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2.
ERJ Open Res ; 10(1)2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38259816

RESUMEN

Introduction: Non-small cell lung cancer (NSCLC) is often associated with compromised lung function. Real-world data on the impact of surgical approach in NSCLC patients with compromised lung function are still lacking. The objective of this study is to assess the potential impact of minimally invasive surgery (MIS) on 90-day post-operative mortality after anatomic lung resection in high-risk operable NSCLC patients. Methods: We conducted a retrospective multicentre study including all patients who underwent anatomic lung resection between January 2010 and October 2021 and registered in the Epithor database. High-risk patients were defined as those with a forced expiratory volume in 1 s (FEV1) or diffusing capacity of the lung for carbon monoxide (DLCO) value below 50%. Co-primary end-points were the impact of risk status on 90-day mortality and the impact of MIS on 90-day mortality in high-risk patients. Results: Of the 46 909 patients who met the inclusion criteria, 42 214 patients (90%) with both preoperative FEV1 and DLCO above 50% were included in the low-risk group, and 4695 patients (10%) with preoperative FEV1 and/or preoperative DLCO below 50% were included in the high-risk group. The 90-day mortality rate was significantly higher in the high-risk group compared to the low-risk group (280 (5.96%) versus 1301 (3.18%); p<0.0001). In high-risk patients, MIS was associated with lower 90-day mortality compared to open surgery in univariate analysis (OR=0.04 (0.02-0.05), p<0.001) and in multivariable analysis after propensity score matching (OR=0.46 (0.30-0.69), p<0.001). High-risk patients operated through MIS had a similar 90-day mortality rate compared to low-risk patients in general (3.10% versus 3.18% respectively). Conclusion: By examining the impact of surgical approaches on 90-day mortality using a nationwide database, we found that either preoperative FEV1 or DLCO below 50% is associated with higher 90-day mortality, which can be reduced by using minimally invasive surgical approaches. High-risk patients operated through MIS have a similar 90-day mortality rate as low-risk patients.

3.
Cell Mol Biol Lett ; 25(1): 50, 2020 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-33292162

RESUMEN

BACKGROUND: Human cardiac stem cells expressing the W8B2 marker (W8B2+ CSCs) were recently identified and proposed as a new model of multipotent CSCs capable of differentiating into smooth muscle cells, endothelial cells and immature myocytes. Nevertheless, no characterization of ion channel or calcium activity during the differentiation of these stem cells has been reported. METHODS: The objectives of this study were thus to analyze (using the TaqMan Low-Density Array technique) the gene profile of W8B2+ CSCs pertaining to the regulation of ion channels, transporters and other players involved in the calcium homeostasis of these cells. We also analyzed spontaneous calcium activity (via the GCaMP calcium probe) during the in vitro differentiation of W8B2+ CSCs into cardiac myocytes. RESULTS: Our results show an entirely different electrophysiological genomic profile between W8B2+ CSCs before and after differentiation. Some specific nodal genes, such as Tbx3, HCN, ICaT, L, KV, and NCX, are overexpressed after this differentiation. In addition, we reveal spontaneous calcium activity or a calcium clock whose kinetics change during the differentiation process. A pharmacological study carried out on differentiated W8B2+ CSCs showed that the NCX exchanger and IP3 stores play a fundamental role in the generation of these calcium oscillations. CONCLUSIONS: Taken together, the present results provide important information on ion channel expression and intrinsic calcium dynamics during the differentiation process of stem cells expressing the W8B2 marker.


