Baylor Research Institute

Posted March 15th 2018

Priapism in a Fabry disease mouse model is associated with upregulated penile nNOS and eNOS expression.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri Ph.D.

Meng, X. L., E. Arning, M. Wight-Carter, T. S. Day, S. Jabbarzadeh-Tabrizi, S. Chen, R. J. Ziegler, T. Bottiglieri, J. W. Schneider, S. H. Cheng, R. Schiffmann and J. S. Shen (2018). “Priapism in a Fabry disease mouse model is associated with upregulated penile nNOS and eNOS expression.” J Inherit Metab Dis 41(2): 231-238.

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Fabry disease is a glycosphingolipidosis caused by deficient activity of alpha-galactosidase A; it is one of a few diseases that are associated with priapism, an abnormal prolonged erection of the penis. The goal of this study was to investigate the pathogenesis of Fabry disease-associated priapism in a mouse model of the disease. We found that Fabry mice develop late-onset priapism. Neuronal nitric oxide synthase (nNOS), which was predominantly present as the 120-kDa N-terminus-truncated form, was significantly upregulated in the penis of 18-month-old Fabry mice compared to wild type controls (~fivefold). Endothelial NOS (eNOS) was also upregulated (~twofold). NO level in penile tissues of Fabry mice was significantly higher than wild type controls at 18 months. Gene transfer-mediated enzyme replacement therapy reversed abnormal nNOS expression in the Fabry mouse penis. The penile nNOS level was restored by antiandrogen treatment, suggesting that hyperactive androgen receptor signaling in Fabry mice may contribute to nNOS upregulation. However, the phosphodiesterase-5A expression level and the adenosine content in the penis, which are known to play roles in the development of priapism in other etiologies, were unchanged in Fabry mice. In conclusion, these data suggested that increased nNOS (and probably eNOS) content and the consequential elevated NO production and high arterial blood flow in the penis may be the underlying mechanism of priapism in Fabry mice. Furthermore, in combination with previous findings, this study suggested that regulation of NOS expression is susceptible to alpha-galactosidase A deficiency, and this may represent a general pathogenic mechanism of Fabry vasculopathy.


Posted February 15th 2018

Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri Ph.D.

Roffman, J. L., L. J. Petruzzi, A. S. Tanner, H. E. Brown, H. Eryilmaz, N. F. Ho, M. Giegold, N. J. Silverstein, T. Bottiglieri, D. S. Manoach, J. W. Smoller, D. C. Henderson and D. C. Goff (2018). “Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial.” Mol Psychiatry 23(2): 316-322.

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Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness. In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials. ClinicalTrials.gov, NCT01091506.


Posted February 15th 2018

Psychometrics of the Self-Report Concise Associated Symptoms Tracking Scale (CAST-SR): Results From the STRIDE (CTN-0037) Study.

Katherine E. Sanchez Ph.D.

Katherine E. Sanchez Ph.D.

Trombello, J. M., M. O. Killian, A. Liao, K. Sanchez, T. L. Greer, R. Walker, B. Grannemann, C. D. Rethorst, T. Carmody and M. H. Trivedi (2018). “Psychometrics of the Self-Report Concise Associated Symptoms Tracking Scale (CAST-SR): Results From the STRIDE (CTN-0037) Study.” J Clin Psychiatry 79(1). Jan 9. [Epub ahead of print].

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OBJECTIVE: The self-report Concise Associated Symptoms Tracking Scale (CAST-SR) was developed to track mania, irritability, anxiety, panic, and insomnia symptoms among depressed outpatients receiving antidepressant medication. Given the overlap between these domains, depression, and stimulant use disorders, we reexamined CAST-SR psychometrics in a novel sample: individuals with stimulant use disorder receiving aerobic exercise or health education interventions. METHODS: Using the subsample of stimulant-dependent (following DSM-IV criteria) individuals prescribed antidepressants (N = 124) from the multisite Stimulant Reduction Intervention Using Dosed Exercise (CTN-0037) trial (total sample N = 302), conducted July 2010 to February 2013, we analyzed CAST-SR data collected at the first assessment after participant’s discharge from residential treatment. We also evaluated the convergent/discriminant validity of the CAST-SR with several self-report questionnaires. RESULTS: Confirmatory factor analysis revealed a 12-item measure composed of 4 factors: irritability, anxiety, panic, and insomnia. This factor structure loaded only in participants prescribed antidepressant medication, not in those who were not prescribed antidepressants. These results replicate the original CAST-SR factor structure, except for the mania factor, which failed to load. Internal consistency was high (alpha = 0.92 for total scale and alpha = 0.78-0.89 for the 4 factors), and convergent validity was established, especially for the insomnia and irritability factors, alongside the total score with depressive symptoms, insomnia, quality of life, suicide risk, and physical health measures. CONCLUSIONS: These results demonstrate the factor structure, reliability, and validity of the CAST-SR in a novel population of only individuals with stimulant use disorders receiving both exercise/health education interventions and antidepressant medication. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01141608.


