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Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca2+-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.I115F mutation recapitulates the main features of the STIM1 gain-of-function disorders: muscle weakness and thrombocytopenia. Similar findings have been found in other mice bearing different mutations on STIM1. At present, no valid treatment is available for these patients. In the present contribution, we report that CIC-39Na, a store-operated Ca2+-entry inhibitor, restores platelet number and counteracts the abnormal bleeding that characterizes these mice. Subtle differences in thrombopoiesis were observed in STIM1 p.I115F mice, but the main difference between wild-type and STIM1 p.I115F mice was in platelet clearance and in the levels of platelet cytosolic basal Ca2+. Both were restored on treatment of animals with CIC-39Na. This finding paves the way to a pharmacological treatment strategy for thrombocytopenia in tubular aggregate myopathy patients.

Store-operated calcium entry (SOCE) is a pivotal mechanism in calcium homeostasis, and, despite still being under investigation, its dysregulation is known to be associated with severe human disorders. SOCE modulators are therefore needed both as chemical probes and as therapeutic agents. While many small molecules have been described so far, their poor properties in terms of drug-likeness have limited their translation into the clinical practice. In this work, we describe the bioisosteric replacement of the ester moiety in pyrazole derivatives with a 1,2,4-oxadiazole ring as a means to afford a class of modulators with high metabolic stability. Moreover, among our derivatives, a compound able to increase the calcium entry was identified, further enriching the library of available SOCE activators.

Store-operated calcium entry (SOCE) is important in the maintenance of calcium homeostasis and alterations in this mechanism are responsible for several pathological conditions, including acute pancreatitis. Since the discovery of SOCE, many inhibitors have been identified and extensively used as chemical probes to better elucidate the role played by this cellular mechanism. Nevertheless, only a few have demonstrated drug-like properties so far. Here, we report a class of biphenyl triazoles among which stands out a lead compound, 34, that is endowed with an inhibitory activity at nanomolar concentrations, suitable pharmacokinetic properties, and in vivo efficacy in a mouse model of acute pancreatitis.

Gain-of-function mutations on STIM1 and ORAI1 genes are responsible for an increased store-operated calcium entry, and underlie the characteristic symptoms of three overlapping ultra-rare genetic disorders (i.e tubular aggregate myopathy, Stormorken syndrome, York platelet syndrome) that can be grouped as tubular aggregate myopathies. These mutations lead to a wide spectrum of defects, which usually include muscle weakness and cramps. Negative modulators of store-operated Ca

Muscular diseases are characterized by a wide genetic diversity and the Ca

Introduction/aims Stromal Interaction Molecule 1 (STIM1) is a reticular Ca2+ sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. We aimed to expand the features related to new variants in STIM1. Methods We performed a cross-sectional study of individuals harboring monoallelic STIM1 variants recruited in five tertiary centers involved in a study of inherited myopathies analyzed with a multigene-targeted panel. Results We identified seven individuals (age range: 26-57 years) harboring variants in STIM1, including five novel changes: three located in the EF-hand domain, one in the sterile α motif (SAM) domain and one in the cytoplasmatic region of the protein. Functional evaluation of the pathogenic variants using a heterologous expression system and measuring store-operated calcium entry demonstrated their causative role and suggested a link of new variants with the clinical phenotype. Muscle contractures, found in three individuals, showed variability in body distribution and in the number of joints involved. Three patients showed cardiac and respiratory involvement. Short stature, hyposplenism, sensorineural hearing loss, hypothyroidism and Gilbert syndrome were variably observed among the patients. Laboratory tests revealed hyperCKemia in six patients, thrombocytopenia in two and hypocalcemia in a single patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and non-specific myopathic changes in two. Discussion Our clinical, histological and molecular data expand the genetic and clinical spectrum of STIM1-related diseases. This article is protected by copyright. All rights reserved.

Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons. Here, we investigated the early impact of oxaliplatin on the proton-sensitive TREK potassium channels. Following a 6-h oxaliplatin treatment, both channels underwent a transcription upregulation that returned to control levels after 42 h. The overexpression of TREK channels was also observed after in vivo treatment in DRG cells from mice exposed to acute treatment with oxaliplatin. Moreover, both intracellular pH and TREK channel transcription were similarly regulated after incubation with amiloride, an inhibitor of the Na+/H+ exchanger. In addition, we studied the role of oxaliplatin-induced acidification on channel behavior, and, as expected, we observed a robust positive modulation of TREK channel activity. Finally, we focused on the impact of this complex modulation on capsaicin-evoked neuronal activity finding a transient decrease in the average firing rate following 6 h of oxaliplatin treatment. In conclusion, the early activation of TREK genes may represent a mechanism of protection against the oxaliplatin-related perturbation of neuronal excitability.

Background Patients with aortic root ectasia and bicuspid aortic valve benefit of the treatment with aortic valve sparing procedure, with excellent long-term results. The Sleeve-procedure is one of the options in patients with aortic root diseases and it might be suitable for patients with a bicuspid valve. Methods From October 2006 to December 2018, 42 consecutive patients with bicuspid aortic valve and aortic root ectasia/aneurysm, with or without aortic regurgitation, were surgically treated with the Sleeve-procedure. Results In 20 patients (48%) leaflets surgery was necessary and consisted of raphe mobilization/resection in 17 patients, plication of both leaflets in 2 patients and a two-commissures resuspension in 1 patient. During a mean clinical follow-up time of 4.4±3.1 years, the survival rate was 100%, 1 patient required a reoperation at 6.1 years postoperatively, with an overall freedom from reoperation of 94±5%. The rest of the patients (41/42), had no more than mild residual aortic valve regurgitation. With a mean follow-up of 4.3±1.7 years the magnetic resonance imaging performed in 26 patients, did not show signs of aortic wall herniation through the key-holes or persisting creases of the aortic wall inside the prosthesis. Conclusions Patients with aortic root disease and bicuspid aortic valve may be treated with Sleeve technique with excellent midterm results. However, a longer follow-up is required before drawing any solid conclusion.

STIM and ORAI proteins play a fundamental role in calcium signaling, allowing for calcium influx through the plasma membrane upon depletion of intracellular stores, in a process known as store-operated Ca2+ entry. Point mutations that lead to gain-of-function activity of either STIM1 or ORAI1 are responsible for a cluster of ultra-rare syndromes characterized by motor disturbances and platelet dysfunction. The prevalence of these disorders is at present unknown. In this study, we describe the generation and characterization of a knock-in mouse model (KI-STIM1I115F) that bears a clinically relevant mutation located in one of the two calcium-sensing EF-hand motifs of STIM1. The mouse colony is viable and fertile. Myotubes from these mice show an increased store-operated Ca2+ entry, as predicted. This most likely causes the dystrophic muscle phenotype observed, which worsens with age. Such histological features are not accompanied by a significant increase in creatine kinase. However, animals have significantly worse performance in rotarod and treadmill tests, showing increased susceptibility to fatigue, in analogy to the human disease. The mice also show increased bleeding time and thrombocytopenia, as well as an unexpected defect in the myeloid lineage and in natural killer cells. The present model, together with recently described models bearing the R304W mutation (located on the coiled-coil domain in the cytosolic side of STIM1), represents an ideal platform to characterize the disorder and test therapeutic strategies for patients with STIM1 mutations, currently without therapeutic solutions. This article has an associated First Person interview with Celia Cordero-Sanchez, co-first author of the paper., Summary: We describe a mouse model (KI-STIM1I115F) that displays the clinical hallmarks of tubular aggregate myopathy. This model provides a new opportunity to characterize the disorder and test novel therapeutic strategies.