Asunto(s)
Antígenos de Superficie/metabolismo , Calcio/metabolismo , Diferenciación Celular/fisiología , Canales Iónicos/metabolismo , Miocitos Cardíacos/metabolismo , Células Madre/metabolismo , Anciano , Proliferación Celular/fisiología , Células Cultivadas , Células Endoteliales/metabolismo , Femenino , Expresión Génica/fisiología , Humanos , Masculino , Células Madre Multipotentes/metabolismo , Miocitos del Músculo Liso/metabolismo
4.
Ann Thorac Surg ; 109(2): e119-e121, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31255612

RESUMEN

We present a case of dissecting aneurysm of ascending aorta in a 15-year-old patient secondary to Takayasu arteritis with concomitant tuberculosis, with an emphasis on multimodality imaging findings and to illustrate preoperative and postoperative medical management. Antituberculosis therapy, high-dose corticosteroids, antiplatelet therapy, and ß-blockers were administrated during the initial active phase. The patient presented with acute chest pain 3 months after medical therapy initiation. We performed an ascending aorta and aortic arch replacement with branched Dacron grafts. Only a handful of similar, but not identical, cases of Takayasu arteritis with concomitant tuberculosis leading to aortic dissection have been described previously.


Asunto(s)
Aneurisma de la Aorta Torácica/etiología , Disección Aórtica/etiología , Implantación de Prótesis Vascular/métodos , Arteritis de Takayasu/complicaciones , Tuberculosis Pulmonar/complicaciones , Adolescente , Disección Aórtica/diagnóstico , Disección Aórtica/cirugía , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/cirugía , Humanos , Imagenología Tridimensional , Angiografía por Resonancia Magnética , Masculino , Arteritis de Takayasu/diagnóstico , Tomografía Computarizada por Rayos X , Tuberculosis Pulmonar/diagnóstico
7.
Talanta ; 199: 228-237, 2019 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-30952251

RESUMEN

Inductively coupled plasma-mass spectrometry (ICP-MS) is currently the reference method for the determination of inorganic elements, and has many applications in healthcare and the environmental field. The objective of the present study was to develop and validate a high-resolution ICP-MS method for the simultaneous quantification of 38 elements in samples of human whole blood, urine, hair and tissues after microwave mineralization. The samples were incubated with nitric acid, hydrogen peroxide and internal standards prior to microwave mineralization for 25 min. The analysis was performed with an Element XR ICP-MS and validated using commercial reference standards (whole blood, urine, and hair) and in-house quality control samples. The 38 elements were detected in low-, medium- or high-resolution mode, depending on interferences and sensitivity. The lower and upper limits of quantification were adjusted for each element. The method was linear for all elements (correlation coefficient >0.996), and the inter- and intraday precision values (coefficient of variation) were below 15%. Samples from a clinical trial were used to confirm the high-resolution ICP-MS method's suitability for the assessment of patient samples.


Asunto(s)
Cabello/química , Pulmón/química , Microondas , Oligoelementos/análisis , Humanos , Espectrometría de Masas , Oligoelementos/sangre , Oligoelementos/orina
8.
Am J Transplant ; 19(3): 737-751, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30091857

RESUMEN

Kidneys from donation after circulatory death (DCD) are highly sensitive to ischemia-reperfusion injury and thus require careful reconditioning, such as normothermic regional perfusion (NRP). However, the optimal NRP protocol remains to be characterized. NRP was modeled in a DCD porcine model (30 minutes of cardiac arrest) for 2, 4, or 6 hours compared to a control group (No-NRP); kidneys were machine-preserved and allotransplanted. NRP appeared to permit recovery from warm ischemia, possibly due to an increased expression of HIF1α-dependent survival pathway. At 2 hours, blood levels of ischemic injury biomarkers increased: creatinine, lactate/pyruvate ratio, LDH, AST, NGAL, KIM-1, CD40 ligand, and soluble-tissue-factor. All these markers then decreased with time; however, AST, NGAL, and KIM-1 increased again at 6 hours. Hemoglobin and platelets decreased at 6 hours, after which the procedure became difficult to maintain. Regarding inflammation, active tissue-factor, cleaved PAR-2 and MCP-1 increased by 4-6 hours, but not TNF-α and iNOS. Compared to No-NRP, NRP kidneys showed lower resistance during hypothermic machine perfusion (HMP), likely associated with pe-NRP eNOS activation. Kidneys transplanted after 4 and 6 hours of NRP showed better function and outcome, compared to No-NRP. In conclusion, our results confirm the mechanistic benefits of NRP and highlight 4 hours as its optimal duration, after which injury markers appear.


