Patellar Impingement on Tibial Polyethylene after Primary Total Knee Arthroplasty without Patellar Resurfacing.

Patellar impingement on tibial polyethylene (PIP) is one potential complication of total knee arthroplasty (TKA). When PIP occurs, it is often related to inaccurate restoration of the joint line or due to soft-tissue contracture. We investigated the prevalence and etiology of PIP in Asian patients with deeply flexed knees following posterior stabilized (PS)-TKA. We retrospectively reviewed 54 patients (65 knees) with PIP after primary PS-TKAs without patellar resurfacing performed between 2008 and 2011. These patients were compared with a group of 124 patients (130 knees) without PIP matched for age, sex, and body mass index (BMI). The minimum follow-up was 5 years (range, 5-8.1 years). Patients were evaluated by blinded, independent observers using the Oxford knee score, the Waters score, and radiographic parameters. Impingement between the patella and the tibial polyethylene had a mean onset of 13.5 months after PS-TKA. The development of PIP was significantly associated with change in patellar tendon length (odds ratio [OR] = 11.4, 95% confidence interval [CI]: 11.2-11.6%), shorter postoperative patellar tendon length (OR = 2.1, 95% CI: 1.8-2.5%), change in the Insall-Salvati ratio (OR = 0.9, 95% CI: 0.8-1.0%), and joint line elevation (OR = 5.3, 95% CI: 4.8-5.8%) on multiple logistic regression analysis. Our findings reinforce the importance of accurate joint line restoration and the avoidance of iatrogenic injury to the patellar tendon, which can lead to shortening of the patellar tendon. This is a retrospective comparative study and its level of evidence is III.

Diesel particulate matter2.5 promotes epithelial-mesenchymal transition of human retinal pigment epithelial cells via generation of reactive oxygen species.

Although several studies have linked PM2.5 (particulate matter with a diameter less than 2.5 µm) to ocular surface diseases such as keratitis and conjunctivitis, very few studies have previously addressed its effect on the retina. Therefore, the aim of this study was to evaluate the effect of PM2.5 on epithelial-mesenchymal transition (EMT), a process involved in disorders of the retinal pigment epithelial (RPE) on APRE-19 cells. PM2.5 changed the phenotype of RPE cells from epithelial to fibroblast-like mesenchymal, and increased cell migration. Exposure to PM2.5 markedly increased the expression of mesenchymal markers, but reduced the levels of epithelial markers. Moreover, PM2.5 promoted the phosphorylation of MAPKs and the expression of transforming growth factor-ß (TGF-ß)-mediated nuclear transcriptional factors. However, these PM2.5-mediated changes were completely reversed by LY2109761, a small molecule inhibitor of the TGF-ß receptor type I/II kinases, and N-acetyl-L-cysteine (NAC), a reactive oxygen species (ROS) scavenger. Interestingly, NAC, but not LY2109761, effectively restored the PM2.5-induced mitochondrial defects, including increased ROS, decreased mitochondrial activity, and mitochondrial membrane potential disruption. Collectively, our findings indicate that the TGF-ß/Smad/ERK/p38 MAPK signaling pathway is activated downstream of cellular ROS during PM2.5-induced EMT. The present study provides the first evidence that EMT of RPE may be one of the mechanisms of PM2.5-induced retinal dysfunction.

Isorhamnetin Induces Cell Cycle Arrest and Apoptosis Via Reactive Oxygen Species-Mediated AMP-Activated Protein Kinase Signaling Pathway Activation in Human Bladder Cancer Cells.

Isorhamnetin is an O-methylated flavonol that is predominantly found in the fruits and leaves of various plants, which have been used for traditional herbal remedies. Although several previous studies have reported that this flavonol has diverse health-promoting effects, evidence is still lacking for the underlying molecular mechanism of its anti-cancer efficacy. In this study, we examined the anti-proliferative effect of isorhamnetin on human bladder cancer cells and found that isorhamnetin triggered the gap 2/ mitosis (G2/M) phase cell arrest and apoptosis. Our data showed that isorhamnetin decreased the expression of Wee1 and cyclin B1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdk1. In addition, isorhamnetin-induced apoptosis was associated with the increased expression of the Fas/Fas ligand, reduced ratio of B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein (Bax) expression, cytosolic release of cytochrome c, and activation of caspases. Moreover, isorhamnetin inactivated the adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway by diminishing the adenosine triphosphate (ATP) production due to impaired mitochondrial function. Furthermore, isorhamnetin stimulated production of intracellular reactive oxygen species (ROS); however, the interruption of ROS generation using a ROS scavenger led to an escape from isorhamnetin-mediated G2/M arrest and apoptosis. Collectively, this is the first report to show that isorhamnetin inhibited the proliferation of human bladder cancer cells by ROS-dependent arrest of the cell cycle at the G2/M phase and induction of apoptosis. Therefore, our results provide an important basis for the interpretation of the anti-cancer mechanism of isorhamnetin in bladder cancer cells and support the rationale for the need to evaluate more precise molecular mechanisms and in vivo anti-cancer properties.

