são o fator de crescimento do entotélio vascular (vegf) e o fator de crescimento fibroblástico básico (bfgf). O objetivo deste estudo foi o de investigar a expressão do b-fgf e a densidade microvascular (dmv) nos oncocitomas e nos carcinomas de células renais (ccrs) e correlacionar estes parâmetros da vascularização tumoral com outros ascpectos clínico-patológicos. Material e métodos. O estudo imunohidtoquímico para o b-fgf e o cd31 (densidade microvascular) foi realizado em material fixado em formalina e incluído em parafina de 36 casos de ccrs (10 convencionais, 10 papilíferos, 8 sarcomatóides e 8 cromófobos) e 5 oncocitomas, oriundos de exames anátomo-patológicos por dois observadpres independentes. Resultados. Nota de Resumo Foi encontrada positividade para o b-fgf em todos os 5 casos de oncocitomas e em 7 dos 36 casos de ccrs: 5 do tipo convencional, um papilífero, e um cromófobo. Todos os carcinomas sarcomatóides mostraram-se negativos. A expressão tumoral do b-fgf não apresentou correlação com tamanho tumora, grau histológico, estadio patológico, ou sobrevida a curto prazo em nenhum dos grupos. O valor médio da dvm foi de 124,16 +/- 50,1 nos oncocitomas e de 91,54 +/- 52,4 nos ccrs. O padrão de vascularização observado nos oncocitomas era caracterizado por um delicado leito vascular envolvendo grupos de celulas tumorais, enquanto que nos ccrs a microvascularização se apresentou de forma mais organizada. Entre os carcinomas, os tumores que se mostraram letais nos 12 primeiros meses após o diagnóstico, apresentaram um ídice angiogênico significativamente maior (124,12 +/- 75,2) em relação aos pacientes que ainda permaneciam vivos um ano após o diagnóstico (80,34 +/- 37,8). Conclusão. Demostramos que o b-fgf está expresso mais freqüentemente nos oncocitomas do que nos ccrs. Nota de Resumo Apesar de as dmv ser semelhante em ambos os grupos tumorais, observou-se um padrão de vascularização característico nos oncocitomas. Uma dvm mais elevada nos ccrs, rapidamente letais é indicativo de que a angiogenese possa estar correlacionada com grau de malignidade destes tumores.

Робота присвячена проблемі встановлення закономірностям структурних змін при пошкодженні стегнового і сідничного нервів. Пошкодження стегнового і сідничного нервів викликали шляхом пережиму задніх кінцівок на рівні верхньої третини стегна за допомогою кровоспинного затиску впродовж 1-4 годин, а також шляхом перерізування цього нерва. Контролем служили задні кінцівки контралатеральной сторони. При перетині сідничного нерва зміни в кінцівки проходять ряд послідовних стадій. Ми досліджували ранні зміни при цих станах. У першу годину після перетину сідничного нерва спостерігається зменшення питомої маси м'язового волокна з її зниженням до четвертого годині експерименту При перетині стегнового нерва зміни в м'язах передньої групи відбуваються аналогічно змінам м'язів задньої групи стегна і відбуваються в тій же послідовності. При перетині стегнового нерва діаметр артеріол до четвертого годині експерименту збільшується в 1,3 рази, а венул в 1,7 рази. Діаметр капілярів при цьому не змінюється.

Дисертаційна робота присвячена вивченню патоморфологічних ознак зобів, аденом та раків щитоподібної залози. Визначені їх основні комплексні диференційно–діагностичні ознаки. Стверджується, що головною передумовою для розвитку патологічних морфогенезів є переважання позасудинних ланцюгів мікроциркуляції, зниження ступеня участі ГК в морфогенетичних процесах в ЩЗ, а також ефективності циркуляції ТР по стромальних каналах. Наведені в роботі комплексні патоморфологічні диференційні ознаки зобів, аденом, фолікулярних та папілярних карцином значно полегшують морфологічний аналіз гістологічних препаратів органа при діагностиці неопластичних процесів щитоподібної залози. Запропоновано способи оцінки прохідності позасудинних шляхів мікроциркуляції за станом колагенових волокон строми при електронномікроскопічному дослідженні та розповсюдженню імуногістохімічних маркерів у крупно- та дрібногранулярних фрагментах цитоплазми фолікулярних тироцитів в стромальних каналах.