Asunto(s)
Funcionamiento Retardado del Injerto/prevención & control , Trasplante de Riñón/efectos adversos , Preservación de Órganos/métodos , Perfusión/métodos , Temperatura , Donantes de Tejidos/provisión & distribución , Recolección de Tejidos y Órganos/normas , Animales , Isquemia Fría , Funcionamiento Retardado del Injerto/etiología , Masculino , Porcinos , Factores de Tiempo , Isquemia Tibia
9.
Biochim Biophys Acta Mol Basis Dis ; 1864(9 Pt B): 3069-3084, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29960042

RESUMEN

Maintaining the equilibrium between saturated and unsaturated fatty acids within membrane phospholipids (PLs) is crucial to sustain the optimal membrane biophysical properties, compatible with selective organelle-based processes. Lipointoxication is a pathological condition under which saturated PLs tend to accumulate within the cell at the expense of unsaturated species, with major impacts on organelle function. Here, we show that human bronchial epithelial cells extracted from lungs of patients with Obstructive Pulmonary Diseases (OPDs), i. e. Cystic Fibrosis (CF) individuals and Smokers, display a characteristic lipointoxication signature, with excessive amounts of saturated PLs. Reconstitution of this signature in cellulo and in silico revealed that such an imbalance results in altered membrane properties and in a dramatic disorganization of the intracellular network of bronchial epithelial cells, in a process which can account for several OPD traits. Such features include Endoplasmic Reticulum-stress, constitutive IL8 secretion, bronchoconstriction and, ultimately, epithelial cell death by apoptosis. We also demonstrate that a recently-identified lipid-like molecule, which has been shown to behave as a "membrane-reshaper", counters all the lipointoxication hallmarks tested. Altogether, these insights highlight the modulation of membrane properties as a potential new strategy to heal and prevent highly detrimental symptoms associated with OPDs.


Asunto(s)
Membrana Celular/efectos de los fármacos , Fibrosis Quística/tratamiento farmacológico , Ácidos Grasos/metabolismo , Manitol/análogos & derivados , Ácidos Oléicos/farmacología , Fosfolípidos/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Adulto , Anciano , Bronquios/citología , Línea Celular , Membrana Celular/metabolismo , Membrana Celular/patología , Simulación por Computador , Fibrosis Quística/patología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Ácidos Grasos/química , Femenino , Humanos , Masculino , Manitol/farmacología , Manitol/uso terapéutico , Persona de Mediana Edad , Simulación de Dinámica Molecular , Ácidos Oléicos/uso terapéutico , Fosfolípidos/química , Cultivo Primario de Células , Enfermedad Pulmonar Obstructiva Crónica/patología , Mucosa Respiratoria/citología
10.
Europace ; 20(5): 873-879, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28460030

RESUMEN

Aims: Totally subcutaneous implantable cardioverter defibrillator (S-ICD) delivers higher shock energy and can have longer time to therapy compared to transvenous implantable cardioverter defibrillator (T-ICD). Aim of the study was to compare time to therapy and to investigate cardiac, cerebral and systemic injuries of S-ICD and T-ICD shocks delivered after ventricular fibrillation (VF) induction. Methods and results: Fourteen pigs were randomly implanted with a S-ICD (n = 7) or a T-ICD (n = 7). Five VF episodes were induced in each pig. For each VF episode, up to two shocks could be delivered by the T-ICD or the S-ICD to terminate the arrhythmia. Cardiac, systemic, and cerebral toxicity were monitored. Mean time to therapy was longer in the S-ICD group compared to the T-ICD group (19[18; 23] s vs. 9 [7; 10] s; P = 0.001, respectively). High-sensitivity troponin T levels were significantly higher in the T-ICD group from 1 to 24 h after the procedure (P ≤ 0.02). Creatine phosphokinase activity levels were significantly higher in the S-ICD group, at 3, 6, and 24 h after the procedure (P ≤ 0.05). Lactate levels were not significantly different between groups. S100 protein level was similar in both groups at 1 h after the procedure and then decreased in the T-ICD group compared to the S-ICD group (P = 0.04). Conclusions: Time to therapy in S-ICD was twice as long as for T-ICD, but didn't induce relevant brain injury. Conversely, S-ICD shocks were less cardiotoxic than T-ICD shocks.