Induction of G2/M Cell Cycle Arrest and Apoptosis by Genistein in Human Bladder Cancer T24 Cells through Inhibition of the ROS-Dependent PI3k/Akt Signal Transduction Pathway.

We examined the anti-cancer effect of genistein, a soy-derived isoflavone, in human bladder transitional cell carcinoma T24 cells. According to our data, genistein induced G2/M phase arrest of the cell cycle and apoptosis. Genistein down-regulated the levels of cyclin A and cyclin B1, but up-regulated the levels of p21WAF1/CIP1, cyclin-dependent kinase (Cdk) inhibitor, that was complexed with Cdc2 and Cdk2. Furthermore, genistein induced the activation of caspases (caspase-3, -8 and -9), and cleavage of poly (ADP-ribose) polymerase cleavage. However, genistein-induced apoptosis was significantly inhibited by a pan-caspase inhibitor, indicating that the induction of apoptosis by genestein was caspase-dependent. In addition, genistein increased the cytosolic release of cytochrome c by increasing the Bax/Bcl-2 ratio and destroying mitochondria integrity. Moreover, genistein inactivated the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, while LY294002, a PI3K/Akt inhibitor, increased the apoptosis-inducing effect of genistein. Genistein further increased the accumulation of reactive oxygen species (ROS), which was significantly suppressed by N-acetyl cysteine (NAC), a ROS scavenger, and in particular, NAC prevented genistein-mediated inactivation of PI3K/Akt signaling, G2/M arrest and apoptosis. Therefore, the present results indicated that genistein promoted apoptosis induction in human bladder cancer T24 cells, which was associated with G2/M phase cell cycle arrest via regulation of ROS-dependent PI3K/Akt signaling pathway.

Anti-Proliferative and Pro-Apoptotic Effects of Licochalcone A through ROS-Mediated Cell Cycle Arrest and Apoptosis in Human Bladder Cancer Cells.

Licochalcone A (LCA) is a chalcone that is predominantly found in the root of Glycyrrhiza species, which is widely used as an herbal medicine. Although previous studies have reported that LCA has a wide range of pharmacological effects, evidence for the underlying molecular mechanism of its anti-cancer efficacy is still lacking. In this study, we investigated the anti-proliferative effect of LCA on human bladder cancer cells, and found that LCA induced cell cycle arrest at G2/M phase and apoptotic cell death. Our data showed that LCA inhibited the expression of cyclin A, cyclin B1, and Wee1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdc2 and Cdk2. LCA activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, LCA increased the Bax/Bcl-2 ratio, and reduced the integrity of mitochondria, which contributed to the discharge of cytochrome c from the mitochondria to the cytoplasm. Moreover, LCA enhanced the intracellular levels of reactive oxygen species (ROS); however, the interruption of ROS generation using ROS scavenger led to escape from LCA-mediated G2/M arrest and apoptosis. Collectively, the present data indicate that LCA can inhibit the proliferation of human bladder cancer cells by inducing ROS-dependent G2/M phase arrest and apoptosis.

Morin enhances auranofin anticancer activity by up-regulation of DR4 and DR5 and modulation of Bcl-2 through reactive oxygen species generation in Hep3B human hepatocellular carcinoma cells.

Evidence suggests that auranofin (AF) exhibits anticancer activity by inhibiting thioredoxin reductase (TrxR). Here, in this study, we have investigated the synergistic effects of AF and morin and their mechanism for the anticancer effects focusing on apoptosis in Hep3B human hepatocellular carcinoma cells. We assessed the anticancer activities by annexin V/PI double staining, caspase, and TrxR activity assay. Morin enhances the inhibitory effects on TrxR activity of AF as well as reducing cell viability. Annexin V/PI double staining revealed that morin/AF cotreatment induced apoptotic cell death. Morin enhances AF-induced mitochondrial membrane potential (ΔΨm) loss and cytochrome c release. Further, morin/AF cotreatment upregulated death receptor DR4/DR5, modulated Bcl-2 family members (upregulation of Bax and downregulation of Bcl-2), and activated caspase-3, -8, and -9. Morin also enhances AF-induced reactive oxygen species (ROS) generation. The anticancer effects results from caspase-dependent apoptosis, which was triggered via extrinsic pathway by upregulating TRAIL receptors (DR4/DR5) and enhanced via intrinsic pathway by modulating Bcl-2 and inhibitor of apoptosis protein family members. These are related to ROS generation. In conclusion, this study provides evidence that morin can enhance the anticancer activity of AF in Hep3B human hepatocellular carcinoma cells, indicating that its combination could be an alternative treatment strategy for the hepatocellular carcinoma.

