Calcium release from intra-axonal endoplasmic reticulum leads to axon degeneration through mitochondrial dysfunction.

Axonal degeneration represents an early pathological event in neurodegeneration, constituting an important target for neuroprotection. Regardless of the initial injury, which could be toxic, mechanical, metabolic, or genetic, degeneration of axons shares a common mechanism involving mitochondrial dysfunction and production of reactive oxygen species. Critical steps in this degenerative process are still unknown. Here we show that calcium release from the axonal endoplasmic reticulum (ER) through ryanodine and IP3 channels activates the mitochondrial permeability transition pore and contributes to axonal degeneration triggered by both mechanical and toxic insults in ex vivo and in vitro mouse and rat model systems. These data reveal a critical and early ER-dependent step during axonal degeneration, providing novel targets for axonal protection in neurodegenerative conditions.

Dynamics of degeneration and regeneration in developing zebrafish peripheral axons reveals a requirement for extrinsic cell types.

BACKGROUND: Understanding the cellular mechanisms regulating axon degeneration and regeneration is crucial for developing treatments for nerve injury and neurodegenerative disease. In neurons, axon degeneration is distinct from cell body death and often precedes or is associated with the onset of disease symptoms. In the peripheral nervous system of both vertebrates and invertebrates, after degeneration of detached fragments, axons can often regenerate to restore function. Many studies of axonal degeneration and regeneration have used in vitro approaches, but the influence of extrinsic cell types on these processes can only be fully addressed in live animals. Because of its simplicity and superficial location, the larval zebrafish posterior lateral line (pLL) nerve is an ideal model system for live studies of axon degeneration and regeneration. RESULTS: We used laser axotomy and time-lapse imaging of pLL axons to characterize the roles of leukocytes, Schwann cells and target sensory hair cells in axon degeneration and regeneration in vivo. Immune cells were essential for efficient removal of axonal debris after axotomy. Schwann cells were required for proper fasciculation and pathfinding of regenerating axons to their target cells. Intact target hair cells were not themselves required for regeneration, but chemical ablation of neuromasts caused axons to transiently deviate from their normal paths. CONCLUSIONS: Macrophages, Schwann cells, and target sensory organs are required for distinct aspects of pLL axon degeneration or regeneration in the zebrafish larva. Our work introduces a powerful vertebrate model for analyzing axonal degeneration and regeneration in the living animal and elucidating the role of extrinsic cell types in these processes.

A BAX/BAK and cyclophilin D-independent intrinsic apoptosis pathway.

Most intrinsic death signals converge into the activation of pro-apoptotic BCL-2 family members BAX and BAK at the mitochondria, resulting in the release of cytochrome c and apoptosome activation. Chronic endoplasmic reticulum (ER) stress leads to apoptosis through the upregulation of a subset of pro-apoptotic BH3-only proteins, activating BAX and BAK at the mitochondria. Here we provide evidence indicating that the full resistance of BAX and BAK double deficient (DKO) cells to ER stress is reverted by stimulation in combination with mild serum withdrawal. Cell death under these conditions was characterized by the appearance of classical apoptosis markers, caspase-9 activation, release of cytochrome c, and was inhibited by knocking down caspase-9, but insensitive to BCL-X(L) overexpression. Similarly, the resistance of BIM and PUMA double deficient cells to ER stress was reverted by mild serum withdrawal. Surprisingly, BAX/BAK-independent cell death did not require Cyclophilin D (CypD) expression, an important regulator of the mitochondrial permeability transition pore. Our results suggest the existence of an alternative intrinsic apoptosis pathway emerging from a cross talk between the ER and the mitochondria.

Lef1-dependent Wnt/ß-catenin signalling drives the proliferative engine that maintains tissue homeostasis during lateral line development.

During tissue morphogenesis and differentiation, cells must self-renew while contemporaneously generating daughters that contribute to the growing tissue. How tissues achieve this precise balance between proliferation and differentiation is, in most instances, poorly understood. This is in part due to the difficulties in dissociating the mechanisms that underlie tissue patterning from those that regulate proliferation. In the migrating posterior lateral line primordium (PLLP), proliferation is predominantly localised to the leading zone. As cells emerge from this zone, they periodically organise into rosettes that subsequently dissociate from the primordium and differentiate as neuromasts. Despite this reiterative loss of cells, the primordium maintains its size through regenerative cell proliferation until it reaches the tail. In this study, we identify a null mutation in the Wnt-pathway transcription factor Lef1 and show that its activity is required to maintain proliferation in the progenitor pool of cells that sustains the PLLP as it undergoes migration, morphogenesis and differentiation. In absence of Lef1, the leading zone becomes depleted of cells during its migration leading to the collapse of the primordium into a couple of terminal neuromasts. We show that this behaviour resembles the process by which the PLLP normally ends its migration, suggesting that suppression of Wnt signalling is required for termination of neuromast production in the tail. Our data support a model in which Lef1 sustains proliferation of leading zone progenitors, maintaining the primordium size and defining neuromast deposition rate.