Asunto(s)
Desfibriladores Implantables/efectos adversos , Cardioversión Eléctrica , Fibrilación Ventricular/terapia , Animales , Creatina Quinasa/análisis , Modelos Animales de Enfermedad , Cardioversión Eléctrica/efectos adversos , Cardioversión Eléctrica/instrumentación , Cardioversión Eléctrica/métodos , Diseño de Equipo , Porcinos , Resultado del Tratamiento , Troponina T/análisis
11.
BMJ Open ; 7(6): e012963, 2017 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-28619764

RESUMEN

INTRODUCTION: In the last decade, video-assisted thoracoscopic surgery (VATS) lobectomy for non-small cell lung cancer (NSCLC) has had a major effect on thoracic surgery. Retrospective series have reported benefits of VATS when compared with open thoracotomy in terms of postoperative pain, postoperative complications and length of hospital stay. However, no large randomised control trial has been conducted to assess the reality of the potential benefits of VATS lobectomy or its medicoeconomic impact. METHODS AND ANALYSIS: The French National Institute of Health funded Lungsco01 to determine whether VATS for lobectomy is superior to open thoracotomy for the treatment of NSCLC in terms of economic cost to society. This trial will also include an analysis of postoperative outcomes, the length of hospital stay, the quality of life, long-term survival and locoregional recurrence. The study design is a two-arm parallel randomised controlled trial comparing VATS lobectomy with lobectomy using thoracotomy for the treatment of NSCLC. Patients will be eligible if they have proven or suspected lung cancer which could be treated by lobectomy. Patients will be randomised via an independent service. All patients will be monitored according to standard thoracic surgical practices. All patients will be evaluated at day 1, day 30, month 3, month 6, month 12 and then every year for 2 years thereafter. The recruitment target is 600 patients. ETHICS AND DISSEMINATION: The protocol has been approved by the French National Research Ethics Committee (CPP Est I: 09/06/2015) and the French Medicines Agency (09/06/2015). Results will be presented at national and international meetings and conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02502318.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neumonectomía , Complicaciones Posoperatorias/economía , Cirugía Torácica Asistida por Video , Toracotomía , Adulto , Carcinoma de Pulmón de Células no Pequeñas/economía , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Análisis Costo-Beneficio , Femenino , Francia , Humanos , Tiempo de Internación/economía , Tiempo de Internación/estadística & datos numéricos , Masculino , Tempo Operativo , Neumonectomía/economía , Neumonectomía/instrumentación , Reproducibilidad de los Resultados , Estudios Retrospectivos , Análisis de Supervivencia , Cirugía Torácica Asistida por Video/economía , Toracotomía/economía , Resultado del Tratamiento
12.
Ann Surg ; 265(1): 45-53, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28009728