Approximately 50% of colorectal cancer (CRC) patients still die from recurrence and metastatic disease, highlighting the need for novel therapeutic strategies. Drug repurposing is attracting increasing attention because, compared to traditional de novo drug discovery processes, it may reduce drug development periods and costs. Epidemiological and preclinical evidence support the antitumor activity of antipsychotic drugs. Herein, we dissect the mechanism of action of the typical antipsychotic spiperone in CRC. Spiperone can reduce the clonogenic potential of stem-like CRC cells (CRC-SCs) and induce cell cycle arrest and apoptosis, in both differentiated and CRC-SCs, at clinically relevant concentrations whose toxicity is negligible for non-neoplastic cells. Analysis of intracellular Ca2+ kinetics upon spiperone treatment revealed a massive phospholipase C (PLC)-dependent endoplasmic reticulum (ER) Ca2+ release, resulting in ER Ca2+ homeostasis disruption. RNA sequencing revealed unfolded protein response (UPR) activation, ER stress, and induction of apoptosis, along with IRE1-dependent decay of mRNA (RIDD) activation. Lipidomic analysis showed a significant alteration of lipid profile and, in particular, of sphingolipids. Damage to the Golgi apparatus was also observed. Our data suggest that spiperone can represent an effective drug in the treatment of CRC, and that ER stress induction, along with lipid metabolism alteration, represents effective druggable pathways in CRC.

Oxaliplatin is a cornerstone chemotherapeutic used in the treatment of colorectal cancer, the third leading cause of death in Western countries. Most side effects of this platinum-containing drug are adequately managed in the clinic, although acute and long-term neurotoxicity still severely compromises the quality of life of patients treated with oxaliplatin. We have previously demonstrated that therapeutically relevant concentrations/doses of oxaliplatin lead to a reduction in intracellular pH in mouse dorsal root ganglion (DRG) neurons in vitro and in vivo and that this alteration sensitizes TRPA1 and TRPV1 channels, which most likely mediate the allodynia associated with treatment. In this study, we show that oxaliplatin leads to a reduction of intracellular pH by forming adducts with neuronal haemoglobin, which acts in this setting as a proton buffer. Furthermore, we show that FDA-approved drugs that inhibit carbonic anhydrase (an enzyme that is linked to haemoglobin in intracellular pH homeostasis), ie, topiramate and acetazolamide, revert (1) oxaliplatin-induced cytosolic acidification and TRPA1 and TRPV1 modulation in DRG neurons in culture, (2) oxaliplatin-induced cytosolic acidification of DRG of treated animals, and (3) oxaliplatin-induced acute cold allodynia in mice while not affecting OHP-induced cytotoxicity on cancer cells. Our data would therefore suggest that reversal of oxaliplatin-induced cytosolic acidification is a viable strategy to minimize acute oxaliplatin-induced symptoms.

In Sleeve procedure, the leaflets-sinus unit is maintained. We hypothesized that this feature partially preserves aortic root (AR) dynamics and leaflets kinematics and limits tensions in the leaflets. We tested our hypothesis based on in vivo and computational assessment of leaflets and AR dynamics. AR and aortic leaflet kinematics was assessed by transthoracic echocardiography in 10 patients treated with the Sleeve procedure and in 10 healthy patients. Numerical calculations with the Finite Element Method were performed to support the analysis of the clinical results and provide a better understanding of the behavior of the AR treated via the Sleeve procedure. Echocardiographic evidence showed that AR expansion in the Sleeve group was partially preserved as compared to the Control group (2.9 ± 2.5% vs 7.7 ± 6.3%, P = 0.038) and of the sinotubular junction (2.9 ± 1.5% vs 7.3 ± 3.8%, P = 0.003), and significantly preserved at the Valsalva sinuses level (6.7 ± 2.6% vs 9.5 ± 4.3%) with not statistically significant differences (P = 0.11). In none of the cardiac phases, differences in aortic valve leaflets kinematics were measured between the 2 groups; computational results were rather consistent with this evidence. Computational results well matched echocardiographic evidences, allowing for their mechanistic interpretation. Near-normal opening and closing characteristics can be accomplished by a technique that preserves the shape and the dynamics of the Valsalva sinuses. Whether the substantial preservation of the AR distensibility and leaflets kinematics observed in this study will favorably affect long-term valve durability it remains to be ascertained.

