AP-1 controls the p11-dependent antidepressant response.

Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed drugs for mood disorders. While the mechanism of SSRI action is still unknown, SSRIs are thought to exert therapeutic effects by elevating extracellular serotonin levels in the brain, and remodel the structural and functional alterations dysregulated during depression. To determine their precise mode of action, we tested whether such neuroadaptive processes are modulated by regulation of specific gene expression programs. Here we identify a transcriptional program regulated by activator protein-1 (AP-1) complex, formed by c-Fos and c-Jun that is selectively activated prior to the onset of the chronic SSRI response. The AP-1 transcriptional program modulates the expression of key neuronal remodeling genes, including S100a10 (p11), linking neuronal plasticity to the antidepressant response. We find that AP-1 function is required for the antidepressant effect in vivo. Furthermore, we demonstrate how neurochemical pathways of BDNF and FGF2, through the MAPK, PI3K, and JNK cascades, regulate AP-1 function to mediate the beneficial effects of the antidepressant response. Here we put forth a sequential molecular network to track the antidepressant response and provide a new avenue that could be used to accelerate or potentiate antidepressant responses by triggering neuroplasticity.

The Utility of the Focused Assessment With Sonography in Trauma Examination in Pediatric Blunt Abdominal Trauma: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the utility of the Point of Care Ultrasound (POCUS) Focused Assessment with Sonography for Trauma (FAST) examination for diagnosis of intra-abdominal injury (IAI) in children presenting with blunt abdominal trauma. METHODS: We searched medical literature from January 1966 to March 2018 in PubMed, EMBASE, and Web of Science. Prospective studies of POCUS FAST examinations in diagnosing IAI in pediatric trauma were included. Sensitivity, specificity, and likelihood ratios (LR) were calculated using a random-effects model (95% confidence interval). Study quality and bias risk were assessed, and test-treatment threshold estimates were performed. RESULTS: Eight prospective studies were included encompassing 2135 patients with a weighted prevalence of IAI of 13.5%. Studies had variable quality, with most at risk for partial and differential verification bias. The results from POCUS FAST examinations for IAI showed a pooled sensitivity of 35%, specificity of 96%, LR+ of 10.84, and LR- of 0.64. A positive POCUS FAST posttest probability for IAI (63%) exceeds the upper limit (57%) of our test-treatment threshold model for computed tomography of the abdomen with contrast. A negative POCUS FAST posttest probability for IAI (9%) does not cross the lower limit (0.23%) of our test-treatment threshold model. CONCLUSIONS: In a hemodynamically stable child presenting with blunt abdominal trauma, a positive POCUS FAST examination result means that IAI is likely, but a negative examination result alone cannot preclude further diagnostic workup for IAI. The need for computed tomography scan may be obviated in a subset of low-risk pediatric blunt abdominal trauma patients presenting with a Glasgow Coma Scale of 14 to 15, a normal abdominal examination result, and a negative POCUS FAST result.

Imaging atrial arrhythmic intracellular calcium in intact heart.

Abnormalities in intracellular Ca(2+) signaling have been proposed to play an essential role in the pathophysiology of atrial arrhythmias. However, a direct observation of intracellular Ca(2+) in atrial myocytes during atrial arrhythmias is lacking. Here, we have developed an ex vivo model of simultaneous Ca(2+) imaging and electrocardiographic recording in cardiac atria. Using this system we were able to record atrial arrhythmic intracellular Ca(2+) activities. Our results indicate that atrial arrhythmias can be tightly linked to intracellular Ca(2+) waves and Ca(2+) alternans. Moreover, we applied this strategy to analyze Ca(2+) signals in the hearts of WT and knock-in mice harboring a 'leaky' type 2 ryanodine receptor (RyR2-R2474S). We showed that sarcoplasmic reticulum (SR) Ca(2+) leak increases the susceptibility to Ca(2+) alternans and Ca(2+) waves increasing the incidence of atrial arrhythmias. Reduction of SR Ca(2+) leak via RyR2 by acute treatment with S107 reduced both Ca(2+) alternans and Ca(2+) waves, and prevented atrial arrhythmias.

Breastfeeding in a Global Context: Epidemiology, Impact, and Future Directions.

INTRODUCTION: More than 98% of infant deaths occur in low- and middle-income countries (LMICs). Breastfeeding improves infant survival and protects against certain illnesses, such as diarrhea and pneumonia, which are leading causes of deaths in those <5 years of age in LMICs. The World Health Organization (WHO) recommends early initiation of breastfeeding within 1 hour of birth, exclusive breastfeeding up to 6 months of age, and continued breastfeeding up to 2 years of age. However, fewer than half of infants in LMICs are breastfed optimally to these standards. The objectives of this article are to describe the global epidemiology and health benefits of breastfeeding with particular focus on LMICs. METHODS: We searched PubMed to identify original research articles on breastfeeding in LMICs and reviews related to the benefits of breastfeeding, with particular focus on articles published in the past 5 years. We used reports and data published by the WHO and the United Nations Children's Fund (UNICEF) related to global breastfeeding rates, targets, and programmatic initiatives. We used the Lives Saved Tool to estimate mortality related to breastfeeding practices. FINDINGS: Less than half of infants globally receive early, exclusive, or continued breastfeeding. Certain high-risk groups, such as premature or HIV-exposed infants, face particular challenges and benefits related to breastfeeding. The WHO, UNICEF, and other global partners have developed a multipronged strategy to promote global breastfeeding, ranging from government-level advocacy to grassroots community support groups. Using the Lives Saved Tool, we estimate that nearly 200,000 lives of those <5 years of age could be saved in LMICs from 2020 to 2030 if early, exclusive, and continued breastfeeding rates were linearly increased from current rates to meet the WHO 2030 goals of 60% to 80% coverage. If this goal were exceeded and near-universal coverage were achieved, the number of lives would increase even further such that >820,000 lives per year could potentially be saved by universal breastfeeding. In this review, we delineate the health and economic benefit of breastfeeding in LMICs, discuss breastfeeding epidemiology in the global context, and describe targeted strategies to improve breastfeeding uptake.

A selective microRNA-based strategy inhibits restenosis while preserving endothelial function.

Drugs currently approved to coat stents used in percutaneous coronary interventions do not discriminate between proliferating vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). This lack of discrimination delays reendothelialization and vascular healing, increasing the risk of late thrombosis following angioplasty. We developed a microRNA-based (miRNA-based) approach to inhibit proliferative VSMCs, thus preventing restenosis, while selectively promoting reendothelialization and preserving EC function. We used an adenoviral (Ad) vector that encodes cyclin-dependent kinase inhibitor p27(Kip1) (p27) with target sequences for EC-specific miR-126-3p at the 3' end (Ad-p27-126TS). Exogenous p27 overexpression was evaluated in vitro and in a rat arterial balloon injury model following transduction with Ad-p27-126TS, Ad-p27 (without miR-126 target sequences), or Ad-GFP (control). In vitro, Ad-p27-126TS protected the ability of ECs to proliferate, migrate, and form networks. At 2 and 4 weeks after injury, Ad-p27-126TS-treated animals exhibited reduced restenosis, complete reendothelialization, reduced hypercoagulability, and restoration of the vasodilatory response to acetylcholine to levels comparable to those in uninjured vessels. By incorporating miR-126-3p target sequences to leverage endogenous EC-specific miR-126, we overexpressed exogenous p27 in VSMCs, while selectively inhibiting p27 overexpression in ECs. Our proof-of-principle study demonstrates the potential of using a miRNA-based strategy as a therapeutic approach to specifically inhibit vascular restenosis while preserving EC function.