RESUMEN

OBJECTIVE: The objective of this study was to determine the efficacy of alginate staple-line reinforcement of fissure openings as compared with stapling alone, with or without tissue sealant or glue, in reducing the incidence and duration of air leakage after pulmonary lobectomy for malignancy. SUMMARY BACKGROUND DATA: No randomized trial evaluating alginate staple-line reinforcement has been performed to date. METHODS: The Staple-line Reinforcement for Prevention of Pulmonary Air Leakage study was a multicenter randomized trial, with blinded evaluation of endpoints. Patients over 18 years of age scheduled for elective open lobectomy or bilobectomy for malignancy were eligible for enrollment. At thoracotomy, patients were deemed ineligible if an unanticipated pneumonectomy was indicated, or if air leakage occurred after the liberation of pleural adhesions. Otherwise, if the fissure was incomplete or the lung had an emphysematous appearance, patients were randomized to either standard management or interventional procedure consisting of fissure opening with linear cutting staplers buttressed with paired alginate sleeves (FOREseal). The number of eligible patients necessary in each randomization arm was estimated to be 190, and an outcomes analysis was performed on an intention-to-treat basis. RESULTS: Of the 611 patients consented to study enrollment, 380 met the inclusion criteria and were randomized. Based on an intention-to-treat analysis, the primary endpoint of air leak duration was not different between the 2 groups: 1 day (range: 0-2 d) in the FOREseal group and 1 day (range: 0-3 d) in the control group (P = 0.8357). In addition, the 2 groups were similar in terms of the proportion of patients presenting with prolonged air leakage (7.8% in the FOREseal group vs 11.3% in the control group, P = 0.264) and the average duration of chest drainage (P = 0.107). Procedure costs were comparable for both groups. CONCLUSIONS: FOREseal did not demonstrate a significant advantage over standard treatment alone.


Asunto(s)
Alginatos/administración & dosificación , Materiales Biocompatibles/administración & dosificación , Neoplasias Pulmonares/cirugía , Neumonectomía/métodos , Neumotórax/prevención & control , Complicaciones Posoperatorias/prevención & control , Técnicas de Cierre de Heridas , Implantes Absorbibles , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Grandes/cirugía , Carcinoma de Células Escamosas/cirugía , Femenino , Ácido Glucurónico/administración & dosificación , Ácidos Hexurónicos/administración & dosificación , Humanos , Análisis de Intención de Tratar , Cooperación Internacional , Masculino , Persona de Mediana Edad , Neumotórax/etiología , Estudios Prospectivos , Método Simple Ciego , Carcinoma Pulmonar de Células Pequeñas/cirugía , Nivel de Atención , Grapado Quirúrgico , Factores de Tiempo , Adhesivos Tisulares/administración & dosificación
13.
Eur J Pharmacol ; 765: 337-45, 2015 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-26265544

RESUMEN

TRPC6 plays important human physiological functions, notably in artery and arterioles constriction, in regulation of vascular volume and in bronchial muscle constriction. It is implicated in pulmonary hypertension, cardiovascular disease, and focal segmental glomerulosclerosis and seems to play a role in cancer development. Previously, we identified Guanabenz, an α2-adrenergic agonist used for hypertension treatment (Wytensin®), as an activator of calcium-dependent chloride channels (CaCC) in human Cystic Fibrosis (CF) nasal epithelial cells by transiently increasing [Ca2+]i via an influx of extracellular Ca2+. In this study, using assays to measure chloride channel activity, we show that guanabenz is an activator of CaCC in freshly dissociated human bronchial epithelial cells from three CF patients with various genotypes (F508del/F508del, F508del/R1066C, F508del/H1085R). We further characterised the effect of guanabenz and show that it is independent of α-adrenergic receptors, is inhibited by the TRPC family inhibitor SKF-96365 but not by the TRPV family inhibitor ruthenium red. Using western-blotting, Ca2+ measurements and iodide efflux assay, we found that TRPC1 siRNA has no effect on guanabenz induced responses whereas TRPC6 siRNA prevented the guanabenz-dependent Ca2+ influx and the CaCC-dependent activity stimulated by guanabenz. In conclusion, we show that TRPC6 channel is pivotal for the activation of CaCC by guanabenz through a α2-adrenergic-independent pathway in human airway epithelial cells. We suggest propose a functional coupling between TRPC6 and CaCC and guanabenz as a potential TRPC6 activator for exploring TRPC6 and CaCC channel functions and corresponding channelopathies.