Дисертація присвячена вивченню діагностичного значення особливостей експресії онкогенез-залежних маркерів в дифузних гліомах головного мозку та встановленню основних та додаткових імуноморфологічних критеріїв для визначення Grade та типу пухлини. Запропоновано оцінку ЩРМ з використанням негативного контрастування стінки і просвіту судин (GFAP, EGFR, IDH1 R132H). Для диференційної діагностики ДГ ГМ Grade II і III запропоновано використовувати Ki-67 з визначенням ІП пухлинних клітин (p<0,0001) та ендотелію (p<0,05), а також GFAP (з метою точної оцінки ЩРМ, p=0,01), MMP3 (p<0,05), EGFR (p<0,05). Основними маркерами для диференційної діагностики гліом Grade III і IV є IDH1 R132H (p<0,001) та віментин (p=0,00001); додатковими – цитокератин AE1/AE3 (p<0,05), MMP9 (p<0,05). При сумнівному типі пухлини (астроцитарний чи олігодендрогліальний) для підвищення ступеня верифікації діагнозу потрібно використовувати рівень експресії віментину (p=0,001) та GFAP (p<0,05).

Дисертація присвячена вивченню експресії маркерів при диспластичних та неопластичних процесах шийки матки для удосконалення їх гістологічної діагностики. В дослідженні вивчена інтенсивність процесів проліферації, диференціювання та онкотрансформації при диспластичних та неопластичних процесах та їх зв’язок з персистуючою інфекцією, викликаною вірусами папіломи людини. Вперше визначено взаємозв’язок між характером та ступенем виразності диспластичних та неопластичних процесів та рівнем експресії імуногістохімічних маркерів. У результаті комплексного дослідження розроблені категорії оцінки експресії імуногістохімічних маркерів. Визначені чутливість, специфічність, негативне передбачувальне число та позитивне передбачувальне число для використання оцінки експресії кожного маркеру для виявлення диспластичних ушкоджень, наявності генетичного матеріалу вірусів папіломи людини високого канцерогенного ризику та ступеня диференціювання пухлин.

Дисертація присвячена вивченню прогностичного та передбачувального значення імуногістохімічних маркерів в ПР ОФО та встановленню основних та додаткових критеріїв для визначення особливостей клінічного перебігу. Вперше були уточнені імунофенотипи ПР ОФО, що мають високий ризик метастазування в регіональні лімфатичні вузли шиї та низьку чутливість до хіміотерапії. Статистично підтверджено, що при виявленні ПР ОФО з високим ризиком метастазування в регіональні лімфатичні вузли шиї, з прогностичною метою, як основні, треба використовувати маркери Е-кадгерин (р<0,001), CD34, -катенін, Кі-67 (р<0,01), як додаткові, ММР-9, VEGF, р21WAF1 (р<0,05). При виявленні ПР ОФО з низькою чутливістю до хіміотерапії в першу чергу з передбачувальною метою треба використовувати як основні маркери р21WAF1 (р<0,001), VEGF, ММР-9 (р<0,01), як додаткові Кі-67, Е-кадгерин, CD34, ММР-1 (р<0,05). Встановлені кореляційні зв’язки між клініко-морфологічними особливостями ПР ОФО та показниками експресії вищезазначених маркерів. Розраховані чутливість, специфічність, НПЧ і ППЧ щодо використання показових маркерів з прогностичною та передбачувальною метою в діагностиці ПР ОФО.

Дисертація присвячена вивченню рівня експресії маркерів біологічних параметрів для доброякісних та злоякісних мезенхімальних пухлин тіла матки. Уточнені імунофенотипи при цих типах патології. Вперше чітко встановлені основні та додаткові критерії при проведенні диференційної діагностики між лейоміомами, лейоміосаркомами, ендометріальними стромальними вузлами та саркомами ендометріальної строми різного ступеня злоякісності. Доведено та статистично підтверджено, що такі маркери як ER, PgR, Ki-67, p-53, p21, bax, cyclin D1, VEGF, TSP-1, CD34, CD-10, α-SMA, десмін, h-кальдесмон можуть бути застосовані в якості діагностичних при неепітеліальних пухлинах тіла матки. Вперше розроблено комплексні диференційно-діагностичні критерії для уточнення злоякісного потенціалу новоутворень тіла матки мезенхімального походження, а також з'ясування їх гістоґенезу. Отримані дані дозволяють на підставі імуноморфологічного профілю пухлин визначитися з гістологічним діагнозом, біологічними параметрами патологічного процесу та оптимізувати лікувальну тактику.

