Les maladies neurodégénératives se caractérisent par une déconnexion synaptique et une dégénérescence des axones (DA) précoces, menant à la mort spécifique d’une population neuronale. Les niveaux intracellulaires de NAD+, co-facteur essentiel dans le maintien de l’intégrité axonale, sont fortement diminués lors de ces pathologies. L’augmentation des taux de NAD+ est ainsi une stratégie thérapeutique dans la prévention de ces maladies. La capacité du nicotinamide riboside (NR) à retarder la DA dans le système nerveux périphérique (SNP) ainsi que la récente mise en évidence d'une conversion extracellulaire du NAD+ en NR dans des lignées cellulaires et dans le SNP soulignent l'intérêt de ce précurseur du NAD+. Mon projet de thèse repose sur la caractérisation des effets du NAD+ et du NR lors de la DA dans des neurones du système nerveux central (SNC). A partir d'un modèle d'excitotoxicité mis au point en dispositifs microfluidiques, nous montrons pour la première fois que le NR protège de la DA dans des neurones corticaux de manière plus efficace que le NAD+. Cet effet différentiel a également été validé dans un modèle ischémique in vivo. De manière surprenante, lors d'une neurodégénérescence induite par une déplétion aigüe en NAD+, un effet protecteur total à la fois du NAD+ et du NR a été mis en évidence. L'analyse de la voie de conversion extracellulaire a ainsi révélée une adaptation du métabolisme du NAD+ et de sa conversion en NR en fonction du paradigme neurotoxique. En conclusion, ce travail démontre un fort effet protecteur du NR dans le SNC et ouvre de nouvelles voies thérapeutiques dans la prévention des processus neurodégénératifs. / Synaptic and axonal degeneration (AxD) are major events in neurodegenerative diseases. Levels of NAD+, an important coenzyme for axonal integrity, are strongly reduced in different degeneration models so enhancing cellular NAD+ is one of the numerous therapeutic strategies against neuronal pathologies. Nicotinamide riboside (NR) is a good NAD+ precursor as it has already been shown to delay AxD in peripheral nervous system (PNS) and extracellular NAD+ conversion to NR was previously described in cell lines and in PNS. During my thesis project, we analyzed the role of NR metabolism to prevent degeneration processes in cortical neurons. Using an excitotoxicity model developed in microfluidic devices, we showed for the first time that both NAD+ and NR delay AxD in cortical neurons, with a more potent effect for NR. We confirm this differential effect in an in vivo ischemic model. Moreover, NR effect is mainly restricted to the axonal compartment and intracellular NAD+ depletion is reverted after NR application, suggesting that axonal integrity is totally dependent on NAD+ local metabolism. Furthermore, in a complete NAD+ depletion paradigm, NAD+ and NR have surprisingly the same strong effect, protecting equally neuronal death and AxD. Examination of the extracellular pathway suggest that NAD+ conversion to NR is limited in excitotoxicity but effective in the NAD+ depletion model. These results reveal that NR and NAD+ metabolism depend on the neurotoxic paradigm. Our results demonstrate that NR has a strong and local neuroprotective effect on AxD in several neurotoxic processes. These findings open new therapeutic strategies to prevent neurodegenerative diseases.