Asunto(s)
Canales de Cloruro/metabolismo , Células Epiteliales/metabolismo , Canales Catiónicos TRPC/metabolismo , Adulto , Amilorida/farmacología , Células Cultivadas , Canales de Cloruro/antagonistas & inhibidores , Células Epiteliales/efectos de los fármacos , Bloqueadores del Canal de Sodio Epitelial/farmacología , Femenino , Humanos , Imidazoles/farmacología , Masculino , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Canales Catiónicos TRPC/antagonistas & inhibidores , Canal Catiónico TRPC6 , Adulto Joven
14.
Eur J Cardiothorac Surg ; 48(6): 968-70, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25669647

RESUMEN

Primary cardiac lymphomas (PCLs) are rare in immunocompetent patients. Their clinical presentation is highly variable and in case of cardiogenic shock, death is often inevitable with a diagnosis made post-mortem. We report the case of a 65-year old immunocompetent man with cardiogenic shock requiring emergent extracorporeal membrane oxygenation (ECMO). Soon after, a diagnosis of PCL was given and chemotherapy was delivered under ECMO support. The patient was progressively weaned from the mechanical support. Six months later, he had fully recovered.


Asunto(s)
Oxigenación por Membrana Extracorpórea/métodos , Neoplasias Cardíacas/complicaciones , Linfoma/complicaciones , Choque Cardiogénico/etiología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/tratamiento farmacológico , Neoplasias Cardíacas/terapia , Humanos , Linfoma/diagnóstico por imagen , Linfoma/tratamiento farmacológico , Linfoma/terapia , Masculino , Choque Cardiogénico/terapia , Tomografía Computarizada por Rayos X
15.
Biomed Res Int ; 2015: 624723, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25710011

RESUMEN

OBJECTIVES: Conservative management of patients with flail chest is the treatment of choice. Rib fracture repair is technically challenging; however, with the advent of specially designed molding titanium clips, surgical management has been simplified. Surgical stabilization has been used with good outcomes. We are reporting on our institutional matched-case-control study. METHODS: Between April 2010 and April 2011, ten polytraumatized patients undergoing rib stabilization for flail chest were matched 1 : 1 to 10 control patients by age ±10 years, sex, neurological or vertebral trauma, abdominal injury, and arm and leg fractures. Surgery was realized in the first 48 hours. RESULTS: There were no significant differences between groups for matched data and prognostic scores: injury severity score, revised trauma score, and trauma injury severity score. Ventilator time (142 ± 224 versus 74 ± 125 hours, P = 0.026) and overall hospital stay (142 ± 224 versus 74 ± 125 hours, P = 0.026) were significantly lower for the surgical group after adjustment on prognostic scores. There was a trend towards shorter ICU stay for operative patients (12.3 ± 8.5 versus 9.0 ± 4.3 days, P = 0.076). CONCLUSIONS: Rib fixation with Stracos is feasible and decreases the length of ventilation and hospital stay. A multicenter randomized study is warranted so as to confirm these results and to evaluate impact on pulmonary function status, pain, and quality of life.


Asunto(s)
Placas Óseas/estadística & datos numéricos , Tórax Paradójico/cirugía , Tiempo de Internación/estadística & datos numéricos , Ventiladores Mecánicos/estadística & datos numéricos , Femenino , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Traumatismo Múltiple/terapia , Resultado del Tratamiento
16.
Cell Calcium ; 57(1): 38-48, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25477137

