Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.

Cambios en la morfología y la microdensidad neovascular corneal inducidos tras la administración tópica de bevacizumab y sunitinib en un modelo animal / Vascular morphological and microdensity changes of corneal neovascularization induced by topical bevacizumab and sunitinib in an animal model

Objetivo: Evaluar los efectos de la administración tópica de bevacizumab y sunitinib sobre la microdensidad vascular y la morfología de la neovascularización (NV) corneal. Método: Se distribuyeron 33 conejos en 3 grupos: grupo 1 (control; n = 11): suero salino; grupo 2 (n = 11): bevacizumab 5 mg/ml y grupo 3 (n = 11): sunitinib 0,5 mg/ml. Se realizó un modelo de NV corneal mediante suturas en el ojo derecho de cada conejo. Se administró cada tratamiento por vía tópica 3 veces al día durante 14 días. Posteriormente, se procesaron las córneas para el estudio de la microdensidad vascular (6 ojos) y el análisis de la morfología vascular (5 ojos) mediante técnicas histológicas de tinción enzimática. Resultados: La respuesta vascular del grupo 3 quedó limitada a unas pequeñas formaciones arborescentes con varios ejes vasculares en comparación con la extensa, frondosa y direccional NV corneal de los grupos 1 y 2. Las secciones histológicas próximas al limbo no mostraron diferencias en los estudios de microdensidad vascular entre los 3 grupos. No obstante, la media del área de sección de los vasos (MASV) del grupo 3 fue un 41,88% menor que la del grupo 1 y un 19,19% menor que la del grupo 2. En las secciones distales, no hubo diferencias entre los grupos 1 y 2. Sin embargo, el grupo 3 se caracterizó por la ausencia de neovasos. Conclusiones: Bevacizumab no produjo cambios en la morfología de los vasos ni en la microdensidad vascular. Sunitinib redujo el calibre de los neovasos e indujo cambios en el árbol vascular(AU)

Objective: To evaluate the effects of topical bevacizumab and topical sunitinib on vascular microdensity and morphology of corneal neovascularization (NV). Methods: A total of 33 rabbits were distributed into 3 groups: group 1 (control; n=11): saline; group 2 (n=11): bevacizumab 5 mg/ml; and group 3 (n=11): sunitinib 0.5 mg/ml. A corneal NV model was used, based on sutures in the right eye of each rabbit. Each treatment was administered topically 3 times daily for 14 days. Corneas were then processed for the study of vascular microdensity (6 eyes) and vascular morphology analysis (5 eyes) using enzymatic staining histological techniques. Results: The vascular response in group 3 was limited to small-sized tree formations with various vascular axes compared with the extensive, lush and directional corneal NV of group 1 and 2. In the histological sections near the limb, there were no differences in vascular microdensity studies between the three groups. However, the mean sectional area of vessels (MSAV) in group 3 was 41.88% lower than in group 1 and 19.19% lower than in group 2. In distal sections, there were no differences between groups 1 and 2. However, group 3 was characterized by absence of vessels. Conclusions: Bevacizumab produced no changes in the morphology of the vessels or the vascular microdensity. Sunitinib reduced the size of the new vessels and induced changes in the vascular tree (AU)

[Vascular morphological and microdensity changes of corneal neovascularization induced by topical bevacizumab and sunitinib in an animal model]. / Cambios en la morfología y la microdensidad neovascular corneal inducidos tras la administración tópica de bevacizumab y sunitinib en un modelo animal.

OBJECTIVE: To evaluate the effects of topical bevacizumab and topical sunitinib on vascular microdensity and morphology of corneal neovascularization (NV). METHODS: A total of 33 rabbits were distributed into 3 groups: group 1 (control; n=11): saline; group 2 (n=11): bevacizumab 5mg/ml; and group 3 (n=11): sunitinib 0.5mg/ml. A corneal NV model was used, based on sutures in the right eye of each rabbit. Each treatment was administered topically 3 times daily for 14 days. Corneas were then processed for the study of vascular microdensity (6 eyes) and vascular morphology analysis (5 eyes) using enzymatic staining histological techniques RESULTS: The vascular response in group 3 was limited to small-sized tree formations with various vascular axes compared with the extensive, lush and directional corneal NV of group 1 and 2. In the histological sections near the limb, there were no differences in vascular microdensity studies between the three groups. However, the mean sectional area of vessels (MSAV) in group 3 was 41.88% lower than in group 1 and 19.19% lower than in group 2. In distal sections, there were no differences between groups 1 and 2. However, group 3 was characterized by absence of vessels. CONCLUSIONS: Bevacizumab produced no changes in the morphology of the vessels or the vascular microdensity. Sunitinib reduced the size of the new vessels and induced changes in the vascular tree.