Esta dissertação tem como objetivo situar o momento cultural vivido por Fialho de Almeida, intercalado à vida e obra do autor para, a partir daí, investigar possíveis críticas de seu trabalho com o intuito de avaliar em que condições escrevia e porque sua obra foi capaz de suscitar inúmeras interpretações. Sendo assim, seu trabalho crítico e alguns contos serão analisados de forma a compreender não só a utilização de características pertencentes a determinadas escolas, mas principalmente, sua posição diante da propagação de questões vividas pela sociedade da época, considerando sua influencia dos autores da Geração de 70 e as duras críticas que proferiu anos mais tarde ao já consagrado Eça de Queirós. Por ter acompanhado intensamente as mudanças sofridas por Portugal ao longo dos anos, buscava retratar o que a sociedade e alguns homens de letras desejavam esconder. A literatura do século XIX revelou conflitos que a exigente moral burguesa impunha e ocultava. Fialho de Almeida faz questão de destacar esses conflitos. Sendo assim, é comum encontrar ambientes insalubres e degradantes em que vivem pessoas em extrema pobreza, assim como as doenças e mazelas humanas ao lado dos chamados vícios e degenerescências. Examinamos também a recepção da obra de Fialho, para indagar os motivos que o levaram a ocupar um lugar secundário na literatura do século XIX / The purpose of this dissertation is to identify the cultural moment lived by Fialho de Almeida, together with his life and works, from there, examinee possible criticism of his work. The purpose is to evaluate the conditions he wrote and why his work promote numerous interpretations. Thus, his critical work and some novels will be analyzed, in order to understand, not only the use of features belonging to certain literary schools, but mainly, his position regarding the spread of issues faced by the society of the time, considering the influence of the authors of the Generation of 70 in his work and the harsh criticism he made years late to Eça de Queiróz. He accompanied the intense changes suffered by Portugal over the years, and sought to portray what the society wanted to hide. The literature of the nineteenth century showed the conflicts demanding bourgeois morality imposed and compelled its followers to hide. Fialho de Almeida wishes to highlight these conflicts. Therefore, it is common to find in his work degrading and unhealthy ambients in which people live in extreme poverty, diseases, addiction and degenerations. In the last chapter, based on the receipt of his novels, we try to get evidences of the reasons that led him to a secondary place in the literature of the nineteenth century

abstract: Introduction. Intervertebral disc degeneration (DD) is one of the most common diagnoses in patients with neck pain and contributes to worldwide disability. Despite the advances in diagnostic imaging today, little is known about functional status of cervical DD. The purpose of this research was to 1) develop and validate an ovine model of cervical spine DD, 2) to quantify and compare the effect of disc lesions on dynamic spinal stiffness, and 3) study the effect of disc lesions on spinal accelerations and displacements during two types of spinal manipulative therapy (SMT). Methods. Fifteen sheep received surgically induced disc injury to the mid-cervical spine via scalpel wound a minimum of five months earlier and 15 sheep served as controls. All animals were biomechanically assessed at the level of the lesion using swept-sine mechanical loads from 0-20 Hz under load control to quantify dynamic dorsoventral (DV) spine stiffness (load/deformation, N/mm). The effect of disc lesion on stiffness was assessed using a one-factor repeated measures ANOVA comparing 32 mechanical excitation frequencies. Tri-axial accelerometers rigidly attached to adjacent vertebrae across the target level further evaluated the effect of disc lesion on spinal motion response during two types of SMTs. A 2x6x2 repeated measures ANOVA examined the effect of disc lesion and SMT force-time profile on spine motion response. Postmortem histological analysis graded specimens at the target site and comparison was made with descriptive statistics. Results. Annular disc tears were only observed in the disc lesion group and the mild degeneration identified was localized to the injured annular tissue that did not progress to affect other areas of the disc. No difference in overall DD grading was found among the groups. DV stiffness was significantly increased in the disc lesion group by approximately 34% at 31 of 32 frequencies examined (p<.05). SMTs resulted in decreased displacements in the disc lesion group (p<.05), and SMT type significantly influenced spinal accelerations for both the DV and axial planes. Conclusion. Disc lesions in the ovine cervical spine produce localized annular degenerative changes that increase the cervical spine dynamic stiffness and reduce its spinal motion response during manual examination and treatment that is further augmented by the force-time profile administered by the clinician. / Dissertation/Thesis / Doctoral Dissertation Kinesiology 2015

