Content, educational value and quality analysis of videos about neurorehabilitation in people with multiple sclerosis on YouTube®. / Análisis de contenido, valor educativo y calidad de los vídeos sobre neurorrehabilitación de la esclerosis múltiple en YouTube®.

INTRODUCTION: The use of YouTube® has spread among patients with chronic diseases such as multiple sclerosis (MS). These patients consult the available videos to learn more about their disease in terms of diagnosis and making decisions about treatments, including rehabilitation. The aim of this study was to evaluate the content, educational value, and quality analysis of MS videos about neurorehabilitation on YouTube® using quantitative instruments. MATERIALS AND METHODS: A search was conducted on YouTube®. The first 30 videos that met the inclusion criteria were reviewed. The videos were classified according to the upload source and the content. All videos included in the review were assessed by the DISCERN questionnaire, the JAMA benchmark, the global quality scale (GQS) and the video information and quality index (VIQI). RESULTS: The mean scores were: 28.3 (±9.33) in DISCERN, 2 (±0.81) in JAMA, 2.57 (±1.22) in GQS, and 11.73 (±4.06) in VIQI. JAMA score statistically significantly differed according to upload source (p = 0.002), video content (p = 0.023) and the speaker (p = 0.002). The DISCERN, JAMA, GQS, and VIQI scores showed significant correlations with each other. CONCLUSIONS: The analyzed videos about neurorehabilitation in people with MS on YouTube® were quite old since the upload, with a moderate duration and number of views, but with a poor quality of the content, educational value, and quality analysis of the videos. Our research showed that there were statistically significant differences in terms of quality, transparency, and reliability of the information, depending on the upload source, video content and the speaker.

TITLE: Análisis de contenido, valor educativo y calidad de los vídeos sobre neurorrehabilitación de la esclerosis múltiple en YouTube®.Introducción. El uso de YouTube® se ha extendido entre los pacientes con enfermedades crónicas como la esclerosis múltiple (EM). Estos pacientes tienden a consultar los vídeos disponibles para aprender más sobre su enfermedad, en términos de diagnóstico y toma de decisiones sobre tratamientos, incluida la rehabilitación. El objetivo de este estudio fue evaluar el contenido, el valor educativo y el análisis de la calidad de los vídeos sobre neurorrehabilitación de la EM en la plataforma YouTube®, empleando instrumentos cuantitativos validados. Materiales y métodos. Se realizó una búsqueda en la plataforma YouTube®. Se revisaron los 30 primeros vídeos que cumplían los criterios de inclusión establecidos. Los vídeos se clasificaron según la fuente de subida y el contenido. Todos los vídeos incluidos en la revisión se evaluaron mediante el cuestionario DISCERN, el índice de referencia JAMA, la escala de calidad global (GQS) y el índice de información y calidad de vídeo (VIQI). Resultados. Las puntuaciones medias fueron: 28,3 (±9,33) en DISCERN, 2 (±0,81) en JAMA, 2,57 (±1,22) en GQS y 11,73 (±4,06) en VIQI. La puntuación en la escala JAMA difirió de forma estadísticamente significativa según la fuente de carga (p = 0,002), el contenido del vídeo (p = 0,023) y el perfil de la persona que lo ejecutaba (p = 0,002). Las puntuaciones en DISCERN, JAMA, GQS y VIQI mostraron correlaciones significativas entre sí. Conclusiones. Los vídeos analizados sobre neurorrehabilitación en personas con EM y que aparecen en la plataforma YouTube® eran bastante antiguos desde su fecha de subida, con una duración y un número de visualizaciones moderados, y con una calidad deficiente en su contenido, en su valor educativo y en el propio análisis de los mismos. Nuestra investigación mostró que había diferencias estadísticamente significativas en términos de calidad, transparencia y fiabilidad de la información, dependiendo de la fuente de subida, el contenido del vídeo y el perfil de la persona que lo ejecutaba.

[Efficacy of virtual reality on balance and gait in multiple sclerosis. Systematic review of randomized controlled trials]. / Eficacia de la realidad virtual sobre el equilibrio y la marcha en esclerosis multiple. Revision sistematica de ensayos controlados aleatorizados.

INTRODUCTION: Multiple sclerosis (MS) is a neurodegenerative disease that causes gait abnormalities and a deficit in balance control in the vast majority of people affected by it. Virtual reality has been proposed as a complementary approach to conventional physiotherapeutic treatment as a way of improving these variables. AIM: To assess the real efficacy of this approach compared to other neurorehabilitation therapies, or no intervention, in MS. PATIENTS AND METHODS: A systematic review of randomized controlled trials was conducted. Studies of the last five years that compare virtual reality with conventional treatment or no intervention, on balance and/or gait, in adults with MS, were included. PEDro scale was used to assess methodological quality and the Oxford scale to determine the level of evidence and grades of recommendations. RESULTS: Eight studies met the eligibility criteria. For balance, the efficacy of virtual reality is, at least, comparable as conventional training. For gait, virtual reality seems not to be superior in improving the speed, compared with the other types of interventions assessed. Methodological quality of studies was low-moderate. CONCLUSIONS: Virtual reality is as effective as conventional training for improving balance in people with MS. No data suggests that virtual reality is superior to other interventions in improving gait speed. For other gait parameters, virtual reality's efficacy remains unknown.

TITLE: Eficacia de la realidad virtual sobre el equilibrio y la marcha en esclerosis multiple. Revision sistematica de ensayos controlados aleatorizados.Introduccion. La esclerosis multiple (EM) es una enfermedad neurodegenerativa que produce alteraciones en el equilibrio y la marcha en la mayoria de los pacientes. La realidad virtual se ha propuesto como un abordaje complementario al tratamiento rehabilitador convencional como medio para mejorar dichas alteraciones. Objetivo. Evaluar la eficacia del abordaje mediante realidad virtual, en comparacion con otras intervenciones de neurorrehabilitacion o la no intervencion, en la EM. Pacientes y metodos. Se realiza una revision sistematica de ensayos controlados aleatorizados. Se incluyeron estudios de los ultimos cinco años que comparasen la intervencion de realidad virtual frente al tratamiento convencional o la no intervencion sobre el equilibrio y la marcha en personas adultas con EM. Se utilizo la escala PEDro para evaluar la calidad metodologica de los estudios incluidos y la escala de Oxford para evaluar el nivel de evidencia y el grado de recomendacion. Resultados. Ocho estudios cumplieron los criterios de elegibilidad. Para el equilibrio, la eficacia de la realidad virtual es, al menos, comparable a la del entrenamiento convencional. Para la marcha, la realidad virtual parece no ser superior en el parametro velocidad, en comparacion con el resto de intervenciones evaluadas. La calidad metodologica de los estudios fue moderada-baja. Conclusiones. La realidad virtual es igual de eficaz que el entrenamiento rehabilitador convencional para mejorar el equilibrio en personas con EM. No se han hallado datos que sugieran que la realidad virtual sea superior a otras intervenciones en la mejora de la velocidad de la marcha, y su eficacia sobre otros parametros de la marcha es aun incierta.

Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma.

The single nucleotide polymorphism (SNP) rs4646437G>A in CYP3A4 was suggested to be related to sunitinib toxicity. Our objective was to perform an in-depth investigation of the association between this SNP and sunitinib toxicity and efficacy using a large cohort of metastatic renal cell carcinoma (mRCC) patients. We collected DNA and clinical information of mRCC patients treated with sunitinib. SNP rs4646437 in CYP3A4 was tested for associations with toxicity using logistic regression. Cox regression modeling was used for association analysis of rs4646437 with progression-free survival (PFS) and overall survival (OS). In a total of 287 patients, the A-allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension (odds ratio=2.4, 95% confidence interval: 1.1-5.2, P=0.021) and showed no significant association with PFS or OS. In conclusion, hypertension is more likely to occur in A-allele carriers of the CYP3A4 rs4646437 variant in our cohort of mRCC patients treated with sunitinib.

Computational comparison of aortic root stresses in presence of stentless and stented aortic valve bio-prostheses.

We provide a computational comparison of the performance of stentless and stented aortic prostheses, in terms of aortic root displacements and internal stresses. To this aim, we consider three real patients; for each of them, we draw the two prostheses configurations, which are characterized by different mechanical properties and we also consider the native configuration. For each of these scenarios, we solve the fluid-structure interaction problem arising between blood and aortic root, through Finite Elements. In particular, the Arbitrary Lagrangian-Eulerian formulation is used for the numerical solution of the fluid-dynamic equations and a hyperelastic material model is adopted to predict the mechanical response of the aortic wall and the two prostheses. The computational results are analyzed in terms of aortic flow, internal wall stresses and aortic wall/prosthesis displacements; a quantitative comparison of the mechanical behavior of the three scenarios is reported. The numerical results highlight a good agreement between stentless and native displacements and internal wall stresses, whereas higher/non-physiological stresses are found for the stented case.

Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE).

BACKGROUND: The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. METHODS: This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. RESULTS: A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively]. CONCLUSIONS: Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). CLINICAL TRIAL NUMBER: NCT01280201.

IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma.

BACKGROUND: We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC). METHODS: The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3). RESULTS: In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients. CONCLUSIONS: Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.

Pharmacogenomic biomarkers for personalized cancer treatment.

Personalized medicine involves the selection of the safest and most effective pharmacological treatment based on the molecular characteristics of the patient. In the case of anticancer drugs, tumour cell alterations can have a great impact on drug activity and, in fact, most biomarkers predicting response originate from these cells. On the other hand, the risk of developing severe toxicity may be related to the genetic background of the patient. Thus, understanding the molecular characteristics of both the tumour and the patient, and establishing their relation with drug outcomes will be critical for the identification of predictive biomarkers and to provide the basis for individualized treatments. This is a complex scenario where multiple genes as well as pathophysiological and environmental factors are important; in addition, tumours exhibit large inter- and intraindividual variability in space and time. Against this background, the huge amounts of biological and genetic data generated by the high-throughput technologies will facilitate pharmacogenomic progress, suggest novel druggable molecules and support the design of future strategies aimed at disease control. Here, we will review the current challenges and opportunities for pharmacogenomic studies in oncology, as well as the clinically established biomarkers. Lung and renal cancer, two areas in which huge progress has been made in the last decade, will be used to illustrate advances in personalized cancer treatment; we will review EGFR mutation as the paradigm of targeted therapies in lung cancer, and discuss the dissection of lung cancer into clinically relevant molecular subsets and novel advances that suggest an important role of single nucleotide polymorphisms in the response to antiangiogenic agents, as well as the challenges that remain in these fields. Finally, we will present new approaches and future prospects for personalizing medicine in oncology.

High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations.

Impact of chemotherapy on telomere length in sporadic and familial breast cancer patients.

Recently, we observed that telomeres of BRCA1/2 mutation carriers were shorter than those of controls or sporadic breast cancer patients, suggesting that mutations in these genes might be responsible for this event. Given the contradictory results reported in the literature, we tested whether other parameters, such as chemotherapy, could be modifying telomere length (TL). We performed a cross-sectional study measuring leukocyte TL of 266 sporadic breasts cancer patients treated with first-line chemotherapy, with a median follow-up of 240 days. Additionally, we performed both cross-sectional and longitudinal studies in a series of 236 familial breast cancer patients that included affected and non-affected BRCA1/2 mutation carriers. We have measured in leukocytes from peripheral blood: the TL, percentage of short telomeres (<3 kb), telomerase activity levels and the annual telomere shortening speed. In sporadic cases we found that chemotherapy exerts a transient telomere shortening effect (around 2 years) that varies depending on the drug combination. In familial cases, only patients receiving treatment were associated with telomere shortening but they recovered normal TL after a period of 2 years. Chemotherapy affects TL and should be considered in the studies that correlate TL with disease susceptibility.

In vitro study of the aortic interleaflet triangle reshaping.

Aortic interleaflet triangle reshaping (AITR) is a surgical approach to aortic valve incontinence that involves placing three stitches at half of the interleaflet triangles height. In this work, the relationship between the actual stitch height and valve functioning, and the safety margin that the surgeon can rely on in applying the stitches were systematically investigated in vitro. AITR surgery was applied to six swine aortic roots placing the stitches empirically at 50%, 60% and 75% of the triangle heights. Then the actual stitch heights were measured and the hydrodynamic performances were evaluated with a pulsatile hydrodynamic mock loop. Actual stitch heights were 45±2%, 61±4% and 79±6%. As compared to untreated conditions, the 50% configuration induced a significant variation in the effective orifice area. With stitches placed at 60%, the mean systolic pressure drop increased significantly with respect to the untreated case, but no significant changes were recorded with respect to the 50% configuration. At 75%, all the hydrodynamic parameters of systolic valve functioning worsened significantly. Summarizing, the AITR technique, when performed in a conservative manner did not induce significant alterations in the hydrodynamics of the aortic root in vitro, while more aggressive configurations did. The absence of a statistically significant difference between the 50% and 60% configurations suggests that there is a reasonably limited risk of inducing valve stenosis in the post-op scenario due to stitch misplacement.