Experiencia y tratamiento anestésico en el implante transcatéter de la prótesis valvular aórtica autoexpandible CoreValve ® / Anesthetic management and experience in the transcatheter implantation of the CoreValve ® self-expanding aortic valve

Objetivo. Analizar la experiencia y el tratamiento anestésico perioperatorio en la implantación transcatéter de la válvula aórtica autoexpandible CoreValve® en un hospital universitario terciario. Material y métodos. Estudio observacional analítico con revisión de datos incorporados a una base mantenida de forma prospectiva de 142 pacientes diagnosticados de estenosis aórtica severa, a los que se implantó una válvula aórtica autoexpandible CoreValve® entre diciembre de 2007 y diciembre de 2012. Resultados. La media de edad de los pacientes fue de 82,5 ± 6,1 años y el EuroSCORE logístico de 14,9 ± 11,2. En 107 pacientes (75,3%) se utilizó anestesia general, y en 35 (24,6%), anestesia local con sedación. La anestesia local con sedación se asoció con un menor requerimiento de fármacos vasoactivos (p = 0,003) durante el implante. No encontramos diferencias estadísticamente significativas entre ambas técnicas anestésicas en el tiempo de duración del procedimiento, en la estancia hospitalaria ni en la morbimortalidad. La tasa de éxito fue del 97,1%. La complicación más frecuente fueron los trastornos de la conducción, que precisaron la implantación de marcapasos definitivo en 46 pacientes (32,3%). No hubo ningún exitus intraoperatorio, la mortalidad por cualquier causa a los 30 días fue del 6,3% y la supervivencia al año estimada por el método de Kaplan-Meier fue de 83,1%. Conclusiones. Este estudio confirma que en pacientes con estenosis aórtica severa y alto riesgo quirúrgico la sustitución valvular aórtica transcatéter es una alternativa efectiva y segura. Tanto la anestesia general como la local con sedación son opciones válidas, dependiendo de la experiencia del equipo (AU)

[Anesthetic management and experience in the transcatheter implantation of the CoreValve(®) self-expanding aortic valve]. / Experiencia y tratamiento anestésico en el implante transcatéter de la prótesis valvular aórtica autoexpandible CoreValve(®)

OBJECTIVE: To analyze the experience and anesthetic management in the transcatheter implantation of the CoreValve(®) self-expanding aortic valve, in a university tertiary hospital. MATERIAL AND METHODS: Observational analytical review of data incorporated into a prospectively maintained database of 142 patients diagnosed with severe aortic stenosis who underwent implantation of a CoreValve(®) aortic self-expanding aortic valve between December 2007 and December 2012. RESULTS: The mean age of patients was 82.5±6.1 years and the logistic EuroSCORE was 14.9±11.2. General anesthesia was used in 107 patients (75.3%), with local anesthesia with sedation in 35 (24.6%). Local anesthesia and sedation was associated with a lower requirement of vasoactive drugs (P=.003) during implantation. No statistically significant differences were found between the 2 anesthetic techniques in the duration of the procedure, hospital stay, or morbimortality. The success rate was 97.1%. The most common complication was conduction disorders that required implantation of a permanent pacemaker in 46 patients (32.3%). There was no intraoperative mortality, and all-cause mortality at 30 days was 6.3%, with a one-year survival estimated by the Kaplan-Meier of 83.1%. CONCLUSIONS: This study confirms that in patients with severe aortic stenosis and high surgical risk, transcatheter implantation of aortic valve is a safe and effective alternative. Both, general anesthesia and local anesthesia with sedation are valid options, depending on the experience of the team.

Age-related functional and structural retinal modifications in the Igf1-/- null mouse.

BACKGROUND: Mutations in the gene encoding human insulin-like growth factor-I (IGF-I) cause syndromic neurosensorial deafness. To understand the precise role of IGF-I in retinal physiology, we have studied the morphology and electrophysiology of the retina of the Igf1(-/-) mice in comparison with that of the Igf1(+/-) and Igf1(+/+) animals during aging. METHODS: Serological concentrations of IGF-I, glycemia and body weight were determined in Igf1(+/+), Igf1(+/-) and Igf1(-/-) mice at different times up to 360days of age. We have analyzed hearing by recording the auditory brainstem responses (ABR), the retinal function by electroretinographic (ERG) responses and the retinal morphology by immunohistochemical labeling on retinal preparations at different ages. RESULTS: IGF-I levels are gradually reduced with aging in the mouse. Deaf Igf1(-/-) mice had an almost flat scotopic ERG response and a photopic ERG response of very small amplitude at postnatal age 360days (P360). At the same age, Igf1(+/-) mice still showed both scotopic and photopic ERG responses, but a significant decrease in the ERG wave amplitudes was observed when compared with those of Igf1(+/+) mice. Immunohistochemical analysis showed that P360 Igf1(-/-) mice suffered important structural modifications in the first synapse of the retinal pathway, that affected mainly the postsynaptic processes from horizontal and bipolar cells. A decrease in bassoon and synaptophysin staining in both rod and cone synaptic terminals suggested a reduced photoreceptor output to the inner retina. Retinal morphology of the P360 Igf1(+/-) mice showed only small alterations in the horizontal and bipolar cell processes, when compared with Igf1(+/+) mice of matched age. CONCLUSIONS: In the mouse, IGF-I deficit causes an age-related visual loss, besides a congenital deafness. The present results support the use of the Igf1(-/-) mouse as a new model for the study of human syndromic deaf-blindness.

