eNOS transfection of adipose-derived stem cells yields bioactive nitric oxide production and improved results in vascular tissue engineering.

This study evaluates the durability of a novel tissue engineered blood vessel (TEBV) created by seeding a natural vascular tissue scaffold (decellularized human saphenous vein allograft) with autologous adipose-derived stem cells (ASC) differentiated into endothelial-like cells. Previous work with this model revealed the graft to be thrombogenic, likely due to inadequate endothelial differentiation as evidenced by minimal production of nitric oxide (NO). To evaluate the importance of NO expression by the seeded cells, we created TEBV using autologous ASC transfected with the endothelial nitric oxide synthase (eNOS) gene to produce NO. We found that transfected ASC produced NO at levels similar to endothelial cell (EC) controls in vitro which was capable of causing vasorelaxation of aortic specimens ex vivo. TEBV (n = 5) created with NO-producing ASC and implanted as interposition grafts within the aorta of rabbits remained patent for two months and demonstrated a non-thrombogenic surface compared to unseeded controls (n = 5). Despite the xenograft nature of the scaffold, the TEBV structure remained well preserved in seeded grafts. In sum, this study demonstrates that upregulation of NO expression within adult stem cells differentiated towards an endothelial-like lineage imparts a non-thrombogenic phenotype and highlights the importance of NO production by cells to be used as endothelial cell substitutes in vascular tissue engineering applications

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Bipolar Transurethral Incision of Bladder Neck Stenoses with Mitomycin C Injection

Introduction. To determine the efficacy of bipolar transurethral incision with mitomycin C (MMC) injection for the treatment of refractory bladder neck stenosis (BNS). Materials and Methods. Patients who underwent bipolar transurethral incision of BNS (TUIBNS) with MMC injection at our institution from 2013 to 2014 were retrospectively reviewed. A total of 2 mg of 40% mitomycin C solution was injected in four quadrants of the treated BNS. Treatment failure was defined as the need for subsequent intervention. Results. Thirteen patients underwent 17 bipolar TUIBNS with MMC injection. Twelve (92%) patients had failed a mean of 2.2 ± 1.1 prior endoscopic procedures. Median follow-up was 16.5 months (IQR: 14–18.4 months). Initial success was 62%; five (38%) patients had a recurrence with a median time to recurrence of 7.3 months. Four patients underwent a repeat procedure, 2 (50%) of which failed. Overall success was achieved in 77% (10/13) of patients after a mean of 1.3 ± 0.5 procedures. BNS recurrence was not significantly associated with history of pelvic radiation (33% versus 43%, p=0.9). There were no serious adverse events. Conclusions. Bipolar TUIBNS with MMC injection was comparable in efficacy to previously reported techniques and did not result in any serious adverse events

Segmental testicular infarction due to minocycline-induced antineutrophil cytoplasmic antibody-positive vasculitis

Segmental testicular infarction is an uncommon clinical entity marked by acute scrotal pain and swelling. Classically, these appear as wedge-shaped, avascular, hypoechoic lesions on a testicular ultrasound. We present a unique case of testicular infarct caused by an antineutrophil cytoplasmic antibody-positive vasculitis secondary to the use of the antibiotic minocycline. The patient\u27s symptoms resolved with cessation of minocycline. We suggest that patients who present with otherwise unexplained testicular infarction undergo a careful review of medications to uncover a potential cause. © 2014 Elsevier Inc

Clinical Study Bipolar Transurethral Incision of Bladder Neck Stenoses with Mitomycin C Injection

Introduction. To determine the efficacy of bipolar transurethral incision with mitomycin C (MMC) injection for the treatment of refractory bladder neck stenosis (BNS). Materials and Methods. Patients who underwent bipolar transurethral incision of BNS (TUIBNS) with MMC injection at our institution from 2013 to 2014 were retrospectively reviewed. A total of 2 mg of 40% mitomycin C solution was injected in four quadrants of the treated BNS. Treatment failure was defined as the need for subsequent intervention. Results. Thirteen patients underwent 17 bipolar TUIBNS with MMC injection. Twelve (92%) patients had failed a mean of 2.2 ± 1.1 prior endoscopic procedures. Median follow-up was 16.5 months (IQR: 14-18.4 months). Initial success was 62%; five (38%) patients had a recurrence with a median time to recurrence of 7.3 months. Four patients underwent a repeat procedure, 2 (50%) of which failed. Overall success was achieved in 77% (10/13) of patients after a mean of 1.3 ± 0.5 procedures. BNS recurrence was not significantly associated with history of pelvic radiation (33% versus 43%, = 0.9). There were no serious adverse events. Conclusions. Bipolar TUIBNS with MMC injection was comparable in efficacy to previously reported techniques and did not result in any serious adverse events

The Role of Interferon in the Management of BCG Refractory Nonmuscle Invasive Bladder Cancer

