Regulation of apoptosis during the pathogenesis of non -melanoma skin cancer

Previous studies from our lab have shown distinctive patterns of expression of bcl-2 gene family members in human nonmelanoma skin cancer (NMSC). To further evaluate the significance of these observations and to study the effects of cell death deregulation during skin carcinogenesis, we generated a transgenic mouse model (HK1.bcl-2) using the human keratin 1 promoter to target the expression of a human bcl-2 minigene to the epidermis. Transgenic protein expression was confirmed in all the layers of the epidermis except the stratum corneum using immunohistochemistry. Multifocal epidermal hyperplasia, without associated hyperkeratosis, was observed in newborn HK1.bcl-2 mice. Immunofluorescence staining using monoclonal antibodies specific for a variety of differentiation markers revealed aberrant expression of keratin 6 (K6) in the transgenic epidermis. Epidermal proliferative indexes, assessed by anti-BrdUrd immunofluorescence staining, were similar in control and transgenic newborn mice, but suprabasal proliferating cells were seen within the hyperplastic areas of the transgenic mouse skin. Spontaneous apoptotic indices of the epidermis were similar in both control and HK1.bcl-2 transgenic newborn mice, however, after UV-B irradiation, the number of "sunburn cells" was significantly higher in the control compared to the HK1.bcl-2 transgenic animals.^ Adult HK1.bcl-2 and control littermate mice were used in UV-B and chemical carcinogenesis protocols including DMBA + TPA. UV-B irradiated control and HK1.bcl-2 mice had comparable incidence of tumors than the controls, but the mean latency period was significantly shorter in the HK1.bcl-2 transgenic. Both control and transgenic animals included in chemical carcinogenesis protocols required application of both the initiating (DMBA) and promoting (TPA) agents to develop tumors. The frequency, number, and latency of tumor formation was similar in both groups of animals, however, HK1.bcl-2 mice exhibited a rate of conversion from benign papilloma to carcinoma 2.5 times greater than controls.^ Similar carcinogenesis experiments were performed using newborn mice. HK1.bcl-2 mice treated with UV-B plus TPA have a three fold greater incidence of tumor formation compared to controls littermates. HK1.bcl-2 transgenic animals also exhibited a shorter latency for papilloma formation when treated with DMBA plus TPA.^ HK1.bcl-2/v-Ha-ras double transgenic mice shared phenotypic features of both HK1.v-Ha-ras and HK1.bcl-2 transgenic mice, and exhibited focal areas of augmented hyperplasia. These double transgenic mice were susceptible to tumor formation by treatment with TPA alone.^ Cultures of primary keratinocytes were established from control, HK1.bcl-2, HK1.Ha-ras, and HK1.bcl-2/v-Ha-ras newborn mice. Cell viability was determined after exposure of the cells to UV-B irradiation, DMBA, TPA, or TGF-$\beta$1. Internucleosomal DNA fragmentation ("ladders") and morphological cellular changes compatible with apoptotic cell death were observed after the application of all these agents. HK1.bcl-2 keratinocytes were resistant to cell death induction by all of these agents except TGF-$\beta$1. HK1.Ha-ras cells had a higher spontaneous rate of cell death which could be compensated by co-expression of bcl-2.^ These findings suggest that bcl-2 dependent cell death suppression may be an important component of multistep skin carcinogenesis. ^

Teoría y práctica de la restauración de la Mezquita-Catedral de Córdoba durante el siglo XX

