Spirometric and rhinomanometric measurements in patients with differing severities of nasal obstruction.

<p>Spirometric and rhinomanometric measurements in patients with differing severities of nasal obstruction.</p

Characteristics of the study population.

<p>Characteristics of the study population.</p

Spirometric and rhinomanometric measurements in patients aged < 12 years.

<p>Spirometric and rhinomanometric measurements in patients aged < 12 years.</p

Spirometric and rhinomanometric measurements in patients differentiated by symptoms of nasal obstruction.

<p>Spirometric and rhinomanometric measurements in patients differentiated by symptoms of nasal obstruction.</p

Family history of allergy from the allergic rhinitis questionnaire survey.

<p>Family history of allergy from the allergic rhinitis questionnaire survey.</p

The role of transthoracic ultrasonography in predicting the outcome of community-acquired pneumonia in hospitalized children - Fig 4

<p>(A) Chest radiograph of a 12-year-old boy with left lower lung pneumonia. (B) Transthoracic ultrasonography revealed multiple B-lines (arrows) in the left anterior lower lung.</p

KMUP-1 Suppresses RANKL-Induced Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss: Roles of MAPKs, Akt, NF-κB and Calcium/Calcineurin/NFATc1 Pathways

<div><p>Background</p><p>KMUP-1 is a xanthine derivative with inhibitory activities on the phosphodiesterase (PDE) 3,4 and 5 isoenzymes to suppress the degradation of cyclic AMP and cyclic GMP. However, the effects of KMUP-1 on osteoclast differentiation are still unclear. In this study, we investigated whether KMUP-1 inhibits osteoclastogenesis induced by RANKL in RAW 264.7 cells and bone loss induced by ovariectomy in mice, and the underlying mechanisms.</p><p>Principal Findings</p><p><i>In vitro</i>, KMUP-1 inhibited RANKL-induced TRAP activity, the formation of multinucleated osteoclasts and resorption-pit formation. It also inhibited key mediators of osteoclastogenesis including IL-1β, IL-6, TNF-α and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-κB), mRNA expression of osteoclastogensis-associated genes (TRAP, MMP-9, Fra-1, and cathepsin K) and transcription factors (c-Fos and NFATc1). Furthermore, most inhibitory effects of KMUP-1 on RANKL-mediated signal activations were reversed by a protein kinase A inhibitor (H89) and a protein kinase G inhibitor (KT5823). <i>In vivo</i>, KMUP-1 prevented loss of bone mineral content, preserved serum alkaline phosphate and reduced serum osteocalcin in ovariectomized mice.</p><p>Conclusions</p><p>KMUP-1 inhibits RANKL-induced osteoclastogenesis <i>in vitro</i> and protects against ovariectomy-induced bone loss <i>in vivo</i>. These effects are mediated, at least in part, by cAMP and cGMP pathways. Therefore, KMUP-1 may have a role in pharmacologic therapy of osteoporosis.</p></div

Effects of KMUP-1 on bone loss in ovariectomized (OVX) mice.

<p>(<b>A</b>) OVX mice were sacrificed after 30 days of KMUP-1 treatment. Images of the longitudinal and transverse sections of the proximal tibia were obtained with a µCT. (<b>B</b>, <b>C</b>) Tibial trabecular bone mineral content (BMC) and bone volume/tissue volume (BV/TV, %) were quantified from data obtained by the µCT. All values are expressed as mean ± S.E.M. ^#<i>P</i><0.05 compared with the Sham group;^*<i>P</i><0.05 compared with the OVX group.</p

Effects of KMUP-1 on RANKL-induced osteoclastogenesis.

<p>RAW264.7 cells were cultured with RANKL (10 ng/ml) for 5 days to induce osteoclast differentiation, with treatment of KMUP-1 (0–10 µM) to assess its anti-osteoclastogenic effects. In addition, cells treated with KMUP-1 (10 µM) had pretreatment of PKA inhibitor H89 (10 µM) and PKG inhibitor KT5823 (3 µM) to determine underlying mechanisms. (<b>A</b>) After 5 days of culture, TRAP positive cells and multinucleated osteoclasts were counted under the microscope. (<b>B</b>) The number of TRAP-positive multinucleated cells was counted. (<b>C</b>) TRAP activity was measured at 405 nm. Each value represents the mean ± S.E.M. of three independent experiments, with triplicate determinations in each experiment. ^##<i>P</i><0.01 compared with control; *<i>P</i><0.05, **<i>P</i><0.01 compared with RANKL alone; ⁺<i>P</i><0.05 compared with KMUP-1 10 µM plus RANKL.</p

Effects of KMUP-1 on RANKL-induced pit formation in mature osteocalsts.

<p>(<b>A</b>) Mature osteoclasts were treated with RANKL (10 ng/ml) and KMUP-1 <b>(</b>1–10<b> </b>µM) for 48 h. Pit formation on the disc was observed by optical microscopy. (<b>B</b>) Pit areas were quantified using Image Pro Plus analyzer Version 4.6 (Media Cybernetics Inc., MD). Each value represents the mean ± S.E.M. of three independent experiments, with triplicate determinations in each experiment. *<i>P</i><0.05, **<i>P</i><0.01 compared with RANKL alone.</p