Loss of HIF-1α accelerates murine FLT-3(ITD)-induced myeloproliferative neoplasia.

Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1α (HIF-1α) has a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs), as well as leukemia-initiating cells (LICs) of acute myeloid leukemia and chronic myeloid leukemia. We have investigated the effect of HIF-1α loss on the phenotype and biology of FLT-3(ITD)-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1α leads to an enhanced MPN phenotype reflected by an increased number of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF-1α loss is cell intrinsic as shown by transplantation into recipient mice. HSC loss and organ-specific changes in the number and percentage of long-term HSCs were the most pronounced effects on a cellular level after HIF-1α deletion. Furthermore, we found a metabolic hyperactivation of malignant cells in the spleen upon loss of HIF-1α. Some of our findings are in contrary to what has been previously described for the role of HIF-1α in other myeloid hematologic malignancies and question the potential of HIF-1α as a therapeutic target.

Eficacia de un programa de escuela de espalda hospitalario / Efficacy of a hospital back school program

Introducción. Las escuelas de espalda sonuna de las intervenciones utilizadas en los programas derehabilitación. El objetivo de nuestro estudio es describirlas características del programa de espalda del Hospital deSan Juan y valorar su eficacia.Material y métodos. Se incluyeron 897 pacientes con dorsalgiay/o lumbalgia, durante el período de enero de 2004 adiciembre de 2006. El programa se desarrolló en 6 sesionescolectivas a lo largo de 3 meses. Se completaron los testsde la ganancia de flexión lumbar protegida (medida como ladistancia en centímetros manos-suelo) y la mejoría subjetivaen actividades de la vida diaria (AVD) (nada, insuficienteo suficiente).Resultados y conclusiones. Completaron el protocolo261 pacientes. El programa mejora el dolor raquídeo medidocon la escala visual analógica (EVA) del dolor en 0,61 mm(intervalo de confianza [IC] 95 %: 0,32-0,9) y la ganancia deflexión lumbar protegida en 5,13 cm (IC 95 %: 4,21-6,05). Lamayoría de los pacientes mejoraron de forma suficiente(51,7 %) sin requerir ningún otro tipo de tratamiento fisioterápico.Estas mejorías encontradas fueron estadísticamen tesignificativas (p < 0,000)(AU)

Introduction. Back school is one of the interventionsused in the Rehabilitation programs. The aim of ourstudy is to describe the characteristics of a program of rachialgiaof San Juan’s Hospital, as well as its effectiveness.Methods. Eight-hundred and ninety-seven patients withdorsalgia and/or lumbalgia were included, during the periodJanuary 2004-December 2006. The program was developedin 6 collective sessions of three months’ duration. The test ofVisual Analogue Scale of the pain, the gain in flexion lumbarprotected (measured in cm as the distance between handsand ground) and the subjective improvement in activity dailylife (nothing, inadequate or sufficient) were completed.Results and conclusions. Two-hundred and sixty-one patientscompleted the protocol. The program improved 0.61 mm (IC95 % ± 0.29) of Visual Analogue Scale measuring spinal pain;5.13 cm (IC 95 % ± 0.92) improvement in protected lumbarflexion. Most patients improved sufficiently (51.7 %), withoutrequiring any other type of physiotherapy treatment. Theseimprovements were statistically significant (p < 0.000)(AU)

Differential regulation of calcium channel coding genes by prolonged depolarization.

Calcium channels must be subjected to a very precise regulation in order to preserve cell function and viability. Voltage gated calcium channels (VGCC) represent the main pathway for calcium entry in excitable cells. This explains why depolarization induces a rapid-onset and short-term inactivation of calcium currents. Contrarily to this well-documented mechanism to maintain calcium below toxic levels, the regulatory pathways inducing longer-lasting changes and cell surface expression of functional calcium channels are largely unknown. Since calcium is a main player in the activity-dependent regulation of many genes, we hypothesize that calcium channel coding genes could be also subjected to activity-dependent regulation. We have used prolonged depolarization to analyze the effects of sustained intracellular calcium elevation on the mRNAs coding for the different alpha(1) pore-forming subunits of the calcium channels expressed in chromaffin cells. Our findings reveal that persistent depolarization is accompanied by a prolonged intracellular calcium elevation and reduction of calcium current. This calcium current inhibition could be mediated, at least partially, by the downregulation of the mRNAs coding for several alpha(1) subunits. Thus, we show here that depolarization inhibits the expression of Ca(V)1.1, Ca(V)1.2, Ca(V)1.3, Ca(V)2.2 and Ca(V)2.3 mRNAs, while the Ca(V)2.1 mRNA remains unmodified. Moreover, such downregulation of channels depends on calcium entry through the L-type calcium channel, as both mRNA and calcium current changes induced by depolarization are abrogated by L-type channel specific blockers.

