Baylor Research Institute

Kevelam, S. H., M. E. Steenweg, S. Srivastava, G. Helman, S. Naidu, R. Schiffmann, S. Blaser, A. Vanderver, N. I. Wolf and M. S. van der Knaap (2016). “Update on leukodystrophies: A historical perspective and adapted definition.” Neuropediatrics 47(6): 349-354.

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Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.

Trammell, M., P. Kapoor, C. Swank and S. Driver (2017). “Improving practice with integration of patient directed activity during inpatient rehabilitation.” Clin Rehabil 31(1): 3-10.

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BACKGROUND: Early initiation of rehabilitation following stroke promotes better long-term outcomes than delayed onset, emphasizing the importance of inpatient therapy. However, literature indicates that following stroke individuals in inpatient rehabilitation spend the majority of their day in their bedroom and inactive. Consequently, since amount of functional activity is posited to relate to outcomes, the current rehabilitation model needs to be challenged with innovative solutions to maximize recovery. RATIONALE: In an attempt to promote greater activity and higher doses of therapy during inpatient rehabilitation, we implemented the “Patient Directed Activity Program” to facilitate specific movement and improve outcomes for patients post stroke. Our interdisciplinary activity program was conceptualized on a theoretical model for stroke recovery and principles of experience-dependent neural plasticity. MAIN FEATURES: The “Patient Directed Activity Program” includes distinct activity stations designed to increase repetition, stimulation, attention, and activity of the affected upper extremities, lower extremities, and trunk. Each task-specific activity was easily graded to achieve moderate- to high-intensity. The activity program prescribed individuals up to three additional 30-minute bouts of activities daily that were to be completed independently, and in addition to standard of care. Clinical application: After implementing this program in our facility for one year as a quality improvement project, the intervention has been delivered as an Institutional Review Board approved randomized controlled trial (Clinical Trial #NCT02446197). Challenges with people and facilities have been overcome, resulting in a feasible program that can be delivered in an inpatient setting. High satisfaction has been reported by patients and clinicians.

Vasudevan, A., T. Bottiglieri, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, C. E. Velasco, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and P. A. McCullough (2016). “Residual thromboxane activity and oxidative stress: Influence on mortality in patients with stable coronary artery disease.” Coron Artery Dis: 2016 Dec [Epub ahead of print].

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BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2alpha (8-IsoPGF2alpha)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2alpha in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2alpha. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2alpha were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2alpha below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2alphaadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2alphaadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2alpha, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin.

Chen, S. and P. A. Grayburn (2017). “Ultrasound-targeted microbubble destruction for cardiac gene delivery.” Methods Mol Biol 1521: 205-218.

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Ultrasound targeted microbubble destruction (UTMD) is a novel technique that is used to deliver a gene or other bioactive substance to organs of living animals in a noninvasive manner. Plasmid DNA binding with cationic liposome into nanoparticles are assembled into the shell of microbubbles, which are circulated by intravenous injection. Intermittent bursts of ultrasound with low frequency and high mechanical index destroys the microbubbles and releases the nanoparticles into targeted organ to transfect local organ cells. Cell-specific promoters can be used to further enhance cell specificity. Here we describe UTMD applied to cardiac gene delivery.

Chen, Y. B., T. Wang, M. T. Hemmer, C. Brady, D. R. Couriel, A. Alousi, J. Pidala, A. Urbano-Ispizua, S. W. Choi, T. Nishihori, T. Teshima, Y. Inamoto, B. Wirk, D. I. Marks, H. Abdel-Azim, L. Lehmann, L. Yu, M. Bitan, M. S. Cairo, M. Qayed, R. Salit, R. P. Gale, R. Martino, S. Jaglowski, A. Bajel, B. Savani, H. Frangoul, I. D. Lewis, J. Storek, M. Askar, M. A. Kharfan-Dabaja, M. Aljurf, O. Ringden, R. Reshef, R. F. Olsson, S. Hashmi, S. Seo, T. R. Spitzer, M. L. MacMillan, A. Lazaryan, S. R. Spellman, M. Arora and C. S. Cutler (2016). “Gvhd after umbilical cord blood transplantation for acute leukemia: An analysis of risk factors and effect on outcomes.” Bone Marrow Transplant: 2016 Dec [Epub ahead of print].

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Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.