La Mezquita-Catedral de Córdoba es un edificio vivo. Un edificio que ha sido transformado sucesivamente por hombres de razas, culturas y religiones distintas durante sus más de 1.200 años de vida y que, a pesar de ello, no ha dejado de estar en uso ni uno solo de esos días de esa larga vida. De esta forma, el edificio se muestra ante el visitante como un complejo objeto arquitectónico, resultado de una continua transformación. La capacidad de la transformación de los edificios es algo inherente a su propia condición arquitectónica, no es un hecho exclusivo de la Mezquita-Catedral. Sin embargo, en este edificio esa transformación se produce con una gran intensidad y sin pérdida de su autenticidad. Tradicionalmente, los edificios se han adaptado a los nuevos requerimientos de cada época en un proceso que ha buscado en el propio edificio las leyes o principios que habían de regir la intervención. De esta forma, tanto las sucesivas ampliaciones de la Mezquita de Abd al-Rahman I como las siguientes intervenciones cristianas debieron asumir lo preexistente como material de trabajo. Así, los arquitectos del califa al-Hakam II dialogaron con sus antecesores complejizando el espacio que recibieron, así como los Hernán Ruiz consiguieron un nuevo organismo resultante de la introducción de su arquitectura luminosa en la trama hispanomusulmana. El siglo XIX confirmó el deseo por descubrir las huellas de un pasado esplendoroso que la intervención barroca había silenciado bajo un tratamiento homogéneo del espacio. La recuperación de esas huellas supuso, hace exactamente dos siglos, el inicio de la última gran etapa en la transformación del edificio, la de la restauración. La fábrica es considerada como objeto a conservar y los esfuerzos desde ese momento se centraron en la recuperación de la arquitectura omeya latente. De este modo, la práctica de la restauración como disciplina se encontró absolutamente influenciada por la Arqueología como única fuente de conocimiento. Las intervenciones buscaban lo original como modo de recuperar espacial y formalmente aquel pasado, concentrándose en los lugares del edificio considerados como esenciales. La declaración del edificio como monumento nacional en 1882 propició que el Estado se hiciera cargo de su mantenimiento y conservación, sustituyendo en esa tarea a los Obispos y Cabildos del siglo XIX, que tuvieron un entendimiento muy avanzado para su época. La llegada del arquitecto Velázquez Bosco en las últimas décadas del siglo XIX supuso un cambio trascendental en la historia del edificio, puesto que recibió un edificio con importantes deterioros y consiguió poner las bases del edificio que hoy contemplamos. El empeño por la recuperación material y espacial devolvió a la Mezquita-Catedral buena parte de su imagen original, reproduciendo con exactitud los modelos hallados en las exploraciones arqueológicas. La llegada de Antonio Flórez tras la muerte de Velázquez Bosco supuso la traslación al edificio del debate disciplinar que se desarrolló en las dos primeras décadas del siglo XX. Flórez procuró un nuevo entendimiento de la intervención, considerando la conservación como actuación prioritaria. En 1926 el Estado reformó la manera en que se atendía al patrimonio con la creación de un sistema de zonas y unos arquitectos a cargo de ellas. La existencia de un nuevo marco legislativo apuntaló esa nueva visión conservativa, avalada por la Carta de Atenas de 1931. Este modelo restauración científica huía de la intervención en estilo y valoraba la necesidad de intervenir de la manera más escueta posible y con un lenguaje diferenciado, basándose en los datos que ofrecía la Arqueología. Por tanto, se continuaba con la valoración del edificio como documento histórico, buscando en este caso una imagen diferenciada de la intervención frente a la actitud mimética de Velázquez. Resulta destacable la manera en la que el historiador Manuel Gómez-Moreno influyó en varias generaciones de arquitectos, arqueólogos e historiadores, tanto en el entendimiento científico de la restauración como en la propia estructura administrativa. La labor desarrollada en el edificio por José Mª Rodríguez Cano primero y Félix Hernández a continuación estuvo influida de manera teórica por el método de Gómez-Moreno, aunque en muchos aspectos su labor no representó una gran diferencia con lo hecho por Velázquez Bosco. La búsqueda de lo original volvió a ser recurrente, pero la carga económica del