Dopamina y neurotoxicidad / Dopamine and neurotoxicity

En este artículo se presenta una revisión del papel de la dopamina en la neurotoxicidad. En primer lugar, se examina la implicación de la mitocondria en la apoptosis y, posteriormente, se analiza la influencia de la oxidación dopaminérgica en los procesos apoptóticos y su relación con la mitocondria. Por último, se describen los posibles factores que pueden potenciar y contribuir a la oxidación de la dopamina, así como las posibles consecuencias funcionales que se derivarían del daño neurotóxico

In this paper a review of the dopamine role in neurotoxicity is presented. Firstly, the implication of mitochondria in the apoptosis is examined, later the influence of the dopaminergic oxidation on the apoptosis processess and their relation to mitochondria is discussed. Finally, the possible factors that can harness and contribute to the oxidation of the dopamine, as well the possible functional consequences that they would be derived from the neurotoxic damage are described

Adrenal medulla calcium channel population is not conserved in bovine chromaffin cells in culture.

During the stress response adrenal medullary chromaffin cells release catecholamines to the bloodstream. Voltage-activated calcium channels present in the cell membrane play a crucial role in this process. Although the electrophysiological and pharmacological properties of chromaffin cell calcium channels have been studied in detail, the molecular composition of these channels has not been defined yet. Another aspect that needs to be explored is the extent to which chromaffin cells in culture reflect the adrenal medulla calcium channel characteristics. In this sense, it has been described that catecholamine release in the intact adrenal gland recruits different calcium channels than those recruited during secretion from cultured chromaffin cells. Additionally, recent electrophysiological studies show that chromaffin cells in culture differ from those located in the intact adrenal medulla in the contribution of several calcium channel types to the whole cell current. However there is not yet any study that compares the population of calcium channels in chromaffin cells with that one present in the adrenal medulla. In order to gain some insight into the roles that calcium channels might play in the adrenal medullary cells we have analyzed the alpha1 subunit mRNA expression profile. We demonstrate that the expression pattern of voltage-dependent calcium channels in cultured bovine chromaffin cells markedly differs from that found in the native adrenal medulla and that glucocorticoids are only partially involved in those differences. Additionally, we show, for the first time, that the cardiac isoform of L-type calcium channel is present in both bovine adrenal medulla and cultured chromaffin cells and that its levels of expression do not vary during culture.

[The role of the mitochondrial permeability transition pore in neurodegenerative processes]. / Papel del poro de permeabilidad transitoria mitocondrial en los procesos neurodegenerativos.

AIMS: To review the role played by the mitochondrial permeability transition pore (MPTP) in different physiological and pathological processes. METHOD: Both genetic and functional alterations in mitochondria can lead to errors that trigger programmed cell death, which in turn give rise to a number of diseases that affect the nervous system. Over the last few years the mitochondrion has been seen as the link between the different signalling pathways involved in some degenerative processes. The mitochondrion seems to play an important part in the cellular decision making that leads, irreversibly, toward the execution phase in cellular death processes. This being the case, the action would be mediated by the permeability of its membranes, through the formation of the mitochondrial permeability transition pore, and would involve phenomena such as the dissipation of the mitochondrial electrochemical potential and the release of substances from within it. These substances include apoptosis inducing factor (AIF), apoptosis protease activating factor 1 (apaf 1), cytochrome c and members of the protease family: the caspases. These alterations have been described in neurodegenerative pathologies such as Alzheimer s and Parkinson s disease, amyotrophic lateral sclerosis and transmissible spongiform encephalopaties. CONCLUSIONS: Designing pharmaceutical products capable of interfering with the functions of MPTP would allow a better therapeutic approach in neurological pathologies.

Papel del poro de permeabilidad transitoria mitocondrialen los procesos neurodegenerativos / The role of the mitochondrial permeability transition pore in neurodegenerative processes

Objetivo. Revisar el papel que desempeña el poro de permeabilidad transitoria mitocondrial (PPTM) en diversos procesos fisiológicos y patológicos. Desarrollo. Alteraciones mitocondriales, tanto genéticas como funcionales, pueden conducir a errores que desencadenan programas de muerte celular, responsables a su vez de numerosas enfermedades del sistema nervioso. Durante los últimos años, la mitocondria se ha considerado el nexo de unión entre diferentes vías de señalización implicadas en algunos procesos degenerativos. La mitocondria parece ocupar un lugar destacado en la toma de decisión celular que conlleva, irreversiblemente, hacia la fase de ejecución en los procesos de muerte celular. Esta acción estaría mediada por la regulación de la permeabilidad de sus membranas, a través de la formación del poro de permeabilidad transitoria mitocondrial, e implicaría fenómenos como la disipación del potencial electroquímico mitocondrial y la liberación de sustancias desde su interior, entre las que se incluyen el factor inductor de apoptosis (AIF), apaf-1, el citocromo c y miembros de la familia de proteasas, las caspasas. Dichas alteraciones se han descrito en patologías neurodegenerativas como la enfermedad de Alzheimer, la de Parkinson, la esclerosis lateral amiotrófica y encefalopatías espongiformes transmisibles. Conclusiones. El diseño de fármacos que pudieran interferir con las funciones del PPTM permitiría un mejor abordaje terapéutico en patologías neurológicas (AU)