Duganamstrup2962

In addition, using CMSPkm2 modRNA, our novel CM-targeted strategy, following acute or chronic MI resulted in increased CM cell division, enhanced cardiac function and improved long-term survival. We mechanistically show that Pkm2 regulates the CM cell cycle and reduces oxidative stress damage through anabolic pathways and β-catenin. Conclusions We demonstrate that Pkm2 is an important intrinsic regulator of the CM cell cycle and oxidative stress and highlight its therapeutic potential using CMSPkm2 modRNA as a gene delivery platform.Hyperglycemia mediates oxidative stress, thus inducing transcription factor nuclear factor kappa B (NF-κB) activation, increasing endothelial adhesion molecule expression and monocyte/endothelial interaction, and resulting in endothelial injury. Ketamine was reported to attenuate oxidative stress in many cases. In this research, we determined whether and how ketamine protects against high-glucose-mediated augmentation of monocyte/endothelial interaction and endothelial adhesion molecule expression in human umbilical vein endothelial cells. High glucose augmented monocyte/endothelial adhesion and endothelial adhesion molecule expression. High glucose induced reactive oxygen species (ROS) production and augmented phospho-protein kinase C (p-PKC) βII expression and PKC activity. Moreover, high glucose inhibited the inhibitory subunit of nuclear factor-κBα (IκBα) expression in the cytoplasm and induced NF-κB nuclear translocation. Importantly, the effects induced by high glucose were counteracted by ketamine treatment. Further, CGP53353, a PKC βII inhibitor, inhibited high-glucose-mediated NF-κB nuclear translocation, attenuated adhesion molecule expression, and reduced monocyte/endothelial interaction. Further, these effects of ketamine against high-glucose-induced endothelial injury were inhibited by phorbol 12-myristate 13-acetate, a PKC βII activator. In conclusion, ketamine, via reducing ROS accumulation, inhibited PKC βII Ser660 phosphorylation and PKC and NF-κB activation and reduced high-glucose-induced expression of endothelial adhesion molecules and monocyte/endothelial interaction.Objective The present study used a longitudinal design to examine associations between paternal depressive symptoms in toddlerhood and children's psychosocial adjustment during the preschool and school-age periods. Maternal depressive symptoms and intervention status were tested as moderators of associations between paternal depressive symptoms and child maladjustment.Method The sample (n = 264, 48% female, 62% White, 14% Black, 14% bi-racial, 11% another racial group, and 86% non-Hispanic/Latinx) represented a subsample of families from the Early Steps Multisite Study, a clinical randomized trial testing the effectiveness of the Family Check-Up among low-income families using Women, Infants, and Children Nutritional Supplement Services in three communities varied in urbanicity. Fathers and mothers reported their levels of depressive symptoms at child age 2, primary caregivers (mostly mothers) contributed measures of child adjustment at ages 5, 8.5, and 9.5, and teachers completed questionnaires about child adjustment at ages 8.5 and 9.5.Results Direct relations were found between paternal depressive symptoms and primary caregivers' reports of children's preschool and school-age internalizing problems. Furthermore, higher levels of paternal depression were associated with higher levels of children's later adjustment problems at preschool-age when maternal depressive symptoms were mild or higher. The Family Check-Up attenuated relations between paternal depressive symptoms and children's internalizing problems at school-age.Conclusions These findings have important implications for future research on preventing children's early-emerging problem behaviors at home, suggesting that addressing paternal depressive symptoms in early childhood may be an important intervention target, especially in the context of maternal depression.Background In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), tafamidis reduces all-cause mortality and cardiovascular hospitalizations, and slows decline in quality-oflife compared with placebo. In May 2019, tafamidis received expedited approval from the US FDA as a breakthrough drug for a rare disease. However, at $225,000 per year, it is the most expensive cardiovascular drug ever launched in the US, and its long-term cost-effectiveness and budget impact are uncertain. We therefore sought to estimate the cost-effectiveness of tafamidis and its potential effect on US health care spending. Methods We developed a Markov model of patients with wild-type or variant ATTR-CM and heart failure (mean age 74.5 years) using inputs from the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), published literature, US Food and Drug Administration review documents, healthcare claims, and national survey data. MK-0859 We compared no disease-specific treatment ("usual care") with tafamidis therapy. ThA 92.6% price reduction from $225,000 to $16,563 would be necessary to make tafamidis cost-effective at $100,000/QALY. Results were sensitive to assumptions related to long-term effectiveness of tafamidis. Treating all eligible patients with ATTR-CM in the US with tafamidis (n = 120,000) was estimated to increase annual healthcare spending by $32.3 billion. Conclusions Treatment with tafamidis is projected to produce substantial clinical benefit but would greatly exceed conventional cost-effectiveness thresholds at the current US list price. Based on recent US experience with high-cost cardiovascular medications, access to and uptake of this effective therapy may be limited unless there is a large reduction in drug