Posted January 15th 2018

Describing Weight Loss Attempts and Physical Activity Among Individuals With TBI Prior to Participation in a Weight-Loss Program.

Simon Driver Ph.D.

Simon Driver Ph.D.

Driver, S., M. Reynolds, M. Douglas and M. Bennett (2018). “Describing Weight Loss Attempts and Physical Activity Among Individuals With TBI Prior to Participation in a Weight-Loss Program.” J Head Trauma Rehabil 33(1): E36-e43.

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OBJECTIVE: Describe (1) weight loss history, (2) perceptions about lifestyle changes, and (3) physical activity among a sample of individuals with traumatic brain injury prior to a 12-month lifestyle change program. SETTING: Community-based. PARTICIPANTS: Individuals enrolled in a lifestyle change program, 6 months or more post-traumatic brain injury, body mass index of 25 or greater, 18 to 64 years of age, with physician’s clearance to participate. DESIGN: Convenience sample. MAIN MEASURES: Self-report data were collected before beginning the lifestyle change program including descriptive, weight loss history and physical activity behavior using the Modifiable Activity Questionnaire. RESULTS: The final sample included 22 participants (M age = 46 years) injured a median of 8 years ago. Mean weight was 208.5 lb (SD = 40.2), with average body mass index of 31.84 (SD = 4.4). Since injury, 72.7% reported prior weight loss attempts, with 50% gaining 10 lb or more. All participants indicated high motivation for lifestyle changes. Perceived benefits included feeling better, improving overall health, and increased energy. Barriers included physical health complications. Types of physical activity completed included walking (68%, 180 min/mo) and swimming (32%, 79 min/mo). CONCLUSION: Results indicate that many individuals gained weight since injury and attempted weight loss, demonstrating a need for evidence-based lifestyle interventions. Future research is needed to determine whether individuals with traumatic brain injury are able to achieve and maintain weigh loss through intervention.


Posted January 15th 2018

Early Experience With New Transcatheter Mitral Valve Replacement.

Michael J. Mack M.D.

Michael J. Mack M.D.

Bapat, V., V. Rajagopal, C. Meduri, R. S. Farivar, A. Walton, S. J. Duffy, R. Gooley, A. Almeida, M. J. Reardon, N. S. Kleiman, K. Spargias, S. Pattakos, M. K. Ng, M. Wilson, D. H. Adams, M. Leon, M. J. Mack, S. Chenoweth and P. Sorajja (2018). “Early Experience With New Transcatheter Mitral Valve Replacement.” J Am Coll Cardiol 71(1): 12-21.

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BACKGROUND: Transcatheter mitral valve replacement (TMVR) is a potential therapy for patients with symptomatic, severe mitral regurgitation (MR). The feasibility of this therapy remains to be defined. OBJECTIVES: The authors report their early experience with TMVR using a new valve system. METHODS: The valve is a self-expanding, nitinol valve with bovine pericardial leaflets that is placed using a transapical delivery system. Patients with symptomatic MR who were deemed high or extreme risk by the local heart teams were enrolled in a global pilot study at 14 sites (United States, Australia, and Europe). RESULTS: Fifty consecutively enrolled patients (mean age: 73 +/- 9 years; 58.0% men; 84% secondary MR) underwent TMVR with the valve. The mean Society for Thoracic Surgery score was 6.4 +/- 5.5%; 86% of patients were New York Heart Association functional class III or IV, and the mean left ventricular ejection fraction was 43 +/- 12%. Device implant was successful in 48 patients with a median deployment time of 14 min (interquartile range: 12 to 17 min). The 30-day mortality was 14%, with no disabling strokes, or repeat interventions. Median follow-up was 173 days (interquartile range: 54 to 342 days). At latest follow-up, echocardiography confirmed mild or no residual MR in all patients who received implants. Improvements in symptom class (79% in New York Heart Association functional class I or II at follow-up; p < 0.0001 vs. baseline) and Minnesota Heart Failure Questionnaire scores (56.2 +/- 26.8 vs. 31.7 +/- 22.1; p = 0.011) were observed. CONCLUSIONS: TMVR with the valve was feasible in a study group at high or extreme risk for conventional mitral valve replacement. These results inform trial design of TMVR in lower-risk patients with severe mitral valve regurgitation (Evaluation of the Safety and Performance of the Twelve Intrepid Transcatheter Mitral Valve Replacement System in High Risk Patients with Severe, Symptomatic Mitral Regurgitation - The Twelve Intrepid TMVR Pilot Study.