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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. In this study 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 at 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 patients, and hypocalcemia in one patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and nonspecific myopathic changes in two patients. DISCUSSION: Our clinical, histological, and molecular data expand the genetic and clinical spectrum of STIM1-related diseases.
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Trastornos de las Plaquetas Sanguíneas , Miopatías Estructurales Congénitas , Trastornos de las Plaquetas Sanguíneas/genética , Trastornos de las Plaquetas Sanguíneas/metabolismo , Trastornos de las Plaquetas Sanguíneas/patología , Calcio/metabolismo , Estudios Transversales , Humanos , Miosis/genética , Miosis/metabolismo , Miosis/patología , Miopatías Estructurales Congénitas/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Molécula de Interacción Estromal 1/genética , Molécula de Interacción Estromal 1/metabolismoRESUMEN
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.
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Antineoplásicos/efectos adversos , Ganglios Espinales/efectos de los fármacos , Neuronas/efectos de los fármacos , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/genética , Canales de Potasio de Dominio Poro en Tándem/genética , Intercambiador 1 de Sodio-Hidrógeno/genética , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Amilorida/farmacología , Animales , Capsaicina/farmacología , Bloqueadores del Canal de Sodio Epitelial/farmacología , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Humanos , Concentración de Iones de Hidrógeno/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Biológicos , Neuronas/metabolismo , Neuronas/patología , Técnicas de Placa-Clamp , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/patología , Canales de Potasio de Dominio Poro en Tándem/agonistas , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Cultivo Primario de Células , Intercambiador 1 de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Activación TranscripcionalRESUMEN
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 < 0.0001). The maximal leaflet displacement reached at the end of rapid valve opening was 16.7 ± 3.2 mm, 17.7 ± 2.3 mm, and 17.7 ± 5.3 mm (P = 0.42) in the Freestyle, Trifecta, and control groups, respectively. The total opening time was shorter in the control group (223 ± 25 ms) than in Freestyle (319 ± 61 ms) and Trifecta (324 ± 46 ms) patients (P < 0.0001). CONCLUSIONS: The Freestyle stentless valve was not superior to the Trifecta valve in terms of kinematics and functions more like a stented bioprosthesis.
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Válvula Aórtica/fisiología , Válvula Aórtica/cirugía , Bioprótesis , Prótesis Valvulares Cardíacas , Stents , Anciano , Anciano de 80 o más Años , Válvula Aórtica/diagnóstico por imagen , Fenómenos Biomecánicos , Ecocardiografía Doppler , Femenino , Implantación de Prótesis de Válvulas Cardíacas , Hemodinámica , Humanos , MasculinoRESUMEN
BACKGROUND AND AIM OF THE STUDY: Aortic valve replacement in patients with a small aortic root may be associated to high residual gradients. In such patients, both stentless valves and aortic annulus enlargement can reduce these residual gradients. Several studies have reported that Trifecta valves yield very good hemodynamic results. The aim of the present study was to compare the hemodynamic performance of Trifecta vs. Freestyle valves at one year in patients with an aortic annulus ≤ 2.3 cm. METHODS: Between September 2011 and September 2013, 40 patients with a native aortic annulus diameter ≤ 2.3 cm and average age of 81 ± 4 years, were randomized to receive either a St-Jude Trifecta stented prosthesis (20 patients) or a Medtronic Freestyle stentless prosthesis (20 patients). RESULTS: No differences between Trifecta and Freestyle were found at one year in mean gradient s: 6.1 ± 3 mmHg and 6.6 ± 3 mmHg (p = 0.796); effective ori fice area: 1.82 ± 0.3 mmHg and 1.76 ± 0.4 mmHg (p = 0.676) or regression of left ventricular mass: - 25% ± 14 vs. -19% ± 16 (p = 0.204), respectively. Only moderate patient -pro sthesis mismatch was found, which affected 3 patient s in each group. CONCLUSION: At one year both stentless and stented prostheses yielded comparable hemodynamic results. These data suggest that Trifecta implantation is a valid means of avoiding patient -prosthesis mismatch in aortic valve replacement in elderly patients with a small native aortic annulus.