Mori Folium water extract alleviates articular cartilage damages and inflammatory responses in monosodium iodoacetate­induced osteoarthritis rats.

Mori folium, the leaf of Morus alba L. (Moraceae), has been widely used in traditional medicine for the treatment of various diseases. It has been recently reported that Mori folium possesses potential chondroprotective effects in interleukin (IL)­1ß­stimulated human chondrocytes; however, its protective and therapeutic potential against osteoarthritis (OA) in an animal model remains unclear. In this study, as part of an ongoing screening program to evaluate the anti­osteoarthritic potential of Mori folium, the protective effects of a water extract of Mori folium (MF) on cartilage degradation and inflammatory responses in a monosodium iodoacetate (MIA)­induced OA rat model were evaluated. The results demonstrated that administration of MF had a tendency to attenuate the damage to articular cartilage induced by MIA, as determined by knee joint swelling and the histological grade of OA. The elevated levels of matrix metalloproteinases­13 and two bio­markers for the diagnosis and progression of OA, such as the cartilage oligomeric matrix protein and C­telopeptide of type II collagen, were markedly ameliorated by MF administration in MIA­induced OA rats. In addition, MF significantly suppressed the production of pro­inflammatory cytokines, including IL­1ß, IL­6 and tumor necrosis factor­α. MF also effectively inhibited the expression of inducible nitric oxide (NO) synthase and cyclooxygenase­2, thus inhibiting the release of NO and prostaglandin E2. Although further work is required to fully understand the critical role and clinical usefulness, these findings indicate that MF may be a potential therapeutic option for the treatment of OA.

Auranofin, an inhibitor of thioredoxin reductase, induces apoptosis in hepatocellular carcinoma Hep3B cells by generation of reactive oxygen species.

Mammalian thioredoxin reductase (TrxR) plays a vital role in restoring cellular redox balance disrupted by reactive oxygen species (ROS) generation and oxidative damage. Here, we evaluated whether auranofin, a selective inhibitor of TrxR, could serve as a potential anti-cancer agent through its selective targeting of TrxR activity in Hep3B hepatocellular carcinoma cells. Auranofin treatment reduced the TrxR activity of these cells and induced apoptosis, which were accompanied by up-regulation of death receptors (DRs) and activation of caspases, as well as promotion of proteolytic degradation of poly(ADP-ribose)-polymerase. Treatment with a pan-caspase inhibitor reversed the auranofin-induced apoptosis and growth suppression, indicating that auranofin may induce apoptosis through a caspase-dependent mechanism involving both the intrinsic and extrinsic apoptotic pathways. Auranofin also significantly altered mitochondrial function, promoting mitochondrial membrane permeabilization and cytochrome c release by regulating Bcl-2 family proteins; these events were accompanied by an accumulation of ROS. Inhibition of ROS generation with the ROS quencher significantly attenuated the inactivation of TrxR in auranofin-treated cells and almost completely suppressed the auranofin-induced up-regulation of DRs and activation of caspases, thereby preventing auranofin-induced apoptosis and loss of cell viability. Taken together, these findings indicate that auranofin inhibition of TrxR activity in Hep3B cells activates ROS- and caspase-dependent apoptotic signaling pathways and triggers cancer cell death.

Clinical significance of microscopic anaplastic focus in papillary thyroid carcinoma.

