Evidence of reverse remodeling after long-term biventricular stimulation for resynchronization in patients with wide QRS selected on the basis of echocardiographic electromechanical delays

Background. There is increasing evidence that cardiac resynchronization therapy (CRT) may trigger an inverse remodeling process leading to decreased left ventricular (LV) volumes in patients with heart failure and wide QRS. However, it is still important to simplify patient selection and achieve a widely applicable parameter to better stratify patients who are candidates for CRT. Methods. Eighteen patients (13 males, 5 females, mean age 67.5 ± 7.2 years) with advanced heart failure due to ischemic (n = 12) or idiopathic dilated cardiomyopathy (n = 6) and complete left bundle branch block received biventricular pacing. The patients were considered eligible in the presence of echocardiographic evidence of intra- and interventricular asynchrony, defined on the basis of LV electromechanical delay. Investigations were performed before pacemaker implantation (at baseline), the day after, and 3 and 6 months later. Results. Two patients died before the first outpatient examination. There were 15 (83%) responders to reverse remodeling among the remainder. In the overall population, there was a significant and progressive improvement in LV sphericity indexes, ejection fraction, mitral regurgitation area and LV volumes (p < 0.001). The improvement in the interventricular mechanical delay after CRT was significantly correlated with the decrease in LV end-systolic volume (r2= 0.2558, p = 0.04). Conclusions. CRT reduces LV volumes in patients with advanced heart failure, complete left bundle branch block and detailed documentation of ventricular asynchrony prior to therapeutic pacing. Broadly applicable Doppler echocardiographic measures may increase the specificity of the longterm response to CRT in terms of LV performance. © 2004 CEPI Srl

Characterization of the most frequent ATP7B mutation causing Wilson disease in hepatocytes from patient induced pluripotent stem cells

H1069Q substitution represents the most frequent mutation of the copper transporter ATP7B causing Wilson disease in Caucasian population. ATP7B localizes to the Golgi complex in hepatocytes but moves in response to copper overload to the endo-lysosomal compartment to support copper excretion via bile canaliculi. In heterologous or hepatoma-derived cell lines, overexpressed ATP7B-H1069Q is strongly retained in the ER and fails to move to the post-Golgi sites, resulting in toxic copper accumulation. However, this pathogenic mechanism has never been tested in patients' hepatocytes, while animal models recapitulating this form of WD are still lacking. To reach this goal, we have reprogrammed skin fibroblasts of homozygous ATP7B-H1069Q patients into induced pluripotent stem cells and differentiated them into hepatocyte-like cells. Surprisingly, in HLCs we found one third of ATP7B-H1069Q localized in the Golgi complex and able to move to the endo-lysosomal compartment upon copper stimulation. However, despite normal mRNA levels, the expression of the mutant protein was only 20% compared to the control because of endoplasmic reticulum-associated degradation. These results pinpoint rapid degradation as the major cause for loss of ATP7B function in H1069Q patients, and thus as the primary target for designing therapeutic strategies to rescue ATP7B-H1069Q function

Expansion of activated regulatory T cells inversely correlates with clinical severity in septic neonates.

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Il rilassamento psico-tonico in psicosomatica

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BCR-ABL prevents c-Jun-mediated and proteasome-dependent FUS (TLS) proteolysis through a protein kinase C beta II-dependent pathway

The DNA binding activity of FUS (also known as TLS), a nuclear pro-oncogene involved in multiple translocations, is regulated by BCR-ABL in a protein kinase cpn (PKC beta II)-dependent manner. We show here that in normal myeloid progenitor cells FUS, although not visibly ubiquitinated, undergoes proteasome-dependent degradation, whereas in BCR-ABL-expressing cells, degradation is suppressed by PKC beta II phosphorylation. Replacement of serine 256 with the phosphomimetic aspartic acid prevents proteasome-dependent proteolysis of FUS, while the serine-256-to-alanine FUS mutant is unstable and susceptible to degradation. Ectopic expression of the phosphomimetic S256D FUS mutant in granulocyte colony-stimulating factor-treated 32Dcl3 cells induces massive apoptosis and inhibits the differentiation of the cells escaping cell death, while the degradation-prone S256A mutant has no effect on either survival or differentiation. FUS proteolysis is induced by c-Jun, is suppressed by BCR-ABL or Jun kinase 1, and does not depend on c-Jun transactivation potential, ubiquitination, or its interaction with Jun kinase 1, In addition, c-Jun induced FUS proteasome-dependent degradation is enhanced by heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and depends on the formation of a FUS-Jun-hnRNP A1-containing complex and on lack of PKC beta II phosphorylation at serine 256 but not on FUS ubiquitination. Thus, novel mechanisms appear to be involved in the degradation of FUS in normal myeloid cells; moreover, the ability of the BCR-ABL oncoprotein to suppress FUS degradation by the induction of posttranslational modifications might contribute to the phenotype of BCR-ABL expressing hematopoietic cells

The impact of cumulus and radiation parameterization schemes on Southern Hemisphere summer climate simulated by CPTEC Atmospheric General Circulation Model

The Southern Hemisphere summer climate is primarily influenced by the Indonesian, African and Amazon intense convection; South Pacific Convergence Zone (SPCZ) and South Atlantic Convergence Zone (SACZ); low pressures over western Australia, southern South America (Gran Chaco) and southern Africa. Numerical experiments with different cumulus and solar radiation parameterization schemes were performed using a CPTEC Atmospheric global circulation model (CPTEC-AGCM) to study the impact of different physical processes on Southern Hemisphere summer climate. The CPTEC-AGCM in comparison with CPTEC/COLA-AGCM contains: a new dynamic code, three cumulus schemes (KUO, Relaxed Arakawa-Schubert, and Grell-ensemble modified by Figueroa, called here Grell2), two shallow convection schemes (Tiedke and Souza) and two solar radiation schemes (of Lacis and Hansen called here Rad1 and Clirad-sw of Chou and Suarez and modified by Tarasova and Fomin, called here Rad2). All remaining physical processes are similar to CPTEC/COLA AGCM. The horizontal resolution of the model is triangular 62 (T62), and vertical resolution is 28 levels (L28).The surface temperature is prescribed, which is updated daily by linear interpolation between monthly climatological blended data sets. The initial conditions were obtained from NCEP analysis. The integration is carried out for 5 years for each experiment. The results for different summers are similar. These results show the importance of convection scheme (deep and shallow) for tropical convection and subtropical convergence zones, and radiation scheme for subtropical low pressures. The main impact of Rad2 in comparison with rad1 is the reduction of downward solar radiation at the surface by approximately 50 W/m2 in the subtropical region. Our conclusion is that the better simulation of Southern Hemisphere summer climate is by combination Grell2 for deep convection, Souza for shallow convection and Rad2 for solar radiation.Pages: 1037-104