Differential regulation of lung homeostasis and silicosis by the TAM receptors MerTk and Axl.

Introduction: TAM receptor-mediated efferocytosis plays an important function in immune regulation and may contribute to antigen tolerance in the lungs, a site with continuous cellular turnover and generation of apoptotic cells. Some studies have identified failures in efferocytosis as a common driver of inflammation and tissue destruction in lung diseases. Our study is the first to characterize the in vivo function of the TAM receptors, Axl and MerTk, in the innate immune cell compartment, cytokine and chemokine production, as well as the alveolar macrophage (AM) phenotype in different settings in the airways and lung parenchyma. Methods: We employed MerTk and Axl defective mice to induce acute silicosis by a single exposure to crystalline silica particles (20 mg/50 µL). Although both mRNA levels of Axl and MerTk receptors were constitutively expressed by lung cells and isolated AMs, we found that MerTk was critical for maintaining lung homeostasis, whereas Axl played a role in the regulation of silica-induced inflammation. Our findings imply that MerTk and Axl differently modulated inflammatory tone via AM and neutrophil recruitment, phenotype and function by flow cytometry, and TGF-ß and CXCL1 protein levels, respectively. Finally, Axl expression was upregulated in both MerTk-/- and WT AMs, confirming its importance during inflammation. Conclusion: This study provides strong evidence that MerTk and Axl are specialized to orchestrate apoptotic cell clearance across different circumstances and may have important implications for the understanding of pulmonary inflammatory disorders as well as for the development of new approaches to therapy.

Physical-Mental Comorbidity of Pediatric Migraine in the Philadelphia Neurodevelopmental Cohort.

OBJECTIVE: To examine the associations between headaches and migraine with physical and mental disorders in a large pediatric registry. STUDY DESIGN: In total, 9329 youth aged 8-21 years from the Philadelphia Neurodevelopmental Cohort were included. Physical conditions, including headache, were ascertained from electronic medical records and in-person interviews. Modified International Classification of Headache Disorders (ICHD-II) criteria were used to classify migraine symptoms. Forty-two other physical conditions were classified into 14 classes of medical disorders. Mental disorders were assessed using an abbreviated version of the Kiddie-Schedule for Affective Disorders and Schizophrenia. RESULTS: Lifetime prevalence of any headache was 45.5%, and of migraine was 22.6%. Any headache was associated with a broad range of physical disorders, attention-deficit/hyperactivity disorder (OR 1.2 [95% CI 1.1-1.4]), and behavior disorders (1.3 [1.1-1.5]). Youth with migraine had greater odds of specific physical conditions and mental disorders, including respiratory, neurologic/central nervous system, developmental, anxiety, behavior, and mood disorders than those with nonmigraine headache (OR ranged from 1.3 to 1.9). CONCLUSIONS: Comorbidity between headaches with a range of physical conditions that have been associated with adult migraine demonstrates that multimorbidity occurs early in development. Comorbidity may be an important index of heterogeneity of migraine that can guide clinical management, genetic investigation, and future research on shared pathophysiology with other disorders.

Sleep Patterns and Mental Health Correlates in US Adolescents.

OBJECTIVE: To investigate systematically the associations of sleep patterns with a range of mental disorders and other outcomes among a nationally representative sample of US adolescents. STUDY DESIGN: Using the National Comorbidity Survey Adolescent Supplement, a nationally representative cross-sectional survey of 10 123 US adolescents 13-18 years of age, we assessed associations between adolescent-reported sleep patterns (tertiles of weeknight bedtime, weeknight sleep duration, weekend bedtime delay, and weekend oversleep) and past-year mental disorders based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, smoking, injury, suicidality, and perceived mental and physical health, assessed via direct diagnostic interview. RESULTS: The average weeknight bedtime was at 22:37 and sleep duration was 7.72 hours. Average weekend bedtime delay was 1.81 hours and average weekend oversleep was 1.17 hours. Later weeknight bedtime, shorter weeknight sleep duration, greater weekend bedtime delay, and both short and long periods of weekend oversleep were associated with increased odds of mood, anxiety, substance use, and behavioral disorders, as well as suicidality, tobacco smoking, and poor perceived mental and physical health. ORs ranged from 1.27 to 2.15. The only outcomes not associated with any sleep patterns were past-year injury and eating disorder. CONCLUSIONS: Suboptimal sleep patterns were associated with an array of mental disorders and other health-related outcomes among adolescents. Abnormal sleep patterns may serve as markers of prodromal or untreated mental disorders among adolescents, and may provide opportunities for prevention and intervention in mental disorders.

Messaging Affects the Behavior of African American Parents with Regards to Soft Bedding in the Infant Sleep Environment: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the impact of specific health messages on the decisions of African American parents regarding soft bedding use, specifically related to the high degree of self-efficacy that African American parents have with regards to preventing infant suffocation vs low self-efficacy with regards to sudden infant death syndrome (SIDS) risk reduction. STUDY DESIGN: We conducted a randomized, controlled clinical trial of African American mothers of infants. The control group received standard messaging emphasizing safe sleep practices recommended by the American Academy of Pediatrics for the purposes of SIDS risk reduction. The intervention group received enhanced messaging emphasizing safe sleep practices for both SIDS risk reduction and suffocation prevention. Participants completed interviews at 2-3 weeks, 2-3 months, and 5-6 months after the infant's birth. RESULTS: Of 1194 mothers enrolled, 637 completed all interviews. The use of soft bedding both in the past week and last night declined with age (P < .001). Infants in the enhanced group had a lower rate of use of soft bedding in the past week (P = .006) and last night (P = .013). Mothers who received the enhanced message were more likely to state that they avoided soft bedding to protect their infant from suffocation. CONCLUSIONS: African American mothers who receive an enhanced message about SIDS risk reduction and suffocation prevention are less likely to use soft bedding in their infant's sleep environment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01361880.

Early Reticulocytosis and Anemia Are Associated with Abnormal and Conditional Transcranial Doppler Velocities in Children with Sickle Cell Anemia.

OBJECTIVE: To improve prediction of sickle cell anemia severity at an early age, we evaluated whether absolute reticulocyte count (ARC) or hemoglobin (Hb) levels during early infancy (2-6 months of age) in patients with sickle cell anemia predict the risk of later developing an abnormal (abTCD) or conditional (cdTCD) Transcranial Doppler (TCD). STUDY DESIGN: We used chart review to identify 121 consecutive patients who underwent TCD screening and had steady state ARC and Hb levels recorded between 2 and 6 months of age. Cox regression analysis was used to determine the relationship between ARC, Hb levels, and risk of developing cdTCD/abTCD over time. RESULTS: Mean ARC in early infancy was highest and mean Hb lowest in those children with abTCDs and cdTCDs. Cox regression analysis revealed that those subjects with an ARC ≥200 K/µL in early infancy had nearly 3 times the risk of having an abTCD/cdTCD than the group with an ARC <200 K/µL, and patients with a Hb <8.5 g/dL had 2.7 times the risk of having an abTCD/cdTCD. CONCLUSIONS: These data suggest that both elevated ARC and low baseline Hb during early infancy are associated with an increased risk of developing a cdTCD or abTCD later in childhood.