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Activation of the Wnt/β-catenin signaling pathway inhibits adipogenesis, while disruption of Wnt signaling leads to spontaneous adipogenesis. CCAAT/enhancer binding protein β (C/EBPβ) is rapidly induced in early stages of adipogenesis and is responsible for transcriptional induction of two major adipogenic transcription factors, peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα. In this study, we examined whether C/EBPβ is involved in the suppression of Wnt/β-catenin signaling during adipogenesis. Knockdown of C/EBPβ expression not only inhibited adipogenesis but also maintained active Wnt/β-catenin signaling, after addition of adipogenic inducers. In contrast, overexpression of C/EBPβ substantially inhibited Wnt signaling. Interestingly, our data showed that C/EBPβ is involved in the expression of Wnt10b, a major Wnt ligand in preadipocytes, even though C/EBPβ is not an essential factor to regulate Wnt10b expression during adipogenesis, and that C/EBPβ inhibits Wnt10b promoter activity by directly binding to specific regions of the promoter. These results suggest a dual function of C/EBPβ: stimulating expression of adipogenic genes and inhibiting Wnt signaling.

Study design Radiological analysis and classification of normal patterns of sagittal alignment of the spine. Objective To classify the patterns of sagittal alignment of the spine in young asymptomatic adults and analyze the differences in the various spinal and pelvic parameters according to these patterns. Summary of background data Previous studies reported that the overall sagittal pattern and balance were more important than the normative values. There are few studies on white populations, classifying the normal patterns of sagittal curvature, and no studies on Asian populations. Methods Whole spine, standing lateral radiographs of 86 Korean volunteers were taken. The pelvic and spinal parameters (total thoracic kyphosis, horizontal thoracic level, thoracolumbar junctional angle (TLJA), total lumbar lordosis, lower lumbar lordosis, horizontal lumbar level (HLL), lumbar inclination, pelvic tilt, sacral slope (SS), pelvic incidence, spinal balance, spinopelvic balance, and sacropelvic balance) were measured and the correlations of all parameters were analyzed. The volunteers were classified in to three types according to their HLL. The data were analyzed statistically to determine the differences in the parameters and balance between the three types. Results The HLL showed a significant correlation with the lumbar inclination, junctional level, TLJA, spinal balance, spinopelvic balance, and SS on analyzing the correlation of the parameters. As HLL moved caudally, the TLJA and lumbar inclination increased, whereas the lower lumbar lordosis, pelvic incidence, and SS decreased and spinal balance became more negative. There were no significant differences in total thoracic kyphosis and sacropelvic balance between the three types. Conclusion The patterns of sagittal alignment could be classified into three types showing that the spinal balance becomes more negative, the lumbar inclination and TLJA increase, the SS and pelvic incidence decrease, and lumbar lordotic curves becomes shorter as the patterns of sagittal curvature move toward type 3. This classification in young adults should be considered individually as a reference for surgeons aiming to restore the lumbar lordosis and sagittal alignment in degenerative lumbar fusion surgery.

Thiazolidinediones (TZDs) are synthetic ligands of peroxisome proliferator-activated receptor-γ (PPARγ), a member of the nuclear receptor superfamily. TZDs are known to increase insulin sensitivity and also to have an antioxidative effect. In this study, we tested whether TZDs protect pancreatic β-cells from oxidative stress, and we investigated the mechanism involved in this process. To generate oxidative stress in pancreatic β-cells (INS-1 and βTC3) or isolated islets, glucose oxidase was added to the media. The extracellular and intracellular reactive oxygen species (ROS) were measured to directly determine the antioxidant effect of TZDs. The phosphorylation of JNK/MAPK after oxidative stress was detected by Western blot analysis, and glucose-stimulated insulin secretion and cell viability were also measured. TZDs significantly reduced the ROS levels that were increased by glucose oxidase, and they effectively prevented β-cell dysfunction. The antioxidative effect of TZDs was abolished in the presence of a PPARγ antagonist, GW9662. Real-time PCR was used to investigate the expression levels of antioxidant genes. The expression of catalase, an antioxidant enzyme, was increased by TZDs in pancreatic β-cells, and the knockdown of catalase significantly inhibited the antioxidant effect of TZDs. These results suggest that TZDs effectively protect pancreatic β-cells from oxidative stress, and this effect is dependent largely on PPARγ. In addition, the expression of catalase is increased by TZDs, and catalase, at least in part, mediates the antioxidant effect of TZDs in pancreatic β-cells.