abstract: Intervertebral Disc Degeneration (IVDD) is a complex phenomenon characterizing the desiccation and structural compromise of the primary joint in the human spine. The intervertebral disc (IVD) serves to connect vertebral bodies, cushion shock, and allow for flexion and extension of the vertebral column. Often presenting in the 4th or 5th decades of life as low back pain, this disease was originally believed to be the result of natural “wear and tear” coupled with repetitive mechanical insult, and as such most studies focus on patients between 40 and 50 years of age. Research over the past two decades, however, has demonstrated that environmental factors have only a modest effect on disc degeneration, with genetic influences playing a much more substantial role. Extensive research has focused on this process, though definitive risk factors and a clear pathophysiology have proven elusive. The aim of this study was to assemble a cohort of patients exhibiting definitive signs of degeneration who were well below the average age of presentation, with minimal or no exposure to suspected environmental risk factors and to conduct a targeted genome analysis in an attempt to elucidate a common genetic component. Through whole genome sequencing and analysis, the results corroborated findings in a previous study, as well as demonstrated a potential connection and influence between mutations found in IVD structural or functional genes, and the provocation of IVDD. Though the sample size was limited in scale and age, these findings suggest that further IVDD research into the association of variants in collagen, aggrecan and the insulin-like growth factor receptor genes of young patients with an early presentation of disc degeneration and minimal exposure to suspected risk factors is merited. / Dissertation/Thesis / Masters Thesis Biology 2016

In vitro disease models are powerful platforms for the development of drugs and novel therapies. Stem-cell based approaches have emerged as cutting-edge tools in disease modelling, allowing for deeper insights into previously unknown disease mechanisms. Hence the significant role of these disease-in-a-dish methods in therapeutics and translational medicine. Impedance sensing is a non-invasive, quantitative technique that can monitor changes in cellular behaviour and morphology in real-time. Bioimpedance measurements can be used to characterize and evaluate the establishment of a valid disease model, without the need for invasive end-point biochemical assays. In this work, two stem cell-based disease models-on-a-chip are proposed for acute liver failure (ALF) and age-related macular degeneration (AMD). The ALF disease model-on-a-chip integrates impedance sensing with the highly-differentiated HepaRG cell line to monitor in real-time quantitative and dynamic response to various hepatotoxins. Bioimpedance analysis and modelling has revealed an unknown mechanism of paracetamol hepatotoxicity; a temporal, dose-dependent disruption of tight junctions (TJs) and cell-substrate adhesion. This disruption has been validated using ultrastructural imaging and immunostaining of the TJ-associated protein ZO-1. Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world with a need for disease models for its currently incurable forms. Human induced pluripotent stem cells (hiPSCs) technology offers a novel approach for disease modelling, with the potential to impact translational retinal research and therapy. Recent developments enable the generation of Retinal Pigment Epithelial cells from patients (hiPSC-RPE), thus allowing for human retinal disease in vitro studies with great clinical and physiological relevance. In the current study, the development of a tissue-on- a-chip AMD disease model has been established using RPE generated from a patient with an inherited macular degeneration (case cell line) and from a healthy sibling (control cell line). A reproducible Electric Cell-substrate Impedance Sensing (ECIS) electrical wounding assay was conducted to mimic RPE damage in AMD. First, a robust and reproducible real-time quantitative monitoring over a 25-day period demonstrated the establishment and maturation of RPE layers on microelectrodes. A spatially-controlled RPE layer damage that mimicked cell loss in AMD was then initiated. Post recovery, significant differences in migration rates were found between case and control cell lines. Data analysis and modelling suggested this was due to the lower cell-substrate adhesion of the control cell line. These findings were confirmed using cell adhesion biochemical assays. Moreover, different-sized, individually-addressed square microelectrode arrays with high spatial resolution were designed and fabricated in-house. ECIS wounding assays were performed on these chips to study immortalized RPE migration. Migration rates comparable to those obtained with ECIS circular microelectrodes were determined. The two proposed disease-models-on-a-chip were then used to explore the therapeutic potential of the antioxidant N-Acetyl-Cysteine (NAC) on hiPSC-RPE and HepaRG cell recovery. Addition of 10 mM NAC at the end of a 24h paracetamol challenge caused a slight increase in the measured impedance, suggesting partial cell recovery. On the other hand, no effect on case hiPSC-RPE migration has been observed. More experiments are needed to examine the effect of different NAC concentrations and incubation periods. The therapeutic potential of electrical stimulation has also been explored. A preliminary study to evaluate the effect of electrical stimulation on RPE migration has been conducted. An externally applied direct current electric field (DC EF) of 300 mV/mm was found to direct the migration of the immortalized RPE cell line (hTERT-RPE1) perpendicular to the EF. The cells were also observed to elongate and to realign their long axes perpendicular to the applied EF. The proposed tissue-on-a-chip disease models are powerful platforms for translational studies. The potential of such platforms has been demonstrated through revealing unknown effects of acetaminophen on the liver as well as providing deeper insights into the underlying mechanisms of macular degeneration. Combining stem cell technology with impedance sensing provides a high throughput platform for studying patient-specific diseases and evaluating potential therapies.