We present three members of an Italian family affected by tubular aggregate myopathy (TAM) and congenital miosis harboring a novel missense mutation in ORAI1. All patients had a mild, late onset TAM revealed by asymptomatic creatine kinase (CK) elevation and congenital miosis consistent with a Stormorken-like Syndrome, in the absence of thrombocytopathy. Muscle biopsies showed classical histological findings but ultrastructural analysis revealed atypical tubular aggregates (TAs). The whole body muscle magnetic resonance imaging (MRI) showed a similar pattern of muscle involvement that correlated with clinical severity. The lower limbs were more severely affected than the scapular girdle, and thighs were more affected than legs. Molecular analysis revealed a novel c.290C>G (p.S97C) mutation in ORAI1 in all affected patients. Functional assays in both human embryonic kidney (HEK) cells and myotubes showed an increased rate of Ca2+ entry due to a constitutive activation of the CRAC channel, consistent with a 'gain-of-function' mutation. In conclusion, we describe an Italian family harboring a novel heterozygous c.290C>G (p.S97C) mutation in ORAI1 causing a mild- and late-onset TAM and congenital miosis via constitutive activation of the CRAC channel. Our findings extend the clinical and genetic spectrum of the ORAI1-related TAM.

Oxaliplatin is a widely used chemotherapeutic drug and represents the cornerstone of colorectal cancer therapy, in combination with 5-fluorouracil and folinic acid. As with many chemotherapeutic agents, its use is associated with a number of side effects, ranging from hypersensitivity reactions to haematological dyscrasias. Oxaliplatin also induces acute and chronic peripheral neuropathy. While it is likely that the haematological side effects are associated with its anti-proliferative effects and with the ability to form DNA adducts, the molecular mechanisms underlying peripheral neuropathy and hypersensitivity reactions are poorly understood, and therefore the choice of adequate supportive therapies is largely empirical. Here we show that an acute low dose oxaliplatin application on DRG neurons is able to induce an increase in intracellular calcium that is dependent on the Histamine 1 receptor (H1). Oxaliplatin-induced intracellular calcium rises are blocked by two selective H1 antagonist, as well as by U73122, a PLC inhibitor, and by 2-APB, a non-specific IP3 receptor blocker. Moreover, expression of the H1 receptor on HEK293 t cells unmasks an oxaliplatin-induced Ca2+-rise. Last, activation of H1 via either histamine or oxaliplatin activates TRPV1 receptors, a mechanism that has been associated with itch. These data, together with literature data that has shown that anti-histamine agents reduce the incidence of oxaliplatin-induced hypersensitivity, may provide a molecular mechanism of this side effect in oncological patients.

Oxaliplatin induced peripheral neurotoxicity is characterized by an acute cold-induced syndrome characterized by cramps, paresthesias/dysesthesias in the distal limbs and perioral region, that develops rapidly and lasts up to one week affecting nearly all the patients as well as by long-lasting symptoms. It has been previously shown that pharmacological or genetic ablation of TRPA1 responses reduces oxaliplatin-induced peripheral neurotoxicity in mouse models. In the present report, we show that treatment with concentrations of oxaliplatin similar to those found in plasma of treated patients leads to an acidification of the cytosol of mouse dorsal root ganglia neurons in culture and this in turn is responsible for sensitization of TRPA1 channels, thereby providing a mechanistic explanation to toxicity of oxaliplatin. Reversal of the acidification indeed leads to a significantly reduced activity of TRPA1 channels. Last, acidification occurs also in vivo after a single injection of therapeutically-relevant doses of oxaliplatin.

Engineered silica nanoparticles (NPs) have attracted increasing interest in several applications, and particularly in the field of nanomedicine, thanks to the high biocompatibility of this material. For their optimal and controlled use, the understanding of the mechanisms elicited by their interaction with the biological target is a prerequisite, especially when dealing with cells particularly vulnerable to environmental stimuli like neurons. Here we have combined different electrophysiological approaches (both at the single cell and at the population level) with a genomic screening in order to analyze, in GT1-7 neuroendocrine cells, the impact of SiO2 NPs (50 ± 3 nm in diameter) on electrical activity and gene expression, providing a detailed analysis of the impact of a nanoparticle on neuronal excitability. We find that 20 µg mL−1 NPs induce depolarization of the membrane potential, with a modulation of the firing of action potentials. Recordings of electrical activity with multielectrode arrays provide further evidence that the NPs evoke a temporary increase in firing frequency, without affecting the functional behavior on a time scale of hours. Finally, NPs incubation up to 24 hours does not induce any change in gene expression.