Background Sulfonylurea primarily stimulates insulin secretion by binding to its receptor on the pancreatic β-cells. Recent studies have suggested that sulfonylureas induce insulin sensitivity through peroxisome proliferator-activated receptor γ (PPARγ), one of the nuclear receptors. In this study, we investigated the effects of sulfonylurea on PPARγ transcriptional activity and on the glucose uptake via PPARγ. Methods Transcription reporter assays using Cos7 cells were performed to determine if specific sulfonylureas stimulate PPARγ transactivation. Glimepiride, gliquidone, and glipizide (1 to 500 µM) were used as treatment, and rosiglitazone at 1 and 10 µM was used as a control. The effects of sulfonylurea and rosiglitazone treatments on the transcriptional activity of endogenous PPARγ were observed. In addition, 3T3-L1 adipocytes were treated with rosiglitazone (10 µM), glimepiride (100 µM) or both to verify the effect of glimepiride on rosiglitazone-induced glucose uptake. Results Sulfonylureas, including glimepiride, gliquidone and glipizide, increased PPARγ transcriptional activity, gliquidone being the most potent PPARγ agonist. However, no additive effects were observed in the presence of rosiglitazone. When rosiglitazone was co-treated with glimepiride, PPARγ transcriptional activity and glucose uptake were reduced compared to those after treatment with rosiglitazone alone. This competitive effect of glimepiride was observed only at high concentrations that are not achieved with clinical doses. Conclusion Sulfonylureas like glimepiride, gliquidone and glipizide increased the transcriptional activity of PPARγ. Also, glimepiride was able to reduce the effect of rosiglitazone on PPARγ agonistic activity and glucose uptake. However, the competitive effect does not seem to occur at clinically feasible concentrations.

BACKGROUND: Correction of deformity in adult isthmic spondylolisthesis can affect the pelvic parameters and sagittal balance. OBJECTIVE: To evaluate the correlation with the amount of deformity correction and the subsequent change in pelvic parameters after surgical correction of adult isthmic spondylolisthesis and to determine which deformity parameter most affects the postoperative restoration of spinopelvic sagittal alignment. METHODS: Fifty-eight patients with 1-level isthmic spondylolisthesis were included. Their average age was 55 years (range, 24-76 years). All patients underwent operation by posterior lumbar interbody fusion and posterior instrumentation. The pre- and postoperative sacral slope, pelvic tilt, lumbar lordosis (LL), and sagittal balance were measured, and then the correlation between these parameters and deformity parameters such as slip degree, slip angle, and height of the intervertebral disc (HOD) was evaluated. RESULTS: The slip degree, slip angle, and HOD were significantly recovered after surgery. Pelvic parameters and sagittal balance changed subsequently. Sacral slope was increased by 4.4 degrees, and pelvic tilt was decreased by 4.4 degrees. LL was increased by 5.2 degrees and sagittal balance was displaced 5.6 mm posteriorly. Only the restoration of the HOD showed a significant correlation with the change in LL (r = 0.305, P = .02) and sagittal balance (r = 0.377, P = .004). CONCLUSION: Surgical correction of adult isthmic spondylolisthesis with posterior lumbar interbody fusion and posterior instrumentation resulted in improvement of sacral slope, pelvic tilt, LL, and sagittal balance. Only restoration of the HOD was significantly correlated with improvement of LL and sagittal balance. Therefore we presume it is important to restore the HOD in surgical correction of adult isthmic spondylolisthesis.

