Prolonged fixation and post-mortem delay impede the study of adult neurogenesis in mice.

Adult hippocampal neurogenesis (AHN) gives rise to new neurons throughout life. This phenomenon takes place in more than 120 mammalian species, including humans, yet its occurrence in the latter was questioned after one study proposed the putative absence of neurogenesis markers in the adult human hippocampus. In this regard, we showed that prolonged fixation impedes the visualization of Doublecortin+ immature neurons in this structure, whereas other authors have suggested that a dilated post-mortem delay (PMD) underlies these discrepancies. Nevertheless, the individual and/or additive contribution of fixation and the PMD to the detection (or lack thereof) of other AHN markers has not been studied to date. To address this pivotal question, we used a tightly controlled experimental design in mice, which allowed the dissection of the relative contribution of the aforementioned factors to the visualization of markers of individual AHN stages. Fixation time emerged as the most prominent factor globally impeding the study of this process in mice. Moreover, the visualization of other particularly sensitive epitopes was further prevented by prolonged PMD. These results are crucial to disambiguate current controversies related to the occurrence of AHN not only in humans but also in other mammalian species.

GSK-3ß orchestrates the inhibitory innervation of adult-born dentate granule cells in vivo.

Adult hippocampal neurogenesis enhances brain plasticity and contributes to the cognitive reserve during aging. Adult hippocampal neurogenesis is impaired in neurological disorders, yet the molecular mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. GABA is a master regulator of adult and developmental neurogenesis. Here we engineered a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during adult hippocampal neurogenesis in vivo. Our data reveal the early assembly of inhibitory postsynaptic densities at 1 week of cell age. Glycogen synthase kinase 3 Beta (GSK-3ß) emerges as a key regulator of inhibitory synapse formation and maturation during adult hippocampal neurogenesis. GSK-3ß-overexpressing newborn neurons show an increased number and altered size of Gephyrin+ postsynaptic clusters, enhanced miniature inhibitory postsynaptic currents, shorter and distanced axon initial segments, reduced synaptic output at the CA3 and CA2 hippocampal regions, and impaired pattern separation. Moreover, GSK-3ß overexpression triggers a depletion of Parvalbumin+ interneuron perineuronal nets. These alterations might be relevant in the context of neurological diseases in which the activity of GSK-3ß is dysregulated.

Response to Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Rakic and colleagues challenge the use of extensively validated adult hippocampal neurogenesis (AHN) markers and postulate an alternative interpretation of some of the data included in our study. In Terreros-Roncal et al., reconstruction of the main stages encompassed by human AHN revealed enhanced vulnerability of this phenomenon to neurodegenerative diseases. Here, we clarify points and ambiguities raised by these authors.

Response to Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Alvarez-Buylla and colleagues provide an alternative interpretation of some of the data included in our manuscript and question whether well-validated markers of adult hippocampal neurogenesis (AHN) are related to this phenomenon in our study. In Terreros-Roncal et al., reconstruction of the main stages of human AHN revealed its enhanced vulnerability to neurodegeneration. Here, we clarify ambiguities raised by these authors.

Impact of neurodegenerative diseases on human adult hippocampal neurogenesis.

Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.

[Tumor necrosis factor blocking agents: a review. Part I: Clinical efficacy evaluation]. / Lugar en terapéutica de los medicamentos antagonistas del factor de necrosis tumoral. Parte I: evaluación clínica.

Blockade of tumor necrosis factor with monoclonal antibodies, has emerged as one of the most promising therapies in some autoimmune conditions as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn s disease. They have shown effectiveness on reducing symptoms and modifying the progression of the disease. However, they disrupt the balance of inflammatory and immune responses and some risks associated with TNF-blockers have become apparent. The purpose of this article is to review the evidence about benefits and risk associated with the use of TNF-blockers in approved indications and to provide practical recommendations for its use in the management of these conditions.

[Tumor necrosis factor blocking agents: a review. Part II: safety and recommendations]. / Lugar en terapéutica de los medicamentos antagonistas del factor de necrosis tumoral. (2da de dos partes): de los efectos indeseados y recomendaciones.

Blockade of tumor necrosis factor with monoclonal antibodies, has emerged as one of the most promising therapies in some autoimmune conditions as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn's disease. They have shown effectiveness on reducing symptoms and modifying the progression of the disease. However, they disrupt the balance of inflammatory and immune responses and some risks associated with TNF-blockers have become apparent. The purpose of this article is to review the evidence about benefits and risk associated with the use of TNF-blockers in approved indications and to provide practical recommendations for its use in the management of this conditions.