Aims The role of chest computed tomography (CT) is not well defined for either diagnosis or management of pericardial disease. The aim of this study was to evaluate the added value of early chest CT in the diagnostic workup for patients presenting with cardiac tamponade or large pericardial effusion of unknown aetiology as the first manifestation of disease. Methods and results We performed CT scan on 55 patients with pericardial effusion as defined above, undergoing echo-guided pericardiocentesis. We compared the success rate in making diagnosis and/or staging the underlying disorder of three sequential workups, including, respectively, (i) clinical presentation, inflammatory markers, chest X-ray imaging, (ii) all of the above and pericardial fluid analysis, and (iii) all of the above and chest CT. We were able to make diagnosis in 53 patients (96%): the major cause of effusion was malignancy (38%). Clinical and biochemical data were not able to differentiate non-tumour from tumour patients. CT revealed pathological findings in all patients with malignancy: tumour mass in 15/21 (71%) and pathological lymphadenopathy in the remaining 6 cases. The workup including CT provided a significantly higher diagnostic yield than the other two workups ( P < 0.0001), both in the overall population and in the two subgroups of neoplastic (Npl) and non-Npl patients. Conclusion In all patients with cardiac tamponade or large pericardial effusion, CT was useful either in identifying the underlying disease or in excluding other potential causes of pericardial effusion. We conclude that chest CT is a very useful non-invasive diagnostic tool to identify and stage pericardial diseases.

Background Patients with a small aortic annulus, that is ≤23 mm, constitute a challenge for the surgeon, because they are at high risk of patient-prosthesis mismatch. Stentless valves provide better hemodynamic performance at rest and during exercise than stented valves, and are advocated in this group of patients. A new-generation stented valve, the Trifecta (St. Jude), has recently become available with improved hemodynamics. The aim of this study was to compare the hemodynamic performance of Freestyle (Medtronic) and Trifecta at rest and during exercise in patients with a small aortic annulus. Methods From September 2012 to September 2014, 22 patients with a native aortic annulus ≤23 mm underwent ergometric stress testing one year after aortic valve replacement with either a Trifecta (12 patients) or a Freestyle (10 patients) bioprosthesis as part of a randomized study. Results The mean gradient at rest was 6.0 ± 2.3 mmHg for Trifecta and 4.3 ± 3.5 for Freestyle (p = 0.213). The mean gradient at peak of exercise was 9.7 ± 3.4 mmHg for Trifecta and 7.4 ± 5 mmHg for Freestyle (p = 0.243). No significant differences were found between the two prostheses regarding other hemodynamic parameters: effective orifice area, velocity index, and performance indexes. Conclusion Both the stented Trifecta and stentless Freestyle prostheses provide excellent hemodynamic results during physical stress in patients with a small aortic annulus. Our study confirms that Trifecta implantation results in low gradients at rest and during exercise and that the performance of Trifecta is similar to that of a stentless valve. doi: 10.1111/jocs.12536 (J Card Surg 2015;30:400–404)

Background Stentless valves have long been considered the ideal valves in terms of hemodynamics. Recently, the Trifecta valve, a stented bioprosthesis with excellent fluid dynamic characteristics, has become available. The aim of the study was to compare the opening/closing pattern of the Freestyle stentless valve and the Trifecta valve with that of the native aortic valve. Methods A total of 12 patients with a Freestyle and 10 with a Trifecta valve were compared to normal native aortic valves in 12 control patients. Leaflet kinematics and hemodynamic parameters were obtained by echocardiographic M-mode and Doppler measurements. Results The control group displayed significantly longer Rapid Valve Opening Time (45 ± 7 ms) and Rapid Valve Closing Time (42 ± 9 ms) than Freestyle patients (Rapid Valve Opening Time: 32 ± 7 ms; Rapid Valve Closing Time: 31 ± 8 ms) and Trifecta patients (Rapid Valve Opening Time: 31 ± 7 ms; Rapid Valve Closing Time: 30 ± 8 ms) (P