A retrospective study.To determine whether angular mismatch between the vertebral endplate and prosthetic endplate during lumbar total disc replacement (L-TDR) affects the radiological and clinical outcomes.A prosthesis anchored to the vertebral body by using a large central keel carries an inherent risk of angular mismatch between the vertebral endplate and prosthetic endplate at a segment with a greater degree of lordosis, such as L5-S1. Theoretically, this angular mismatch can cause several problems, such as segmental hyperlordosis, anterior positioning of the upper prosthesis, posterior prosthetic edge subsidence, decreased range of motion (ROM), and a poor clinical outcome.This study evaluated 64 prosthetic levels of 56 patients who were implanted with L-TDR between June 2002 and February 2006. There were 38 and 26 prosthetic levels at the L4-5 and L5-S1, respectively. The mean follow-up period was 25.6 (12 to 49) months. The angle of mismatch between the lower endplate of the upper vertebral body and the upper prosthetic plate, segmental flexion/extension ROM, segmental lordosis angle at extension, distance from the posterior wall of the vertebral body to the posterior prosthetic edge were measured by obtaining radiographs. Clinically, the Visual Analogue Scale and Oswestry Disability Index were also evaluated.The angular mismatches between the upper vertebra and prosthesis at L4-5 and L5-S1 were 1.6 degree and 5.6 degree, respectively (P0.001), at the final follow-up; these angles were not significantly different from those measured on radiographs obtained postoperatively (2.3 degree and 4.9 degree in L4-5 and L5-S1, respectively, P=0.324 in L4-5 and P=0.620 in L5-S1). The mean segmental ROM of the operated levels was 10.6 degree (4 to 22) and 6.1 degree (2 to 13) in the L4-5 and L5-S1, respectively (P0.001). The mean segmental ROM, mean segmental lordosis angle, and mean distance from the posterior margin of the vertebral body to the posterior edge of the prosthesis in L5-S1 were 6.8 degree (4 to 13), 12.8 degree (8 to 17), and 3.8 mm (1 to 6 mm) in patients with an angular mismatch of10 degree, and were 4.6 degree (2 to 7), 21.3 degree (19 to 25), and 6.0 mm (2 to 8 mm) in patients with an angular mismatch of more than 10 degree (P=0.024,0.001, and 0.039), respectively. In L4-5, there were only 2 cases with an angular mismatch of more than 5 degree, which had no statistical significance. There were no significant differences in the clinical outcomes, Visual Analogue Scale, and Oswestry Disability Index between patients with an angular mismatch of10 degree and those with an angular mismatch of more than 10 degree (P0.05).Angular mismatch was more common in L5-S1 than in L4-5. L-TDR at the most lordotic level, L5-S1, and implantation of an upper prosthesis with a mismatched angle seem to be the causes of a reduced segmental ROM, increased segmental lordosis, and anterior malpositioning of the prosthesis. However, these changes do not affect the clinical outcomes of patients.

