Characterization of the mechanism of action of lanraplenib, a novel spleen tyrosine kinase inhibitor, in models of lupus nephritis.

BACKGROUND: B cells are critical mediators of systemic lupus erythematosus (SLE) and lupus nephritis (LN), and antinuclear antibodies can be found in the serum of approximately 98% of patients with SLE. Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that mediates signaling from immunoreceptors, including the B cell receptor. Active, phosphorylated SYK has been observed in tissues from patients with SLE or cutaneous lupus erythematosus, and its inhibition is hypothesized to ameliorate disease pathogenesis. We sought to evaluate the efficacy and characterize the mechanism of action of lanraplenib, a selective oral SYK inhibitor, in the New Zealand black/white (NZB/W) murine model of SLE and LN. METHODS: Lanraplenib was evaluated for inhibition of primary human B cell functions in vitro. Furthermore, the effect of SYK inhibition on ameliorating LN-like disease in vivo was determined by treating NZB/W mice with lanraplenib, cyclophosphamide, or a vehicle control. Glomerulopathy and immunoglobulin G (IgG) deposition were quantified in kidneys. The concentration of proinflammatory cytokines was measured in serum. Splenocytes were analyzed by flow cytometry for B cell maturation and T cell memory maturation, and the presence of T follicular helper and dendritic cells. RESULTS: In human B cells in vitro, lanraplenib inhibited B cell activating factor-mediated survival as well as activation, maturation, and immunoglobulin M production. Treatment of NZB/W mice with lanraplenib improved overall survival, prevented the development of proteinuria, and reduced blood urea nitrogen concentrations. Kidney morphology was significantly preserved by treatment with lanraplenib as measured by glomerular diameter, protein cast severity, interstitial inflammation, vasculitis, and frequency of glomerular crescents; treatment with lanraplenib reduced glomerular IgG deposition. Mice treated with lanraplenib had reduced concentrations of serum proinflammatory cytokines. Lanraplenib blocked disease-driven B cell maturation and T cell memory maturation in the spleen. CONCLUSIONS: Lanraplenib blocked the progression of LN-like disease in NZB/W mice. Human in vitro and murine in vivo data suggest that lanraplenib may be efficacious in preventing disease progression in patients with LN at least in part by inhibiting B cell maturation. These data provide additional rationale for the use of lanraplenib in the treatment of SLE and LN.

Early adolescent Body Mass Index and the constructed environment.

Previous research has shown that macro-level environmental features such as access to walking trails and recreational facilities are correlated with adolescent weight. Additionally, a handful of studies have documented relationships between micro-level environmental features, such as the presence (or absence) of a television in the bedroom, and adolescent weight. In this exploratory study we focus exclusively on features of the micro-level environment by examining objects that are found within adolescent personal bedrooms in relation to the adolescent occupant's Body Mass Index score (BMI). Participants were 234 early adolescents (eighth graders and ninth graders) who lived with both biological parents and who had their own private bedroom. Discriminant analyses were used to identify the bedrooms belonging to adolescents with below and above average BMI using objects contained within the micro-level environment as discriminating variables. Bedrooms belonging to adolescents with above average BMI were more likely to contain objects associated with sedentary behavior (e.g., magazines, electronic games, dolls), whereas the bedrooms belonging to the average and below average BMI adolescents were more likely to contain objects that reflect past physical activity (e.g., trophies, souvenirs, pictures of places that they had visited). If causal connections between micro-environmental variables and adolescent BMI can be established in future longitudinal research, environmental manipulations may affect adolescent BMI.

Texting and accessing the web while driving: traffic citations and crashes among young adult drivers.

OBJECTIVE: We examined relations between young adult texting and accessing the web while driving with driving outcomes (viz. crashes and traffic citations). Our premise is that engaging in texting and accessing the web while driving is not only distracting but that these activities represent a pattern of behavior that leads to an increase in unwanted outcomes, such as crashes and citations. METHODS: College students (N = 274) on 3 campuses (one in California and 2 in Utah) completed an electronic questionnaire regarding their driving experience and cell phone use. RESULTS: Our data indicate that 3 out of 4 (74.3%) young adults engage in texting while driving, over half on a weekly basis (51.8%), and some engage in accessing the web while driving (16.8%). Data analysis revealed a relationship between these cell phone behaviors and traffic citations and crashes. CONCLUSION: The findings support Jessor and Jessor's (1977) "problem behavior syndrome" by showing that traffic citations are related to texting and accessing the web while driving and that crashes are related to accessing the web while driving. Limitations and recommendations are discussed.

Bedroom design and decoration: gender differences in preference and activity.

This investigation examined gender differences in niche-building preference and activity among 238 8th and 9th grade boys and girls. A questionnaire was developed to measure both the actual and preferred bedroom content, bedroom design activity, and the level of perceived influence by the immediate and extended family, friends, and social institutions. Gender differences were identified for preference, activity, and influence in bedroom design and decoration. Girls and boys differed in the type of items contained in their bedrooms. Girls' rooms contained stuffed animals and pictures of people, including themselves, more frequently than the boys' rooms. In contrast, boys' rooms contained sports-related items, and things for building or that they had built themselves. Although bedroom design activity for both boys and girls was influenced by older teens, friends, media, and popular culture, boys (but not girls) were also influenced by their mothers, fathers, girlfriends, and activities such as sports, Boy or Girl Scouts, and music lessons.