Background. Thirty to forty percent of patients with high grade nonmuscle invasive bladder cancer (NMIBC) fail to respond to intravesical therapy with bacillus Calmette-Guerin (BCG). Interferon-α2B plus BCG has been shown to be effective in a subset of patients with NMIBC BCG refractory disease. Here we present a contemporary series on the effectiveness and safety of intravesical BCG plus interferon-α2B therapy in patients with BCG refractory NMIBC. Methods. From January of 2005 to April of 2014 we retrospectively found 44 patients who underwent induction with combination IFN/BCG for the management of BCG refractory NMIBC. A chart review was performed to assess initial pathological stage/grade, pathological stage/grade at the time of induction, time to IFN/BCG failure, pathological stage/grade at failure, postfailure therapy, and current disease state. Results. Of the 44 patients who met criteria for the analysis. High risk disease was found in 88.6% of patients at induction. The 12-month and 24-month recurrence-free survival were 38.6% and 18.2%, respectively. 25 (56.8%) ultimately had disease recurrence. Radical cystectomy was performed in 16 (36.4%) patients. Conclusion. Combination BCG plus interferon-α2B remains a reasonably safe alternative treatment for select patients with BCG refractory disease prior to proceeding to radical cystectomy

Research and Evaluation in a Child-Focused Place-Based Initiative: West Philly Promise Neighborhood

Place-based initiatives attempt to reduce persistent health inequities through multisectoral, cross-system collaborations incorporating multiple interventions targeted at varying levels from individuals to systems. Evaluations of these initiatives may be thought of as part of the community change process itself with a focus on real-time learning and accountability. We described the design, implementation, challenges, and initial results of an evaluation of the West Philly Promise Neighborhood, which is a comprehensive, child-focused place-based initiative in Philadelphia, Pennsylvania. Priorities for the evaluation were to build processes for and a culture of ongoing data collection, monitoring, and communication, with a focus on transparency, accountability, and data democratization; establish systems to collect data at multiple levels, with a focus on multiple uses of the data and future sustainability; and adhere to grant requirements on data collection and reporting. Data collection activities included the compilation of neighborhood-level indicators; the implementation of a program-tracking system; administrative data linkage; and neighborhood, school, and organizational surveys. Baseline results pointed to existing strengths in the neighborhood, such as the overwhelming majority of caregivers reporting that they read to their young children (86.9%), while other indicators showed areas of need for additional supports and were programmatic focuses for the initiative (e.g., about one-quarter of young children were not engaged in an early childhood education setting). Results were communicated in multiple formats. Challenges included aligning timelines, the measurement of relationship-building and other process-focused outcomes, data and technology limitations, and administrative and legal barriers. Evaluation approaches and funding models that acknowledge the importance of capacity-building processes and allow the development and measurement of population-level outcomes in a realistic timeframe are critical for measuring the success of place-based approaches

Effect of atrial fibrillation on atrial thrombogenesis in humans: Impact of rate and rhythm

OBJECTIVES We sought to assess the effect of atrial fibrillation (AF) on atrial thrombogenesis in humans by determining the impact of rate and rhythm. BACKGROUND Although AF is known to increase the risk of thromboembolic stroke from the left atrium (LA), the exact mechanisms remain poorly understood. METHODS We studied 55 patients with AF who underwent catheter ablation while in sinus rhythm; 20 patients were induced into AF, 20 patients were atrial paced at 150 beats/min, and 15 were control patients. Blood samples were taken from the LA, right atrium, and femoral vein at baseline and at 15 min in all 3 groups. Platelet activation (P-selectin) was measured by flow cytometry. Thrombin generation (thrombin-antithrombin [TAT] complex), endothelial dysfunction (asymmetric dimethylarginine [ADMA]), and platelet-derived inflammation (soluble CD40 ligand [sCD40L]) were measured using enzyme-linked immunosorbent assay. RESULTS Platelet activation increased significantly in both the AF (p < 0.001) and pacing (p < 0.05) groups, but decreased in control patients (p < 0.001). Thrombin generation increased specifically in the LA compared with the periphery in both the AF (p < 0.01) and pacing (p < 0.01) groups, but decreased in control patients (p < 0.001). With AF, ADMA (p < 0.01) and sCD40L (p < 0.001) levels increased significantly at all sites, but were unchanged with pacing (ADMA, p = 0.5; sCD40L, p = 0.8) or in control patients (ADMA, p = 0.6; sCD40L, p = 0.9). CONCLUSIONS Rapid atrial rates and AF in humans both result in increased platelet activation and thrombin generation. Prothrombotic activation occurs to a greater extent in the human LA compared with systemic circulation. AF additionally induces endothelial dysfunction and inflammation. These findings suggest that although rapid atrial rates increase the thrombogenic risk, AF may further potentiate this risk.Han S. Lim, Scott R. Willoughby, Carlee Schultz, Cheryl Gan, Muayad Alasady, Dennis H. Lau, Darryl P. Leong, Anthony G. Brooks, Glenn D. Young, Peter M. Kistler, Jonathan M. Kalman, Matthew I. Worthley, Prashanthan Sander