Orientador: Aparecido Antonio Camacho / Banca: Marlos Gonçalves Sousa / Banca: Tatiana Champion / Resumo: Estudo da variabilidade da frequência cardíaca, no domínio do tempo, realizado em 48 cães de diferentes raças de pequeno a médio porte, com degeneração mixomatosa crônica da valva mitral, estadiados em classes de insuficiência cardíaca congestiva (ICC) proposta pela ISACHC. Os animais apresentaram sinais clínicos de: tosse, cansaço, dispneia no grupo classe 2, em ordem de prevalência. No exame eletrocardiográfico os cães perdem arritmia sinusal respiratória, passando para ritmo sinusal, junto podem apresentar: aumento da onda P em duração e amplitude, complexo QRS em duração e amplitude da onda R quando desenvolvem esta doença valvular e aumentam de classe. Os cães com DMVM em estádios de ICC moderados (classe 2) em comparação com estágios iniciais (classe 1a e classe 1b) da doença apresentaram maiores valores ecocardiográficos: relação AE/Ao, DIVEd/Ao, DIVEs/Ao, ESIVs/Ao, EPPVEd/Ao, EPPVEs/Ao, FE%,FEC%, PVE e PVA mitral. O presente estudo mostrou que a insuficiência cardíaca em cães com DMVM, tinha diminuído os valores de NN médio (NNm), SDNN, SDNNindex e pNN50%. Inferindo uma diminuição da participação do sistema nervoso parassimpático e um aumento da participação do sistema nervoso simpático. Além disso, foi observado um aumento da FC média e aumento número de complexos QRS (NQRS) que também são indicadores de maior participação do sistema simpático. Determinou-se um predomínio das arritmias ventriculares nos três grupos, com semelhante proporção das arritmias supraventricular no grupo clínico. As arritmias tanto ventriculares como as arritmias supraventriculares foram de caráter isolado nos grupos pré-clínicos e de caráter complexo no grupo clínico. As correlações obtidas no exame Holter foram correlação positiva entre: NNm v/s NQRS na classe 2, classe 1b e classe 1a (r= 0,978, r= 0,932, r= 0,962); NNm v/s pNN50% na classe 2 e classe ... / Abstract: Study of heart rate variability in the time domain, performed in 48 dogs of different breeds of small to medium sized, with chronic myxomatous degeneration of the mitral valve, aged in heart failure classes (CHF) proposed by ISACHC. The animals showed clinical signs of: cough, fatigue, dyspnea group class 2, in order of prevalence. Electrocardiographic examination in dogs lose respiratory sinus arrhythmia, going to sinus rhythm, with display: increase in p wave duration and amplitude, QRS duration and in R wave amplitude when developing this valvular disease and increase class. Dogs with MMVD in stages of ICC moderate (class 2) compared with early stages (class 1a and class 1b) of the disease had higher echocardiographic values: Relations LA/Ao, DIVEd/Ao, DIVEs/Ao, ESIVs/Ao, EPPVEd/Ao, EPPVEs/Ao, FE%,FEC%, PVE e PVA mitral. The present study showed that heart failure in dogs with MMVD, had decreased values of NN medium (NNM), SDNN, SDNNindex and pNN50%. Implying a decrease in the participation of the parasympathetic nervous system and an increase in the participation of the sympathetic nervous system. Furthermore, we observed an increase in mean HR and increased QRS complexes (NQRS) which are also indicators of increased participation of the sympathetic system. We determined the prevalence of ventricular arrhythmias in the three groups, with a similar proportion of supraventricular arrhythmias in the clinical group. Both ventricular arrhythmias and supraventricular arrhythmias were isolated character in the pre-clinical and complex character in the clinical group. Especially supraventricular arrhythmias and ventricular arrhythmias may manifest themselves throughout the progression of the disease, initial ventricular arrhythmias, with further increase supraventricular arrhythmias as a consequence of atrial dilation. The correlations obtained in Holter examination were, positive correlation ... / Mestre

Made available in DSpace on 2014-06-11T19:23:46Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-04-27Bitstream added on 2014-06-13T19:30:22Z : No. of bitstreams: 1 franco_rp_me_jabo.pdf: 1325167 bytes, checksum: c0d65b611313afe6bf052d1a43166362 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A endocardiose da válvula mitral é uma cardiopatia de alta incidência na clínica médica de pequenos animais, com maior acometimento de cães idosos e de raças de pequeno porte. Realizou-se então um estudo para avaliar clinicamente a utilização do maleato de enalapril, furosemida, espironolactona e suas associações, em cães com endocardiose de válvula mitral classes funcionais Ib e II, antes e após a terapêutica implantada. Para isso, utilizaram-se 36 animais portadores desta afecção, distribuídos em quatro grupos, conforme as classes funcionais de ICC, com terapêutica específica implantada durante 56 dias em cada grupo estudado. Animais portadores da classe funcional Ib foram distribuídos em dois grupos, com o primeiro recebendo furosemida (n=8) e o outro maleato de enalapril (n=8). Igualmente, distribuíram-se os animais da classe funcional II, com um grupo recebendo maleato de enalapril e furosemida (n=10) e o segundo, enalapril associado à espironolactona e furosemida (n=10). Todos os grupos foram avaliados em quatro momentos (T0, T14, T28 e T56 dias) quanto aos parâmetros e sinais clínicos, exames hematológicos e bioquímico-séricos, que incluíram enzima conversora da angiotensina (ECA) e aldosterona; avaliações radiográficas, eletrocardiográficas, ecodopplercardiográficas e da pressão arterial. Os resultados demonstraram uma redução dos sinais clínicos nos animais classe II, com a estabilização dos parâmetros em ambos os grupos. As avaliações hematológica e bioquímico sérica não revelaram alterações significativas nas classes estudadas, mas uma redução significativa dos valores de ECA e aldosterona foram observadas nos grupos que receberam enalapril como terapêutica. Ao exame radiográfico observou-se redução dos valores de VHS e, ao eletrocardiograma as variáveis onda Pms e Complexo QRSms apresentaram diminuições significativas... / The endocardiosis of mitral valve is a high incidence of heart disease in the medical clinic for small animals, with the involvement of older dogs and small breeds. This is a clinical study to evaluate the use of the enalapril maleate, furosemide, spironolactone and their associations in dogs with mitral valve endocardiosis of class Ib and II, before and after therapy implanted. It was used 36 animals with this endocardiosis, divided into four groups according to class of congestive heart failure, implanted with a specific therapy for 56 days in each group. The animals classified in class Ib was divided into two groups, with the first receiving furosemide (n = 8) and the other of maleate of enalapril (n = 8). It is also divided the animals of Class II, with a group of receiving maleate of enalapril and furosemide (n = 10) and second, enalapril combined with spironolactone and furosemide (n = 10). Every groups were available in four moments (T0, T14, T28, e T56 days) as to clinical parameters, symptoms, serum biochemical and hematological tests, which included the angiotensin converting enzyme (ACE) and aldosterone; radiographic evaluations ECG, Dopplerechocardiography and blood pressure. The results showed a reduction of clinical signs in animals Class II, with stabilization of physiological parameters in both groups. The serum biochemical and hematological evaluation showed no significant changes in the classes studied, but a significant reduction of the values of ACE and Aldosterone were seen in the groups receiving enalapril as therapy. By radiographic examination, we observed a reduction of the values of VHS, and the variables Pms wave and QRSms Complex in electrocardiogram showed significant variations in groups of Class II. The absence of variations in blood pressure was observed in both groups. But the Dopplerechocardiogram showed a ventricular remodeling with a significant decrease... (Complete abstract click electronic access below)