// Beatrice Riva 1 , Marco De Dominici 2 , Ilaria Gnemmi 1 , Samanta A. Mariani 3 , Alberto Minassi 1 , Valentina Minieri 2 , Paolo Salomoni 4 , Pier Luigi Canonico 1 , Armando A. Genazzani 1 , Bruno Calabretta 2 , and Fabrizio Condorelli 1 1 Department of Pharmacological Sciences, Universita del Piemonte Orientale “A. Avogadro”, 28100 Novara, Italy 2 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia 19107, PA, USA 3 MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH16 4TJ, UK 4 Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, UK Correspondence to: Fabrizio Condorelli, email: fabrizio.condorelli@uniupo.it Keywords: celecoxib, chronic myelogenous leukemia, cyclooxygenase-2, beta-catenin, AMP-activated kinase Received: May 27, 2016 Accepted: October 19, 2016 Published: November 07, 2016 ABSTRACT CML is effectively treated with tyrosine kinase inhibitors (TKIs). However, the efficacy of these drugs is confined to the chronic phase of the disease and development of resistance to TKIs remains a pressing issue. The anti-inflammatory COX2 inhibitor celecoxib has been utilized as anti-tumour drug due to its anti-proliferative activity. However, its effects in hematological malignancies, in particular CML, have not been investigated yet. Thus, we tested biological effects and mechanisms of action of celecoxib in Philadelphia-positive (Ph + ) CML and ALL cells. We show here that celecoxib suppresses the growth of Ph + cell lines by increasing G1-phase and apoptotic cells and reducing S- and G2-phase cells. These effects were independent of COX2 inhibition but required the rapid activation of AMP-activated protein kinase (AMPK) and the consequent inhibition mTORC1 and 2. Treatment with celecoxib also restored GSK3β function and led to down-regulation of β-catenin activity through transcriptional and post-translational mechanisms, two effects likely to contribute to Ph + cell growth suppression by celecoxib. Celecoxib inhibited colony formation of TKI-resistant Ph + cell lines including those with the T315I BCR-ABL mutation and acted synergistically with imatinib in suppressing colony formation of TKI-sensitive Ph + cell lines. Finally, it suppressed colony formation of CD34 + cells from CML patients, while sparing most CD34 + progenitors from healthy donors, and induced apoptosis of primary Ph + ALL cells. Together, these findings indicate that celecoxib may serve as a COX2-independent lead compound to simultaneously target the mTOR and β-catenin pathways, key players in the resistance of CML stem cells to TKIs.

In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of disorders, spanning from immune disorders to acute pancreatitis and have been suggested to be druggable targets. In the present contribution, we exploited the click chemistry approach to synthesize a class of SOCE modulators where the arylamide substructure that characterizes most inhibitors so far described is substituted by a 1,4-disubstituted 1,2,3-triazole ring. Within this series, inhibitors of SOCE were identified and the best compound proved effective in an animal model of acute pancreatitis, a disease characterized by a hyperactivation of SOCE. Strikingly, two enhancers of the process were discovered, affording invaluable research tools to further explore the (patho)physiological role of capacitative calcium entry.

