Baylor Research Institute

Dixon-Ibarra, A., S. Driver, H. VanVolkenburg and K. Humphries (2016). “Formative evaluation on a physical activity health promotion program for the group home setting.” Eval Program Plann 60: 81-90.

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Physical inactivity and high rates of chronic conditions is a public health concern for adults with intellectual disability. Few health promotion programs target the group home setting which is the pre-dominant form of residential accommodation for persons with intellectual disability. A process evaluation of a physical activity health promotion program, Menu-Choice, was conducted with five group home sites for adults with intellectual and developmental disabilities. Menu-Choice assists group home staff in including physical activity goals within resident schedules. The physical activity program was designed based on theoretical frameworks, community-based participatory approaches, and established health promotion guidelines for adults with disabilities. Fourteen program coordinators (age M 39; 77% females), 22 staff (age M 39; 82% females), and 18 residents (age M 59; 72% females; 56% ambulatory) participated. Results from the fidelity survey and program completion highlight potential challenges with implementation. Findings will assist with the refinement of the program for continued implementation trials in the group home community.

Vogel, K. R., E. Arning, T. Bottiglieri and K. M. Gibson (2016). “Multicompartment analysis of protein-restricted phenylketonuric mice reveals amino acid imbalances in brain.” J Inherit Metab Dis: 2016 Oct [Epub ahead of print].

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BACKGROUND: The mainstay of therapy for phenylketonuria (PKU) remains dietary protein restriction. Developmental and neurocognitive outcomes for patients, however, remain suboptimal. We tested the hypothesis that mice with PKU receiving protein-restricted diets would reveal disruptions of brain amino acids that shed light on these neurocognitive deficits. METHOD: Phenylalanine hydroxylase-deficient (PKU) mice and parallel controls (both wild-type and heterozygous) were fed custom diets containing 18, 6, and 4 % protein for 3 weeks, after which tissues (brain, liver, sera) were collected for amino acid analysis profiling. RESULTS: Phenylalanine (phe) was increased in all tissues (p < 0.0001) of PKU mice and improved with protein restriction. In sera, decreased tyrosine (p < 0.01) was corrected (defined as not significantly different from the level in control mice receiving 18 % chow) with protein restriction, whereas protein restriction significantly increased many other amino acids. A similar trend for increased amino acid levels with protein restriction was also observed in liver. In brain, the effects of protein restriction on large neutral amino acids (LNAAs) were variable, with some deficit correction (threonine, methionine, glutamine) and no correction of tyrosine under any dietary paradigm. Protein restriction (4 % diet) in PKU mice significantly decreased lysine, arginine, taurine, glutamate, asparagine, and serine which had been comparable to control mice under 18 % protein intake. CONCLUSION: Depletion of taurine, glutamate, and serine in the brain of PKU mice with dietary protein restriction may provide new insight into neurocognitive deficits of PKU.

Dahdah, M. N., S. Barnes, A. Buros, R. Dubiel, C. Dunklin, L. Callender, C. Harper, A. Wilson, R. Diaz-Arrastia, T. Bergquist, M. Sherer, G. Whiteneck, C. Pretz, R. D. Vanderploeg and S. Shafi (2016). “Variations in inpatient rehabilitation functional outcomes across centers in the traumatic brain injury model systems study and the influence of demographics and injury severity on patient outcomes.” Arch Phys Med Rehabil 97(11): 1821-1831.

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OBJECTIVE: To compare patient functional outcomes across Traumatic Brain Injury Model Systems (TBIMS) rehabilitation centers using an enhanced statistical model and to determine factors that influence those outcomes. DESIGN: Multicenter observational cohort study. SETTING: TBIMS centers. PARTICIPANTS: Patients with traumatic brain injury (TBI) admitted to 19 TBIMS rehabilitation centers from 2003-2012 (N=5505). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional outcomes of patients with TBI. RESULTS: Individuals with lower functional status at the time of admission, longer duration of posttraumatic amnesia, and higher burden of medical comorbidities continued to have worse functional outcomes at discharge from inpatient rehabilitation and at the 1-year follow-up, whereas those who were employed at the time of injury had better outcomes at both time periods. Risk-adjusted patient functional outcomes for patients in most TBIMS centers were consistent with previous research. However, there were wide performance differences for a few centers even after using more recently collected data, improving on the regression models by adding predictors known to influence functional outcomes, and using bootstrapping to eliminate confounds. CONCLUSIONS: Specific patient, injury, and clinical factors are associated with differences in functional outcomes within and across TBIMS rehabilitation centers. However, these factors did not explain all the variance in patient outcomes, suggesting a role of some other predictors that remain unknown.

Zhong, X. Z., X. Sun, Q. Cao, G. Dong, R. Schiffmann and X. P. Dong (2016). “Bk channel agonist represents a potential therapeutic approach for lysosomal storage diseases.” Sci Rep 16(1): 503.

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Efficient lysosomal Ca2+ release plays an essential role in lysosomal trafficking. We have recently shown that lysosomal big conductance Ca2+-activated potassium (BK) channel forms a physical and functional coupling with the lysosomal Ca2+ release channel Transient Receptor Potential Mucolipin-1 (TRPML1). BK and TRPML1 forms a positive feedback loop to facilitate lysosomal Ca2+ release and subsequent lysosome membrane trafficking. However, it is unclear whether the positive feedback mechanism is common for other lysosomal storage diseases (LSDs) and whether BK channel agonists rescue abnormal lysosomal storage in LSDs. In this study, we assessed the effect of BK agonist, NS1619 and NS11021 in a number of LSDs including NPC1, mild cases of mucolipidosis type IV (ML4) (TRPML1-F408), Niemann-Pick type A (NPA) and Fabry disease. We found that TRPML1-mediated Ca2+ release was compromised in these LSDs. BK activation corrected the impaired Ca2+ release in these LSDs and successfully rescued the abnormal lysosomal storage of these diseases by promoting TRPML1-mediated lysosomal exocytosis. Our study suggests that BK channel activation stimulates the TRPML1-BK positive reinforcing loop to correct abnormal lysosomal storage in LSDs. Drugs targeting BK channel represent a potential therapeutic approach for LSDs.

Benjamin, E. R., M. C. Della Valle, X. Wu, E. Katz, F. Pruthi, S. Bond, B. Bronfin, H. Williams, J. Yu, D. G. Bichet, D. P. Germain, R. Giugliani, D. Hughes, R. Schiffmann, W. R. Wilcox, R. J. Desnick, J. Kirk, J. Barth, C. Barlow, K. J. Valenzano, J. Castelli and D. J. Lockhart (2016). “The validation of pharmacogenetics for the identification of fabry patients to be treated with migalastat.” Genet Med: 2016 Sep [Epub ahead of print].

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PURPOSE: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of alpha-galactosidase A to restore lysosomal activity. METHODS: A pharmacogenetic assay was used to identify the alpha-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in alpha-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies. RESULTS: Comparison of the GLP HEK assay results in in vivo white blood cell alpha-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (>/=0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay. CONCLUSION: The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.