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Agarwal S.,Brigham and Womens Hospital | Loh Y.-H.,Brigham and Womens Hospital | McLoughlin E.M.,Brigham and Womens Hospital | Huang J.,University of South Florida | And 15 more authors.
Nature | Year: 2010

Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues. Patient-specific induced pluripotent stem (iPS) cells represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT). We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3′ deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients. © 2010 Macmillan Publishers Limited. All rights reserved. Source

Tanner S.M.,University of Alabama at Birmingham | Berryhill T.F.,University of Alabama at Birmingham | Ellenburg J.L.,University of Alabama at Birmingham | Jilling T.,University of Alabama at Birmingham | And 3 more authors.
American Journal of Pathology | Year: 2015

Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants. The pathophysiology is likely secondary to innate immune responses to intestinal microbiota by the premature infant's intestinal tract, leading to inflammation and injury. This review provides an updated summary of the components of the innate immune system involved in NEC pathogenesis. In addition, we evaluate the animal models that have been used to study NEC with regard to the involvement of innate immune factors and histopathological changes as compared to those seen in infants with NEC. Finally, we discuss new approaches to studying NEC, including mathematical models of intestinal injury and the use of humanized mice. © 2015 American Society for Investigative Pathology Published by Elsevier Inc. All rights reserved. Source

Vetter T.R.,University of Alabama at Birmingham | Bridgewater C.L.,Childrens Hospital of Alabama | McGwin Jr G.,University of Alabama at Birmingham
Health and Quality of Life Outcomes | Year: 2012

Background: Previous pediatric studies have observed a cross-informant variance in patient self-reported health-related quality of life (HRQoL) versus parent proxy-reported HRQoL. This study assessed in older children and adolescents with a variety of chronic pain conditions: 1) the consistency and agreement between pediatric patients' self-report and their parents' proxy-report of their child's HRQoL; 2) whether this patient-parent agreement is dependent on additional demographic and clinical factors; and 3) the relationship between pediatric patient HRQoL and parental reported HRQoL.Methods: The 99 enrolled patients (mean age 13.2 years, 71% female, 81% Caucasian) and an accompanying parent completed the PedsQLTM 4.0 and 36-Item Short-Form Health Survey Version 2 (SF-36v2) at the time of their initial appointment in a pediatric chronic pain medicine clinic. Patients' and parents' total, physical, and psychosocial HRQoL scores were analyzed via an intra-class correlation coefficient, Spearman's correlation coefficient, Wilcoxon signed rank test, and Bland-Altman plot. A multivariable linear regression model was used to evaluate the association between clinical and demographic variables and the difference in patient and proxy scores for the Total Scale Score on the PedsQL™.Results: With the exception of the psychosocial health domain, there were no statistically significant differences between pediatric patients' self-report and their parents' proxy-report of their child's HRQoL. However, clinically significant patient-parent variation in pediatric HRQoL was observed. Differences in patient-parent proxy PedsQL™ Total Scale Score Scores were not significantly associated with patient age, gender, race, intensity and duration of patient's pain, household income, parental marital status, and the parent's own HRQoL on the SF-36v2. No significant relationship existed among patients' self-reported HRQoL (PedsQL™), parental proxy-reports of the child's HRQoL, and parents' own self-reported HRQoL on the SF-36v2.Conclusions: We observed clinically significant variation between pediatric chronic pain patients' self-reports and their parents' proxy-reports of their child's HRQoL. While whenever possible the pediatric chronic pain patient's own perspective should be directly solicited, equal attention and merit should be given to the parent's proxy-report of HRQoL. To do otherwise will obviate the opportunity to use any discordance as the basis for a therapeutic discussion about the contributing dynamic with in parent-child dyad. © 2012 Vetter et al.; licensee BioMed Central Ltd. Source

Shenai M.B.,University of Alabama at Birmingham | Tubbs R.S.,Childrens Hospital of Alabama | Guthrie B.L.,University of Alabama at Birmingham | Cohen-Gadol A.A.,Indiana University
Journal of Neurosurgery | Year: 2014

Object. The shortage of surgeons compels the development of novel technologies that geographically extend the capabilities of individual surgeons and enhance surgical skills. The authors have developed "Virtual Interactive Presence" (VIP), a platform that allows remote participants to simultaneously view each other's visual field, creating a shared field of view for real-time surgical telecollaboration. Methods. The authors demonstrate the capability of VIP to facilitate long-distance telecollaboration during cadaveric dissection. Virtual Interactive Presence consists of local and remote workstations with integrated video capture devices and video displays. Each workstation mutually connects via commercial teleconferencing devices, allowing worldwide point-to-point communication. Software composites the local and remote video feeds, displaying a hybrid perspective to each participant. For demonstration, local and remote VIP stations were situated in Indianapolis, Indiana, and Birmingham, Alabama, respectively. A suboccipital craniotomy and microsurgical dissection of the pineal region was performed in a cadaveric specimen using VIP. Task and system performance were subjectively evaluated, while additional video analysis was used for objective assessment of delay and resolution. Results. Participants at both stations were able to visually and verbally interact while identifying anatomical structures, guiding surgical maneuvers, and discussing overall surgical strategy. Video analysis of 3 separate video clips yielded a mean compositing delay of 760 ± 606 msec (when compared with the audio signal). Image resolution was adequate to visualize complex intracranial anatomy and provide interactive guidance. Conclusions. Virtual Interactive Presence is a feasible paradigm for real-time, long-distance surgical telecollaboration. Delay, resolution, scaling, and registration are parameters that require further optimization, but are within the realm of current technology. The paradigm potentially enables remotely located experts to mentor less experienced personnel located at the surgical site with applications in surgical training programs, remote proctoring for proficiency, and expert support for rural settings and across different counties. ©AANS, 2014. Source

Becker M.L.,Section of Rheumatology | Rose C.D.,DuPont Company | Cron R.Q.,Childrens Hospital of Alabama | Sherry D.D.,Childrens Hospital of Philadelphia | And 2 more authors.
Journal of Rheumatology | Year: 2010

Objective. To compare the incidence of liver toxicity and clinical response between 2 initial dosing regimens of methotrexate (MTX) for treatment of juvenile idiopathic arthritis (JIA). Methods. Clinical and laboratory data were abstracted from the medical records of 220 children newly prescribed MTX from the same geographic region. One cohort received initial doses of MTX > 0.5 mg/kg/week ("high-dose") and one cohort received initial doses of MTX ≤ 0.5 mg/kg/week ("low-dose"). Toxicity was defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) above the normal range, and positive clinical response was defined as a reduction in active joint count during the first 6 months of MTX therapy. Results. One hundred twenty-six children were in the high-dose MTX group, 94 in the low-dose MTX group. At 6 months, the high-dose group was more likely to have an elevated AST or ALT (adjusted OR 3.89, 95% CI 1.82-.29, p < 0.0001). Subjects receiving both MTX and nonsteroidal antiinflammatory drugs (NSAID) had no significant difference between groups in change of active joint count, while subjects in the high-dose group but not taking NSAID had more active joints (p = 0.036) at 6 months compared to the low-dose group. Conclusion. Initial high-dose MTX was associated with an increased risk of at least one liver enzyme abnormality with no significant improvement in active joint count. This suggests that there is no apparent benefit, while the potential for liver toxicity is increased, when using higher doses of MTX at treatment inception in patients with JIA. The Journal of Rheumatology Copyright © 2010. All rights reserved. Source

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