Aortic valve replacement (AVR) in patients with a small aortic root is often associated with some degree of obstruction and residual gradients. Stentless valves display better hemodynamic performance than stented valves, and might be ideal in patients with a small aortic annulus. A new stented bioprosthesis, the Trifecta valve, has recently become available and has yielded interesting early results. The study aim was to compare the hemodynamic performance of the Trifecta valve with that of the Freestyle valve in patients with an aortic annulus ≤ 2.3 cm.Between September 2011 and September 2013, a total of 40 patients with pure aortic stenosis and native aortic annulus diameter ≤ 2.3 cm was randomized to receive either a St. Jude Medical Trifecta stented prosthesis (n = 20) or a Medtronic Freestyle stentless prosthesis (n = 20). Hemodynamics results were compared between the two groups on discharge from hospital.The Trifecta valve showed slightly better hemodynamics, with peak gradients of 11 ± 5 mmHg and 17 ± 9 mmHg (p = 0.009), and mean gradients of 5.5 ± 3 mmHg and 7.5 ± 4 mmHg (p = 0.06) for the Trifecta and Freestyle valves, respectively. The average indexed effective orifice area (EOAi) was 1.14 ± 0.23 cm2/m2 and 1.09 ± 0.20 cm2/m2 (p = 0.520) for the Trifecta and Freestyle, respectively. Patient-prosthesis mismatch (PPM) occurred in two patients of the Freestyle group, and in three patients of the Trifecta group.In the present study, the stentless and stented prostheses each yielded comparable and excellent early hemodynamics results. The data obtained suggest that Trifecta valve implantation is a valid means of avoiding PPM after AVR in patients with a small native aortic annulus.

Patients with a small aortic annulus, that is ≤ 23 mm, constitute a challenge for the surgeon, because they are at high risk of patient-prosthesis mismatch. Stentless valves provide better hemodynamic performance at rest and during exercise than stented valves, and are advocated in this group of patients. A new-generation stented valve, the Trifecta (St. Jude), has recently become available with improved hemodynamics. The aim of this study was to compare the hemodynamic performance of Freestyle (Medtronic) and Trifecta at rest and during exercise in patients with a small aortic annulus.From September 2012 to September 2014, 22 patients with a native aortic annulus ≤ 23 mm underwent ergometric stress testing one year after aortic valve replacement with either a Trifecta (12 patients) or a Freestyle (10 patients) bioprosthesis as part of a randomized study.The mean gradient at rest was 6.0 ± 2.3 mmHg for Trifecta and 4.3 ± 3.5 for Freestyle (p = 0.213). The mean gradient at peak of exercise was 9.7 ± 3.4 mmHg for Trifecta and 7.4 ± 5 mmHg for Freestyle (p = 0.243). No significant differences were found between the two prostheses regarding other hemodynamic parameters: effective orifice area, velocity index, and performance indexes.Both the stented Trifecta and stentless Freestyle prostheses provide excellent hemodynamic results during physical stress in patients with a small aortic annulus. Our study confirms that Trifecta implantation results in low gradients at rest and during exercise and that the performance of Trifecta is similar to that of a stentless valve.

Oxaliplatin is one of the most widely used anticancer drugs representing the cornerstone of the treatment of colorectal cancer. Yet a number of side effects, including oxaliplatin- induced peripheral neurotoxicity (OIPN) which represents a dose-limiting side effect in the clinical use of oxaliplatin, limit its use and a better understanding of its pathogenesis would offer a great opportunity to improve the "quality of survival" of cancer patients. So far, no treatment able to prevent or limit OIPN has been approved, and one of the reasons for this unmet clinical need is the incomplete knowledge of its pathogenesis preventing the development of rationalebased pharmacological interventions. Preclinical and clinical evidence raised the hypothesis that intracellular calcium-related events might play an important role in the onset of OIPN. Yet, the results of mechanistic pre-clinical studies appear inconsistent and, therefore, their relevance in neuroprotective drugs design is still uncertain. Indeed, it is at present unclear whether aberrant calcium signalling is the key pathogenetic moment or whether it just constitutes the mediator of the clinical phenotype. This review will summarize the preclinical results involving calcium-related events and OIPN with the aim to provide an updated overview of the available evidence and highlight the most promising strategies to design effective neuroprotective drugs. In particular, we will focus on the pre-clinical evidence suggesting that TRPV1, TRPM8 or TRPA1 might be involved, as these appear particularly amenable to pharmacological modulation.

