Leou-Chyr Lin

In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share structural similarity with quercetin, a potent anti-inflammatory flavonoid present in many different fruits and vegetables. We investigated the immunomodulatory effects of this compound, namely 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02), in a side-by-side comparison with quercetin. Chondrocytes were isolated from pig joints or the joints of patients with osteoarthritis that had undergone total knee replacement surgery. Several measures were used to assess the immunomodulatory potency of these compounds in tumor necrosis factor (TNF-α)-stimulated chondrocytes. Characterization included the protein and mRNA levels of molecules associated with arthritis pathogenesis as well as the inducible nitric oxide synthase (iNOS)–nitric oxide (NO) system and matrix metalloproteinases (MMPs) in cultured chondrocytes and proteoglycan, and aggrecan degradation in cartilage explants. We also examined the activation of several important transcription factors, including nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-3 (STAT-3), and activator protein-1 (AP-1). Our overall results indicate that the immunomodulatory potency of Cf-02 is fifty-fold more efficient than that of quercetin without any indication of cytotoxicity. When tested in vivo using the induced edema method, Cf-02 was shown to suppress inflammation and cartilage damage. The proposed method shows considerable promise for the identification of candidate disease-modifying immunomodulatory drugs and leads compounds for arthritis therapeutics.

Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only limited or no toxicity for long-term use. Because the antitussive medication dextromethorphan (DXM) is protective in atherosclerosis and neurological diseases, two common disorders in aged people, we examined whether DXM can be protective in pro-inflammatory cytokine-stimulated chondrocytes and in a collagen-induced arthritis (CIA) animal model in this study. Chondrocytes were prepared from cartilage specimens taken from pigs or OA patients. Western blotting, quantitative PCR, and immunohistochemistry were adopted to measure the expression of collagen II (Col II) and matrix metalloproteinases (MMP). DXM significantly restored tumor necrosis factor-alpha (TNF-α)-mediated reduction of collagen II and decreased TNF-α-induced MMP-13 production. To inhibit the synthesis of MMP-13, DXM blocked TNF-α downstream signaling, including I kappa B kinase (IKK)α/β-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) activation. Besides this, DXM protected the CIA mice from severe inflammation and cartilage destruction. DXM seemed to protect cartilage from inflammation-mediated matrix degradation, which is an irreversible status in the disease progression of osteoarthritis. The results suggested that testing DXM as an osteoarthritis therapeutic should be a focus in further research.

A triangle or an inverted triangle configuration, using failure of fixation as the primary outcome. Methods: Clinical and radiographic data for patients with intracapsular femoral neck fractures treated with either triangle fixation (one proximal screw and two distal screws) or inverted triangle fixation (two proximal screws and one distal screw), between January 1, 2000, and July 30, 2009, were analyzed. Results: A total of 202 patients, seventy-six men and 126 women with an average age (and standard deviation) of 64.53 ± 15.81 years (range, nineteen to ninety-three years), were included in the analysis. Union occurred in 158 patients, and nonunion occurred in forty-four. There were no differences between the union and nonunion groups with respect to age, sex, fracture side, fracture angle, fracture level, or estimated bone density. There were significant differences in fracture type, fixation configuration, reduction quality, and screw-tip subchondral purchase between patients with and without union. The estimated odds ratio for fracture nonunion was 2.93 (95% confidence interval [CI], 1.08, 7.96) in subjects with displaced fractures compared with those without displaced fractures (p = 0.035), 18.92 (95% CI, 1.91, 187.09) in subjects with borderline and unacceptable reduction compared with those with anatomic reduction (p = 0.012), and 2.92 (95% CI, 1.27, 6.69) for internal fixation with a triangle configuration compared with fixation with an inverted triangle configuration (p = 0.010). Conclusions: Screw fixation with a triangle configuration, a displaced fracture, and poor reduction are risk factors for nonunion in intracapsular femoral neck fractures treated with fixation with multiple screws. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence....