Neural correlates of embodied action language processing: a systematic review and meta-analytic study

Brain Imaging and Behavior - The neural correlates of action language processing are still debated within embodied cognition research and little is known about the flexible involvement of...     

Fatal neonatal nephrocutaneous syndrome in 18 Roma children with EGFR deficiency

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine-kinase signaling activity, involved in many cellular functions including cell growth and differentiation. Germ line loss-of-function mutations in EGFR lead to a severe neonatal skin disorder (Online Mendelian Inheritance in Man #131550). We report 18 premature Roma children from 16 families with birthweights ranging 440–1470 g and multisystem diseases due to the homozygous mutation c.1283G˃A (p.Gly428Asp) in EGFR. They presented with thin, translucent, fragile skin (14/15), skin desquamation (10/17), ichthyosis (9/17), recurrent skin infections and sepsis (9/12), nephromegaly (10/16) and congenital heart defects (7/17). Their prognosis was poor, and all died before the age of 6 months except one 13-year-old boy with a severe skin disorder, dentinogenesis imperfecta, Fanconi-like syndrome and secondary hyperaldosteronism. Management of ion and water imbalances and extremely demanding skin care may improve the unfavorable outcome of such patients.     

Spontaneous reports of adverse drug reactions related to oral anticoagulants in the Czech Republic

International Journal of Clinical Pharmacy - Background Oral anticoagulants are established drugs of choice for the prevention and treatment of thromboembolic events. However, monitoring their...     

Melatonin down‐regulates MDM2 gene expression and enhances p53 acetylation in MCF‐7 cells

Compelling evidence demonstrated that melatonin increases p53 activity in cancer cells. p53 undergoes acetylation to be stabilized and activated for driving cells destined for apoptosis/growth inhibition. Over‐expression of p300 induces p53 acetylation, leading to cell growth arrest by increasing p21 expression. In turn, p53 activation is mainly regulated in the nucleus by MDM2. MDM2 also acts as E3 ubiquitin ligase, promoting the proteasome‐dependent p53 degradation. MDM2 entry into the nucleus is finely tuned by two different modulations: the ribosomal protein L11, acts by sequestering MDM2 in the cytosol, whereas the PI3K‐AkT‐dependent MDM2 phosphorylation is mandatory for MDM2 translocation across the nuclear membrane. In addition, MDM2‐dependent targeting of p53 is regulated in a nonlinear fashion by MDM2/MDMX interplay. Melatonin induces both cell growth inhibition and apoptosis in MCF7 breast cancer cells. We previously reported that this effect is associated with reduced MDM2 levels and increased p53 activity. Herein, we demonstrated that melatonin drastically down‐regulates MDM2 gene expression and inhibits MDM2 shuttling into the nucleus, given that melatonin increases L11 and inhibits Akt‐PI3K‐dependent MDM2 phosphorylation. Melatonin induces a 3‐fold increase in both MDMX and p300 levels, decreasing simultaneously Sirt1, a specific inhibitor of p300 activity. Consequently, melatonin‐treated cells display significantly higher values of both p53 and acetylated p53. Thus, a 15‐fold increase in p21 levels was observed in melatonin‐treated cancer cells. Our results provide evidence that melatonin enhances p53 acetylation by modulating the MDM2/MDMX/p300 pathway, disclosing new insights for understanding its anticancer effect.     

Effectiveness of primary percutaneous coronary intervention for acute ST-elevation myocardial infarction from a 5-year single-center experience

Primary percutaneous coronary intervention (PCI) is currently viewed as the preferred reperfusion strategy in patients with ST-elevation acute myocardial infarction (STEMI). This method was introduced in our hospital in 2000. From January 1, 2000, to December 31, 2004, a total of 2,393 consecutive patients with STEMI were admitted (27% transferred from 9 non-PCI hospitals and 31 prehospital emergency units/outpatient clinics). Of these patients, 1,666 (70%) underwent urgent coronary angiography and primary PCI. Platelet glycoprotein llb/llla inhibitors were used in 40% and stent placement, in 78%. Postprocedural Thrombolysis In Myocardial Infarction (TIMI) 3 flow was documented in 86%. Intra-aortic balloon counterpulsation was used in 6%; mechanical ventilation, in 8.6%; and inotropic drugs/vasopressors, in 15.8%. Mortality rates in patients with Killip's class I or II ranged from 1% to 4.9% without negative influence of ischemic time. In patients with Killip's class III or IV, mortality rates increased from 18% to 54% with increasing ischemic delay up to 6 hours (p = 0.06) and remained at around 40% afterward. Independent predictors of mortality were age (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.01 to 1.64, p = 0.04), resuscitated cardiac arrest (OR 2.44, 95% CI 1.18 to 5.05, p = 0.02), and postprocedural TIMI flow (OR 0.31, 95% CI 0.16 to 0.59). Overall mortality rates of patients who underwent a primary PCI strategy from 2000 to 2004 were significantly lower than in the control group of 152 consecutive patients who underwent thrombolysis from 1995 to 1996 (6.2% vs 16.4%; p <0.001). In conclusion, introduction of a primary PCI strategy significantly decreased hospital mortality in our unselected group of patients with STEMI compared with the thrombolytic era. Our study further emphasized the importance of shortening myocardial ischemic time, particularly in the presence of severe heart failure on admission.     

Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients older than 60 years with acute myelogenous leukaemia

This randomized phase III clinical trial explored the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) in acute myeloid leukaemia (AML) patients aged >60 years. Three hundred and one AML patients were randomized to receive DNR (45 mg/m(2) days 1-3) or DNX (80 mg/m(2) days 1-3) plus cytarabine (AraC; 100 mg/m(2) days 1-7). Patients in complete remission (CR) received a course of the same drugs as consolidation and then were randomized for maintenance with AraC+ all trans retinoic acid or no further treatment. Among 153 patients in the DNR arm, 78 (51.0%) achieved CR, 55 (35.9%) were resistant and 20 (13.1%) died during induction. Among 148 patients in the DNX arm, 73 (49.3%) achieved CR, 47 (31.8%) were resistant and 28 (18.9%) died during induction. Univariate analysis showed no difference as to induction results. After CR, DNX showed a higher incidence of early deaths (12.5% vs. 2.6% at 6 months, P = 0.053) but a lower incidence of relapse beyond 6 months (59% vs. 78% at 24 months, P = 0.064), with a cross in overall survival (OS) and disease-free survival (DFS) curves and a later advantage for DNX arm after 12 months from diagnosis. DNX seems to improve OS and DFS in the long-term follow-up, because of a reduction in late relapses.     

Pharmacological modulation of the hyperpolarization-activated current (I f) in human atrial myocytes: focus on G protein-coupled receptors

AIMS: In human atrial myocytes (HuAM) two beta-adrenergic receptors (beta-AR) and four splicing-variants of the serotonin 5-HT(4) receptor are present. Multiple coupling with G stimulatory (G(s)) and G inhibitory (G(i)) proteins has been proposed for both beta(2)-AR and 5-HT((4b)) subtypes, but no functional data exist in HuAM. Serotonin (5-HT) and catecholamines are able to trigger arrhythmias in human atrium, but the underlying cellular mechanisms are not completely understood. The pacemaker current (I(f)) is an inward Na(+)/K(+) current, constitutively present in HuAM and directly modulated by cAMP; I(f) could play a role in triggering human atrial arrhythmias. This study evaluated the different G protein coupling of beta(1)-AR, beta(2)-AR and 5-HT(4) receptors by assessing the modulation of I(f) by selective stimuli. METHODS: HuAM were isolated from right atrial appendages and utilized for patch-clamp recording. The coupling of receptor subtypes with G(i) proteins was tested by incubating HuAM in pertussis toxin (PTX). RESULTS: Beta(1)-AR stimulation (Isoprenaline [ISO] + ICI 118,551), and 5-HT caused a concentration-dependent significant shift of the half activation potential of I(f) activation curve (DeltaV(h)), P < 0.01. beta(2)-AR stimulation (ISO 1 microM + CGP 20712A) also significantly shifted V(h) (P < 0.0001), but with DeltaV(h)[beta(2)-AR] significantly smaller than the effect caused by 1 microM beta(1)-AR stimulation (P < 0.05). Pre-treatment of HuAM with PTX did not alter the effect of beta(1)-AR stimulation (both 0.1 and 1 microM) and 1 microM 5-HT on I(f), but significantly increased the effect in response to beta(2)-AR stimulation and 0.1 microM 5-HT (P < 0.05 for both), thus suggesting a G(i) protein coupling of these receptors. CONCLUSIONS: Our results provide the first functional evidence of the different G protein coupling of beta(1)-AR, beta(2)-AR and 5-HT(4) receptors in HuAM. Further they support the view that I(f) current might play an important role in triggering catecholamines and serotonin-induced atrial arrhythmias.