Lugar en terapéutica de los medicamentos antagonistas del factor de necrosis tumoral. (2ª de dos partes): de los efectos indeseados y recomendaciones / Tumor necrosis factor blocking agents: a review. Part II: safety and recommendations

Los anticuerpos monoclonales que antagonizan el factor de necrosis tumoral (ATNF) son uno de los avances terapéuticos de mayor importancia de los últimos años. Han demostrado, no sólo poder controlar los síntomas de pacientes que no responden a fármacos modificadores de la enfermedad, sino tambien detener la progresión, en enfermedades con un componente autoinmune como la artritis reumatoide, la espondiloartritis, la artritis psoriásica y la enfermedad de Crohn. Sin embargo, los ATNF alteran el delicado y complejo equilibrio de las respuestas inflamatoria e inmune del organismo por lo que es de temer que su utilización conlleve efectos indeseados importantes y frecuentes. En este artículo hemos revisado la evaluación clínica publicada orientada a valorar su eficacia en las indicaciones donde su uso está autorizado, los datos existentes sobre su toxicidad y efectos indeseados en los pacientes que los han recibido y las recomendaciones sobre su utilización orientadas a mejorar su relación beneficio/riesgo

Blockade of tumor necrosis factor with monoclonal antibodies, has emerged as one of the most promising therapies in some autoimmune conditions as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn’s disease. They have shown effectiveness on reducing symptoms and modifying the progression of the disease. However, they disrupt the balance of inflammatory and immune responses and some risks associated with TNF-blockers have become apparent. The purpose of this article is to review the evidence about benefits and risk associated with the use of TNF-blockers in approved indications and to provide practical recommendations for its use in the management of this conditions

Lugar en terapéutica de los medicamentos antagonistas del factor de necrosis tumoral. Parte I: evaluación clínica / Tumor necrosis factor blocking agents: a review. Part I: clincial efficacy evaluation

Los anticuerpos monoclonales que antagonizan el factor de necrosis tumoral (ATNF) son uno de los avances terapéuticos de mayor importancia de los últimos años. Han demostrado, no sólo poder controlar los síntomas de pacientes que no responden a fármacos modificadores de la enfermedad, sino tambien detener la progresión, en enfermedades con un componente autoinmune como la artritis reumatoide, la espondiloartritis, la artritis psoriásica y la enfermedad de Crohn. Sin embargo, los ATNF alteran el delicado y complejo equilibrio de las respuestas inflamatoria e inmune del organismo por lo que es de temer que su utilización conlleve efectos indeseados importantes y frecuentes. En este artículo hemos revisado la evaluación clínica publicada orientada a valorar su eficacia en las indicaciones donde su uso está autorizado, los datos existentes sobre su toxicidad y efectos indeseados en los pacientes que los han recibido y las recomendaciones sobre su utilización orientadas a mejorar su relación beneficio/riesgo

Blockade of tumor necrosis factor with monoclonal antibodies, has emerged as one of the most promising therapies in some autoimmune conditions as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn’s disease. They have shown effectiveness on reducing symptoms and modifying the progression of the disease. However, they disrupt the balance of inflammatory and immune responses and some risks associated with TNF-blockers have become apparent. The purpose of this article is to review the evidence about benefits and risk associated with the use of TNF-blockers in approved indications and to provide practical recommendations for its use in the management of this conditions

[Drug interactions in the prescription of medical patients at hospital discharge]. / Interacciones entre medicamentos prescritos al alta en un Servicio de Medicina Interna.

OBJECTIVES: To detect and evaluate the clinical significance of drugs interactions in patients discharged from hospital. MATERIAL AND METHODS: We retrospectively screened the medication for potential drug interactions of 412 patients discharged. Interactions were catalogued according to clinical importance following the Hansten and Horn's classification. RESULTS: Three hundred twenty-nine potential interactions were detected. The 39.9% of the patients had at least one potentially interacting drug combination. The 52.6% of the interactions were catalogued as Class 3, bearing in mind minimizing the risk of the interaction. We did not find any Class 1 or 2 interactions, which have potentially major severity. Oral anticoagulants and digoxin were the most frequently implicated drugs. The patient monitoring was well done in the 100% of the interactions of Oral anticoagulants with other drug, but in the interactions of digoxin with another, this control was not done adequately. One patient was rehospitalised due to high levels of digoxin, he had been discharged with two potential interactions. CONCLUSIONS: The frequently of potential drug interactions in medical patients at hospital discharged was high, but the clinical significance appear to be low.

[Partial bilateral rupture of the Achilles tendon associated to levofloxacin]. / Rotura parcial bilateral aquílea asociada a levofloxacino.

