Socioeconomic status moderates associations between CNS serotonin and expression of β2-integrins CD11b and CD11c

One of the first steps in the development of atherogenesis is adhesion of circulating monocytes to the vascular endothelium that is stimulated by β₂-integrins. Stress has been associated with enhanced expression of β₂-integrins on monocyte cell surface (Greeson et al., 2008). Central nervous system (CNS) serotonin regulates aspects of the stress response that can influence inflammatory processes that increase risk for atherosclerosis. This study examines effects of an environmental stressor (indexed by socioeconomic status (SES)) and CNS serotonin (indexed by CSF 5HIAA level), on the expression of β₂-integrins (CD11a, CD11b, and CD11c) on circulating monocytes in 131 volunteers. Participants completed a protocol consisting of a lumbar puncture for assessment of CSF 5HIAA levels (day 1) followed by an experimental protocol (day 2). Blood samples for the present analyses were obtained at baseline on day 2. The interaction of SES × 5HIAA was a significant predictor of levels of CD11b and CD11c expression (p = .02, and p = .05, respectively); the mean CD11b difference between Hi and Lo SES subjects was significant (p = .003) only in those with Lo levels of 5HIAA, while SES differences in CD11b among those with Mid and Hi levels of 5HIAA did not vary statistically. The pattern of findings was similar for CD11c. The present results suggest that the combination of high environmental stress and low CNS serotonin function could contribute to atherogenesis through processes that lead to increased expression of the β₂-integrins CD11b and CD11c on monocyte cell surfaces.     

Psychosocial factors associated with non-smoking adolescents' intentions to smoke

Smoking is the most preventable cause of death in the United States. Most adult smokers began smoking during adolescence, making youth tobacco prevention an especially important public health goal. Guided by an extension of the theory of planned behavior (TPB), this study examined the role of psychosocial factors in accounting for adolescents' smoking intentions. Participants from three high schools (n = 785) were surveyed to assess smoking-related characteristics and behaviors as part of a statewide evaluation of tobacco prevention programming. Attitudes, subjective norms (and other normative factors) and perceived behavioral control were all associated with non-smokers' intentions to smoke. Having more favorable attitudes toward remaining tobacco free and perceiving that friends would not be supportive of smoking were both associated with decreased likelihood of intending to smoke. Normative influence and peer use were significant factors, such that having more friends who smoke was associated with increased odds of intent to smoke. Lastly, perceived difficulty to quit was related to smoking intentions, with higher confidence to quit significantly associated with intentions to smoke. Findings are consistent with the TPB--attitudes, normative factors and perceived behavioral control each helped account for non-smoking adolescents' intentions to smoke. Implications for theory and intervention building are discussed.     

Characterization of breakthrough hemolysis events observed in the phase III randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria

Eculizumab is first-line treatment for paroxysmal nocturnal hemoglobinuria (PNH); however, approximately 11-27% of patients may experience breakthrough hemolysis (BTH) on approved doses of eculizumab. Ravulizumab, a new long-acting C5 inhibitor with a four times longer mean half-life than eculizumab, provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals. In two phase III studies, ravulizumab was non-inferior to eculizumab (Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with ravulizumab versus eculizumab in both studies (301 [complement inhibitor−naïve patients], 4.0% vs. 10.7%; 302 [patients stabilized on eculizumab at baseline], 0% vs. 5.1%). In the current analysis, patientlevel data were evaluated to assess causes and clinical parameters associated with incidents of BTH reported during the 26-week treatment periods in the ravulizumab phase III PNH studies. Of the five BTH events occurring in ravulizumab-treated patients across the studies, none were temporally associated with suboptimal C5 inhibition (free C5 ≥0.5 mg/mL); four (80%) were temporally associated with complement-amplifying conditions (CAC). Of the 22 events occurring in eculizumab-treated patients, 11 were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant infection. Six events were associated with CAC only. Five events were unrelated to free C5 elevation or reported CAC. These results suggest that the immediate, complete, and sustained C5 inhibition achieved through weight-based dosing of ravulizumab reduces the risk of BTH by eliminating BTH associated with suboptimal C5 inhibition in patients with PNH. (Registered at clinicaltrials.gov identifiers: Study 301, {"type":"clinical-trial","attrs":{"text":"NCT02946463","term_id":"NCT02946463"}}NCT02946463; Study 302, {"type":"clinical-trial","attrs":{"text":"NCT03056040","term_id":"NCT03056040"}}NCT03056040.)     

Vitamin D, osteocalcin, and risk for adiposity as comorbidities in middle school children

Nonclassic actions of vitamin D include potential regulation of immune function and glucose homeostasis. The bone-metabolism loop has recently been expanded to include osteocalcin, which appears to play a more direct role in pancreatic beta cell function and energy metabolism. We hypothesized that both vitamin D and osteocalcin would correlate negatively with indices of adiposity-related comorbidity risk in periadolescents, varying by ethnic group. We analyzed anthropometric, metabolic, and inflammatory markers from a multiethnic population of 106 school children 11 to 14 years of age studied as part of the Reduce Obesity and Diabetes (ROAD) consortium. As expected, 25-hydroxyvitamin D (25-OH vitamin D) was inversely correlated with intact parathyroid hormone (iPTH); total osteocalcin (OCN) and uncarboxylated osteocalcin (uOCN) were directly correlated with each other. OCN and uOCN concentrations correlated inversely with age. Vitamin D deficiency was most prevalent among East Asians (EA) and African Americans (AA). The highest lipid risk scores and homeostatic model for assessment of insulin resistance (HOMA-IR) values were seen in the South Asian (SA) group. Overall, adiposity measures were inversely correlated with OCN and iPTH, whereas such relationships were not observed for vitamin D. Acute insulin response to glucose challenge correlated negatively with uOCN in all subjects; however, lipid risk score correlated negatively with uOCN only in whites. The relationships between markers of calcium metabolism and body composition, glucose homeostasis, lipids, and inflammation all showed racial and ethnic differences. No consistent relationship was found between vitamin D and adiposity or vitamin D and glucose metabolism; instead vitamin D levels varied by race and ethnicity in this school-based group. These findings are consistent with the hypothesis that markers of calcium and bone metabolism may reflect risk for adiposity-related comorbidities in children.