Retinal degeneration in two lines of transgenic S334ter rats.

Aim of this study was to examine synaptic connectivity changes in the retina and the location and rate of apoptosis in transgenic S334ter line-3 and line-5 rats with photoreceptor degeneration. Heterozygous S334ter-line-3 and line-5 at P11-13, P30, P60, P90 and several control non-dystrophic rats (Long Evans and Sprague-Dawley) at P60, were studied anatomically by immunohistochemistry for various cell and synaptic markers, and by PNA and TUNEL label.- S334ter line-3 exhibited the fastest rate of degeneration with an early loss of photoreceptors, with 1-2 layers remaining at P30, and only cones left at P60. Line-5 had 4-5 layers left at P30, and very few rods left at P60-90. In both lines, horizontal cell processes (including dendrites and axon) were diminished at P11-13, showing gaps in the outer plexiform layer (OPL) at P60, and at P90, almost no terminal tips could be seen. Bipolar cells showed a retraction of their dendrites forming clusters along the OPL. Synaptic terminals of A-II amacrine cells in the IPL lost most of their parvalbumin-immunoreactivity. The apoptosis rate was different in both lines. Line-3 rats showed many photoreceptors affected at P11, occupying the innermost part of the outer nuclear layer. Line-5 showed a lower number of apoptotic cells within the same location at P13. In summary, the S334ter line-3 rat has a faster progression of degeneration than line-5. The horizontal and bipolar terminals are already affected at P11-P13 in both models. Apoptosis is related to the mutated rhodopsin transgene; the first photoreceptor cells affected are those close to the OPL.

Functional and structural modifications during retinal degeneration in the rd10 mouse.

Mouse models of retinal degeneration are useful tools to study therapeutic approaches for patients affected by hereditary retinal dystrophies. We have studied degeneration in the rd10 mice both by immunocytochemistry and TUNEL-labeling of retinal cells, and through electrophysiological recordings. The cell degeneration in the retina of rd10 mice produced appreciable morphological changes in rod and cone cells by P20. Retinal cell death is clearly observed in the central retina and it peaked at P25 when there were 800 TUNEL-positive cells per mm(2). In the central retina, only one row of photoreceptors remained in the outer nuclear layer by P40 and there was a remarkable deterioration of bipolar cell dendrites postsynaptic to photoreceptors. The axon terminals of bipolar cells also underwent atrophy and the inner retina was subject to further changes, including a reduction and disorganization of AII amacrine cell population. Glutamate sensitivity was tested in rod bipolar cells with the single cell patch-clamp technique in slice preparations, although at P60 no significant differences were observed with age-matched controls. Thus, we conclude that rod and cone degeneration in the rd10 mouse model is followed by deterioration of their postsynaptic cells and the cells in the inner retina. However, the functional preservation of receptors for photoreceptor transmission in bipolar cells may open new therapeutic possibilities.

Tratamiento perioperatorio de una gestante con infarto cerebral reciente secundario a miocardiopatía no compactada / Perioperative treatment of a pregnant woman with recent cerebral infarction secondary to noncompaction cardiomyopathy

La miocardiopatía no compactada (MNC) es una entidadde reciente acuñamiento, de presentación infrecuentepero con manifestaciones clínicas importantes y pronósticosombrío. El infarto cerebral es una de sus formasde presentación; y el embarazo, estado de hipercoagulabilidad,lo favorece. Se presenta el caso de una mujerembarazada que fue llevada a urgencias con un infartocerebral isquémico, en cuyo estudio se demostró etiologíacardioembólica, con diagnóstico de MNC. Días después,tras su estabilización, fue sometida a cesárea electivabajo anestesia general. La intervención transcurriósin incidencias, al igual que el postoperatorio, tras elcual fue trasladada al Servicio de Rehabilitación. Esobligatorio en estos casos evitar el daño miocárdico y laprogresión del accidente cerebrovascular; para ello previoa la cirugía se debe estabilizar al paciente e iniciartratamiento antiagregante y/o anticoagulante. Es necesariomantener la estabilidad hemodinámica durante todoel perioperatorio, evitando en lo posible la depresión delneonato tras su extracción. Para ello existen diferentesestrategias, que deben adecuarse al estado y al momentoen el que se encuentre la paciente