Дисертаційна робота присвячена вивченню експресії молекулярних маркерів в плоскоклітинних раках гортані для удосконалення діагностики та прогнозування подальшого клінічного перебігу захворювання. В дослідженні проведено аналіз експресії фракцій цитокератинів, онкопротеїнів р53 та bcl-2, проліферативної активності (на основі експресії Кі-67) в пухлинах в залежності від ступеня диференціювання, наявності метастазів, виникнення рецидивів, ефективності проведеного хіміопроменевого лікування. Визначено діагностичне, прогностичне й передбачувальне значення кожного маркера біологічних властивостей. Встановлено імунофенотипи раків гортані, що відповідають кожному ступеню диференціювання пухлин з високим ризиком метастазування, рецидивування, ймовірною чутливістю до хіміотерапії і променевого лікування. Запропоновано комплекс маркерів, що дозволяють уточнити гістологічний ступінь диференціювання пухлини (фракції цитокератинів), прогнозувати ймовірність метастазування та розвитку рецидивів протягом першого року (експресія онкобілків р53 і bcl-2, висока проліферативна активність), передбачати можливу ефективність проведення хіміотерапевтичного (відсутність експресії онкобілку р53) та променевого лікування (відсутність експресії онкобілку bcl-2, висока проліферативна активність).