Object Thoracic ossification of the ligamentum flavum (OLF), a main cause of thoracic myelopathy, is an uncommon disease entity. It is seen mostly in East Asia, although the majority of reports have issued from Japan. In the present study, the clinical features and prognostic factors of thoracic OLF were examined in a large number of Korean patients. Methods Data from 51 consecutive patients who underwent decompressive laminectomy with or without fusion for thoracic OLF between 1998 and 2008 were retrospectively analyzed. Patients were evaluated pre- and postoperatively using the modified Japanese Orthopedic Association (JOA) scale (maximum total score of 11). Patient age, sex, preoperative symptoms, duration of initial symptoms, number of involved segments, duration of follow-up, presence of dural adhesion (dural tearing), intramedullary high signal intensity, morphological classification of OLF (axial or sagittal), coexisting disease, and fusion or no fusion were also evaluated. Surgical outcomes were assessed using JOA recovery rate/outcome scores, and patient satisfaction grades and prognostic factors were analyzed. Results There were 18 men and 33 women with a mean age of 60.9 years (range 38–80 years). A mean preoperative JOA score of 5.5 improved to a mean score of 7.4 at the last follow-up (mean 52 months after surgery). The mean duration of the initial symptoms was 34.5 months (range 0.1–240 months) prior to surgery. The most common symptoms were motor dysfunction (80%); sensory deficit (67%); and pain, numbness, and claudication (59%) in the lower extremities. Knee hyperreflexia appeared in 69% of the patients. There were a total of 130 ossified segments, and the mean number of segments per patient was 2.6. Ninety-two (71%) of 130 segments were located below T-8. Recovery outcomes were good (18 patients), fair (16 patients), unchanged (11 patients), or worse (6 patients). Thirty-one patients (61%) were satisfied with their operations. Patients with a beak type of OLF on sagittal MR images experienced a higher recovery rate and a better satisfaction grade than did those with a round OLF. The patients with higher preoperative JOA scores demonstrated significantly higher JOA scores postoperatively (p < 0.001), and the preoperative JOA score had a significant correlation with the recovery rate in patients exhibiting mainly motor dysfunction (p = 0.040, r = 0.330). Conclusions Of the thoracic OLF studies published to date, the present analysis involves the largest Korean population. The most common symptoms of thoracic OLF were motor dysfunction and sensory deficit in the lower extremities, although pain, numbness, and claudication were observed in some patients and were notably accompanied by knee hyperreflexia. At a minimum of 2 years after surgery for thoracic OLF, operative outcomes were generally good, and the prognostic factors affecting good surgical outcomes included a beak type of OLF and a preoperative JOA score > 6.

PPAR (peroxisome-proliferator-activated receptor) γ, a nuclear receptor, can be conjugated with SUMO (small ubiquitin-like modifier), which results in the negative regulation of its transcriptional activity. In the present study, we tested whether de-SUMOylation of PPARγ affects the expression of PPARγ target genes in mouse muscle cells and investigated the mechanism by which de-SUMOylation increases PPARγ transcriptional activity. We found that the SUMO-specific protease SENP2 [SUMO1/sentrin/SMT3 (suppressor of mif two 3 homologue 1)-specific peptidase 2] effectively de-SUMOylates PPARγ–SUMO conjugates. Overexpression of SENP2 in C2C12 cells increased the expression of some PPARγ target genes, such as FABP3 (fatty-acid-binding protein 3) and CD36 (fatty acid translocase), both in the absence and presence of rosiglitazone. In contrast, overexpression of SENP2 did not affect the expression of another PPARγ target gene ADRP (adipose differentiation-related protein). De-SUMOylation of PPARγ increased ChIP (chromatin immunoprecipitation) of both a recombinant PPRE (PPAR-response element) and endogenous PPREs of the target genes CD36 and FABP3, but ChIP of the PPRE in the ADRP promoter was not affected by SENP2 overexpression. In conclusion, these results indicate that SENP2 de-SUMOylates PPARγ in myotubes, and de-SUMOylation of PPARγ selectively increases the expression of some PPARγ target genes.