Recent-onset noncompaction of the myocardium is arare but serious entity with uncertain prognosis. Cerebralinfarction is among the forms of presentation, andpregnancy and hypercoagulability increase risk. Wereport the case of a pregnant woman brought to theemergency department with ischemic cerebral infarction.Investigation demonstrated the cause to be cardiac embolism,and noncompaction of the myocardium was diagnosed.She was stabilized and a few days later underwentelective cesarean section under general anesthesia. Surgeryand postoperative recovery were uneventful, and shewas transferred for rehabilitation. Myocardial injury andprogression to cerebrovascular accident must beprevented in such cases; the patient must be stabilizedand antiplatelet and/or anticoagulant therapy initiatedbefore surgery. Hemodynamic stability must be maintainedthroughout the perioperative period and neonataldepression avoided after delivery. Various approaches areavailable to be adapted to the patient's situation

[Perioperative treatment of a pregnant woman with recent cerebral infarction secondary to noncompaction cardiomyopathy]. / Tratamiento perioperatorio de una gestante con infarto cerebral reciente secundario a miocardiopatía no compactada.

Recent-onset noncompaction of the myocardium is a rare but serious entity with uncertain prognosis. Cerebral infarction is among the forms of presentation, and pregnancy and hypercoagulability increase risk. We report the case of a pregnant woman brought to the emergency department with ischemic cerebral infarction. Investigation demonstrated the cause to be cardiac embolism, and noncompaction of the myocardium was diagnosed. She was stabilized and a few days later underwent elective cesarean section under general anesthesia. Surgery and postoperative recovery were uneventful, and she was transferred for rehabilitation. Myocardial injury and progression to cerebrovascular accident must be prevented in such cases; the patient must be stabilized and antiplatelet and/or anticoagulant therapy initiated before surgery. Hemodynamic stability must be maintained throughout the perioperative period and neonatal depression avoided after delivery. Various approaches are available to be adapted to the patient's situation.

Siringomielia y malformación de Chiari tipo I, con parálisis bilateral de cuerdas vocales y síndrome de apnea obstructiva del sueño asociadas / Syringomyelia and Chiari type 1 malformation with associated bilateral vocal cord paralysis and obstructive sleep apnea syndrome

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Anestesia con flujos bajos: aspectos teórico-prácticos / No disponible

La práctica de anestesia con flujos bajos es cada día más frecuente en nuestro entorno, debido al desarrollo de las modernas estaciones de trabajo, que incorporan circuitos circulares y sistemas de monitorización de gases espirados y de parámetros ventilatorios que hacen la técnica segura. Son escasas las contraindicaciones a su uso y puede llevarse a cabo en ventilación mecánica y espontánea, con tubo endotraqueal o mascarilla laríngea, en adultos y en niños. Las ventajas de la anestesia con flujos bajos son numerosas; económicas, docentes, ecológicas. Los riesgos vienen dados, en general, por la posibilidad de fugas en los aparatos, el acúmulo de sustancias extrañas, bien sea endógenas o exógenas y por el desconocimiento de la técnica. Para la práctica segura de estas técnicas, es recomendable el conocimiento de algunas leyes físicas, así como los fundamentos de la anestesia inhalatoria, junto con el estudio de las características de los elementos de un sistema circular, su funcionamiento y en qué medida influye la reducción del flujo de gases en lo que se denomina comportamiento dinámico del circuito. Desde el punto de vista práctico, hay varios métodos para hacer la anestesia con flujos bajos y mínimos fácil y asequible al principiante, sin olvidar que la base de estos métodos son los principios de la anestesia inhalatoria

Low flow anesthesia is nowadays an often practice in our hospitals. Workstations development, with circular circuits and complexes monitoring modules, such as, expired gases and ventilatory parameters, are the causes of the actual development of these old techniques and make them secure. Its contraindications are very few, and low flow anesthesia can be perfomed under spontaneous or mechanical ventilation, with the trachea intubated or with laryngeal mask, in adults and children. It has economical, docent and ecological advantages. The risks of its use come from the possibility of leaks, endogenous and exogenous accumulus of strange compounds in the circuit, and lack of knowledge about the technique. For safety reasons it is recommended to study fundamental of some physical laws and principles of inhalatory anesthesia, circular circuits and its dynamics when low flow is used. From a practical point of view, there are a few methods to perfome low or minimal flow anesthesia in an easy way for the beginner, attending anyway, that they are supported in the inhalatory anesthesia principles