Thesis (Ph.D.)--University of the Witwatersrand, Faculty of Health Sciences, 2012
Background and Purposes Suicide by hanging is a relatively common occurrence. The actual cause of death in suicidal hanging is, however, controversial, having been attributed variously to asphyxia, carotid artery compression and vagal nerve stimulation. The aim of this Ph.D thesis was to determine the possible neurovascular cause of death in suicides by hanging by careful study of the anatomy and physiology of the neck region in relation to the ensuing pathology. The study was, therefore, approached from an anatomical, physiological, histological and pathological pespective. It therefore comprised a detailed exploration of the anatomy and physiology of the neck structures to match these with the underlying traumatised neurovascular structures, the latter trauma being brought about by the suicidal hanging process. Methods The methods used in the study included an investigation of the ligature and position of the ligature in relation to the level of the neck and the physical effects of the ligature on the skin and underlying anatomical structures. A careful and detailed dissection of the neck was undertaken and samples of the vessels and nerves were processed for histological study. Fifty consecutive cases of suicidal hanging and five “non-hanging” cases which served as controls were used in the study. In addition, ten cases of suicidal hanging not included in the study were subjected to occlusion studies by means of probe exploration. This technique and procedure was not carried out or applied to the cases included in the study for fear that the probe itself might produce artefactual damage to the delicate endothelium lining the inner layer of the vessel wall. The study was classified into various components such as: 1. Examination of the type and structure of the ligature material; 2. The position of the ligature on the neck, i.e. whether involving upper, middle, or lower third of neck and to correlate this position with the underlying anatomical structures subjected to the accompanying tensile, compressive and haemodynamic forces; 3. The physical effects of the ligature upon the skin and the underlying deeper neurovascular structures of the neck; 4. Meticulous “bloodless” dissection of the neck structures to corroborate any pathology noted with the above three criteria. Currently, all putative causes of death remain speculative; 5. Particular attention was paid to those structures most vulnerable to the compressive forces, tensile forces and haemodynamic forces operative in hanging. These comprise the neurovascular structures contained within the fibrous carotid sheath and the phrenic nerves in the neck, in particular with regard to the anatomical relationship of these structures to the positioning of the ligature. As far as analysing the forces involved, the engineering principles pertaining to these were interpreted in consultation with the Faculty of Engineering at the University of the Witwatersrand. Results The main findings of the study showed damage to vascular, neural (including phrenic nerve), carotid bodies and accessory glomal bodies. The vascular findings emerged following an examination of the total number of arteries in the study, namely, 300, the figure derived as follows: six arteries in each of the fifty hanging subjects, viz., the left common carotid artery, the right common carotid artery, the left internal carotid artery, the right internal carotid artery, the left external carotid artery and the right external carotid artery (6 x 50 = 300). The damage shown was particularly the case with regard to the finding of tears in the various layers of the vessel wall. These extended from the intima through to the adventitia or outermost layer of the vessel wall and these were further subdivided into being either single or multiple. The tears found ranged from those involving the intima alone (single tears being found in 17 (5.6%) of the 300 arteries examined and multiple tears in 37 (12.3%) of the 300 arteries examined., the intima extending to the internal elastic lamina (single tears being found in 20 (6.6%) of the 300 arteries examined and multiple tears in 8 (2.6%) of the 300 arteries examined), tears involving the intima and extending through to involve the media, i.e. intimomedial tears and whether these latter tears involved the inner-, middle-, or outer-thirds of the media (single or multiple). Single intimo-medial tears extending through the intima to involve the inner-third of the media comprised 6 (2.0%) of the arteries examined, those extending from the intima to involve the middle-third of the media comprised 3 (1.0%) of the 300 arteries examined and single intimo-medial tears extending through the intima to involve the outeriv third of the media similarly comprised 3 (1%) of the arteries examined. Multiple intimo-medial tears extending through from intima to inner-, middle-, and outerthirds of the media respectively, comprised 3 (1.0%), 5 (1.6%) and 1 (0.3%) of the arteries examined. Single tears involving the inner-third of the media alone comrised 6 (2.0%) of the 300 arteries examined, single tears involving the middle-third of the media comprised 9 (3.0%) of the arteries examined and single tears involving the outer-third of the media alone comprised 8 (2.6%) of the arteries examined. Multiple tears involving the inner-, middle and outer-thirds of the media respectively comprised 6 (2.0%), 13 (4.3%) and 16 (5.3%) of the arteries examined. Single tears involving both adventitia and media, i.e. adventitio-medial tears extending through the inner-, middle-, or outer-thirds of the media to involve the adventitia comprised 1 (0.3%), 2 (0.6%) and 6 (2.0%) respectively of the 300 arteries examined. Multiple adventitio-medial tears of the inner-, middle-, and outer-thirds of the media, respectively, comprised 0 (0.0%), 3 (1.0%) and 2 (0.6%) of the 300 arteries examined. Single tears of the adventitia alone comprised 21 (7.0%) of the arteries examined while multiple tears comprised 7 (2.3%). Complete circumferential transverse rupture of the vessel wall was found in 3 (1.0%) of the arteries examined while adventitial haemorrhage was found in 103 (34.3%) of the 300 arteries examined. The vascular findings were represented numerically in tabular form in the 50 hanging subjects in Table III and were further analysed and compared with regard to either unilateral or bilateral vessel involvement in the fifty (50) suicidal hanging subjects and the findings represented in Tables IIIa (unilateral involvement) and IIIb (bilateral involvement). Additional vascular findings comprised endothelial elevation/avulsion, internal elastic lamina dehiscence, subendothelial clefts, multiple medial fenestrations, adventitio-medial separation, vascular congestion and a vascular plane of cleavage. These were similarly represented in Table IV and analysed with regard to unilateral or bilateral involvement in Tables IVa and IVb. Endothelial elevation/avulsion was found in 295 (98.3%) of the 300 arteries examined, internal elastic lamina dehiscence in 290 (96.6%) of the arteries examined, subendothelial clefts in 289 (96.3%) of the arteries examined, multiple medial fenestrations in 17 (5.6%) of the arteries examined, adventitiomedial separation in 273 (91.0%) of the arteries examined, vascular congestion in 224 (74.6%) of the arteries examined and a vascular plane of cleavage in 98 (32.6%) of the arteries examined. These findings, unexpected, showed the extreme fragility and vulnerability of the intima and adventitia to the compressive and tensile forces acting on the vessel wall during hanging, being explicable not only on the basis of the various complex forces interacting simultaneously during hanging but on the magnitude of forces applied. A mathematical analysis, found at the end of the Discussion chapter, conducted in order to estimate the minimum peak pressure applied and exerted on the vessel wall during hanging, in collaboration with the School of Mechanical, Industrial and Aeronautical Engineering at the University of the Witwatersrand, confirmed the magnitude of these forces. The neural findings (Table V) were divided into neural congestion, neural haemorrhage, neural internal dehiscence, neural tearing and perineural separation and these were similarly analysed with regard to either unilateral or bilateral involvement in the fifty hanging subjects (Tables Va and Vb). Neural congestion was found in association with 20 (6.6%) of the 300 arteries examined, neural haemorrhage in14 (4.6%), neural internal dehiscence in 54 (18.0%), neural tearing in 35 (11.6%) and perineural separation in 112 (37.3%). Neural ganglionic findings were similarly divided into ganglionic congestion, ganglionic haemorrhage, ganglionic internal dehiscence and ganglionic tearing. Ganglionic congestion, in association with the 300 arteries examined, was found in 20 (6.6%), ganglionic haemorrhage in 8 (2.6%), ganglionic internal dehiscence in 15 (5.0%) and ganglionic tearing in 6 (2.0%). The findings in the carotid bodies were divided into carotid body congestion, carotid body haemorrhage, carotid body internal dehiscence and carotid body tearing. Carotid body congestion, in association with the 300 arteries examined, was found in 8 (2.6%), carotid body haemorrhage in 2 (0.6%), carotid body internal dehiscence in 4 (1.3%) and carotid body tearing in 2 (0.6%). Accessory glomal body findings were, once again, divided into accessory glomal congestion, accessory glomal haemorrhage, accessory glomal internal dehiscence and accessory glomal tearing. However, in view of the close anatomical association between the accessory glomal bodies and the adventitia of the arterial walls, an additional pathological finding of accessory glomal adventitial separation emerged. Accessory glomal congestion, in association with the 300 arteries examined, was found in 20 (6.6%), accessory glomal haemorrhage in 7 (2.3%), accessory glomal internal dehiscence in 50 (16.6%), accessory glomal tearing in 18 (6.0%) and accessory glomal adventitial separation in 124 (41.3%). This latter finding once again demonstrated the vulnerability of the adventitial layer of the vessel wall to tensile forces, separating it from its associated structures. Damage to the phrenic nerves and surrounding muscles, underlying the site of ligature application, was similarly found, suggesting a role for phrenic nerve stimulation with consequent diaphragmatic paralysis in contributing to death in the hanging process. Discussion and Conclusion In this Ph.D thesis the principles of dimensional analysis i.e., the breaking down of a complex phenomenon into its component parts, have been applied. However, in view of the complexity and proximity of structures to one another in the neck, consisting not only of the rigid hyoid-larynx complex and vertebral column but also the integrated vascular and neural structures, it appears that not one single biological mechanism can be ascribed and attributed to the cause of death in suicidal hanging. Rather, it appears that unconsciousness and death causation appears to be multifactorial. Both the sympathetic and parasympathetic arms of the autonomic nervous system are involved, often with antagonistic and therefore paradoxical effects. In a ddition, pressure to the phrenic nerve, not previously considered in playing a role in death causation in hanging, may, it is suggested, be a major contributory factor in death causation. This nerve, the innervation to the major muscle of respiration, i.e. the diaphragm, in a neural response to the compressive and tensile forces in hanging, fixes the diaphragm in a state of inspiratory paralysis. This latter effect would be further augmented by neural stimulation of the accessory muscles of respiration, i.e. the sternocleidomastoid and scaleni muscles, similarly lying deep to the site of ligature application, contributing to the thoracic cage becoming fixed in a state of inspiratory paralysis. This latter effect, as described in that section of the Discussion chapter dealing with an analysis of the physiological functions at play, is brought about by initiation of the dynamic and static stretch reflexes occurring in these muscles on application of a compressive or tensile stimulus. Compression of the carotid arteries, on the other hand, results, as shown, not only in major damage to these vessels and their accompanying veins, but, in addition, must produce a dramatic element of cerebral ischaemia with ensuing loss of consciousness. It thus appears that loss of consciousness is the critical factor for it is the state when the victim is no longer able to save himself or herself. Without loss of consciousness survival may occur, but with it, death becomes inevitable. The question then arises :- what is the cause of unconsciousness? In physiological terms, carotid artery occlusion induces rapid unconsciousness, i.e. within 11 to 12 seconds, resulting ultimately in death. In other words, the sudden application and unremitting pressure of the ligature must inevitably result in death. On the other hand, the sudden application of a ligature with consequent vagal nerve compression may produce instantaneous cardiac arrest with cessation of blood flow to the brain and resultant loss of consciousness. This event would produce unconsciousness in less than the time period of 11 seconds of carotid artery occlusion (although the brain continues to survive for several minutes thereafter despite cessation of heart beat). If, however, unconsciousness is contributed to by phrenic nerve compression, it would not be instantaneous as shown by the fact that one can normally hold one’s breath for several minutes (as underwater swimmers do) and unconsciousness does not supervene either instantaneously or within 11 seconds. In short, unconsciousness would not occur within 11 seconds in the case of compression of the phrenic nerve unless a more critical factor supervenes.Thus, the rapidity of onset of unconsciousness appears to be the critical factor in determining the progression to ultimate (and inevitable) death. Moreover, as pointed out in the Materials and Methods chapter, the carotid arteries in several tested cases would not allow the passage of a probe through the obstructed arteries beneath a tightly applied ligature. This obstruction would, therefore, appear to be the initiator of the deadly unconsciousness factor, although respiratory arrest would be compounded by neural and muscular factors. While in this thesis the principles of dimensional analysis i.e., the breaking down of a complex phenomenon into its component parts have been applied, the principles of integrated analysis i.e., the combining and synthesis of separate parts into a whole have also been attempted. In essence, while it is suggested that the neural elements play a pivotal role in the hanging process due to the neural effect on both brain and heart as a result of autonomic nervous system stimulation and the function of the phrenic nerve in respiration, it appears that multiple factors, acting in concert, simultaneously or in rapid sequence to one another, all play a role in contributing to death causation in the hanging process.

