Small-molecule inhibition of extracellular proteins that activate membrane receptors has proved to be extremely challenging. Diversity-oriented synthesis and small-molecule microarrays enabled the discovery of robotnikinin, a small molecule that binds the extracellular Sonic Hedgehog (Shh) protein and blocks Shh-signaling in cell lines, human primary keratinocytes and a synthetic model of human skin. Shh pathway activity is rescued by small-molecule agonists of Smoothened, which functions immediately downstream of the Shh receptor Patched.
Palladium(0)-catalyzed reactions of
N-methanesulfonyl- or
N-(arenesulfonyl)-3-alkyl-2-vinylaziridines reveal that 2,3-cis-isomers are more stable than the
corresponding 2,3-trans-isomers in accord
with ab initio calculations. A highly stereoselective
synthetic route to (E)-alkene dipeptide
isosteres
having desired stereochemistries from
2,3-cis-3-isobutyl-2-vinylaziridine by the use of
organocopper
chemistry is also presented.
To compare the efficacy and adherence rates of two parallel home exercise therapy programs-multiple exercise (training and stretching the knee and hip muscles) and control (training the quadriceps muscles)-on knee pain, physical function, and knee extension strength in community-dwelling elderly individuals with pre-radiographic knee osteoarthritis (OA). One hundred patients with medial knee pain were randomly allocated to one of two 4-week home exercise programs. Individuals with a Kellgren/Lawrence (K/L) grade 0 or 1 OA (pre-radiographic knee OA) in the medial compartment were enrolled. Primary outcomes were knee pain (visual analog scale), self-reported physical function (Japanese Knee Osteoarthritis Measure [JKOM]), and isometric maximum muscle strength of the knee extensor measured using a hand-held dynamometer. A total of 52 patients (28 [53.8%] in the multiple exercise group, 24 [46.2%] in the control group) completed the trial. The JKOM activities of daily living and general health conditions outcomes improved significantly in the multiple exercise group compared to the control group (JKOM activities of daily living, beta = - 0.76; 95% confidence interval [CI], - 1.39 to - 0.13; p = 0.01; JKOM general health conditions, beta = - 0.25; 95% CI, - 0.48 to - 0.01; p = 0.03). The home exercise compliance rates of the multiple exercise and control groups were 96.6 and 100%, respectively. When targeting pre-radiographic knee OA in community-dwelling elderly, it is important to implement home exercise programs that aim to improve muscle strength and joint flexibility rather than knee extension muscle power only.
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