mantenimiento de un edificio tan extenso conllevó la no realización de muchos de los proyectos más ambiciosos. Esta obsesiva búsqueda de la imagen original del edificio tuvo su última y anacrónica etapa con la intervención de la Dirección General de Arquitectura en los 70. Sin embargo, el agotamiento del modelo científico ya había propiciado un nuevo escenario a nivel europeo, que cristalizó en la Carta de Venecia de 1964 y en una nueva definición del objeto a preservar, más allá del valor como documento histórico. Esta nueva posición teórica tuvo su traslación al modelo restaurador español en el último cuarto de siglo XX, coincidiendo con la Transición. El arquitecto Dionisio Hernández Gil defendió una interpretación distinta a la de los arqueólogos y de los historiadores, que había prevalecido durante todo el siglo. En opinión de Hernández Gil, los problemas de intervención debían enfocarse fundamentalmente como problemas de Arquitectura, abandonando la idea de que solamente podían ser resueltos por especialistas. Esta convicción teórica fue defendida desde la nueva Administración y deparó la utilización de unos criterios de intervención particularizados, provenientes del análisis multifocal de cada situación y no sólo desde el valor de los edificios como documentos históricos. Y este cambio tuvo su traslación a la Mezquita-Catedral con la práctica de Gabriel Ruiz Cabrero y Gabriel Rebollo. En consecuencia con esa nueva perspectiva, aceptaron el edificio que recibieron, sustituyendo la búsqueda de aquella página original por la aceptación de cada una de las páginas de su historia y el respeto a las técnicas constructivas del pasado. La búsqueda de soluciones específicas desde el propio objeto arquitectónico significó la renovada atención a la potente estructura formal-constructiva como origen de toda reflexión. Considerar la Mezquita-Catedral en primer lugar como Arquitectura implicaba la atención a todo tipo de factores además de los históricos, como medio para preservar su autenticidad. Esta tesis pretende demostrar que la práctica de la restauración realizada en la Mezquita-Catedral a lo largo del siglo XX ha evolucionado desde la búsqueda de lo original hasta la búsqueda de lo auténtico, como reflejo de una visión basada en lo arqueológico frente a una renovada visión arquitectónica más completa, que incluye a la anterior. La consideración de la intervención en este edificio como otra página más de su historia y no como la última, significa la reedición de un mecanismo recurrente en la vida del edificio y un nuevo impulso en ese proceso de continua transformación. ABSTRACT The Mosque-Cathedral of Cordoba is a living building. A building transformed by men of different races, cultures and religions during more than 1.200 years old and that, nevertheless, it has continued to be in use all days in that long life. Thus, the building shows to the visitor as a complex architectural object, the result of continuous transformation. This transformation capacity of the buildings is inherent in their own architectural condition, it’s not an exclusive fact of the Mosque-Cathedral. However, in this building that transformation happens with a great intensity, without losing their authenticity. Traditionally, buildings have been adapted to the new requirements of times in a process that looked for laws or principles in order to guide the intervention. Thus, both the successive enlargements of the Mosque of Abd al-Rahman and Christian interventions must assume the preexistence as a working material. So, the architects of the caliph al-Hakam II spoke to their predecessors, complexing the receiving space, as well as Hernan Ruiz got a new organism as result the introduction of his luminous architecture into hispanic-muslim weft. The nineteenth century confirmed the desire to discover the traces of a glorious past that Baroque intervention had silenced, under a uniform space treatment. Exactly two centuries ago, the recovery of these traces meant the start of the last major phase in the transformation of the building: the restoration. The building was considered subject to conserve and since then, efforts focused on the recovery of latent Umayyad architecture. Thus, the practice of restoration as a discipline was absolutely influenced by Archaeology as the only source of knowledge. Interventions were seeking the original as the way to recover that past in a space and formal way, concentrating on essential