Orientador: Aparecido Antonio Camacho / Banca: Áureo evangelista Santana / Banca: Wagner Luís Ferreira / Resumo: A endocardiose da válvula mitral é uma cardiopatia de alta incidência na clínica médica de pequenos animais, com maior acometimento de cães idosos e de raças de pequeno porte. Realizou-se então um estudo para avaliar clinicamente a utilização do maleato de enalapril, furosemida, espironolactona e suas associações, em cães com endocardiose de válvula mitral classes funcionais Ib e II, antes e após a terapêutica implantada. Para isso, utilizaram-se 36 animais portadores desta afecção, distribuídos em quatro grupos, conforme as classes funcionais de ICC, com terapêutica específica implantada durante 56 dias em cada grupo estudado. Animais portadores da classe funcional Ib foram distribuídos em dois grupos, com o primeiro recebendo furosemida (n=8) e o outro maleato de enalapril (n=8). Igualmente, distribuíram-se os animais da classe funcional II, com um grupo recebendo maleato de enalapril e furosemida (n=10) e o segundo, enalapril associado à espironolactona e furosemida (n=10). Todos os grupos foram avaliados em quatro momentos (T0, T14, T28 e T56 dias) quanto aos parâmetros e sinais clínicos, exames hematológicos e bioquímico-séricos, que incluíram enzima conversora da angiotensina (ECA) e aldosterona; avaliações radiográficas, eletrocardiográficas, ecodopplercardiográficas e da pressão arterial. Os resultados demonstraram uma redução dos sinais clínicos nos animais classe II, com a estabilização dos parâmetros em ambos os grupos. As avaliações hematológica e bioquímico sérica não revelaram alterações significativas nas classes estudadas, mas uma redução significativa dos valores de ECA e aldosterona foram observadas nos grupos que receberam enalapril como terapêutica. Ao exame radiográfico observou-se redução dos valores de VHS e, ao eletrocardiograma as variáveis onda Pms e Complexo QRSms apresentaram diminuições significativas... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The endocardiosis of mitral valve is a high incidence of heart disease in the medical clinic for small animals, with the involvement of older dogs and small breeds. This is a clinical study to evaluate the use of the enalapril maleate, furosemide, spironolactone and their associations in dogs with mitral valve endocardiosis of class Ib and II, before and after therapy implanted. It was used 36 animals with this endocardiosis, divided into four groups according to class of congestive heart failure, implanted with a specific therapy for 56 days in each group. The animals classified in class Ib was divided into two groups, with the first receiving furosemide (n = 8) and the other of maleate of enalapril (n = 8). It is also divided the animals of Class II, with a group of receiving maleate of enalapril and furosemide (n = 10) and second, enalapril combined with spironolactone and furosemide (n = 10). Every groups were available in four moments (T0, T14, T28, e T56 days) as to clinical parameters, symptoms, serum biochemical and hematological tests, which included the angiotensin converting enzyme (ACE) and aldosterone; radiographic evaluations ECG, Dopplerechocardiography and blood pressure. The results showed a reduction of clinical signs in animals Class II, with stabilization of physiological parameters in both groups. The serum biochemical and hematological evaluation showed no significant changes in the classes studied, but a significant reduction of the values of ACE and Aldosterone were seen in the groups receiving enalapril as therapy. By radiographic examination, we observed a reduction of the values of VHS, and the variables Pms wave and QRSms Complex in electrocardiogram showed significant variations in groups of Class II. The absence of variations in blood pressure was observed in both groups. But the Dopplerechocardiogram showed a ventricular remodeling with a significant decrease... (Complete abstract click electronic access below) / Mestre