RESUMEN

Increase of Ca(2+) influx in Cystic Fibrosis (CF) cells has been reported to be related to Transient Receptor Potential Canonical (TRPC6) channel, which is implicated in a functional coupling with Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Several members of the Transient Receptor Potential Vanilloid (TRPV) channels family have already been described as emerging target for respiratory diseases. Two specific isoforms, TRPV5 and TRPV6 are of particular interest in the context of CF Ca(2+) homeostasis as they are highly selective toward Ca(2+) and constitutively activated. Thus, we investigated the involvement of these channels in Ca(2+) influx in CF and non-CF human bronchial epithelial cell lines. 16HBE14o-, CFBE41o- cell lines, primary human airway epithelial cells (hAEC) and freshly isolated human airway epithelial cells from CF and non-CF individuals were used. We showed that both channels are expressed in CF and non-CF cells and constitutive Ca(2+) influx was significantly higher (85%) in cells from CF individuals compared to cells from non-CF ones. Using the selective inhibitor of TRPV6 channel SOR-C27 and a siRNA strategy, our results revealed that TRPV6 was mostly involved in the increase of Ca(2+) influx. TRPV6 channel is negatively regulated by the PLC-PIP2 pathway. We measured the Ca(2+) influx in the presence of the non-specific PLC inhibitor, U73122, in non-CF human bronchial epithelial cells. Ca(2+) influx was increased by 33% with U73122 and this increase was largely reduced in the presence of SOR-C27. PLC inhibition in CF cells by U73122 had no effect on Ca(2+) influx. These results showed that PLC-PIP2 pathway is dysregulated in CF cells and leads to the increase of TRPV6 activity. The regulation of TRPV6 by PLC-PIP2 pathway implicates the specific PLC isoform, PLC-δ1. Immunoblot experiments revealed that expression of PLC-δ1 was decreased by 70% in CF cells. TRPV6 activity was normalized but not the level of expression of PLC-δ1 protein after F508del-CFTR rescue by low temperature for 48 h or treated for 24 h by 10 µM VX-809 in CF cells. This study revealed TRPV6 and PLC-δ1 as critical actor of Ca(2+) homeostasis in CF human bronchial epithelial cells.


Asunto(s)
Fosfolipasa C delta/metabolismo , Canales Catiónicos TRPV/metabolismo , Adulto , Calcio/metabolismo , Células Cultivadas , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Células Epiteliales/citología , Células Epiteliales/metabolismo , Estrenos/farmacología , Femenino , Humanos , Transporte Iónico/efectos de los fármacos , Masculino , Persona de Mediana Edad , Mutación , Fosfolipasa C delta/antagonistas & inhibidores , Fosfolipasa C delta/genética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Pirrolidinonas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/genética , Regulación hacia Arriba/efectos de los fármacos
17.
Ann Thorac Surg ; 98(4): e101-2, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25282243

RESUMEN

We describe the replacement of a single cusp in two patients with severe aortic regurgitation due to endocarditis with a one third stentless bioprosthesis, with excellent results in both.


Asunto(s)
Válvula Aórtica/cirugía , Bioprótesis , Endocarditis/cirugía , Implantación de Prótesis de Válvulas Cardíacas/métodos , Anciano , Humanos , Masculino , Persona de Mediana Edad
18.
Transplant Res ; 3: 13, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24999383

RESUMEN

BACKGROUND: Extracorporeal membranous oxygenation is proposed for abdominal organ procurement from donation after circulatory determination of death (DCD). In France, the national Agency of Biomedicine supervises the procurement of kidneys from DCD, specifying the durations of tolerated warm and cold ischemia. However, no study has determined the optimal conditions of this technique. The aim of this work was to develop a preclinical model of DCD using abdominal normothermic oxygenated recirculation (ANOR). In short, our objectives are to characterize the mechanisms involved during ANOR and its impact on abdominal organs. METHODS: We used Large White pigs weighing between 45 and 55 kg. After 30 minutes of potassium-induced cardiac arrest, the descending thoracic aorta was clamped and ANOR set up between the inferior vena cava and the abdominal aorta for 4 hours. Hemodynamic, respiratory and biochemical parameters were collected. Blood gasometry and biochemistry analysis were performed during the ANOR procedure. RESULTS: Six ANOR procedures were performed. The surgical procedure is described and intraoperative parameters and biological data are presented. Pump flow rates were between 2.5 and 3 l/min. Hemodynamic, respiratory, and biochemical objectives were achieved under reproducible conditions. Interestingly, animals remained hemodynamically stable following the targeted protocol. Arterial pH was controlled, and natremia and renal function remained stable 4 hours after the procedure was started. Decreased hemoglobin and serum proteins levels, concomitant with increased lactate dehydrogenase activity, were observed as a consequence of the surgery. The serum potassium level was increased, owing to the extracorporeal circulation circuit. CONCLUSIONS: Our ANOR model is the closest to clinical conditions reported in the literature and will allow the study of the systemic and abdominal organ impact of this technique. The translational relevance of the pig will permit the determination of new biomarkers and protocols to improve DCD donor management.