The purpose of the study was to investigate the static and dynamic architecture of supraspinatus throughout its volume in the normal and pathological state. The architecture was first investigated in cadaveric specimens free of any tendon pathology. Using a serial dissection and digitization method tailored for supraspinatus, the musculotendinous architecture was modeled in situ. The 3D model reconstructed in Autodesk MayaTM allowed for visualization and quantification of the fiber bundle architecture i.e. fiber bundle length (FBL), pennation angle (PA), muscle volume (MV) and tendon dimensions. Based on attachment sites and architectural parameters, the supraspinatus was found to have two architecturally distinct regions, anterior and posterior, each with three subdivisions. The findings from the cadaveric investigation served as a map and platform for the development of an ultrasound (US) protocol that allowed for the dynamic fiber bundle architecture to be quantified in vivo in normal subjects and subjects with a full-thickness supraspinatus tendon tear. The architecture was studied in the relaxed state and in three contracted states (60º abduction with either neutral rotation, 80º external rotation, or 80º internal rotation). The dynamic changes in the architecture within the distinct regions of the muscle were not uniform and varied as a function of joint position. Mean FBL in the anterior region shortened significantly with contraction (p<0.05) but not in the posterior. In the anterior region, mean PA was significantly smaller in the middle part compared to the deep (p<0.05). Comparison of the normal and pathological muscle found large differences in the percentage change of FBL and PA with contraction. The architectural parameter that showed the largest changes with tendon pathology was PA. In sum, the results showed that the static and dynamic fiber bundle architecture of supraspinatus is heterogeneous throughout the muscle volume and may influence tendon stresses. The architectural data collected in this study and the 3D muscle model can be used to develop future contractile models. The US protocol may serve as an assessment tool to predict the functional outcome of rehabilitative exercises and surgery.