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Válvula Aórtica/anatomía & histología , Válvula Aórtica/cirugía , Velocidad del Flujo Sanguíneo , Prótesis Valvulares Cardíacas , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/cirugía , Ecocardiografía Doppler , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Masculino , Estudios Prospectivos , Diseño de Prótesis , Ajuste de PrótesisAsunto(s)
Isquemia Encefálica/diagnóstico por imagen , Neoplasias del Colon/diagnóstico por imagen , Endocarditis Bacteriana/diagnóstico por imagen , Aneurisma Intracraneal/diagnóstico por imagen , Infecciones Estreptocócicas/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagen , Adenocarcinoma/complicaciones , Adenocarcinoma/diagnóstico por imagen , Adulto , Isquemia Encefálica/etiología , Neoplasias del Colon/complicaciones , Diagnóstico Diferencial , Endocarditis Bacteriana/etiología , Humanos , Aneurisma Intracraneal/etiología , Aneurisma Intracraneal/microbiología , Masculino , Infecciones Estreptocócicas/complicaciones , Streptococcus gallolyticus/aislamiento & purificación , Accidente Cerebrovascular/etiologíaRESUMEN
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.
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Válvula Aórtica/fisiología , Ejercicio Físico/fisiología , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Prótesis Valvulares Cardíacas , Hemodinámica , Anciano , Anciano de 80 o más Años , Válvula Aórtica/cirugía , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Evaluación de Resultado en la Atención de Salud , Diseño de PrótesisRESUMEN
BACKGROUND AND AIM OF THE STUDY: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/cirugía , Válvula Aórtica/patología , Válvula Aórtica/cirugía , Bioprótesis , Prótesis Valvulares Cardíacas , Hemodinámica , Anciano de 80 o más Años , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/fisiopatología , Femenino , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Masculino , Estudios Prospectivos , Diseño de Prótesis , Stents , Resultado del Tratamiento , UltrasonografíaRESUMEN
Bitter taste receptors are involved not only in taste perception but in various physiological functions as their anatomical location is not restricted to the gustatory system. We previously demonstrated expression and activity of the subtype hTAS2R46 in human airway smooth muscle and broncho-epithelial cells, and here we show its expression and functionality in human skeletal muscle cells. Three different cellular models were used: micro-dissected human skeletal tissues, human myoblasts/myotubes and human skeletal muscle cells differentiated from urine stem cells of healthy donors. We used qPCR, immunohistochemistry and immunofluorescence analysis to evaluate gene and protein hTAS2R46 expression. In order to explore receptor activity, cells were incubated with the specific bitter ligands absinthin and 3ß-hydroxydihydrocostunolide, and calcium oscillation and relaxation were evaluated by calcium imaging and collagen assay, respectively, after a cholinergic stimulus. We show, for the first time, experimentally the presence and functionality of a type 2 bitter receptor in human skeletal muscle cells. Given the tendentially protective role of the bitter receptors starting from the oral cavity and following also in the other ectopic sites, and given its expression already at the myoblast level, we hypothesize that the bitter receptor can play an important role in the development, maintenance and in the protection of muscle tissue functions.
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Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN), one of the major dose-limiting side effects of colorectal cancer treatment, is characterized by both acute and chronic syndromes. Acute exposure to low dose OHP on dorsal root ganglion (DRG) neurons is able to induce an increase in intracellular calcium and proton concentration, thus influencing ion channels activity and neuronal excitability. The Na+/H+ exchanger isoform-1 (NHE1) is a plasma membrane protein that plays a pivotal role in intracellular pH (pHi) homeostasis in many cell types, including nociceptors. Here we show that OHP has early effects on NHE1 activity in cultured mouse DRG neurons: the mean rate of pHi recovery was strongly reduced compared to vehicle-treated controls, reaching levels similar to those obtained in the presence of cariporide (Car), a specific NHE1 antagonist. The effect of OHP on NHE1 activity was sensitive to FK506, a specific calcineurin (CaN) inhibitor. Lastly, molecular analyses revealed transcriptional downregulation of NHE1 both in vitro, in mouse primary DRG neurons, and in vivo, in an OIPN rat model. Altogether, these data suggest that OHP-induced intracellular acidification of DRG neurons largely depends on CaN-mediated NHE1 inhibition, revealing new mechanisms that OHP could exert to alter neuronal excitability, and providing novel druggable targets.
