A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine.

OBJECTIVE: To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified. METHODS: Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed. RESULTS: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma. CONCLUSION: We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.

Chronotropic, inotropic and lusitropic effects of capsaicin on isolated rat Atria

This work includes results on chronotropic, inotropic and lusitropic changes induced by capsaicin on isolated rat atria. As regards spontaneous frequency, it was stimulated from 10(-9) M up to 7 x 10(-7) M of capsaicin. A simultaneous depression in developed force (F) showed a signigicant correlation with this positive chronotropic effect up to 7 X 10(-8) M of capsaicin, which is the result of the negative staircase phenomenon in the rat heart. The correlation was lost at 2 and 7 x 10(-7) M of capsaicin since in spite of the sustained increase in atrial rate the decrease in F was reversed and then depressed again at 2 and 7x 10(-6) M of capsaicin without changes in frequency. A concentration of capsaicin that overcome the negative staircase phenomenon, 5 x 10(-7) M, was tested as unique dose resulting in stimulation of the chronotropic, inotropic and lusitropic states of the atria. Percentual differences with respect to control values were maximal after 1-3 minutes for frequency (10+3 per cent), F (29+4 per cent), maximal velocity of force development (+F=50+12 per cent) (in all cases +F and -F,bold indicates +F and -F, respectively) and maximal velocity of relaxation (-F=64+13 per cent); a positive lusitropic effect was significant after 8-10 minutes (+F/-F=-17+7 per cent). Capsaicin did not affect the rat atria in the presence of 10(-6) M of ruthenium red, a blocker of capsaicin activation of sensory nerves, indicating that the stimulatory effects were entirely mediated by the release of neurotransmitters and that this concentration of capsaicin was not deleterous "per se". Capsaicin elicited similar inotropic responses in electrically driven isolated atria (+F=41+9 per cent) but the positive lusitropic effect was lost suggesting that capsaicin-induced increases in -F are limited at a frequency higher than the spontaneous frequency (11+6 vs. 32+4 per cent, respectively). 10(-6) M of CGRP8(-37), an antagonist of CGRP1 receptors, suppress the stimulatory effects of capsaicin on atrial contraction. In summary, atrial rate as compared to atrial contraction is more sensitive to the neurotransmitter released by capsaicin, which results in mechanical effects expressing the negative staircase phenomenon in the rat at low concentrations of capsaicin. The positive chronotropic, inotropic and lusitropic responses elicited by capsaicin are mediated by the reelease of neurotransmitters from sensory fibbers and no deletereous effects...

Chronotropic, inotropic and lusitropic effects of capsaicin on isolated rat Atria

This work includes results on chronotropic, inotropic and lusitropic changes induced by capsaicin on isolated rat atria. As regards spontaneous frequency, it was stimulated from 10(-9) M up to 7 x 10(-7) M of capsaicin. A simultaneous depression in developed force (F) showed a signigicant correlation with this positive chronotropic effect up to 7 X 10(-8) M of capsaicin, which is the result of the negative staircase phenomenon in the rat heart. The correlation was lost at 2 and 7 x 10(-7) M of capsaicin since in spite of the sustained increase in atrial rate the decrease in F was reversed and then depressed again at 2 and 7x 10(-6) M of capsaicin without changes in frequency. A concentration of capsaicin that overcome the negative staircase phenomenon, 5 x 10(-7) M, was tested as unique dose resulting in stimulation of the chronotropic, inotropic and lusitropic states of the atria. Percentual differences with respect to control values were maximal after 1-3 minutes for frequency (10+3 per cent), F (29+4 per cent), maximal velocity of force development (+F=50+12 per cent) (in all cases +F and -F,bold indicates +F and -F, respectively) and maximal velocity of relaxation (-F=64+13 per cent); a positive lusitropic effect was significant after 8-10 minutes (+F/-F=-17+7 per cent). Capsaicin did not affect the rat atria in the presence of 10(-6) M of ruthenium red, a blocker of capsaicin activation of sensory nerves, indicating that the stimulatory effects were entirely mediated by the release of neurotransmitters and that this concentration of capsaicin was not deleterous "per se". Capsaicin elicited similar inotropic responses in electrically driven isolated atria (+F=41+9 per cent) but the positive lusitropic effect was lost suggesting that capsaicin-induced increases in -F are limited at a frequency higher than the spontaneous frequency (11+6 vs. 32+4 per cent, respectively). 10(-6) M of CGRP8(-37), an antagonist of CGRP1 receptors, suppress the stimulatory effects of capsaicin on atrial contraction. In summary, atrial rate as compared to atrial contraction is more sensitive to the neurotransmitter released by capsaicin, which results in mechanical effects expressing the negative staircase phenomenon in the rat at low concentrations of capsaicin. The positive chronotropic, inotropic and lusitropic responses elicited by capsaicin are mediated by the reelease of neurotransmitters from sensory fibbers and no deletereous effects...(AU)

Luz verde para el desarrollo; bases para una politica ambiental en Argentina

Se presentan las bases de la politica ambiental argentina, tomando en consideracion la historia de la ecologia hasta nuestros tiempos, la dimension politica de la problematica ambiental, la situacion actual del pais, los criterios para la seleccion de las prioridades, el rol del Estado, la legislacion y los recursos, los principales problemas y las propuestas para resolverlos

Luz verde para el desarrollo: bases para una politica ambiental en Argentina

Propone un modelo de desarrollo ambientalmente sustentable para la Argentina, que satisfaga las necesidades de las mas amplias capas de la poblacion; y revaloriza el rol del Estado como regulador e intermediario frente a los conflictos que surgen como consecuencia de la explotacion y la preservacion del medio ambiente

Luz verde para el desarrollo; bases para una politica ambiental en Argentina

Se presentan las bases de la politica ambiental argentina, tomando en consideracion la historia de la ecologia hasta nuestros tiempos, la dimension politica de la problematica ambiental, la situacion actual del pais, los criterios para la seleccion de las prioridades, el rol del Estado, la legislacion y los recursos, los principales problemas y las propuestas para resolverlos