abstract: The unique anatomical and functional properties of vasculature determine the susceptibility of the spinal cord to ischemia. The spinal cord vascular architecture is designed to withstand major ischemic events by compensating blood supply via important anastomotic channels. One of the important compensatory channels of the arterial basket of the conus medullaris (ABCM). ABCM consists of one or two arteries arising from the anterior spinal artery (ASA) and circumferentially connecting the ASA and the posterior spinal arteries. In addition to compensatory function, the arterial basket can be involved in arteriovenous fistulae and malformations of the conus. The morphometric anatomical analysis of the ABCM was performed with emphasis on vessel diameters and branching patterns. A significant ischemic event that overcomes vascular compensatory capacity causes spinal cord injury (SCI). For example, SCI complicating thoracoabdominal aortic aneurysm repair is associated with ischemic injury. The rate of this devastating complication has been decreased significantly by instituting physiological methods of protection. Traumatic spinal cord injury causes complex changes in spinal cord blood flow (SCBF), which are closely related to a severity of injury. Manipulating physiological parameters such as mean arterial pressure (MAP) and intrathecal pressure (ITP) may be beneficial for patients with a spinal cord injury. It was discovered in a pig model of SCI that the combination of MAP elevation and cerebrospinal fluid drainage (CSFD) significantly and sustainably improved SCBF and spinal cord perfusion pressure. In animal models of SCI, regeneration is usually evaluated histologically, requiring animal sacrifice. Thus, there is a need for a technique to detect changes in SCI noninvasively over time. The study was performed comparing manganese-enhanced magnetic resonance imaging (MEMRI) in hemisection and transection SCI rat models with diffusion tensor imaging (DTI) and histology. MEMERI ratio differed among transection and hemisection groups, correlating to a severity of SCI measured by fraction anisotropy and myelin load. MEMRI is a useful noninvasive tool to assess a degree of neuronal damage after SCI.
Dissertation/Thesis
Doctoral Dissertation Neuroscience 2016