sites of the building. The statement as a national monument in 1882 prompted the State take charge of its maintenance and preservation, replacing to the nineteenth century Bishops and Cabildos, which had a very advanced understanding for that time. The arrival of the architect Velazquez Bosco in the last decades of the nineteenth century involved a momentous change in the history of the building, since he received a building with significant damage and he achieved the foundations of the building that we can see today. Efforts to a material and space recover returned the Mosque-Cathedral to its original image, accurately reproducing the models found in archaeological explorations. The arrival of Antonio Florez after Velazquez’s death involved the translation of discipline debate, which was developed in the first two decades of the twentieth century. Florez tried a new understanding of the intervention, considering conservation as a priority action. In 1926, the State reformed the way in which heritage was attended, creating a zones system with a few architects in charge of them. The existence of a new legislative framework, underpinned this new conservative vision, supported by the Athens Charter of 1931. This scientific restoration model fleeing from intervention in style and it appreciated the need to intervene in the most concise way, with a distinct language based on the data offered by Archaeology. Therefore, it continued with the appraisement of the building as a historical document, seeking in this case a differentiated image of intervention, against Velazquez mimetic attitude. It is remarkable the way in which the historian Manuel Gomez-Moreno influenced several generations of architects, archaeologists and historians, both in the scientific understanding of the restoration and the administrative structure. The work of Jose Maria Rodriguez Cano first and then Felix Hernandez was theoretically influenced by the Gomez-Moreno’s method, although in many respects their work did not represent a great difference to Velazquez Bosco. The search of the original returned to recur, but the economic charge of maintaining such a large building led to the non-realization of many of the most ambitious projects. This obsessive search for the original image of the building had its last and anachronistic stage with the intervention of the Department of Architecture at 70’s. However, the exhaustion of the scientific model had already led to a new scenario at European level, which crystallized in the Venice Charter of 1964 and a new definition of the object to be preserved beyond the value as a historical document. This new theoretical position had its translation to Spanish restaurateur model in the last quarter of the twentieth century, coinciding with the Transition. The architect Dionisio Hernandez Gil defended a different interpretation from archaeologists and historians, that had prevailed throughout the century. According to Hernandez Gil, the problems of intervention should focus primarily as architectural issues, abandoning the idea that they could only be determined by specialist. This theoretical conviction was defended from the new administration and led to the use of particularized criteria, from a multifocal analysis of each situation. And this change had its translation to the Mosque with the practice of Gabriel Ruiz Cabrero and Gabriel Rebollo. Consistent with this new perspective, they accepted the receiving building, replacing the search on original page for acceptance of all historical pages and respecting the constructive techniques of the past. The search for specific solutions from the architectural object meant the renewed attention to the powerful formal-constructive structure as the origin of all thought. Consider the Mosque-Cathedral as Architecture, involved the attention to all kinds of factors in addition to the historical, as a means to preserve its authenticity. This thesis aims to demonstrate that the practice of restoration in the Mosque-Cathedral throughout the twentieth century has evolved from the search of the original to the search for the authentic, reflecting a vision based on the archaeological against a renewed more complete architectural vision, including the above. Consideration of intervention in this building as another page in its history and not the last one, means the reissue of an own mechanism and a new impetus in that continuous transformation process.