Fluoroquinolones-associated tendonitis and tendon rupture are well described in the literature but these are not frequently observed and related to the new agents of this group, as levofloxacin. This is probably due to the recent introduction and expansion. Although epidemiological studies are needed to know the frequency of that levofloxacin-induced tendinopathies, case-report could alert to the physicians about this possible severe adverse reaction. We present a case of bilateral Achilles tendonitis with partial spontaneous rupture probably associated to levofloxacin.

Interacciones entre medicamentos prescritos al alta en un Servicio de Medicina Interna / Drug interactions in the prescription of medical patients at hospital discharge

Objetivos: Estimar la frecuencia y valorar la relevancia teórica y repercusión clínica real de las interacciones medicamentosas en pacientes dados de alta desde un área médica. Material y métodos: Se revisan los tratamientos al alta de 412 pacientes de forma aleatoria. Se identifican las potenciales interacciones usando la Guía de Terapia Farmacológica Medimecum. Para la clasificaciónsegún su relevancia clínica teórica se usa la propuesta por Hansten y Horn. Resultados: Se encuentran 329 interacciones teóricas. El 39,9% de los pacientes presentaban al menos una interacción [IC 95%, 34,9%-44,9%]. El 52,6% de las interacciones eran clase 3 según Hansten, aquellas en las que ha de tomarse alguna medida para disminuir el riesgo de efectos indeseables. No se encontró ninguna interacción clase 1 ó 2 de Hansten, categorías de mayor gravedad. Las interacciones clase 3 más frecuentes implican a anticoagulantes orales y digoxina. Las medidas de control fueron realizadas en el 100% de los casos para las interacciones entre anticoagulantes orales y otros fármacos. En las interacciones de digoxina y otros fármacos las medidas de control recomendadas no fueron realizadas suficientemente. Un paciente reingresó con niveles porencima de rango de digoxina, habiendo sido dado de alta con dos potenciales interacciones. Conclusiones: La frecuencia de interacciones en pacientes dados dealta desde el área médica es alta. La relevancia teórica y la práctica parece ser baja

Objectives: To detect and evaluate the clinical significance of drugs interactions in patients discharged from hospital. Material and methods: We retrospectively screened the medication for potential drug interactions of 412 patients discharged. Interactions were catalogued according to clinical importance following the Hanstenand Horn’s classification. Results: Three hundred twenty-nine potential interactions were detected. The 39.9% of the patients had at least one potentially interactingdrug combination. The 52.6% of the interactions were catalogued as Class 3, bearing in mind minimizing the risk of the interaction. We did not find any Class 1 or 2 interactions, which have potentially major severity.Oral anticoagulants and digoxin were the most frequently implicated drugs. The patient monitoring was well done in the 100% of the interactions of Oral anticoagulants with other drug, but in the interactions of digoxin with another, this control was not done adequately. One patientwas re-hospitalised due to high levels of digoxin, he had been discharged with two potential interactions. Conclusions: The frequently of potential drug interactions in medical patients at hospital discharged was high, but the clinical significance appear to be low

Rotura parcial bilateral aquílea asociada a levofloxacino / Partial bilateral rupture of the achilles tendon associated to levofloxacin

La tendinitis y rotura de tendón es un efecto indeseado bien conocido para fluoroquinolonas que también puede producirse con las nuevos agentes de este grupo. Aunque no existen muchos casos publicados para levofloxacino, esto es probablemente debido a lo reciente de su expansión. Aunque la descripción de casos no es el mejor método de valoración de la frecuencia de este problema, puede servir para alertar a los clínicos sobre la importancia de este efecto grave cuya frecuencia consideramos que ha sido infravalorada. En esta nota clínica presentamos un caso de rotura bilateral parcial del tendón aquíleo, probablemente asociado a levofloxacino

Fluoroquinolones-associated tendonitis and tendon rupture are well described in the literature but these are not frequently observed and related to the new agents of this group, as levofloxacin. This is probably due to the recent introduction and expansion. Although epidemiological studies are needed to know the frequency of that levofloxacin-induced tendinopathies, case-report could alert to the physicians about this possible severe adverse reaction. We present a case of bilateral Achiles tendonitis with partial spontaneous rupture probably associated to levofloxacin

[Statin-induced rhabdomyolysis and renal failure: also with fluvastatine]. / Rabdomiolisis y fallo renal por estatinas: también con fluvastatina.

Hydroximetilglutaril-coenzima A reductase inhibitors (statin) have the potential to cause rhabdomyolysis. However, fluvastatin is rarely associated with rhabdomyolysis when compared to other statins. Differences in biochemical and pharmacokinetic properties between fluvastatin and the other statins have been invocated in order to explain the apparent comparative safety of fluvastatin. We present a case of rhabdomyolysis with acute renal failure in a patient receiving fluvastatin and, following the Karch-Lasagne algorithm, we present evidence that this case was an adverse reactions to fluvastatin.

