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Rochester, MN, United States

Ramanan V.K.,Indiana University | Kim S.,Indiana University | Holohan K.,Indiana University | Shen L.,Indiana University | And 10 more authors.
Brain Imaging and Behavior | Year: 2012

Memory deficits are prominent features of mild cognitive impairment (MCI) and Alzheimer's disease (AD). The genetic architecture underlying these memory deficits likely involves the combined effects of multiple genetic variants operative within numerous biological pathways. In order to identify functional pathways associated with memory impairment, we performed a pathway enrichment analysis on genome-wide association data from 742 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. A composite measure of memory was generated as the phenotype for this analysis by applying modern psychometric theory to item-level data from the ADNI neuropsychological test battery. Using the GSA-SNP software tool, we identified 27 canonical, expertly-curated pathways with enrichment (FDR-corrected p-value < 0. 05) against this composite memory score. Processes classically understood to be involved in memory consolidation, such as neurotransmitter receptor-mediated calcium signaling and long-term potentiation, were highly represented among the enriched pathways. In addition, pathways related to cell adhesion, neuronal differentiation and guided outgrowth, and glucose- and inflammation-related signaling were also enriched. Among genes that were highly-represented in these enriched pathways, we found indications of coordinated relationships, including one large gene set that is subject to regulation by the SP1 transcription factor, and another set that displays co-localized expression in normal brain tissue along with known AD risk genes. These results 1) demonstrate that psychometrically-derived composite memory scores are an effective phenotype for genetic investigations of memory impairment and 2) highlight the promise of pathway analysis in elucidating key mechanistic targets for future studies and for therapeutic interventions. © 2012 Springer Science+Business Media, LLC.

Shaheen N.J.,University of North Carolina at Chapel Hill | Falk G.W.,University of Pennsylvania | Iyer P.G.,Mayo Clinic Minnesota | Gerson L.B.,University of California at San Francisco
American Journal of Gastroenterology | Year: 2016

Barrett's esophagus (BE) is among the most common conditions encountered by the gastroenterologist. In this document, the American College of Gastroenterology updates its guidance for the best practices in caring for these patients. These guidelines continue to endorse screening of high-risk patients for BE; however, routine screening is limited to men with reflux symptoms and multiple other risk factors. Acknowledging recent data on the low risk of malignant progression in patients with nondysplastic BE, endoscopic surveillance intervals are attenuated in this population; patients with nondysplastic BE should undergo endoscopic surveillance no more frequently than every 3-5 years. Neither routine use of biomarker panels nor advanced endoscopic imaging techniques (beyond high-definition endoscopy) is recommended at this time. Endoscopic ablative therapy is recommended for patients with BE and high-grade dysplasia, as well as T1a esophageal adenocarcinoma. Based on recent level 1 evidence, endoscopic ablative therapy is also recommended for patients with BE and low-grade dysplasia, although endoscopic surveillance continues to be an acceptable alternative. Given the relatively common recurrence of BE after ablation, we suggest postablation endoscopic surveillance intervals. Although many of the recommendations provided are based on weak evidence or expert opinion, this document provides a pragmatic framework for the care of the patient with BE. © 2016 by the American College of Gastroenterology.

Smith N.D.,University of Chicago | Gonzalgo M.L.,Stanford University | Svatek R.S.,University of Texas at San Antonio | Weizer A.Z.,University of Michigan | And 12 more authors.
BJU International | Year: 2015