O EFEITO DO CONTROLE RESPIRATÓRIO EM VARIÁVEIS ELETROFISIOLÓGICAS DA ATENÇÃO

A prática do ioga tem se tornado cada vez mais popular, não apenas pelos benefícios físicos, mas principalmente pelo bem-estar psicológico trazido pela sua prática. Um dos componentes do ioga é o Prãnãyama, ou controle da respiração. A atenção e a respiração são dois mecanismos fisiológicos e involuntários requeridos para a execução do Prãnãyama. O principal objetivo desse estudo foi verificar se variáveis contínuas do EEG (potência de diferentes faixas que o compõem) seriam moduladas pelo controle respiratório, comparando-se separadamente as duas fases do ciclo respiratório (inspiração e expiração), na situação de respiração espontânea e controlada. Fizeram parte do estudo 19 sujeitos (7 homens/12 mulheres, idade média de 36,89 e DP = ± 14,46) que foram convidados a participar da pesquisa nas dependências da Faculdade de Saúde da Universidade Metodista de São Paulo. Para o registro do eletroencefalograma foi utilizado um sistema de posicionamento de cinco eletrodos Ag AgCl (FPz, Fz, Cz, Pz e Oz) fixados a uma touca de posicionamento rápido (Quick-Cap, Neuromedical Supplies®), em sistema 10-20. Foram obtidos valores de máxima amplitude de potência (espectro de potência no domínio da frequência) nas frequências teta, alfa e beta e delta e calculada a razão teta/beta nas diferentes fases do ciclo respiratório (inspiração e expiração), separadamente, nas condições de respiração espontânea e de controle respiratório. Para o registro do ciclo respiratório, foi utilizada uma cinta de esforço respiratório M01 (Pletismógrafo). Os resultados mostram diferenças significativas entre as condições de respiração espontânea e de controle com valores das médias da razão teta/beta menores na respiração controlada do que na respiração espontânea e valores de média da potência alfa sempre maiores no controle respiratório. Diferenças significativas foram encontradas na comparação entre inspiração e expiração da respiração controlada com diminuição dos valores das médias da razão teta/beta na inspiração e aumento nos valores das médias da potência alfa, sobretudo na expiração. Os achados deste estudo trazem evidências de que o controle respiratório modula variáveis eletrofisiológicas relativas à atenção refletindo um estado de alerta, porém mais relaxado do que na situação de respiração espontânea.

Typing of urinary JC virus DNA offers a novel means of tracing human migrations

Although polyomavirus JC (JCV) is the proven pathogen of progressive multifocal leukoencephalopathy, the fatal demyelinating disease, this virus is ubiquitous as a usually harmless symbiote among human beings. JCV propagates in the adult kidney and excretes its progeny in urine, from which JCV DNA can readily be recovered. The main mode of transmission of JCV is from parents to children through long cohabitation. In this study, we collected a substantial number of urine samples from native inhabitants of 34 countries in Europe, Africa, and Asia. A 610-bp segment of JCV DNA was amplified from each urine sample, and its DNA sequence was determined. A worldwide phylogenetic tree subsequently constructed revealed the presence of nine subtypes including minor ones. Five subtypes (EU, Af2, B1, SC, and CY) occupied rather large territories that overlapped with each other at their boundaries. The entire Europe, northern Africa, and western Asia were the domain of EU, whereas the domain of Af2 included nearly all of Africa and southwestern Asia all the way to the northeastern edge of India. Partially overlapping domains in Asia were occupied by subtypes B1, SC, and CY. Of particular interest was the recovery of JCV subtypes in a pocket or pockets that were separated by great geographic distances from the main domains of those subtypes. Certain of these pockets can readily be explained by recent migrations of human populations carrying these subtypes. Overall, it appears that JCV genotyping promises to reveal previously unknown human migration routes: ancient as well as recent.

Targeted overexpression of protein kinase C β2 isoform in myocardium causes cardiomyopathy

Increased cardiovascular mortality occurs in diabetic patients with or without coronary artery disease and is attributed to the presence of diabetic cardiomyopathy. One potential mechanism is hyperglycemia that has been reported to activate protein kinase C (PKC), preferentially the β isoform, which has been associated with the development of micro- and macrovascular pathologies in diabetes mellitus. To establish that the activation of the PKCβ isoform can cause cardiac dysfunctions, we have established lines of transgenic mice with the specific overexpression of PKCβ2 isoform in the myocardium. These mice overexpressed the PKCβ2 isoform transgene by 2- to 10-fold as measured by mRNA, and proteins exhibited left ventricular hypertrophy, cardiac myocyte necrosis, multifocal fibrosis, and decreased left ventricular performance without vascular lesions. The severity of the phenotypes exhibited gene dose-dependence. Up-regulation of mRNAs for fetal type myosin heavy chain, atrial natriuretic factor, c-fos, transforming growth factor, and collagens was also observed. Moreover, treatment with a PKCβ-specific inhibitor resulted in functional and histological improvement. These findings have firmly established that the activation of the PKCβ2 isoform can cause specific cardiac cellular and functional changes leading to cardiomyopathy of diabetic or nondiabetic etiology.

