Faculty Bibliography

AIM/OBJECTIVE:The aim of this study was to compare the symptomatic and clinical features of depression among five groups of patients with major depressive disorder (MDD) living in China, Korea, Malaysia/Singapore, Taiwan, and Thailand. METHODS:Consecutive consenting adults (aged 18-65) who met DSM-IV criteria for non-psychotic MDD – based on the Mini International Neuropsychiatric Interview – and who were free of psychotropic medication were evaluated in a cross-sectional study. Depressive symptoms were evaluated using the 10-item Montgomery–Asberg Depression Rating Scale (MADRS) and the 13-item depression subscale of the Symptoms Checklist 90-Revised (SCL-90-R). In addition, the 10-item SCL-90-R Anxiety Subscale was completed. ancova were conducted, adjusting for confounders: age, completion of secondary education, marital status, work status, religion, index episode duration, and depressive severity. For the magnitude of differences, a threshold of 0.10 was taken as the minimum effect size representing clinical significance, and an effect size of 0.25 was considered moderate. RESULTS:Four MADRS symptoms differentiated these five groups, the most prominent being ‘lassitude’ and ‘inner tension’. Nine SCL-90-R depression items also differentiated the groups, as did eight SCL-90-R Anxiety Subscale items. The MADRS lassitude item had the largest effect size (0.131). The rest of those statistically significant differences did not exceed 0.10. CONCLUSION/CONCLUSIONS:MDD is more similar than different among outpatients in these diverse Asian countries. The between-country differences, while present and not due to chance, are small enough to enable the use of common clinician and self-report rating scales in studies involving Asians with MDD from various ethnic backgrounds.

Activation of adenosine A2A receptor (A2AR) promotes fibrosis and collagen synthesis. However, the underlying mechanism is still unclear, not least because cAMP, its principal effector, has been found to inhibit TGFbeta1-induced collagen synthesis. Here, we show that in primary normal human dermal fibroblasts, A2AR stimulation with CGS21680 elicits a modest cAMP increase (150+/-12% of control; EC50 54.8 nM), which stimulates collagen1 (Col1) and collagen3 (Col3), but maximal cAMP resulting from direct activation of adenylyl cyclase by forskolin (15,689+/-7038% of control; EC50 360.7 nM) inhibits Col1 and increases Col3. Similar to Col1 expression, fibroblast proliferation increased following physiological cAMP increases by CGS21680 but was inhibited by cAMP increases beyond the physiological range by forskolin. The A2AR-mediated increase of Col1 and Col3 was mediated by AKT, while Col3, but not Col1, expression was dependent on p38 and repressed by ERK. TGFbeta1 induced phosphorylation of Smad2/3 and increased Col3 expression, which was prevented by Smad3 depletion. In contrast, CGS21680 did not activate Smad2/3, and Smad2/3 knockdown did not prevent CGS21680-induced Col1 or Col3 increases. Our results indicate that cAMP is a concentration-dependent switch for collagen production via noncanonical, AKT-dependent, Smad2/3-independent signaling. These observations explain the paradoxical effects of cAMP on collagen expression.-Perez-Aso, M., Fernandez, P., Mediero, A., Chan, E. S., and Cronstein, B. N. Adenosine 2A receptor promotes collagen production by human fibroblasts via pathways involving cyclic AMP and AKT but independent of Smad2/3.

Adenosine has an important role in inflammation and tissue remodeling and promotes dermal fibrosis by adenosine receptor (A2AR) activation. Adenosine may be formed intracellularly from adenine nucleotides or extracellularly through sequential phosphohydrolysis of released ATP by nucleoside triphosphate diphosphohydrolase (CD39) and ecto-5'-nucleotidase (CD73). Because the role of these ecto-enzymes in fibrosis appears to be tissue specific, we determined whether these ectonucleotidases were directly involved in diffuse dermal fibrosis. Wild-type and mice globally deficient in CD39 knockout (CD39KO), CD73 (CD73KO), or both (CD39/CD73DKO) were challenged with bleomycin. Extracellular adenosine levels and dermal fibrosis were quantitated. Adenosine release from skin cultured ex vivo was increased in wild-type mice after bleomycin treatment but remained low in skin from CD39KO, CD73KO, or CD39/CD73DKO bleomycin-treated mice. Deletion of CD39 and/or CD73 decreased the collagen content, and prevented skin thickening and tensile strength increase after bleomycin challenge. Decreased dermal fibrotic features were associated with reduced expression of the profibrotic mediators, transforming growth factor-beta1 and connective tissue growth factor, and diminished myofibroblast population in CD39- and/or CD73-deficient mice. Our work supports the hypothesis that extracellular adenosine, generated in tandem by ecto-enzymes CD39 and CD73, promotes dermal fibrogenesis. We suggest that biochemical or biological inhibitors of CD39 and/or CD73 may hold promise in the treatment of dermal fibrosis in diseases such as scleroderma.

As one of the most utilized disease-modifying anti-rheumatic drugs, methotrexate (MTX) has revolutionized the treatment of rheumatoid arthritis as well as many other non-rheumatic chronic inflammatory diseases. Far from a simple anti- proliferative agent as was once thought, our understanding of how it exerts its anti-inflammatory effects has grown over the years. The mechanisms of action of MTX are reviewed here, and we look at how this knowledge helps to explain some of its most common side effects.