Expression profiling identifies novel Hh/Gli-regulated genes in developing zebrafish embryos.

The Hedgehog (Hh) signaling pathway plays critical instructional roles during embryonic development. Misregulation of Hh/Gli signaling is a major causative factor in human congenital disorders and in a variety of cancers. The zebrafish is a powerful genetic model for the study of Hh signaling during embryogenesis, as a large number of mutants that affect different components of the Hh/Gli signaling system have been identified. By performing global profiling of gene expression in different Hh/Gli gain- and loss-of-function scenarios we identified known (e.g., ptc1 and nkx2.2a) and novel Hh-regulated genes that are differentially expressed in embryos with altered Hh/Gli signaling function. By uncovering changes in tissue-specific gene expression, we revealed new embryological processes that are influenced by Hh signaling. We thus provide a comprehensive survey of Hh/Gli-regulated genes during embryogenesis and we identify new Hh-regulated genes that may be targets of misregulation during tumorigenesis.

Programa educativo dirigido a pacientes con hipertensión arterial sistémica en la consulta externa del Hospital Obrero Numero 1 gestión 2001 / Educative program directed patients with sitemica arterial hypertension in the external consultation of the Hospital Obrero N§ 1 management 2001

Con elpropósito de contribuir de manera favorable a disminuir los factores de riesgo y prevenir las complicaciones en pacientes de hipertensión arterial, se ha diseñado este trabajo considerando que en muchos de ellos: la ignorancia, el conocimiento parcial o inexacto ejerce una influencia importante en el incumplimiento y abandono terapéutico. Por ello se plantea la necesidad de diseñar un programa a través de un instrumento de la Salud Pública, " la educación para la salud" bajo dos modalidades: de sesiones individuales y grupales que permitan la modificación de los comportamientos nocivos y alcanzar una cultura saludable respecto a su enfermedad. El objeto que se persigue particularmente es evaluar la eficacia de este programa educativo, a través de una metodología que permita cumplir este propósito, ya que es un elemento insoslayable y necesario en todo proceso educativo para determinar el cumplimiento de os bjetivos propuestos. A partir de los resutlados obtenidos, este trabajo representa un aporte a la ciencia de la salud, porque en la actualidad no se cuenta con programas que coadyuven al mejoramiento en la terapia de este grupo importante de pacientes que le permita mejorar su esperanza y calidad de vida. Particularmente, representa un especial aporte a la práctica de enfermería porque permite elevar cualitativamente el rol profesional, fortalecer el prestigio de la enfermera a partir de una mejora en su desempeño ya que retomará una de sus funciones especiíficas que es: la educación.

Programa educativo dirigido a pacientes con hipertensión arterial sistémica en la consulta externa del Hospital Obrero Nº 1 gestión 2001 / Educative program directed patients with sitemica arterial hypertension in the external consultation of the Hospital Obrero Nº 1 management 2001

Con el proposito de contribuir de manera favorable a disminuir los factores de riesgo y prevenir las complicaciones en pacientes de hipertension arterial, se ha diseñado este trabajo considerando que en muchos de ellos: la ignorancia, el conocimiento parcial o inexacto ejerce una influencia importante en el incumplimiento y abandono terapeutico. Por ello se plantea la necesidad de diseñar un programa a través de un instrumento de la Salud Pública, " la educación para la salud" bajo dos modalidades: de sesiones individuales y grupales que permitan la modificación de los comportamientos nocivos y alcanzar una cultura saludable respecto a su enfermedad. El objeto que se persigue particularmente es evaluar la eficacia de este programa educativo, a través de una metodología que permita cumplir este propósito, ya que es un elemento insoslayable y necesario en todo proceso educativo para determinar el cumplimiento de os bjetivos propuestos. A partir de los resutlados obtenidos, este trabajo representa un aporte a la ciencia de la salud, porque en la actualidad no se cuenta con programas que coadyuven al mejoramiento en la terapia de este grupo importante de pacientes que le permita mejorar su esperanza y calidad de vida. Particularmente, representa un especial aporte a la práctica de enfermería porque permite elevar cualitativamente el rol profesional, fortalecer el prestigio de la enfermera a partir de una mejora en su desempeño ya que retomará una de sus funciones especiíficas que es: la educación