Rabdomiolisis y fallo renal por estatinas: también con fluvastatina / Statin-induced rhabdomyolysis and renal failure: also for fluvastatine

La rabdomiolisis es un efecto adverso plenamente descrito para los inhibidores de la Hidroximetil-glutaril Coenzima A reductasa (estatinas). Sin embargo la evidencia de esta asociación es menor para la fluvastatina y se ha argumentado que sus diferencias bioquímicas y farmacocinéticas con el resto de estatinas explicaría esta aparente inocuidad comparativa. Presentamos un caso de rabdomiolisis con fallo renal en una paciente que recibía tratamiento con fluvastatina y, mediante el algoritmo de causalidad de reacciones adversas de Karch y Lasagna, proporcionamos evidencia de que se trata de una efecto adverso atribuible a la fluvastatina (AU)

[Oral anticoagulation]. / Anticoagulación oral.

The use of oral anticoagulants in the prevention of thrombotics processes, has experienced a considerable increase. In addition, there are a growing experience on the medical and socials consequences of the use of this drug. This has originated a much more pragmatic vision of the daily handling of the anticoagulated patient. In this article, we made are vision about the indications and the practical use, including some useful advices and criteria for the concomitant drug selection.

Anticoagulación oral / Oral anticoagulation

En los últimos años ha aumentado considerablemente la utilización de anticoagulantes orales en la prevención de procesos tromboembólicos. Además de un mayor número de pacientes en tratamiento anticoagulante, actualmente se dispone de una amplísima experiencia sobre las consecuencias médicas y sociales que implica este tratamiento lo que ha originado una visión mucho mas pragmática del manejo cotidiano del paciente anticoagulado. En este artículo se realiza una revisión sobre anticoagulación oral en base a las recomendaciones actuales existentes en la literatura médica (AU)

[Use of beta-blockers for treatment of cardiac failure]. / Utilización de betabloqueadores en el tratamiento de la insuficiencia cardiaca.

The rationale for betablocker use in heart failure, based on neurohormonal physiology, has been established over the past 20 years. Recent trials have shown the unequivocal benefits of betablockers in patients with chronic systolic heart failure. The benefits include improve survival (35%) reduced need for hospitalization and improve of left ventricular function. However, betablockers may also make a patient with heart failure worse, especially when treatment begins and there is reluctance to use betablockade therapy. Complications can generally be avoided by starting with extremely low doses and increasing the dose very slowly. Despite this, further questions remain regarding the use of these agents in cardiac failure, including the role in the progression of the disease, the selection of individual betablocker, and the use in very severe disease or very old patients.

Utilización de betabloqueadores en el tratamiento de la insuficiencia cardiaca / Use of betablockers on treatment of cardiac failure

El conocimiento de la implicación del sistema adrenérgico en la fisiopatología de la insuficiencia cardiaca (ICC) ha justificado una intensa investigación sobre el papel de los betabloqueadores en el tratamiento de esta enfermedad. Recientemente se han publicado varios ensayos clínicos de gran calidad que demuestran claramente que el tratamiento de la ICC sistólica con betabloqueadores disminuye la mortalidad en un 35 por ciento, la frecuencia de hospitalización y mejora la función ventricular. Sin embargo, existen muchas reticencias para su uso debido a que pueden empeorar el cuadro en algunos pacientes, sobre todo al principio del tratamiento. Esto puede evitarse con un cuidadoso comienzo y un progresivo ajuste de dosis. Todavía quedan cuestiones por responder como la elección del betabloqueador, el efecto del tratamiento en la progresión de la enfermedad y su utilidad en pacientes muy graves o muy ancianos (AU)

Fármacos en la profilaxis de la gastropatía por antiinflamatorios no esteroideos

La gastropatía inducida por antiinflamatorios no esteroideos es muy frecuente. Las lesiones gástricas ocasionadas por el uso de estos fármacos son subclínicas e intrascendentes en la mayoría de ocasiones, pero algunas veces los antiinflamatorios determinan la aparición de úlceras gástricas o duodenales que pueden complicarse con la aparición de hemorragia digestiva o de perforación. La prevención de estas alteraciones pasa, en primer lugar, por el uso más juicioso de los antiinflamatorios y, en segundo lugar, por la administración de algunos fármacos con finalidad protectora. Sin embargo, está plenamente demostrado que el uso de estos fármacos con fines profilácticos es necesario en pocos casos. En este artículo se revisan las recomendaciones actuales de la profilaxis farmacológica de la gastropatía inducida por antiinflamatorios no esteroideos (AU)