costs.Abnormal blood pressure during pregnancy is associated with impaired fetal growth, predisposing the offspring to cardiometabolic abnormalities over the life-course. Placental DNA methylation may be the regulatory pathway through which maternal blood pressure influences fetal and adult health outcomes. Epigenome-wide association study of 301 participants with placenta sample examined associations between DNA methylation and millimetre of mercury increases in systolic and diastolic blood pressure in each trimester. Findings were further examined using gene expression, gene pathway, and functional annotation analyses. Cytosine-(phosphate)-guanine (CpGs) known to be associated with cardiometabolic traits were evaluated. Increased maternal systolic and diastolic blood pressure were associated with methylation of 3 CpGs in the first, 6 CpGs in the second, and 15 CpGs in the third trimester at 5% false discovery rate (P values ranging from 6.6×10-15 to 2.3×10-7). Several CpGs were enriched in pathways including cardiovascular-metabolic development (P=1.0×10-45). Increased systolic and diastolic blood pressure were associated with increased CpG methylation and gene expression at COL12A1, a collagen family gene known for regulatory functions in the heart. Out of 304 previously reported CpGs known to be associated with cardiometabolic traits, 36 placental CpGs were associated with systolic and diastolic blood pressure in our data. The present study provides the first evidence for associations between placental DNA methylation and increased maternal blood pressure during pregnancy at genes implicated in cardiometabolic diseases. Identification of blood pressure-associated methylated sites in the placenta may provide clues to early origins of cardiometabolic dysfunction and inform guidelines for early prevention. Registration- URL http//www.clinicaltrials.gov. Unique identifier NCT00912132.Background Myocardial perfusion reflects the macro- and microvascular coronary circulation. Recent quantitation developments using cardiovascular magnetic resonance (CMR) perfusion permit automated measurement clinically. We explored the prognostic significance of stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR, the ratio of stress to rest MBF). Methods A two center study of patients with both suspected and known coronary artery disease referred clinically for perfusion assessment. link2 Image analysis was performed automatically using a novel artificial intelligence approach deriving global and regional stress and rest MBF and MPR. Cox proportional hazard models adjusting for co-morbidities and CMR parameters sought associations of stress MBF and MPR with death and major adverse cardiovascular events (MACE), including myocardial infarction, stroke, heart failure hospitalization, late (>90 day) revascularization and death. Results 1049 patients were included with median follow-up 605 (inter independent predictor of adverse cardiovascular outcomes.Objective Children with early-onset behavioral issues are at high risk for ongoing behavioral, psychological, and social issues.Method This study examined the efficacy of the first phase of Parent-Child Interaction Therapy with Toddlers, Child-Directed Interaction - Toddler, using a randomized control design. Sixty-six mother-toddler dyads (Child Mage = 19.13 months; 63% male; 34% from a non-English speaking background) referred to a community-based child behavior clinic in Australia received CDI-T immediately or were assigned to a waitlist control condition. At baseline (Time 1) and post-treatment/post-waitlist (Time 2), mothers completed questionnaires (Child Behavior Checklist, Edinburgh Postnatal Depression Scale, Parenting Stress Index - Short Form) and participated in a structured parent-child dyadic play-based interaction later coded using the Dyadic Parent-Child Interaction Coding System and the Emotional Availability Scales.Results Compared to those who did not receive treatment, mother-child dyads who received the intervention showed significantly better parenting skills (increases in positive parenting skills and decreases in negative parenting skills), emotional availability (increases in parental sensitivity and parental non-intrusiveness), child behavior (decreases in externalizing and internalizing behaviors) and parental perceptions of child difficulty.Conclusions Results suggest that the CDI-T phase of PCIT-T is a promising intervention for toddlers presenting with behavioral issues. Future studies should be conducted to assess efficacy in other settings and to assess longer-term outcomes.Objective Safety behaviors have been found to undermine successful exposure in the treatment of anxiety disorders for both adults and children. Although reliable measures of safety behaviors have been developed for use with adults, no such measure has been developed specifically for pediatric populations. link3 In light of this limitation, the current study aimed to develop and validate a measure of the use of safety behaviors suitable for children The Subtle Avoidance Measure for Youth (SAMY).Methods Clinical (n = 174) and community (n = 138) young people, aged 7-13 years, provided data.Results Both exploratory and confirmatory factor analyses supported a three-factor solution of the SAMY, which reflected checking behaviors, behaviors related to image management, and behaviors related to physical protection. The SAMY and its subscales demonstrated strong internal consistency, test-retest reliability, construct validity, and the ability to discriminate between clinical and community participants.Conclusions Given its solid psychometric properties, the SAMY will prove useful for both research and clinical work with anxious young people.