Prospective study assessing hypoxia-related proteins as markers for the outcome of treatment with sunitinib in advanced clear-cell renal cell carcinoma.

BACKGROUND: Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: The expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib. RESULTS: High expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023). CONCLUSIONS: We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.

[Obstetric brachial palsy, a historical review]. / Paralisis braquial obstetrica, una revision historica.

INTRODUCTION: Lesions of the peripheral nerves have been known since ancient times, but there are few references to the treatments that were used in the past. AIM. To analyse obstetric brachial palsy and its treatments throughout history. DEVELOPMENT: There are a number of different references to the peripheral nerves and their lesions, although little is known about the treatments that were applied in the past. William Smellie first reported obstetric brachial palsy in 1764 and the term was coined by Duchenne de Boulogne in 1872. In 1877, Erb analysed four cases of obstetric brachial palsy and conducted studies on the excitation of the brachial plexus with electric currents. In 1885, Klumpke described palsy of the lower roots of the brachial plexus. In the late 19th century pathophysiology studies were carried out and at the beginning of the 20th century the first surgical interventions were performed. Today, microsurgery techniques, protocols on how to proceed, and rehabilitation treatment of this lesion are all available and offer good outcomes. CONCLUSIONS: Since the first clinical description of obstetric brachial palsy by Smellie and the reports of the different types of brachial palsy by Duchenne, Erb and Klumpke, many pathophysiological studies have been conducted. Notable developments have been made in conservative and surgical treatments, with very favourable recoveries being observed in children with obstetric brachial palsy.

Parálisis braquial obstétrica, una revisión histórica / Obstetric brachial palsy, a historical review

Introducción. Las lesiones de los nervios periféricos se conocen desde antiguo, pero existen escasas referencias acerca de los tratamientos utilizados en el pasado. Objetivo. Analizar la parálisis braquial obstétrica y sus tratamientos a lo largo de la historia. Desarrollo. Existen diversas referencias sobre los nervios periféricos y sus lesiones, aunque se conoce poco sobre los tratamientos practicados en el pasado. William Smellie realizó la primera descripción de la parálisis braquial obstétrica en 1764 y Duchenne de Boulogne acuñó el término en 1872. En 1877, Erb analizó cuatro casos de parálisis braquial obstétrica y realizó estudios acerca de la excitación del plexo braquial con corrientes eléctricas. Klumpke describió, en 1885, la parálisis de las raíces inferiores del plexo braquial. A finales del siglo xix se realizaron estudios sobre la fisiopatología, y a principiosdel siglo xx se empezaron a practicar intervenciones quirúrgicas. En la actualidad se cuenta con técnicas de microcirugía, protocolos de actuación y tratamiento rehabilitador de esta lesión, con buenos resultados. Conclusiones. Desde la primera descripción clínica de la parálisis braquial obstétrica por Smellie y la descripción de los distintos tipos de parálisis braquial por Duchenne, Erb y Klumpke, se han llevado a cabo múltiples estudios fisiopatológicos y se han desarrollado de manera notable los tratamientos conservador y quirúrgico, observándose recuperaciones muy favorables en los niños con parálisis braquial obstétrica (AU)

Introduction. Lesions of the peripheral nerves have been known since ancient times, but there are few references to the treatments that were used in the past. Aim. To analyse obstetric brachial palsy and its treatments throughout history. Development. There are a number of different references to the peripheral nerves and their lesions, although little is known about the treatments that were applied in the past. William Smellie first reported obstetric brachial palsy in 1764 and the term was coined by Duchenne de Boulogne in 1872. In 1877, Erb analysed four cases of obstetric brachial palsy and conducted studies on the excitation of the brachial plexus with electric currents. In 1885, Klumpke described palsy of the lower roots of the brachial plexus. In the late 19th century pathophysiology studies were carried out and at the beginning of the 20th century the first surgical interventions were performed. Today, microsurgery techniques, protocols on how to proceed, and rehabilitation treatment of this lesion are all available and offer good outcomes. Conclusions. Since the first clinical description of obstetric brachial palsy by Smellie and the reports of the different types of brachial palsy by Duchenne, Erb and Klumpke, many pathophysiological studies have been conducted. Notable developments have been made in conservative and surgical treatments, with very favourable recoveries being observed in children with obstetric brachial palsy (AU)

In vitro hemodynamics and valve imaging in passive beating hearts.

