Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis.

BACKGROUND: Retinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression. Previous work indicated that Rbbp4 cooperates with the Rb tumor suppressor to block cell cycle entry. Here, we use genetic analysis to examine the interactions of Rbbp4, Rb, and Tp53 in zebrafish neural progenitor cell cycle regulation and survival. RESULTS: Rbbp4 is upregulated across the spectrum of human embryonal and glial brain cancers. Transgenic rescue of rbbp4 mutant embryos shows Rbbp4 is essential for zebrafish neurogenesis. Rbbp4 loss leads to apoptosis and γ-H2AX in the developing brain that is suppressed by tp53 knockdown or maternal zygotic deletion. Mutant retinal neural precursors accumulate in M phase and fail to initiate G0 gene expression. rbbp4; rb1 mutants show an additive effect on the number of M phase cells. In rbbp4 mutants, Tp53 acetylation is detected; however, Rbbp4 overexpression did not rescue DNA damage-induced apoptosis. CONCLUSION: Rbbp4 is necessary for neural progenitor cell cycle progression and initiation of G0 independent of Rb. Tp53-dependent apoptosis in the absence of Rbpb4 correlates with Tp53 acetylation. Together these results suggest that Rbbp4 is required for cell cycle exit and contributes to neural progenitor survival through the regulation of Tp53 acetylation.

Ferumoxytol-enhanced MRI for surveillance of pediatric cerebral arteriovenous malformations.

OBJECTIVE: Children with intracranial arteriovenous malformations (AVMs) undergo digital DSA for lesion surveillance following their initial diagnosis. However, DSA carries risks of radiation exposure, particularly for the growing pediatric brain and over lifetime. The authors evaluated whether MRI enhanced with a blood pool ferumoxytol (Fe) contrast agent (Fe-MRI) can be used for surveillance of residual or recurrent AVMs. METHODS: A retrospective cohort was assembled of children with an established AVM diagnosis who underwent surveillance by both DSA and 3-T Fe-MRI from 2014 to 2016. Two neuroradiologists blinded to the DSA results independently assessed Fe-enhanced T1-weighted spoiled gradient recalled acquisition in steady state (Fe-SPGR) scans and, if available, arterial spin labeling (ASL) perfusion scans for residual or recurrent AVMs. Diagnostic confidence was examined using a Likert scale. Sensitivity, specificity, and intermodality reliability were determined using DSA studies as the gold standard. Radiation exposure related to DSA was calculated as total dose area product (TDAP) and effective dose. RESULTS: Fifteen patients were included in this study (mean age 10 years, range 3-15 years). The mean time between the first surveillance DSA and Fe-MRI studies was 17 days (SD 47). Intermodality agreement was excellent between Fe-SPGR and DSA (κ = 1.00) but poor between ASL and DSA (κ = 0.53; 95% CI 0.18-0.89). The sensitivity and specificity for detecting residual AVMs using Fe-SPGR were 100% and 100%, and using ASL they were 72% and 100%, respectively. Radiologists reported overall high diagnostic confidence using Fe-SPGR. On average, patients received two surveillance DSA studies over the study period, which on average equated to a TDAP of 117.2 Gy×cm2 (95% CI 77.2-157.4 Gy×cm2) and an effective dose of 7.8 mSv (95% CI 4.4-8.8 mSv). CONCLUSIONS: Fe-MRI performed similarly to DSA for the surveillance of residual AVMs. Future multicenter studies could further investigate the efficacy of Fe-MRI as a noninvasive alternative to DSA for monitoring AVMs in children.

How Therapists Use Visualizations of Upper Limb Movement Information From Stroke Patients: A Qualitative Study With Simulated Information.

BACKGROUND: Stroke is a leading cause of disability worldwide, with upper limb deficits affecting an estimated 30% to 60% of survivors. The effectiveness of upper limb rehabilitation relies on numerous factors, particularly patient compliance to home programs and exercises set by therapists. However, therapists lack objective information about their patients' adherence to rehabilitation exercises as well as other uses of the affected arm and hand in everyday life outside the clinic. We developed a system that consists of wearable sensor technology to monitor a patient's arm movement and a Web-based dashboard to visualize this information for therapists. OBJECTIVE: The aim of our study was to evaluate how therapists use upper limb movement information visualized on a dashboard to support the rehabilitation process. METHODS: An interactive dashboard prototype with simulated movement information was created and evaluated through a user-centered design process with therapists (N=8) at a rehabilitation clinic. Data were collected through observations of therapists interacting with an interactive dashboard prototype, think-aloud data, and interviews. Data were analyzed qualitatively through thematic analysis. RESULTS: Therapists use visualizations of upper limb information in the following ways: (1) to obtain objective data of patients' activity levels, exercise, and neglect outside the clinic, (2) to engage patients in the rehabilitation process through education, motivation, and discussion of experiences with activities of daily living, and (3) to engage with other clinicians and researchers based on objective data. A major limitation is the lack of contextual data, which is needed by therapists to discern how movement data visualized on the dashboard relate to activities of daily living. CONCLUSIONS: Upper limb information captured through wearable devices provides novel insights for therapists and helps to engage patients and other clinicians in therapy. Consideration needs to be given to the collection and visualization of contextual information to provide meaningful insights into patient engagement in activities of daily living. These findings open the door for further work to develop a fully functioning system and to trial it with patients and clinicians during therapy.