Background and purpose: Stimulation of astrocytes by the a 2 -adrenoceptor agonist dexmedetomidine, a neuroprotective drug, transactivates epidermal growth factor (EGF) receptors. The present study investigates signal pathways leading to release of an EGF receptor ligand and those activated during EGF receptor stimulation, and the response of neurons to dexmedetomidine and to astrocyte-conditioned medium. Experimental approach: Phosphorylation of ERK 1/2 was determined by western blotting and immunocytochemistry, and phosphorylation of EGF receptors by immunoprecipitation and western blotting. mRNA expression of fos family was measured by RT-PCR. Key results: Pertussis toxin (0.2 mg ml À1 ) an inhibitor of bg subunit dissociation from Ga i protein, and GF 109203X (500 nM), a protein kinase C inhibitor, abolished ERK 1/2 phosphorylation. PP1 (10 mM), inhibiting Src kinase and GM 6001 (10 mM), an inhibitor of Zn-dependent metalloproteinase, abolished ERK 1/2 phosphorylation by dexmedetomidine (50 nM), but not that by EGF (10 ng ml À1 ), showing Src kinase and metalloproteinase activation during the first stage only; AG 1478 (1 mM), an inhibitor of the EGF receptor tyrosine kinase, abolished ERK 1/2 phosphorylation. Dexmedetomidine-induced EGF receptor phosphorylation was prevented by AG 1478, GM 6001, PP1 and GF 109203X and its induction of cfos and fosB by AG 1478 and by U0126 (10 mM), an inhibitor of ERK phosphorylation, indicating downstream effects of ERK 1/2 phosphorylation. EGF and conditioned medium from dexmedetomidine-treated astrocytes, but not dexmedetomidine itself, induced ERK phosphorylation in primary cultures of cerebellar neurons. Conclusions and implications: Dexmedetomidine-induced transactivation pathways were delineated. Its paracrine effect on neurons may account for its neuroprotective effects.

OBJECTIVE:To compare clinical outcomes between patellar resurfacing and nonresurfacing in total knee arthroplasty (TKA). METHODS: Data from osteoarthritis patients who underwent TKA and were followed up for ≥ 9 years were analysed retrospectively. Patients were divided into two groups: patellar nonresurfacing group and patellar resurfacing group. In the nonresurfacing group, the partial lateral facet of the patella was removed, the patella was reshaped to match the trochlea of the femoral prosthesis and circumpatellar denervation was performed. In the resurfacing group, the patella was resurfaced with a cemented component. Clinical outcomes included incidence of anterior knee pain, Knee Society Score, patient satisfaction, revision rate and radiographic findings. RESULTS: Of the 130 patients included, 71 were assigned to the nonresurfacing group and 59 to the resurfacing group. No significant between-group differences were observed for any clinical outcomes measured. The incidence of anterior knee pain was 14.1% (nonresurfacing group) and 5.1% (resurfacing group). The revision rate was 9.89% (nonresurfacing group) and 3.4% (resurfacing group). CONCLUSION: Clinical outcomes for patellar nonresurfacing, including patelloplasty and circumpatellar denervation, are similar to those for patellar resurfacing, in TKA.

Terbinafine inhibits the proliferation of many types of cancer cells, but the underlying mechanism remains to be determined. By computer simulation, we found that kinase suppressor of Ras 1 (KSR1) is a possible target of terbinafine. Treatment of human oral squamous cell carcinoma (OSCC) KB cells with either terbinafine or siRNA to knockdown KSR1 reduced proliferation and induced apoptosis, which was accompanied by suppression of the Raf-MEK-ERK pathway. In vivo, KSR1 expression was significantly associated with the clinical staging of OSCC and the smoking habit of patients. Kaplan Meyer survival analysis demonstrated that the cumulative survival time of patients without KSR1 expression was significantly longer than those with KSR1 overexpression. Our data provide the basis for developing terbinafine to treat OSCC.

We investigated the development of the sinus node of the heart conduction system by localizing hyperpolarization-activated cyclic nucleotide-gated cation channel 4 (HCN4) and connexin43 (Cx43) in the hearts of fetal day 13 mice. Horizontal serial sections of day 13 whole fetuses were stained by hematoxylin and eosin and immunofluorescence to identify myocardial cells that express HCN4, hyperpolarization-activated cyclic nucleotide-gated cation channel 2 (HCN2) and Cx43. Expression levels of HCN4 and Cx43 were determined by quantitative RT-PCR in both fetal day 13 and adult mice. We found that both Cx43 and HCN4 expressions were located on the cell membranes in the hearts of fetal day 13 mice, but Cx43 was distributed throughout the myocardial cells. HCN4 expression was concentrated mainly in the left dorsal epicardium of the right atrium where Cx43 expression was low or absent. Quantitative RT-PCR demonstrated that HCN4 expression was significantly higher and HCN2 expression was significantly lower in fetal day 13 mice than in adults. We found no statistically significant difference in Cx43 expression between fetal day 13 mice and adults. HCN4 stained myocardial cells in the left dorsal epicardium of the right atrium are the origin of the sinus node and the remainder of the heart conduction system.