Asian genotypes of JC virus in Native Americans and in a Pacific Island population: Markers of viral evolution and human migration

The human polyomavirus JC (JCV) causes the central nervous system demyelinating disease progressive multifocal leukoencephalopathy. Previously, we showed that 40% of Caucasians in the United States excrete JCV in the urine as detected by PCR. We have now studied 68 Navaho from New Mexico, 25 Flathead from Montana, and 29 Chamorro from Guam. By using PCR amplification of a fragment of the VP1 gene, JCV DNA was detected in the urine of 45 (66%) Navaho, 14 (56%) Flathead, and 20 (69%) Chamorro. Genotyping of viral DNAs in these cohorts by cycle sequencing showed predominantly type 2 (Asian), rather than type 1 (European). Type 1 is the major type in the United States and Hungary. Type 2 can be further subdivided into 2A, 2B, and 2C. Type 2A is found in China and Japan. Type 2B is a subtype related to the East Asian type, and is now found in Europe and the United States. The large majority (56–89%) of strains excreted by Native Americans and Pacific Islanders were the type 2A subtype, consistent with the origin of these strains in Asia. These findings indicate that JCV infection of Native Americans predates contact with Europeans, and likely predates migration of Amerind ancestors across the Bering land bridge around 12,000–30,000 years ago. If JCV had already differentiated into stable modern genotypes and subtypes prior to first settlement, the origin of JCV in humans may date from 50,000 to 100,000 years ago or more. We conclude that JCV may have coevolved with the human species, and that it provides a convenient marker for human migrations in both prehistoric and modern times.

Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation

Jaagsiekte sheep retrovirus (JSRV) can induce rapid, multifocal lung cancer, but JSRV is a simple retrovirus having no known oncogenes. Here we show that the envelope (env) gene of JSRV has the unusual property that it can induce transformation in rat fibroblasts, and thus is likely to be responsible for oncogenesis in animals. Retrovirus entry into cells is mediated by Env interaction with particular cell-surface receptors, and we have used phenotypic screening of radiation hybrid cell lines to identify the candidate lung cancer tumor suppressor HYAL2/LUCA2 as the receptor for JSRV. HYAL2 was previously described as a lysosomal hyaluronidase, but we show that HYAL2 is actually a glycosylphosphatidylinositol (GPI)-anchored cell-surface protein. Furthermore, we could not detect hyaluronidase activity associated with or secreted by cells expressing HYAL2, whereas we could easily detect such activity from cells expressing the related serum hyaluronidase HYAL1. Although the function of HYAL2 is currently unknown, other GPI-anchored proteins are involved in signal transduction, and some mediate mitogenic responses, suggesting a potential role of HYAL2 in JSRV Env-mediated oncogenesis. Lung cancer induced by JSRV closely resembles human bronchiolo-alveolar carcinoma, a disease that is increasing in frequency and now accounts for ≈25% of all lung cancer. The finding that JSRV env is oncogenic and the identification of HYAL2 as the JSRV receptor provide tools for further investigation of the mechanism of JSRV oncogenesis and its relationship to human bronchiolo-alveolar carcinoma.

Detection of JC virus DNA sequence and expression of the viral oncoprotein, tumor antigen, in brain of immunocompetent patient with oligoastrocytoma.