BACKGROUND: On occasion, a microscopic anaplastic focus (MAF) is discovered in papillary thyroid carcinoma (PTC). The relevance of MAF has not been well studied with regard to its clinical implications. MAF is defined as the microscopic presence of focally dedifferentiated follicular cells within the PTC. METHODS: A total of 3,606 patients who underwent primary thyroid surgery between 1995 and 2007 were selected from the database of Seoul National University Hospital. Patients were divided into 3 groups based on histology: PTC without MAF (3,574 patients), PTC with MAF (13 patients), and anaplastic thyroid carcinoma (19 patients). RESULTS: Mean ± standard deviation age was 48 ± 12 years (range, 17-83) in the PTC without MAF group, 57 ± 14 years (range, 29-76) in the PTC with MAF group, and 64 ± 14 years (range, 24-86) in the ATC group (P < .001). Mean tumor sizes were 1.2 ± 0.9 cm (range, 0.5-13), 2.1 ± 1.2 cm (range, 0.7-5), and 3.7 ± 1.4 cm (range, 0.4-6), respectively (P < .001). The median follow-up was 32 months. The cause-specific survival at 5 years was 98% in the PTC without MAF group, 64% in the PTC with MAF group, and 11% in the ATC group (P < .001). Multivariate analysis showed that MAF was a prognostic factor for the outcome of PTC patients (hazard ratio, 12.9; 95% confidence interval, 3.1-54.1; P < .001). CONCLUSION: MAF negatively influenced the prognosis of patients with PTC. Further research and the design of more aggressive treatment strategies for MAF might be helpful for patients with PTC.

Extra-adrenal pheochromocytoma after operation of congenital heart disease: a case report of 18-year-old boy.

Extra-adrenal pheochromocytoma is rare and presents variable symptoms. Its difficulty to diagnosis delays appropriate treatment. We would like to report an unusual case of extra-adrenal pheochromocytoma. The patient came to the emergency room with dyspnea, palpitation, and cyanosis. He had a history of hospitalization for Fontan operation due to congenital heart disease. Despite medication, his blood pressure remained high. After additional laboratory and image exams, he was diagnosed with extra-adrenal pheochromocytoma and had surgical treatment. The final pathology report was extra-adrenal pheochromocytoma with high risk of malignancy. The postoperative course was uneventful and showed normal laboratory results even after 3 months of outpatient follow-up. Extra-adrenal pheochromocytoma presents variable symptoms. We should consider endocrinologic diseases like extra-adrenal pheochromocytoma in cases presenting with palpitation and high blood pressure, even with a past history of cardiac surgery.

Comparison of patellar retention versus resurfacing in LCS mobile-bearing total knee arthroplasty.

PURPOSE: The aim of this retrospective study was to compare clinical outcomes of total knee arthroplasty (TKA) with and without patellar resurfacing using the Low Contact Stress (LCS) mobile-bearing prosthesis in 275 osteoarthritic knees (199 patients) after a minimum of 7 years of follow-up. METHODS: Patients were divided into a patellar retention group (132 knees) and a resurfacing group (143 knees), with median follow-up durations of 7.8 years (range, 7-8.5 years) and 8.5 years (range, 7-10.6 years), respectively. The demographics of the two groups were otherwise matched. The patelloplasty was performed for patellar retention. Patients were evaluated by a blinded, independent observer using Feller's patellar score, the Knee Society score, patient satisfaction, patellar tilt, and lateral displacement. RESULTS: Patellar resurfacing was not superior to retention with respect to any of the measured variables. Eight knees (6.1%) without and 6 (4.2%) with patellar resurfacing had anterior knee pain related to the patellofemoral joint (n.s.). The reoperation rate related to the patellofemoral joint was 0.8% (n = 1) in the retention group compared with 2.8% (n = 4) in the resurfacing group (n.s.). In the 35 patients who underwent bilateral TKA with patellar resurfacing on only one side, there were no significant differences between the two sides in subjective preference, clinical scores, or functional ability. CONCLUSIONS: The clinical and radiographic outcomes of TKA with the LCS mobile-bearing prosthesis showed no significant difference between the two groups after a minimum of 7 years of follow-up. The findings in this study suggest that patellar retention with a patelloplasty may be viable as a routine procedure, even in knees with advanced patellofemoral arthritis, if soft tissue balancing and a patella-friendly prosthetic design are properly used. LEVEL OF EVIDENCE: Therapeutic, retrospective, comparative study, Level III.

Straight tapered titanium stem with alumina bearing in cementless primary total hip arthroplasty: a minimum 5-year follow-up.

The aim of this study was to assess the midterm results of primary cementless total hip arthroplasty using a tapered stem and alumina bearing couple in active patients. After a minimum of 5 years of follow-up, 78 arthroplasties in 72 patients were reviewed retrospectively. The mean Harris hip score was 94 points, and 2 hips had thigh pain. All components radiographically demonstrated stable fixation by bone ingrowth and mild stress shielding of the proximal femur were noted in 14% of hips. There was no significant osteolysis or aseptic loosening. There was a ceramic head fracture in 1 hip and audible sounds in 2 hips. The results of total hip arthroplasty with a straight, tapered, proximally porous-coated stem and alumina-on-alumina bearing were encouraging for active patients.