Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1

Angioplasty and stenting is the primary treatment for flow-limiting atherosclerosis; however, this strategy is limited by pathological vascular remodeling. Using a systems approach, we identified a role for the network hub gene glutathione peroxidase-1 (GPX1) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Gpx1 in atherosclerotic mice recapitulated this phenotype of increased vascular smooth muscle cell (VSMC) proliferation and plaque formation. In an independent patient cohort, gene variant pair analysis identified an interaction of GPX1 with the orphan protooncogene receptor tyrosine kinase ROS1. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS1 variant with pathological remodeling. Decreased GPX1 expression in atherosclerotic mice led to reductive stress via a time-dependent increase in glutathione, corresponding to phosphorylation of the ROS1 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving ROS1 activity via s-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2. ROS1 inhibition with crizotinib and deglutathiolation of SHP-2 abolished GPX1-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido-reductive stress promote ROS1 activation and mediate vascular remodeling.     

Valve-in-Valve-in-Valve Transcatheter Aortic Valve Implantation to Treat a Degenerated Surgical Bioprosthesis in a Subaortic Position

Transcatheter aortic valve implantation for aortic stenosis has evolved as an alternative treatment for patients who are at high or excessive surgical risk. We report the case of an 84-year-old man with a degenerated surgically implanted valve in a subaortic position (9 mm below the native annulus) who underwent “valve-in-valve” transcatheter aortic valve implantation with use of a Medtronic CoreValve system. We planned to deploy the CoreValve at a conventional depth in the left ventricular outflow tract; we realized that this might result in paravalvular regurgitation, but it would also afford a “deep” landing site for a second valve, if necessary. Ultimately, we implanted a second CoreValve deep in the left ventricular outflow tract to seal a paravalvular leak. The frame of the first valve—positioned at the conventional depth—enabled secure anchoring of the second valve in a deeper position, which in turn effected successful treatment of the failing subaortic surgical prosthesis without paravalvular regurgitation.Key words: Aortic valve insufficiency/surgery, bioprosthesis, heart valve prosthesis implantation/instrumentation/methods, intention-to-treat analysis, reoperation/methods, risk assessment, treatment outcomeTranscatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement for the treatment of aortic stenosis in patients who are at high or excessive operative risk.¹ It has been shown that implanting a transcatheter valve within a failing surgical valve (“valve-in-valve”) is safe and effective.² However, the feasibility of this intervention for failing valves in subaortic position has not been reported. The implantation of a self-expandable transcatheter valve at a deep level in the left ventricular outflow tract (LVOT) (with inflow portion >8 mm below the noncoronary cusp) could expectedly be associated with an increased risk of paravalvular regurgitation, valve dislodgment, or both, because of insecure anchoring of the prosthesis in the lower anatomic structures of the LVOT.³ We report the case of a patient in whom we implanted 2 CoreValve® devices (Medtronic, Inc.; Minneapolis, Minn), to safely replace a failing surgical bioprosthesis in a subaortic position.     

Neurophysiological Attributes of the Hypnotic State and the Utility of Hypnosis in Pediatric Medicine and Burn Care

Three articles of special interest to the hypnosis community recently appeared in the general scientific and medical literatures. The first paper is a thoughtful review of the clinical applications of hypnosis in pediatric settings. The second article reports the findings of a randomized, controlled trial of hypnosis for burn-wound care, carried out at the University of Washington Medical School. The third article describes an innovative EEG laboratory case study tracking the cortex functional connectivity of a highly hypnotizable subject across various baseline and experimental conditions. These three articles are sturdy examples of how hypnosis illuminates (and is illuminated by) medical and psychological science.     

Culturally Sensitive OCD Research: Lessons from the U.S.-Mexico Border

This paper explores culturally-related concerns that arose during a multi-year study of obsessive-compulsive disorder (OCD) along the U.S.-Mexico border and describes adaptations made to better connect the research process to study participants. The purpose of this exploration is two-fold: (1) to offer suggestions for culturally sensitive borderland mental health research; and (2) to enhance dialog focused on culture, mental health research and the U.S.-Mexico border. Systematic coding of the written record of weekly research team meetings identified six recurring cultural concerns: emotionally charged and poorly understood terminology; differing meanings of ethnicity and acculturation; quality of life—regional variation and uncertainty; overlap of research and care; hopeful but hesitant; and fatalism. We conclude that diligence in the initial planning phase of a study is only part of the challenge in doing culturally sensitive research. Equally important is an ongoing process of evaluation to make explicit cultural concerns that arise during research, as well as a readiness to implement culturally sensitive research adaptations.     

SEOM clinical guideline in nasopharynx cancer (2017)

Nasopharyngeal carcinoma (NPC) is distinct from other cancers of the head and neck in biology, epidemiology, histology, natural history, and response to treatment. Radiation therapy is an essential component of curative-intent of non-disseminated disease and the association of chemotherapy improves the rates of survival. In the case of metastatic disease stages, treatment requires platinum/gemcitabine-based chemotherapy and patients may achieve a long survival time.