Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation.

Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.

Voxel-based analysis of gray matter and CSF space in idiopathic normal pressure hydrocephalus.

AIMS: To investigate regional morphologic changes in idiopathic normal pressure hydrocephalus (INPH) based on diagnosis with INPH Guidelines using voxel-based morphometry. METHOD: Three-dimensional magnetic resonance imaging was performed in 34 INPH patients, who met probable INPH criteria, probable 34 Alzheimer disease patients, and 34 normal control subjects. RESULTS: Statistical parametric mapping was used to conduct voxel-based morphometry analysis of the morphologic data and revealed enlarged ventricles and sylvian fissures and stenotic sulci of high convexity, especially in the precuneus in the INPH group, with decreased gray matter density in the insula, caudate and thalamus. CONCLUSION: In INPH, morphologic change occurs in the frontoparietal high convexity with ventricular dilatations, dilated sylvian fissures and tight sulci in the medial parietal lobes.

Fexofenadine improves the quality of life and work productivity in Japanese patients with seasonal allergic rhinitis during the peak cedar pollinosis season.

BACKGROUND: Although currently in its infancy, quality of life (QOL) research in Japan is rapidly expanding and is expected to become a standard outcome measure in clinical trials. In Japan, QOL has not previously been assessed in patients with allergic rhinitis (AR); we report the first clinical study applying the recently validated Japanese translations of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) Questionnaire to assess the effects of the oral antihistamine, fexofenadine, on QOL and work productivity due to cedar pollinosis. PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled, single-site study was conducted during the peak cedar pollinosis season in Japan. After a 7-day run-in period, subjects were randomized to receive fexofenadine HCl 60 mg twice daily (bid) or placebo for 2 weeks. RESULTS: Overall, 206 Japanese subjects with AR were included in the intention-to- treat population (fexofenadine, n = 104, and placebo, n = 102). Fexofenadine statistically significantly improved overall QOL compared with placebo (p = 0.005) and improvements were reported in the RQLQ domains: activities (p = 0.047), practical problems (p = 0.003), nasal symptoms (p = 0.003) and eye symptoms (p