Esta dissertação tem como objetivo situar o momento cultural vivido por Fialho de Almeida, intercalado à vida e obra do autor para, a partir daí, investigar possíveis críticas de seu trabalho com o intuito de avaliar em que condições escrevia e porque sua obra foi capaz de suscitar inúmeras interpretações. Sendo assim, seu trabalho crítico e alguns contos serão analisados de forma a compreender não só a utilização de características pertencentes a determinadas escolas, mas principalmente, sua posição diante da propagação de questões vividas pela sociedade da época, considerando sua influencia dos autores da Geração de 70 e as duras críticas que proferiu anos mais tarde ao já consagrado Eça de Queirós. Por ter acompanhado intensamente as mudanças sofridas por Portugal ao longo dos anos, buscava retratar o que a sociedade e alguns homens de letras desejavam esconder. A literatura do século XIX revelou conflitos que a exigente moral burguesa impunha e ocultava. Fialho de Almeida faz questão de destacar esses conflitos. Sendo assim, é comum encontrar ambientes insalubres e degradantes em que vivem pessoas em extrema pobreza, assim como as doenças e mazelas humanas ao lado dos chamados vícios e degenerescências. Examinamos também a recepção da obra de Fialho, para indagar os motivos que o levaram a ocupar um lugar secundário na literatura do século XIX / The purpose of this dissertation is to identify the cultural moment lived by Fialho de Almeida, together with his life and works, from there, examinee possible criticism of his work. The purpose is to evaluate the conditions he wrote and why his work promote numerous interpretations. Thus, his critical work and some novels will be analyzed, in order to understand, not only the use of features belonging to certain literary schools, but mainly, his position regarding the spread of issues faced by the society of the time, considering the influence of the authors of the Generation of 70 in his work and the harsh criticism he made years late to Eça de Queiróz. He accompanied the intense changes suffered by Portugal over the years, and sought to portray what the society wanted to hide. The literature of the nineteenth century showed the conflicts demanding bourgeois morality imposed and compelled its followers to hide. Fialho de Almeida wishes to highlight these conflicts. Therefore, it is common to find in his work degrading and unhealthy ambients in which people live in extreme poverty, diseases, addiction and degenerations. In the last chapter, based on the receipt of his novels, we try to get evidences of the reasons that led him to a secondary place in the literature of the nineteenth century

A hipóxia-isquemia (HI) encefálica neonatal causa diversas seqüelas motoras e cognitivas permanentes devido à grande degeneração celular que ocorre no encéfalo dos neonatos. Esse dano é progressivo e gera atrofias visíveis em diversas estruturas encefálicas, principalmente hipocampo, estriado e córtex cerebral. Um estudo recente do nosso grupo de pesquisa mostrou que o tratamento com ácido fólico (AF) reverteu o déficit cognitivo e a diminuição da atividade da enzima Na+, K+-ATPase, em ratos submetidos à HI neonatal. Assim, buscando compreender melhor a possível eficácia do ácido fólico em tratar e/ou prevenir o dano causado pela HI neonatal, o objetivo desse estudo foi avaliar os efeitos do tratamento com ácido fólico na degeneração celular na região CA1 do hipocampo dorsal 24 horas após o evento lesivo e em diferentes marcos do desenvolvimento de animais submetidos à hipóxia-isquemia neonatal. Foram utilizados