The purpose of the RAZOR (randomized open vs robotic cystectomy) study is to compare open radical cystectomy (ORC) vs robot-assisted RC (RARC), pelvic lymph node dissection (PLND) and urinary diversion for oncological outcomes, complications and health-related quality of life (HRQL) measures with a primary endpoint of 2-year progression-free survival (PFS). RAZOR is a multi-institutional, randomized, non-inferior, phase III trial that will enrol at least 320 patients with T1-T4, N0-N1, M0 bladder cancer with ≈160 patients in both the RARC and ORC arms at 15 participating institutions. Data will be collected prospectively at each institution for cancer outcomes, complications of surgery and HRQL measures, and then submitted to trial data management services Cancer Research and Biostatistics (CRAB) for final analyses. To date, 306 patients have been randomized and accrual to the RAZOR trial is expected to conclude in 2014. In this study, we report the RAZOR trial experimental design, objectives, data safety, and monitoring, and accrual update. The RAZOR trial is a landmark study in urological oncology, randomizing T1-T4, N0-N1, M0 patients with bladder cancer to ORC vs RARC, PLND and urinary diversion. RAZOR is a multi-institutional, non-inferiority trial evaluating cancer outcomes, surgical complications and HRQL measures of ORC vs RARC with a primary endpoint of 2-year PFS. Full data from the RAZOR trial are not expected until 2016-2017. © 2014 The Authors. BJU International © 2014 BJU International.

Sheehan K.A.,University of Illinois at Chicago | Arteaga G.M.,Mayo Clinic Minnesota | Hinken A.C.,University of Illinois at Chicago | Dias F.A.,University of Illinois at Chicago | And 4 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2011

Familial hypertrophic cardiomyopathy (FHC) is a leading cause of sudden cardiac death among young athletes but the functional effects of the myofilament mutations during FHC-associated ischemia and acidosis, due in part to increased extravascular compressive forces and microvascular dysfunction, are not well characterized. We tested the hypothesis that the FHC-linked tropomyosin (Tm) mutation Tm-E180G alters the contractile response to acidosis via increased myofilament Ca2+ sensitivity. Intact papillary muscles from transgenic (TG) mice expressing Tm-E180G and exposed to acidic conditions (pH 6.9) exhibited a significantly smaller decrease in normalized isometric tension compared to non-transgenic (NTG) preparations. Times to peak tension and to 90% of twitch force relaxation in TG papillary muscles were significantly prolonged. Intact single ventricular TG myocytes demonstrated significantly less inhibition of unloaded shortening during moderate acidosis (pH 7.1) than NTG myocytes. The peak Ca2+ transients were not different for TG or NTG at any pH tested. The time constant of re-lengthening was slower in TG myocytes, but not the rate of Ca2+ decline. TG detergent-extracted fibers demonstrated increased Ca2+ sensitivity of force and maximal tension compared to NTG at both normal and acidic pH (pH 6.5). Tm phosphorylation was not different between TG and NTG muscles at either pH. Our data indicate that acidic pH diminished developed force in hearts of TG mice less than in NTG due to their inherently increased myofilament Ca2+ sensitivity, thus potentially contributing to altered energy demands and increased propensity for contractile dysfunction. © 2010 Elsevier Ltd.

OBJECTIVE:: While reducing pain catastrophizing has been shown to contribute to functional improvement in patients receiving interdisciplinary pain care, little is known about how changes in the different dimensions of pain catastrophizing uniquely contributes to improvement in outcome. The proposed study examined the unique relationship between changes in the three distinct factors of pain catastrophizing - helplessness, rumination, and magnification - and changes in pain outcomes. METHODS:: In this non-randomized study, 641 patients who completed treatment in a three-week interdisciplinary pain rehabilitation program between the years 2013-2014 completed a battery of psychometrically validated measures of pain catastrophizing, pain severity, pain interference, mental and physical-health related quality of life, and depressive symptoms at pre- and post-treatment. RESULTS:: A series of within groups (repeated measures) mediation analyses were conducted. Change in the helplessness, rumination and magnification subscales were entered as multiple mediators in the model. Analyses revealed that change in helplessness partially mediated improvement in all outcome variables beyond the influence of change in other variables in the model, while change in rumination partially mediated improvement in pain severity, interference and depressive symptoms. Change in magnification had the least impact on outcome, partially mediating improvements in only mental health quality of life. DISCUSSION:: Results suggest that changes in the three dimensions of pain catastrophizing differentially mediate improvement in pain outcome. Treatment approaches that specifically target helplessness and rumination may be particularly useful in improving the outcomes of patients with refractory pain conditions enrolled in interdisciplinary pain rehabilitation program. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

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