We describe molecular and clinical findings in an immunocompetent patient with an oligoastrocytoma and the concomitant presence of the human papovavirus, JC virus (JCV), which is the etiologic agent of the subacute, debilitating demyelinating disease, progressive multifocal leukoencephalopathy. Histologic review revealed a glial neoplasm consisting primarily of a moderately cellular oligodendroglioma with distinct areas of a fibrillary astrocytoma. Immunohistochemical analysis revealed nuclear staining of tumor cells with antibodies against the viral oncoprotein [tumor antigen (T antigen)], the proliferation marker (Ki67), and the cellular proliferation regulator (p53). Using primers specific to the JCV control region, PCR yielded amplified DNA that was identical to the control region of the Mad-4 strain of the virus. PCR analysis demonstrated the presence of the genome for the viral oncoprotein, T antigen, and results from primer extension studies revealed synthesis of the viral early RNA for T antigen in the tumor tissues. The presence of viral T antigen in the tumor tissue was further demonstrated by immunoblot assay. To our knowledge, this is the first report of the presence of JCV DNA, RNA, and T antigen in tissue in which viral T antigen is localized to tumor cell nuclei and suggests the possible association of JCV with some glial neoplasms.

Antiangiogenic therapy of transgenic mice impairs de novo tumor growth.

Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have tested the proposition that treatment with angiogenesis inhibitors can inhibit the progression of tumorigenesis after the switch to the angiogenic phenotype. In this model, islet cell carcinomas develop from multifocal, hyperproliferative nodules that show the histological hallmarks of human carcinoma in situ. Mice were treated with a combination of the angiogenesis inhibitor AGM-1470 (TNP-470), the antibiotic minocycline, and interferon alpha/beta. The treatment regimen markedly attenuated tumor growth but did not prevent tumor formation; tumor volume was reduced to 11% and capillary density to 40% of controls. The proliferation index of tumor cells in treated and control mice was similar, whereas the apoptotic index was doubled in treated tumors. This study shows that de novo tumor progression can be restricted solely by antiangiogenic therapy. The results suggest that angiogenesis inhibitors represent a valid component of anticancer strategies aimed at progression from discrete stages of tumorigenesis and demonstrate that transgenic mouse models can be used to evaluate efficacy of candidate antiangiogenic agents.

Single-optic positional accommodating intraocular lenses: a review

Presbyopia is an age-related physiological condition that causes a gradual loss in the ability to focus on near objects, secondary to changes in zonular fibers, ciliary muscle and crystalline lens. Different surgical approaches are being pursued to surgically compensate presbyopia, such as corneal techniques or implantation of multifocal intraocular lenses (IOLs); however, their inability to restore accommodation has led to the development of single-optic positional accommodative IOLs. The axial shift, with the contraction of the ciliary muscle, of these IOLs increases the refractive power of the eye, improving the level of uncorrected near vision. Single-optic positional accommodative IOLs present few disturbances and larger ocular aberrations that improve near vision. However, reduced amplitudes of accommodation are obtained, little IOL shifts are measured and overall visual outcomes are limited.

Lentes intraoculares trifocales: revisión bibliográfica

El objetivo del presente estudio ha sido evaluar y analizar resultados tanto clínicos como teóricos para proporcionar un mayor entendimiento del funcionamiento de las lentes intraoculares (LIOs) trifocales. Para ello, se ha realizado una búsqueda bibliográfica, incluyendo tanto artículos de simulaciones en banco óptico como aquellos que muestran resultados clínicos. En la búsqueda se han encontrado artículos sobre tres LIOs trifocales: AT.LISA tri839MP (Carl Zeiss Meditec), FineVision (PhysIOL) y MIOL-Record (Repper-NN). En los estudios teóricos se ha demostrado que las LIOs trifocales presentan una mejora con respecto a las LIOs bifocales en cuanto a visión intermedia pero con una disminución en cuanto a calidad óptica en distancias lejanas y cercanas. Por el contrario, en cuanto a resultados clínicos, las LIOs trifocales proporcionan buenas agudezas visuales en visión lejana y agudezas visuales variables pero siempre aceptables en visión intermedia y cercana. En conclusión, LIOs trifocales ofrecen una opción a aquellos pacientes que necesitan trabajar en visión intermedia y buscan no tener que depender del uso de gafas tras cirugía de catarata.