ratos Wistar de ambos os sexos que foram submetidos ao modelo de Levine-Rice no 7º dia de vida pós-natal, sendo divididos em quatro grupos experimentais: 1) controle tratado com salina (CTS); 2) controle tratado com ácido fólico (CTAF); 3) HI tratado com salina (HIS); 4) HI tratado com ácido fólico (HIAF). Os animais receberam uma dose intraperitoneal de AF (0,011 μmol/g de peso corporal) 24 horas antes, imediatamente antes e 24 horas após a HI ou, diariamente, até o 14° DPN. Não foram encontradas diferenças na quantificação de células imunomarcadas para caspase-3 clivada pela técnica de imunoistoquímica, porém na avaliação da densidade celular observou-se uma diminuição de células no grupo HIS 13 quando comparado com os grupos CTAF e HIAF no hipocampo direito. Tanto na análise qualitativa quanto quantitativa da ultraestrutura dos neurônios piramidais da região CA1 hipocampal também foi possível encontrar uma importante degeneração celular nos grupos submetidos à HI neonatal, predominantemente caracterizada pelo padrão necrótico, porém no grupo tratado com AF essa degeneração foi menos expressiva. Quanto aos marcos do desenvolvimento, não verificou-se diferença nem pela lesão nem pelo tratamento. A partir desse estudo, portanto, podemos concluir que 24h após a HI ocorre diminuição da densidade celular e evidente processo lesivo ao tecido hipocampal, mais expressivamente por necrose. Ainda, a suplementação com ácido fólico foi capaz de reduzir e/ou prevenir o dano celular na região CA1 do hipocampo ipsilateral à oclusão arterial. / Neonatal hypoxia-ischemia (HI) causes diverse permanent motor and cognitive sequelae due to extensive cellular degeneration that occurs in the brain of neonates. This damage is progressive and generates visible atrophy in several brain structures, particularly the hippocampus, cerebral cortex and striatum. A recent study from our research group demonstrated that treatment with folic acid (FA) reversed cognitive deficits and decreased activity of the enzyme Na+, K+-ATPase in rats submitted to neonatal HI. Thus, in order to better understand the possible effectiveness of folic acid in recovering and / or preventing the damage caused by neonatal HI, the aim of this study was to evaluate the effects of treatment with folic acid on cell degeneration in the CA1 region of the dorsal hippocampus 24 hours after neonatal hypoxia-ischemia and at different developmental milestones of animals submitted to neonatal hypoxia-ischemia. Wistar rats of both sexes were submitted to the Levine - Rice model on the 7th postnatal day, being divided into four experimental groups: 1) control treated with saline (CTS); 2) control treated with folic acid (CTAF); 3) HI treated with saline (HIS) 4) HI treated with folic acid (HIAF). Animals received an intraperitoneal dose of FA (0.011μmol/g of body weight) 24 hours before, immediately before and 24 hours after the HI. No differences were found in the quantification of positive cells for cleaved caspase-3 by immunohistochemistry, but in the assessment of cell density was observed a decrease of cells in the HIS group when compared with the CTFA and HIFA groups in the right hippocampus. In the analysis of the ultrastructure of pyramidal neurons of the 15 hippocampal CA1 region was also possible to find an important cellular degeneration in the groups subjected to neonatal HI, predominantly characterized by necrotic pattern, but in the group treated with FA this degeneration was less expressive. As for developmental milestones, no significant difference was observed either by injury or by treatment. Concluding, 24 hours after HI occurs decreased cell density and evident degeneration process to hippocampal tissue, most significantly with death by necrosis. Yet, supplementation with folic acid was able to reduce and / or prevent cell damage in the CA1 region of the hippocampus ipsilateral to the arterial occlusion.