Due to their high complexity, surgical approaches to valve repair may benefit from the use of in vitro simulators both for training and for the investigation of those measures which can lead to better clinical results. In vitro tests are intrinsically more effective when all the anatomical substructures of the valvular complexes are preserved. In this work, a mock apparatus able to house an entire explanted porcine heart and subject it to pulsatile fluid-dynamic conditions was developed, in order to enable the hemodynamic analysis of simulated surgical procedures and the imaging of the valvular structures. The mock loop's hydrodynamic design was based on an ad-hoc defined lumped-parameter model. The left ventricle of an entire swine heart was dynamically pressurized by an external computer-controlled pulse duplicator. The ascending aorta was connected to a hydraulic circuit which simulated the input impedance of the systemic circulation; a reservoir passively filled the left atrium. Accesses for endoscopic imaging were located in the apex of the left ventricle and in the aortic root. The experimental pressure and flow tracings were comparable with the typical in vivo curves; a mean flow of 3.5±0.1l pm and a mean arterial pressure of 101±2 mmHg was obtained. High-quality echographic and endoscopic video recordings demonstrated the system's excellent potential in the observation of the cardiac structures dynamics. The proposed mock loop represents a suitable in vitro system for the testing of minimally-invasive cardiovascular devices and surgical procedures for heart valve repair.

In vitro study of aortic valves treated with neo-chordae grafts: hydrodynamics and tensile force measurements.

Reparative surgery of the aortic root functional unit (ARFU) allows for a better preservation of the functionality of the native structure compared to prosthesis implantation. Post-operative results are satisfactory, whereas mid- and long-term results are challenging, for example in terms of cusps prolapse recurrence. At the Cardiothoracic Surgery Unit of the Sacco Hospital, a new surgical technique aimed at the stabilization in time of the results of standard ARFU repair operations has been applied. This technique, inspired by the mitral neo-chordae (NC) implantation, consists of implanting an e-PTFE suture thread between the prolapsed cusp and the sinotubular junction. Aim of this study was to assess the influence of NC implantation on the ARFU functioning by evaluating with an owned pulsatile in vitro apparatus the force magnitude acting on the NC and the dynamic behavior of porcine ARFUs treated according to the operating-room procedures. The maximum recorded values of the mean and peak diastolic forces were 0.064 and 0.186 N, respectively, and were linearly dependent upon the mean diastolic pressure across the valve. In addition, the measurements of the opening-closing times and valve leakage volumes, performed at pre- and post-surgeries, yielded that the valve functionality was not significantly influenced by NC implantation.

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity.

Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele)=0.55; 95% confidence interval (CI)=0.34-0.89; P=0.014 and HR (per allele)=0.51; 95%CI=0.30-0.86; and P=0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele)=1.72; 95%CI=1.05-2.82; and P=0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR=1.64 (95% CI=1.26-2.14; P=0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.

Hybrid aortic arch repair procedure: reinforcement of the aorta for a safe and durable landing zone.

OBJECTIVES: Hybrid aortic arch repair procedure was introduced to reduce invasiveness in high-risk patients with aortic arch pathology. The good results are expanding its application, but endoleak, particularly type I, remains its Achilles' heel. DESIGN: We describe our experience with hybrid treatment of aortic arch diseases focussing on techniques and results to avoid type I endoleak. MATERIALS AND METHODS: A total of 15 high-risk patients with zone 0-2 aortic arch pathology underwent supra-aortic debranching on ascending aorta and proximal aortic arch reinforcement with a Dacron prosthesis. Metachronously, the procedure was completed with endovascular stent grafting (ESG). RESULTS: Median age was 70 years with a mean European System for Cardiac Operative Risk Evaluation (EuroSCORE) of 12.7±6.8. One patient died between aortic debranching and ESG. Mean time between surgical debranching and ESG was 32±27.7 days. No major neurological events occurred. Mean length of the landing zone for ESG was 3.8±0.8 cm. Computed tomography (CT) angiography scan performed soon after operation, and at 3, 6, and 12 months did not show any type I endoleak. CONCLUSIONS: Supra-aortic debranching on ascending aorta with proximal aortic arch reinforcement is a useful step to ensure a safe landing zone for ESG, reducing risk early to midterm of endoleak. Longer term follow-up is required to confirm the viability of this technique.

Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma.

Hereditary susceptibility to pheochromocytoma (PCC) and paraganglioma (PGL) represents a very complex genetic scenario. It has been reported that the absence of familial antecedents of the disease does not preclude the existence of a mutation affecting any of the five major susceptibility genes. In fact, 11-24% of apparently sporadic cases (without familial or syndromic antecedents) harbor an unexpected germline mutation, but we do not know what is happening in "truly apparently" sporadic patients (i.e., apparently sporadic cases diagnosed with only one tumor). In the present study, we have analyzed 135 apparently sporadic patients developing a single tumor for the five major susceptibility genes: VHL, RET, SDHB, SDHC, and SDHD. Fourteen percent of cases were found to harbor a germline mutation, and only 2.2% of patients were older than 45 years at onset. By taking into account the tumor location and a threshold age at onset of 45 years, we propose a rational scheme for genetic testing. Analyzing VHL and RET genes would be recommended only in young patients developing a single PCC. On the other hand, genetic testing of SDHD should be done in all patients developing an extra-adrenal tumor before the age of 45, and SDHC could be the responsible gene in cases developing a single head and neck tumor, independently of age. Finally, the analysis of SDHB should always be performed because of its association to malignancy and the low penetrance of mutations affecting this gene.

Should pregnancy be considered a risk factor for aortic dissection? Two cases of acute aortic dissection following cesarean section in non-Marfan nor bicuspid aortic valve patients.

Acute aortic dissection in pregnancy is a rare event and rarer still in healthy young women; however, women with a bicuspid aortic valve or the Marfan syndrome are at a higher risk of dissection. The relationship between pregnancy and aortic dissection is still unclear. We describe the cases of two women with no history of cardiovascular disease who developed an acute aortic type A dissection within a few days after term delivery. Surgical repair was performed with ascending aorta replacement and aortic valve sparing. In both cases, the dissection was diagnosed within a few days following cesarean section done neither because of fetal or maternal distress. To date, only one case of type A and two cases of type B aortic dissection following cesarean section have been reported. Compared with spontaneous delivery, scheduled cesarean section, as in our cases, allows for better control of hemodynamic parameters and should protect against aortic dissection. Postoperative screening for inherent connective tissue disorders detected no mutations within the fibrillin and collagen gene chromosome in either patient. Postoperative recovery was uneventful, and the patients were discharged on postoperative days 7 and 8, respectively.

Molecular characterisation of a common SDHB deletion in paraganglioma patients.

BACKGROUND: Hereditary susceptibility to familial paraganglioma syndromes is mainly due to mutations in one of six genes, including three of the four genes encoding the subunits of the mitochondrial succinate dehydrogenase complex II. Although prevalence, penetrance and clinical characteristics of patients carrying point mutations affecting the genes encoding succinate dehydrogenase have been well studied, little is known regarding these clinical features in patients with gross deletions. Recently, we found two unrelated Spanish families carrying the previously reported SDHB exon 1 deletion, and suggested that this chromosomal region could be a hotspot deletion area. METHODS: We present the molecular characterisation of this apparently prevalent mutation in three new families, and discuss whether this recurrent mutation is due either to the presence of a founder effect or to a hotspot. RESULTS: The breakpoint analysis showed that all Iberian Peninsular families described harbour the same exon 1 deletion, and that a different breakpoint junction segregates in an affected French pedigree. CONCLUSIONS: After haplotyping the SDHB region, we concluded that the deletion detected in Iberian Peninsular people is probably due to a founder effect. Regarding the clinical characteristics of patients with this alteration, it seems that the presence of gross deletions rather than point mutations is more likely related to abdominal presentations and younger age at onset. Moreover, we found for the first time a patient with neuroblastoma and a germline SDHB deletion, but it seems that this paediatric neoplasia in a pheochromocytoma family is not a key component of this disease.