Interleukin (IL)-13 is a major inducer of fibrosis in many chronic infectious and autoimmune diseases. In studies of the mechanisms underlying such induction, we found that IL-13 induces transforming growth factor (TGF)-beta(1) in macrophages through a two-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL-13Ralpha(2). Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-alpha. Second, it involves IL-13 signaling through IL-13Ralpha(2) to activate an AP-1 variant containing c-jun and Fra-2, which then activates the TGFB1 promoter. In vivo, we found that prevention of IL-13Ralpha(2) expression reduced production of TGF-beta(1) in oxazolone-induced colitis and that prevention of IL-13Ralpha(2) expression, Il13ra2 gene silencing or blockade of IL-13Ralpha(2) signaling led to marked downregulation of TGF-beta(1) production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13Ralpha(2) signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-beta(1)-mediated fibrosis.

The objective of this study was to assess international trends in antipsychotic use, using a standardised methodology. A repeated cross-sectional design was applied to data extracts from the years 2005 to 2014 from 16 countries worldwide. During the study period, the overall prevalence of antipsychotic use increased in 10 of the 16 studied countries. In 2014, the overall prevalence of antipsychotic use was highest in Taiwan (78.2/1000 persons), and lowest in Colombia (3.2/1000). In children and adolescents (0-19 years), antipsychotic use ranged from 0.5/1000 (Lithuania) to 30.8/1000 (Taiwan). In adults (20-64 years), the range was 2.8/1000 (Colombia) to 78.9/1000 (publicly insured US population), and in older adults (65+ years), antipsychotic use ranged from 19.0/1000 (Colombia) to 149.0/1000 (Taiwan). Atypical antipsychotic use increased in all populations (range of atypical/typical ratio: 0.7 (Taiwan) to 6.1 (New Zealand, Australia)). Quetiapine, risperidone, and olanzapine were most frequently prescribed. Prevalence and patterns of antipsychotic use varied markedly between countries. In the majority of populations, antipsychotic utilisation and especially the use of atypical antipsychotics increased over time. The high rates of antipsychotic prescriptions in older adults and in youths in some countries merit further investigation and systematic pharmacoepidemiologic monitoring.

IntroductionInterleukin-13 (IL-13) and IL-4 are related multifunctional cytokines with similar biological activities on human B cells and monocytes. [1][2][3][4][5][6][7] The cognate receptors for these cytokines are complex and have been shown to share 2 chains with each other. [8][9][10][11][12] The IL-4 receptor system is well characterized and has been shown to be composed of a primary IL-4 binding protein, IL-4R␣ (also known as IL-4R␤). 13 This chain forms a heterodimer with either the IL-2R␥ c chain (type I IL-4R) or IL-13R␣1 (also known as IL-13R␣Ј) (type II IL-4R) for signaling. 11,[14][15][16][17] In some situations, all 3 chains (IL-4R␣, IL-2R␥ c , and IL-13R␣1) may constitute the IL-4R complex; however, whether all 3 chains are simultaneously required for IL-4 function is not known.In contrast, the receptor for IL-13 is less well characterized. We have studied the structure of IL-13R in various cell types and reported that IL-13 binds to 2 isoforms of an approximate 65-kDa protein in human renal cell carcinoma cells. [8][9][10][11][12] One of these proteins also binds 14 On the basis of the binding characteristics, cross-linking, and displacement of radiolabeled IL-4 and IL-13 in various cell types, we hypothesized that, as is the case for the IL-4R system, IL-13R may also be composed of 3 different types. [9][10][11][12] More recently, 2 different chains of the IL-13R system have been cloned. The murine and human IL-13R␣1 chain was first cloned. 14,18 This chain can bind IL-13 with low affinity, but, when coupled with the IL-4R␣ chain, the heterodimer binds IL-13 with high affinity and mediates IL-13-induced signaling. 14,18 The second chain of the IL-13R, termed IL-13R␣2 (also known as IL-13R␣), has also been cloned from a human renal cell carcinoma cell line (Caki-1). This chain shares approximately 50% homology with the IL-5R at the DNA level. It contains a very short intracellular domain and binds IL-13 with high affinity. 19 On the basis of the above studies, we have proposed that the type I IL-13R complex is composed of both chains of IL-13R (IL-13R␣1 and IL-13R␣2) and IL-4R␣ chain. Although IL-13 binds to all 3 chains, only the IL-13R␣1 and IL-4R␣ chains form a productive complex. Because of this arrangement, IL-13 binds to these cells strongly. Only IL-13, not IL-4, is able to displace the binding of 125 I-IL-13. In the type II IL-13R system, IL-13R␣2 is not present, and the IL-13R␣1 chain forms a complex with the IL-4R␣ chain. In these cells both interleukins compete for the binding of their radiolabeled cognaters. 12 The structure of the type III IL-13R is similar to that of type II receptors except that these cells also express the IL-2R␥ c chain. Although it appears that the IL-2R␥ c chain does not bind IL-13, it does affect IL-13 binding and function in some cell types. 20,21 After binding to their receptors, both IL-4 and IL-13 signal through phosphorylation-dependent activation of Jak kinases and signal transduction and activator of transcription (STAT) protein. 11,17,22 In particular,...