Middle cerebral artery velocity dynamic response profile during exercise is attenuated following multiple ischemic strokes: A case report

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Blood flow regulation is impaired in people with stroke. However, the time course of change in middle cerebral artery velocity (MCAv) following repeated stroke at rest and during exercise remains unknown. In this case study, we provide novel characterization of the dynamic kinetic MCAv response profile to moderate‐intensity exercise before and after repeated ischemic MCA stroke. The initial stroke occurred in the left MCA. At 3 months poststroke, left MCAv amplitude (Amp) was ~50% lower than the right. At the 6‐month follow‐up visit, MCAv Amp declined in both MCA with the left MCAv Amp ~50% lower than the right MCAv Amp. Following a second right MCA stroke, we report further decline in Amp for the left MCA. At the 3‐ and 6‐month visit following the second stroke, the left MCAv Amp declined further (~10%). The right MCAv Amp dramatically decreased by 81.3% when compared to the initial study visit. The MCAv kinetic analysis revealed a marked impairment in the cerebrovascular response to exercise following stroke. We discuss potential pathophysiological mechanisms contributing to poststroke cerebrovascular dysfunction and the need to test therapeutic interventions (such as exercise) that might attenuate cerebrovascular decline in people following stroke.Eunice Kennedy Shriver National Institute of Child Health and Human Development (K01HD067318)CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366)CTSA Award # UL1TR000001 from NCRR and NCATSGeorgia Holland Endowment Fun

Dual Functions of ASCIZ in the DNA Base Damage Response and Pulmonary Organogenesis

Zn2+-finger proteins comprise one of the largest protein superfamilies with diverse biological functions. The ATM substrate Chk2-interacting Zn2+-finger protein (ASCIZ; also known as ATMIN and ZNF822) was originally linked to functions in the DNA base damage response and has also been proposed to be an essential cofactor of the ATM kinase. Here we show that absence of ASCIZ leads to p53-independent late-embryonic lethality in mice. Asciz-deficient primary fibroblasts exhibit increased sensitivity to DNA base damaging agents MMS and H2O2, but Asciz deletion or knock-down does not affect ATM levels and activation in mouse, chicken, or human cells. Unexpectedly, Asciz-deficient embryos also exhibit severe respiratory tract defects with complete pulmonary agenesis and severe tracheal atresia. Nkx2.1-expressing respiratory precursors are still specified in the absence of ASCIZ, but fail to segregate properly within the ventral foregut, and as a consequence lung buds never form and separation of the trachea from the oesophagus stalls early. Comparison of phenotypes suggests that ASCIZ functions between Wnt2-2b/ß-catenin and FGF10/FGF-receptor 2b signaling pathways in the mesodermal/endodermal crosstalk regulating early respiratory development. We also find that ASCIZ can activate expression of reporter genes via its SQ/TQ-cluster domain in vitro, suggesting that it may exert its developmental functions as a transcription factor. Altogether, the data indicate that, in addition to its role in the DNA base damage response, ASCIZ has separate developmental functions as an essential regulator of respiratory organogenesis

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Pilot Study to Characterize Middle Cerebral Artery Dynamic Response to an Acute Bout of Moderate Intensity Exercise at 3‐ and 6‐Months Poststroke

Background The primary aim of this study was to characterize the middle cerebral artery blood velocity (MCAv) dynamic response to an acute bout of exercise in humans at 3- and 6-months poststroke. As a secondary objective, we grouped individuals according to the MCAv dynamic response to the exercise bout as responder or nonresponder. We tested whether physical activity, aerobic fitness, and exercise mean arterial blood pressure differed between groups. Methods and Results Transcranial Doppler ultrasound measured MCAv during a 90-second baseline followed by a 6-minute moderate intensity exercise bout. Heart rate, mean arterial blood pressure, and end-tidal CO2 were additional variables of interest. The MCAv dynamic response variables included the following: baseline, time delay, amplitude, and time constant. Linear mixed model revealed no significant differences in our selected outcomes between 3- and 6-months poststroke. Individuals characterized as responders demonstrated a faster time delay, higher amplitude, and reported higher levels of physical activity and aerobic fitness when compared with the nonresponders. No between-group differences were identified for baseline, time constant, or exercise mean arterial blood pressure. In the nonresponders, we observed an immediate rise in MCAv following exercise onset followed by an immediate decline to near baseline values, while the responders showed an exponential rise until steady state was reached. Conclusions The MCAv dynamic response profile has the potential to provide valuable information during an acute exercise bout following stroke. Individuals with a greater MCAv response to the exercise stimulus reported statin use and regular participation in exercise

Are Executive Functioning Deficits Concurrently and Predictively Associated with Depressive and Anxiety Symptoms in Adolescents?

BACKGROUND: The central objective of the current study was to evaluate how executive functions (EF), and specifically cognitive flexibility, were concurrently and predictively associated with anxiety and depressive symptoms in adolescence. METHOD: Adolescents (N = 220) and their parents participated in this longitudinal investigation. Adolescents’ EF was assessed by the Wisconsin Card Sorting Test (WCST) during the initial assessment, and symptoms of depressive and anxiety disorders were reported by mothers and youths concurrently and two years later. RESULTS: Correlational analyses suggested that youths who made more total errors (TE), including both perseverative errors (PE) and non-perseverative errors (NPE), concurrently exhibited significantly more depressive symptoms. Adolescents who made more TE and those who made more NPE tended to have more anxiety symptoms two years later. SEM analyses accounting for key explanatory variables (e.g., IQ, disruptive behavior disorders, and attention deficit hyperactive disorder) showed that TE was concurrently associated with parent reports of adolescent depressive symptoms. DISCUSSION: The results suggest internalizing psychopathology is associated with global (TE) and nonspecific (NPE) EF difficulties, but not robustly associated with cognitive inflexibility (PE). Future research with the WCST should consider different sources of errors which are posited to reflect divergent underlying neural mechanisms, conferring differential vulnerability for emerging mental health problems