19.
Stem Cells Transl Med ; 3(7): 809-20, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24797827

RESUMEN

It is well known that ischemia/reperfusion injuries strongly affect the success of human organ transplantation. Development of interstitial fibrosis and tubular atrophy is the main deleterious phenomenon involved. Stem cells are a promising therapeutic tool already validated in various ischemic diseases. Amniotic fluid-derived mesenchymal stem cells (af-MSCs), a subpopulation of multipotent cells identified in amniotic fluid, are known to secrete growth factors and anti-inflammatory cytokines. In addition, these cells are easy to collect, present higher proliferation and self-renewal rates compared with other adult stem cells (ASCs), and are suitable for banking. Consequently, af-MSCs represent a promising source of stem cells for regenerative therapies in humans. To determine the efficiency and the safety of af-MSC infusion in a preclinical porcine model of renal autotransplantation, we injected autologous af-MSCs in the renal artery 6 days after transplantation. The af-MSC injection improved glomerular and tubular functions, leading to full renal function recovery and abrogated fibrosis development at 3 months. The strong proof of concept generated by this translational porcine model is a first step toward evaluation of af-MSC-based therapies in human kidney transplantation.


Asunto(s)
Líquido Amniótico/citología , Trasplante de Riñón/efectos adversos , Riñón/cirugía , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Células Madre Multipotentes/trasplante , Daño por Reperfusión/prevención & control , Animales , Rastreo Celular , Células Cultivadas , Femenino , Fibrosis , Supervivencia de Injerto , Proteínas Fluorescentes Verdes/biosíntesis , Proteínas Fluorescentes Verdes/genética , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Células Madre Mesenquimatosas/metabolismo , Células Madre Multipotentes/metabolismo , Embarazo , Recuperación de la Función , Daño por Reperfusión/etiología , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatología , Porcinos , Factores de Tiempo , Transducción Genética , Transfección/métodos , Trasplante Autólogo
20.
PLoS One ; 9(2): e89044, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24586495

RESUMEN

The F508del-CFTR mutation, responsible for Cystic Fibrosis (CF), leads to the retention of the protein in the endoplasmic reticulum (ER). The mistrafficking of this mutant form can be corrected by pharmacological chaperones, but these molecules showed limitations in clinical trials. We therefore hypothesized that important factors in CF patients may have not been considered in the in vitro assays. CF has also been associated with an altered lipid homeostasis, i. e. a decrease in polyunsaturated fatty acid levels in plasma and tissues. However, the precise fatty acyl content of membrane phospholipids from human CF bronchial epithelial cells had not been studied to date. Since the saturation level of phospholipids can modulate crucial membrane properties, with potential impacts on membrane protein folding/trafficking, we analyzed this parameter for freshly isolated bronchial epithelial cells from CF patients. Interestingly, we could show that Palmitate, a saturated fatty acid, accumulates within Phosphatidylcholine (PC) in CF freshly isolated cells, in a process that could result from hypoxia. The observed PC pattern can be recapitulated in the CFBE41o(-) cell line by incubation with 100 µM Palmitate. At this concentration, Palmitate induces an ER stress, impacts calcium homeostasis and leads to a decrease in the activity of the corrected F508del-CFTR. Overall, these data suggest that bronchial epithelial cells are lipointoxicated by hypoxia-related Palmitate accumulation in CF patients. We propose that this phenomenon could be an important bottleneck for F508del-CFTR trafficking correction by pharmacological agents in clinical trials.


Asunto(s)
Membrana Celular/metabolismo , Fibrosis Quística/patología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Ácido Palmítico/toxicidad , Mucosa Respiratoria/metabolismo , Adulto , Anciano , Membrana Celular/efectos de los fármacos , Células Cultivadas , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ácido Palmítico/aislamiento & purificación , Ácido Palmítico/metabolismo , Transporte de Proteínas/efectos de los fármacos , Mucosa Respiratoria/patología
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