Determining the Role of Casz1 in Heart Development

Castor (Casz1) is a zinc finger transcription factor that has been shown to be required for heart development in Xenopus. Casz1 has also been linked to high blood pressure and hypertension in humans through a recent Genome Wide Association Study. The purpose of this research was to determine the role of Casz1 in cardiac development and how Casz1 fits into the cardiac transcription program. A mouse model was used because of the high genomic conservation between mice and humans. To determine the spatial and temporal expression of Casz1 mRNA during murine heart development, I utilized in situ hybridization. In addition, to confirm that CASZ1 protein is present in the developing heart, I performed immunohistochemistry. My studies showed that Casz1 is expressed in the atria and left ventricle of the developing heart. To determine the role of Casz1 in cardiac development, I examined the cardiomyocyte mitotic index of wild type embryos and Casz1 mutant embryos, and demonstrated that cardiomyocytes lacking Casz1 over-proliferate. This indicates that Casz1 regulates cardiomyocyte proliferation. Future studies are aimed at identifying genes that Casz1 regulates, providing further insight into the cardiac gene program. These studies hold implications for understanding congenital heart defects by giving us further insight into the molecular mechanisms that regulate cardiac development.Bachelor of Scienc

Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development

Organ growth occurs through the integration of external growth signals during the G1 phase of the cell cycle to initiate DNA replication. Although numerous growth factor signals have been shown to be required for the proliferation of cardiomyocytes, genetic studies have only identified a very limited number of transcription factors that act to regulate the entry of cardiomyocytes into S phase. Here, we report that the cardiac para-zinc-finger protein CASZ1 is expressed in murine cardiomyocytes. Genetic fate mapping with an inducible Casz1 allele demonstrates that CASZ1-expressing cells give rise to cardiomyocytes in the first and second heart fields. We show through the generation of a cardiac conditional null mutation that Casz1 is essential for the proliferation of cardiomyocytes in both heart fields and that loss of Casz1 leads to a decrease in cardiomyocyte cell number. We further report that the loss of Casz1 leads to a prolonged or arrested S phase, a decrease in DNA synthesis, an increase in phospho-RB and a concomitant decrease in the cardiac mitotic index. Taken together, these studies establish a role for CASZ1 in mammalian cardiomyocyte cell cycle progression in both the first and second heart fields

Bright environmental light improves the sleepiness of nightshift ICU nurses

Abstract Background Shift work can disturb circadian homeostasis and result in fatigue, excessive sleepiness, and reduced quality of life. Light therapy has been shown to impart positive effects in night shift workers. We sought to determine whether or not prolonged exposure to bright light during a night shift reduces sleepiness and enhances psychomotor performance among ICU nurses. Methods This is a single-center randomized, crossover clinical trial at a surgical trauma ICU. ICU nurses working a night shift were exposed to a 10-h period of high illuminance (1500–2000 lx) white light compared to standard ambient fluorescent lighting of the hospital. They then completed the Stanford Sleepiness Scale and the Psychomotor Vigilance Test. The primary and secondary endpoints were analyzed using the paired t test. A p value <0.05 was considered significant. Results A total of 43 matched pairs completed both lighting exposures and were analyzed. When exposed to high illuminance lighting subjects experienced reduced sleepiness scores on the Stanford Sleepiness Scale than when exposed to standard hospital lighting: mean (sem) 2.6 (0.2) vs. 3.0 (0.2), p = 0.03. However, they committed more psychomotor errors: 2.3 (0.2) vs. 1.7 (0.2), p = 0.03. Conclusions A bright lighting environment for ICU nurses working the night shift reduces sleepiness but increases the number of psychomotor errors. Trial registration ClinicalTrials.gov, NCT03331822. Retrospectively registered on 6 November 2017

Behavioral Outcomes and Neurodevelopmental Disorders Among Children of Women With Epilepsy

IMPORTANCE The association of fetal exposure to antiseizure medications (ASMs) with outcomes in childhood are not well delineated. OBJECTIVE To examine the association of fetal ASM exposure with subsequent adaptive, behavioral or emotional, and neurodevelopmental disorder outcomes at 2, 3, and 4.5 years of age. DESIGN, SETTING, AND PARTICIPANTS The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational cohort study conducted at 20 epilepsy centers in the US. A total of 456 pregnant women with epilepsy or without epilepsy were enrolled from December 19, 2012, to January 13, 2016. Children of enrolled women were followed up with formal assessments at 2, 3, 4.5, and 6 years of age. Statistical analysis took place from August 2022 to May 2023. EXPOSURES Exposures included mother’s epilepsy status as well as mother’s ASM blood concentration in the third trimester (for children of women with epilepsy). Women with epilepsy were enrolled regardless of ASM regimen. MAIN OUTCOMES AND MEASURES The primary outcome was the Adaptive Behavior Assessment System, Third Edition (ABAS-3) General Adaptive Composite (GAC) score among children at 4.5 years of age. Children of women with epilepsy and children of women without epilepsy were compared, and the associations of ASM exposures with outcomes among exposed children were assessed. Secondary outcomes involved similar analyses of other related measures. RESULTS Primary analysis included 302 children of women with epilepsy (143 boys [47.4%]) and 84 children of women without epilepsy (45 boys [53.6%]). Overall adaptive functioning (ABAS-3 GAC score at 4.5 years) did not significantly differ between children of women with epilepsy and children of women without epilepsy (parameter estimate [PE], 0.4 [95% CI, −2.5 to 3.4]; P = .77). However, in adjusted analyses, a significant decrease in functioning was seen with increasing third-trimester maximum ASM blood concentrations (PE, −7.8 [95% CI, −12.6 to −3.1]; P = .001). This decrease in functioning was evident for levetiracetam (PE, −18.9 [95% CI, −26.8 to −10.9]; P < .001) and lamotrigine (PE, −12.0 [95% CI, −23.7 to −0.3]; P = .04), the ASMs with sample sizes large enough for analysis. Results were similar with third-trimester maximum daily dose. CONCLUSIONS AND RELEVANCE This study suggests that adaptive functioning of children of women with epilepsy taking commonly used ASMs did not significantly differ from that of children of women without epilepsy, but there was an exposure-dependent association of ASMs with functioning. Thus, psychiatric or psychological screening and referral of women with epilepsy and their offspring are recommended when appropriate. Additional research is needed to confirm these findings. © 2023 American Medical Association. All rights reserved.12 month embargo; first published 20 November 2023This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]