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Síndromes de Neurotoxicidad , Intercambiadores de Sodio-Hidrógeno , Animales , Ratones , Ratas , Ganglios Espinales/metabolismo , Concentración de Iones de Hidrógeno , Neuronas/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Oxaliplatino/farmacología , Dolor/metabolismo , Intercambiadores de Sodio-Hidrógeno/genética , Intercambiadores de Sodio-Hidrógeno/metabolismo , Transcripción GenéticaRESUMEN
Muscular diseases are characterized by a wide genetic diversity and the Ca2+-signalling machinery is often perturbed. Its characterization is therefore pivotal and requires appropriate cellular models. Muscle biopsies are the best approach but are invasive for the patient and difficult to justify if the biopsy is not for diagnostic purposes. To circumvent this, interest is mounting in urine-derived stem cells that can be differentiated into skeletal muscle cells. In the present study, we isolated stem cells from urine (USC) samples of healthy donors and differentiated them by MyoD lentiviral vector transduction into skeletal muscle cells (USC-SkMC). As expected, USCs and USC-SkMCs are characterized by a radically different pattern of expression of stem and skeletal muscle markers. Characterization of cells in the present manuscript focused on Ca2+-signalling. Undifferentiated and differentiated cells differed in the expression of key proteins involved in Ca2+-homeostasis and also displayed different Ca2+-responses to external stimuli, confirming that during differentiation there was a transition from a non-excitable to an excitable phenotype. In USCs, the main mechanism of calcium entry was IP3 dependent, suggesting a major involvement of receptor-operated Ca2+ entry. Indeed, U-73122 (a PLC inhibitor) significantly inhibited the Ca2+increase triggered by ATP both in calcium and calcium-free conditions. In USC-SkMCs both store- and receptor-operated calcium entry were active. Furthermore, a caffeine challenge led to Ca2+ release both in the presence or absence of extracellular calcium, which was inhibited by ryanodine, suggesting the presence and functionality of ryanodine receptors in USC-SkMCs. Lastly, the voltage-operated calcium channels are operative in USC-SkMCs, unlike in USCs, since stimulation with high concentration of KCl induced a significant calcium transient, partially reversed by verapamil. Our data therefore support the use of skeletal muscle cells derived from USCs as an easily amenable tool to investigate Ca2+-homeostasis, in particular in those (neuro)muscular diseases that lack valid alternative models.
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Calcio , Células Madre , Calcio/metabolismo , Humanos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Células Madre/metabolismoRESUMEN
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 Ca2+-entry targeting wild-type STIM1 and ORAI1 have entered clinical trials for a different array of disorders, including pancreatitis, COVID-19, cancer, and autoimmune disorders and, while efficacy data is awaited, safety data indicates tolerability of this STIM1/ORAI1 mutations are amenable to pharmacological intervention. If this were so, given that there are no approved treatments or clinical trials ongoing for these rare disorders, it could be envisaged that these agents could also rehabilitate tubular aggregate myopathy patients. In the present contribution we characterized the Ca2+-entry patterns induced by eleven STIM1 and three ORAI1 mutations in heterologous systems or in patient-derived cells, i.e. fibroblasts and myotubes, and evaluated the effect of CIC-37 and CIC-39, two novel store-operated calcium entry modulators. Our data show that all STIM1 and ORAI1 gain-of-function mutations tested, with the possible exception of the R304Q STIM1 mutation, are amenable to inhibition, albeit with slightly different sensitivities, paving the way to the development of SOCE modulators in tubular aggregate myopathies.