Adenocarcinoma da próstata incidental : um estudo retrospectivo

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Epileptic networks are strongly connected with and without the effects of interictal discharges

OBJECTIVE Epilepsy is increasingly considered as the dysfunction of a pathologic neuronal network (epileptic network) rather than a single focal source. We aimed to assess the interactions between the regions that comprise the epileptic network and to investigate their dependence on the occurrence of interictal epileptiform discharges (IEDs). METHODS We analyzed resting state simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) recordings in 10 patients with drug-resistant focal epilepsy with multifocal IED-related blood oxygen level-dependent (BOLD) responses and a maximum t-value in the IED field. We computed functional connectivity (FC) maps of the epileptic network using two types of seed: (1) a 10-mm diameter sphere centered in the global maximum of IED-related BOLD map, and (2) the independent component with highest correlation to the IED-related BOLD map, named epileptic component. For both approaches, we compared FC maps before and after regressing out the effect of IEDs in terms of maximum and mean t-values and percentage of map overlap. RESULTS Maximum and mean FC maps t-values were significantly lower after regressing out IEDs at the group level (p < 0.01). Overlap extent was 85% ± 12% and 87% ± 12% when the seed was the 10-mm diameter sphere and the epileptic component, respectively. SIGNIFICANCE Regions involved in a specific epileptic network show coherent BOLD fluctuations independent of scalp EEG IEDs. FC topography and strength is largely preserved by removing the IED effect. This could represent a signature of a sustained pathologic network with contribution from epileptic activity invisible to the scalp EEG.

Simultaneous detection and differentiation of human Polyomaviruses JC and BK by a rapid and sensitive PCR-ELAHA assay and a survey of the JCV subtypes within an Australian population

Human polyomaviruses JCV and BKV can cause several clinical manifestations in immunocompromised hosts, including progressive multifocal leukoencephalopathy (PML) and haemorrhagic cystitis. Molecular detection by polymerase chain reaction (PCR) is recognised as a sensitive and specific method for detecting human polyomaviruses in clinical samples. In this study, we developed a PCR assay using a single primer pair to amplify a segment of the VP1 gene of JCV and BKV. An enzyme linked amplicon hybridisation assay (ELAHA) using species-specific biotinylated oligonucleotide probes was used to differentiate between JCV and BKV. This assay (VP1-PCR-ELAHA) was evaluated and compared to a PCR assay targeting the human polyomavirus T antigen gene (pol-PCR). DNA sequencing was used to confirm the polyomavirus species identified by the VP1-PCR-ELAHA and to determine the subtype of each JCV isolate. A total of 297 urine specimens were tested and human polyomavirus was detected in 105 specimens (35.4%) by both PCR assays. The differentiation of JCV and BKV by the VP1-PCR-ELAHA showed good agreement with the results of DNA sequencing. Further, DNA sequencing of the JCV positive specimens showed the most prevalent JCV subtype in our cohort was 2a (27%) followed by 1b (20%), 1a (15%), 2c (14%), 4 (14%) and 2b (10%). The results of this study show that the VP1-PCR-ELAHA is a sensitive, specific and rapid method for detecting and differentiating human polyomaviruses JC and BK and is highly suitable for routine use in the clinical laboratory. (C) 2004 Wiley-Liss, Inc.

Suspected immune-mediated myositis in a pony

Immune-mediated myositis and other forms of inflammatory myopathy are well recognised in dogs and man (Griffiths 1991). In equine medicine, inflammatory muscle disease is less well documented. Only a single report could be found in the literature containing mention of immune-mediated myositis in a horse unassociated with systemic disease, in which case the condition was multifocal (Beech 2000). We report a case of localised muscle atrophy and weakness in a pony. A diagnosis of chronic myositis was made after histological examination of biopsies of affected muscles. The histological appearance, elimination of other causes and response to treatment suggested an immune-mediated aetiology.