Aims: Aim of this work is to analyze the various field of application of Magnetic Resonance Imaging in endodontics and highlight its current advantages and limitations due to understand its future application in research and clinical practice. The effectiveness in revealing the presence or absence of a pathological condition affecting enamel, dentin, endodontic space and the quality of the apical seal of an endodontic sealing technique was investigated. Materials and methods: Three extracted monoradicular teeth were analyzed using a Bruker Avance-400 high-resolution spectrometer operating at 9.4 T with a microimaging probe (10 mm internal diameter), equipped with a gradient unit characterized by a maximum gradient strength of 1200 mT/m and a rise time of 100 μs. XWINNMR® and ParaVision® 3.0 software were employed for data acquisition and analysis. Images of teeth were weighted in T2 at different TE to measure T2 relaxation times and in Apparent Diffusion Coefficient (ADC) in different regions of interest (ROI). Results: T2 and ADC values were obtained at different ROI. Clear images of carious lesions, periodontal tissues, pulpar remnants and endodontic materials such as guttapercha cones were acquired. Presence of microcracks and a calcification of the pulp were also clearly differentiated. Conclusions: Micro MRI is a non-invasive, non-destructive tool for the assessment of pathological conditions affecting dental hard and soft tissues, and it may help in finding endodontic procedural mistreatments such as incomplete detersion or inadeguate tridimensional filling in vitro.

Univerzita Karlova v Praze Přírodovědecká fakulta Studijní program: Filosofie a dějiny přírodních věd MUDr. Jan Hrudka Nádory v dějinném a kulturním kontextu v novověku Tumours in historical and social context in the modern period Disertační práce Školitel / Supervisor: Prof. RNDr. Stanislav Komárek, Dr. Praha, 2017 SUMMARY: The PhD thesis called Tumours in historical and social context in the modern period is an attempt to describe a change of medical thinking in modern period; science and medicine turns from antique humoral pathology, explaining all diseases as an imbalance of the four body humours, to pathological anatomy and experimental physiology. In the point of view of pathological anatomy, the viscera of diseased person are no more "screen" or "mirror" of the disease, but it becomes directly the "stage" or "theatre" of the acting disease. This shift in the thought may be labelled as movement from humoralism to localism or ontologism; the disease isn't just abnormal amount of some natural juice any more, but becomes new original entity. This change undergoes the understanding of tumours and cancerous disease as well. Instead of antique understanding tumours as precipitates of black bile, the cell theory occurs in the 19th century. This theory explains tumours as a mass of cells undergoing excessive...

This thesis concisely describes transformation of medical way of thinking in Eu- rope from hippocrato-galenic tradition to anatomo-pathological understanding of human body. It aims to trace conditions, that allowed rise of organic and later tissual pathology. Thesis also shows ideological shift in medical thinking concer- ning localization faculties of soul (shift from so called ventricular paradigm to localization faculties of soul into solid parts of brain). These ideas also affected reception of causes of mental illness. 1