Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management

AKAP7 Regulates CaM Kinase Activation in MCF-7 Cells

Abstract Estrogen (E2) activates calcium/calmodulin-dependent protein kinases (CaM Kinases) in MCF-7 breast cancer cells. In particular E2 activates a CaM KK, CaM KI, and ERK pathway to promote proliferation. CaM Kinase activation of ERK may be blocked by PKA in certain cell types through direct phosphorylation and inhibition of CaM KK. The ability of PKA to phosphorylate its cellular targets may be dictated by protein kinase A anchoring proteins (AKAPs). Hormones that elevate cAMP and activate PKA may utilize AKAPs to regulate signal transduction. Our goal was to evaluate the role of AKAPs in regulating E2 activation of the CaM KK and CaM KI pathway in MCF-7 cells. We also examined the ability of vitamin D (VitD) working through cAMP and PKA to block CaM KK signaling in breast cancer cells. Our results suggest that E2 activates CaM KK and CaM KI within 5 minutes. VitD promoted PKA-dependent phosphorylation of CaM KK. VitD and epinephrine treatment of cells triggered a potent increase in cAMP levels. Interestingly, purified GST-RII pulled down both CaM KK and CaM KI. Similarly, purified AKAP7 but not AKAP5 bound CaM KK and CaM KI an effect that is enhanced with E2. Endogenous AKAP7 and CaM KK associated in E2-stimulated but not in VitD-treated cells and VitD also blocked CaM KK activation in MCF-7 cells. Our results suggest that VitD blocks E2 activation of CaM Kinases and their association with AKAP7 in MCF-7 cells

In Children with Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis is Associated with Advanced Fibrosis

Background & Aims Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. Methods We performed a cross-sectional study of baseline data from 813 children (age <18 years; mean age, 12.8 ± 2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. Results Zone 1 steatosis was present in 18% of children with NAFLD (n = 146) and zone 3 steatosis was present in 32% (n = 244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P < .001) and a significantly higher proportion had any fibrosis (81% vs 51%; P < .001) or advanced fibrosis (13% vs 5%; P < .001) compared with children with zone 3 steatosis. In contrast, children with zone 3 steatosis were significantly more likely to have steatohepatitis (30% vs 6% in children with zone 1 steatosis; P < .001). Conclusions Children with zone 1 or zone 3 distribution of steatosis have an important subphenotype of pediatric NAFLD. Children with zone 1 steatosis are more likely to have advanced fibrosis and children with zone 3 steatosis are more likely to have steatohepatitis. To achieve a comprehensive understanding of pediatric NAFLD, studies of pathophysiology, natural history, and response to treatment should account for the zonality of steatosis

LKB1 Destabilizes Microtubules in Myoblasts and Contributes to Myoblast Differentiation

Background: Skeletal muscle myoblast differentiation and fusion into multinucleate myotubes is associated with dramatic cytoskeletal changes. We find that microtubules in differentiated myotubes are highly stabilized, but premature microtubule stabilization blocks differentiation. Factors responsible for microtubule destabilization in myoblasts have not been identified. Findings: We find that a transient decrease in microtubule stabilization early during myoblast differentiation precedes the ultimate microtubule stabilization seen in differentiated myotubes. We report a role for the serine-threonine kinase LKB1 in both microtubule destabilization and myoblast differentiation. LKB1 overexpression reduced microtubule elongation in a Nocodazole washout assay, and LKB1 RNAi increased it, showing LKB1 destabilizes microtubule assembly in myoblasts. LKB1 levels and activity increased during myoblast differentiation, along with activation of the known LKB1 substrates AMPactivated protein kinase (AMPK) and microtubule affinity regulating kinases (MARKs). LKB1 overexpression accelerated differentiation, whereas RNAi impaired it. Conclusions: Reduced microtubule stability precedes myoblast differentiation and the associated ultimate microtubule stabilization seen in myotubes. LKB1 plays a positive role in microtubule destabilization in myoblasts and in myoblast differentiation. This work suggests a model by which LKB1-induced microtubule destabilization facilitates the cytoskeleta

Battling Bullying: An Intervention to Improve Civility Among Nurses

DNP ProjectIntroduction: Incivility among nurses in contemporary healthcare settings poses significant challenges impacting individuals, organizations, and patients alike, yet there is a lack of standardized, evidence-based interventions to address this issue. Existing literature advocates for the assessment of workplace incivility, continuous education, and cognitive rehearsal training. This project sought to evaluate whether a combination of e-learning and cognitive rehearsal training enhances the ability of first-year registered nurses to identify, recognize, and respond to incivility, while also promoting a culture of civility in the workplace. Methods: First-year pediatric critical care nurses at a nationally recognized Magnet®-designated children's hospital participated in a self-paced e-learning module, followed by a two-hour cognitive rehearsal session. The e-learning segment aimed to raise awareness of incivility and encourage effective communication. The cognitive rehearsal training involved role-playing structured scenarios, allowing participants to practice responses to typical uncivil behaviors utilizing evidence-based techniques. The Workplace Civility Index (WCI) was utilized to measure outcomes at three intervals including pre- and post-intervention and one-month post-intervention. Results: WCI scores demonstrated a significant improvement (p<.001) both post-intervention and at one-month post-intervention compared to pre-intervention measures. Participants also expressed a higher likelihood of directly addressing workplace issues (p<.001). Post-course evaluations revealed high levels of satisfaction and perceived usefulness of the training. Discussion: The results of this project indicate that integration of e-learning with cognitive rehearsal training effectively improves nurses' skills in recognizing and responding to incivility. The increased confidence in tackling workplace issues underscores the importance of structured training in fostering a positive workplace culture. These findings emphasize the necessity for ongoing educational initiatives to encourage civility within nursing practice. Incorporating such interventions into professional development programs may lead to healthier work environments and improved patient care. Future studies should investigate the long-term impacts and the potential for scalability across various healthcare contexts

The mAKAP signaling complex: Integration of cAMP, calcium, and MAP kinase signaling pathways

Following its production by adenylyl cyclases, the second messenger cAMP is in involved in pleiotrophic signal transduction. The effectors of cAMP include the cAMP-dependent protein kinase (PKA), the guanine nucleotide exchange factor Epac (exchange protein activated by cAMP), and cAMP-dependent ion channels. In turn, cAMP signaling is attenuated by phosphodiesterase-catalyzed degradation. The association of cAMP effectors and the enzymes that regulate cAMP concentration into signaling complexes helps to explain the differential signaling initiated by members of the G s-protein coupled receptor family. The signal transduction complex formed by the scaffold protein mAKAP (muscle A kinase-anchoring protein) at the nuclear envelope of both striated myocytes and neurons contains three cAMP-binding proteins, PKA, Epac1, and the phosphodiesterase PDE4D3. In addition, the mAKAP complex also contains components of the ERK5 MAP kinase signaling pathway, the calcium release channel ryanodine receptor and the phosphatases PP2A as well as calcineurin. Analysis of the mAKAP complex illustrates how a macromolecular complex can serve as a node in the intracellular signaling network of cardiac myocytes to integrate multiple cAMP signals with those of calcium and MAP kinases to regulate the hypertrophic actions of several hormones