Background: A gradual worsening of autonomic control of cardiovascular function accompanies the progression of heart failure. Exercise training modulates autonomic balance, and may affect the prognosis of the disease. Aims: The sympathovagal balance was studied after 3 months of low-intensity rehabilitation compared with conventional therapy in 45 patients with heart failure (52% ischemic, 48% idiopathic), of whom 30 underwent rehabilitation and 15 did not. In 11 rehabilitated patients we also studied the effects on autonomic profile of 6 additional months of home-based training. Rehabilitated and non-rehabilitated patients had similar NYHA class, ejection fraction, exercise pVO2; 50% assumed carvedilol (39±5 mg/day). Methods and results: Autoregressive power spectral density of RR intervals variability were assessed during 10 min of: (1) supine rest and free breathing; (2) supine rest and breathing at 20 acts/min (- vagal stimulus); (3) standing (- sympathetic stimulus). During each period, the ratio LF/HF of the individual autospectrum indicated the sympathovagal balance. After 3 months of rehabilitation, pVO2 increased (20%); LF/HF at rest was unchanged (8.7±1.2 vs. 9.2±1.2); it decreased with controlled breathing (−18%) and increased during standing (+79%) (P

We examined if the aetiology of heart failure could influence the favourable autonomic response to cardiovascular rehabilitation. We used the autoregressive spectral analysis of RR intervals variability, obtained from 10 minutes of ECG recording: within each autospectrum, we calculated the power of the low (LH) and high frequency (HF) oscillations: their ratio LF/HF is a useful, well accepted index of the sympathovagal balance. In 43 patients with heart failure we evaluated the autonomic tone at rest, during regular breathing (= stimulation of cardiopulmonary receptors, i.e. a parasympathetic challenge) and during active standing (= sympathetic stimulation). The shift in such autonomic response to 3 months of cardiovascular rehabilitation was analyzed separately for patients with ischemic (n = 19) and non-ischemic (n = 24) cardiomyopathy. Before rehabilitation, patients with ischemic cardiomyopathy had a higher sympathetic activity at rest, and a preserved response to parasympathetic stimulation. After rehabilitation, both groups of patients showed an improvement in exercise tolerance and performance, no deterioration in ventricular pump function, and a change in the autonomic profile. Thus, the aetiology of heart failure, despite a different baseline sympathovagal balance, does not influence the favourable clinical and autonomic modulation induced by rehabilitation. Independently from the underlying disease, all clinically stable patients with heart failure can benefit from rehabilitation.

The authors performed two studies on the effects of carvedilol on autonomic tone and responsiveness in patients with heart failure. In study 1, the autonomic responses of 25 patients (age, 60 years ± 2; New York Heart Association [NYHA] class, 2.6 ± 0.5; pVO 2 , 16.6 mL/Kg/min ± 1.1) treated with angiotensin-converting enzyme inhibitors, diuretics, and carvedilol (38.0 mg/d ± 2.5) were compared to those of 25 patients of similar age, therapy, NYHA class, and pVO 2 in whom carvedilol was not yet administered. In study 2, autonomic tone and responsiveness were studied in 20 patients (age, 57 years ± 9; NYHA class, 2.5 ± 0.2; pVO 2 , 15.6 mL/Kg/min ± 3.4), before and 6 months after additional carvedilol treatment (40.0 mg/d ± 12.5). Autonomic evaluation was performed with autoregressive power spectral analysis of RR variability during 10 minutes of supine rest (control), breathing 20 times per minute (vagal stimulus), and standing (sympathetic activation). The ratio between low-frequency (LF) and high-frequency (HF) components of the autospectra indicated the sympathovagal interaction. In study 1, spectral analysis in controls showed sympathetic hyperactivity which was blunted in patients receiving carvedilol (LF/HF ratio: 10.4 ± 1.4 vs. 7.0 ± 1.1; P< 0.05) who responded to vagal and adrenergic stimuli (LF/HF, -35% with regular breathing and 72% standing). In study 2, left ventricular function, volumes, and exercise performance improved with carvedilol (EF, 31%; EDLV volume, -22%; pVO 2 , 11%; P < 0.05). Sympathetic hyperactivity in control was reduced (LF/HF ratio, 4.9 ± 0.8 from 7.9 ± 1.3; P < 0.05), whereas a response to vagal and adrenergic activation on breathing and standing reemerged (LF/HF ratio, -31% during regular breathing and 88% on standing). Therefore, combined autonomic and hemodynamic effects may determine the favorable effects of β-blockers in heart failure.