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COVID-19 , Miopatías Estructurales Congénitas , Trastornos de las Plaquetas Sanguíneas , Calcio/metabolismo , Dislexia , Eritrocitos Anormales , Humanos , Ictiosis , Trastornos Migrañosos , Miosis , Fatiga Muscular , Mutación/genética , Miopatías Estructurales Congénitas/genética , Proteínas de Neoplasias/genética , Proteína ORAI1/genética , Bazo/anomalías , Molécula de Interacción Estromal 1/genéticaRESUMEN
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.
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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.
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Miopatías Estructurales Congénitas , Trombocitopenia , Animales , Calcio/metabolismo , Ratones , Mutación , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Trombocitopenia/genéticaRESUMEN
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.
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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.
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Aneurisma de la Aorta Torácica/cirugía , Insuficiencia de la Válvula Aórtica/cirugía , Válvula Aórtica/anomalías , Procedimientos Quirúrgicos Cardíacos/métodos , Enfermedades de las Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas/métodos , Monitoreo Fisiológico/métodos , Adulto , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/mortalidad , Enfermedad de la Válvula Aórtica Bicúspide , Procedimientos Quirúrgicos Cardíacos/mortalidad , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Humanos , Imagen por Resonancia Cinemagnética/métodos , Masculino , Persona de Mediana Edad , Tratamientos Conservadores del Órgano , Estudios Retrospectivos , Medición de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
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Aorta/cirugía , Aneurisma de la Aorta/cirugía , Insuficiencia de la Válvula Aórtica/cirugía , Válvula Aórtica/cirugía , Ecocardiografía , Modelos Cardiovasculares , Modelación Específica para el Paciente , Procedimientos Quirúrgicos Vasculares , Adulto , Aorta/diagnóstico por imagen , Aorta/fisiopatología , Aneurisma de la Aorta/diagnóstico por imagen , Aneurisma de la Aorta/fisiopatología , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/fisiopatología , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/fisiopatología , Fenómenos Biomecánicos , Estudios de Casos y Controles , Femenino , Análisis de Elementos Finitos , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Recuperación de la Función , Resultado del Tratamiento , Procedimientos Quirúrgicos Vasculares/efectos adversosRESUMEN
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.
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Antineoplásicos/toxicidad , Inhibidores de Anhidrasa Carbónica/farmacología , Hemoglobinas/efectos de los fármacos , Concentración de Iones de Hidrógeno/efectos de los fármacos , Neuronas/efectos de los fármacos , Oxaliplatino/toxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Acetazolamida/farmacología , Animales , Tampones (Química) , Ganglios Espinales/citología , Células HEK293 , Hemoglobinas/genética , Hemoglobinas/metabolismo , Humanos , Hiperalgesia , Ratones , Ratones Endogámicos BALB C , Neuronas/metabolismo , Cultivo Primario de Células , Protones , Topiramato/farmacología , Canales de Potencial de Receptor TransitorioRESUMEN
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.
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Compuestos de Bifenilo/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Calcio/metabolismo , Pancreatitis/tratamiento farmacológico , Triazoles/uso terapéutico , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/metabolismo , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/metabolismo , Línea Celular , Dihidroorotato Deshidrogenasa , Descubrimiento de Drogas , Estabilidad de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Humanos , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Pancreatitis/metabolismo , Pancreatitis/patología , Solubilidad , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/metabolismoRESUMEN
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.
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Motivos EF Hand/genética , Mutación/genética , Miopatías Estructurales Congénitas/genética , Molécula de Interacción Estromal 1/química , Molécula de Interacción Estromal 1/genética , Animales , Calcio/metabolismo , Femenino , Masculino , Ratones Endogámicos C57BL , Desarrollo de Músculos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/ultraestructura , Miopatías Estructurales Congénitas/patología , FenotipoRESUMEN
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.