Background context Advantages of cervical artificial disc replacement (ADR) are to preserve segmental range of motion (ROM) and avoid adjacent segmental disease. To achieve successful outcome after cervical ADR, ROM maintenance is important, but few authors have investigated the factors that influence the postoperative segmental ROM. Purpose To evaluate the factors that influence the postoperative segmental ROM after cervical ADR. Study design/setting A retrospective clinical study. Patient sample Forty-one consecutive cervical ADR cases were analyzed. Outcome measures Disc height, segmental and overall ROM, and clinical parameters checked with Neck Disability Index (NDI) and visual analog scale (VAS) in neck and arm pain were assessed. Methods There were 21 men and 20 women with a mean age of 45 years (range, 27–61 years). All cases were followed up for more than 2 years (range, 24–54 months; average, 31 months). Angles of the inserted implant on the immediate postoperative lateral radiographs, segmental and overall ROM (full flexion angle−full extension angle), disc height increment (immediate postoperative disc height−preoperative disc height), and adjacent segment changes at cephalad and caudal disc space were measured. Correlations between the factors and segmental ROM at last follow-up were analyzed. Results Mean preoperative NDI was improved from 61.0 preoperatively to 11.5 at last follow-up, and mean VAS in the neck pain decreased from 56.8 preoperatively to 11.8 postoperatively and arm pain decreased from 68.1 to 18.0. The mean preoperative segmental ROM changed from 7.4±3.2° preoperatively to 10.4±5.9° at last follow-up, and mean preoperative disc height increased from 6.4±1.0 (4.1–8.4) mm preoperatively to 7.9±1.0 (6.3–9.9) mm postoperatively. The segmental ROM at last follow-up was not significantly correlated with preoperative segmental and overall ROM, angle of inserted implant, VAS, or age (p>.05). However, the segmental ROM at last follow-up was significantly correlated with the disc height increment (p=.046, r=0.374) and preoperative NDI (p=.026, r=0.412). The patient group with the postoperative segmental ROM greater than 10° had a significantly lower mean preoperative disc height than the group with the segmental ROM less than 10° (p=.050). Conclusions At a minimum of 2 years after cervical ADR, clinical outcomes were satisfactory in terms of function and pain scores. Within our results, the segmental ROM was not affected by preoperative ROM but postoperative disc height increment positively and preoperative disc height negatively.

The exposure to acute or chronic endoplasmic reticulum (ER) stress has been known to induce dysfunction of islets, leading to apoptosis. The reduction of ER stress in islet isolation for transplantation is critical for islet protection. In this study, we investigated whether tauroursodeoxycholate (TUDCA) could inhibit ER stress induced by thapsigargin, and restore the decreased glucose stimulation index of islets. In pig islets, thapsigargin decreased the insulin secretion by high glucose stimulation in a time-dependent manner (1h, 1.35+/-0.16; 2h, 1.21+/-0.13; 4h, 1.17+/-0.16 vs. 0h, 1.81+/-0.15, n=4, p

Here, we demonstrate that SENP2, a desumoylating enzyme, plays a critical role in the control of adipogenesis. SENP2 expression was markedly increased upon the induction of adipocyte differentiation, and this increase was dependent on protein kinase A activation. Remarkably, knockdown of SENP2 led to a dramatic attenuation of adipogenesis with a marked decrease in PPARgamma and C/EBPalpha mRNA levels. Knockdown of SENP2 also caused a marked reduction in the level of C/EBPbeta protein but not in that of C/EBPbeta mRNA. Interestingly, sumoylation of C/EBPbeta dramatically increased its ubiquitination and destabilization, and this increase could be reversed by SENP2. In addition, overexpression of C/EBPbeta could overcome the inhibitory effect of SENP2 knockdown on adipogenesis. Furthermore, SENP2 was absolutely required for adipogenesis of preadipocytes implanted into mice. These results establish a critical role for SENP2 in the regulation of adipogenesis by desumoylation and stabilization of C/EBPbeta and in turn by promoting the expression of its downstream effectors, such as PPARgamma and C/EBPalpha.

STUDY DESIGN A retrospective study. OBJECTIVE To determine the critical length of fusion that warrants additional stronger fixation in lumbosacral (L-S) fusion, and to analyze the risk factors of nonunion at the L-S junction. SUMMARY OF BACKGROUND DATA Long lever arm fusion down to S1 requires stronger fixation than short lever arm fusion. However, no published criteria are available about the critical length of fusion requiring stronger fixation to the ilium or S2 to obtain adequate stability for union at the L-S junction. METHODS A total of 327 adult patients with degenerative lumbar disease, who were treated with instrumented fusion, including the L-S junction, were included in this study. Mean patient age was 59.7 (20-79) years and the minimum follow-up was 12 months. Union rates were compared using univariate and multivariate logistic regression analysis. Length of fusion, age, sex, lumbar lordosis at preoperative, early postoperative and final follow-ups, BMD, smoking history, associated morbidities, fat content of paraspinal muscle, methods of fusion, and levels of intercristal line were examined as independent variables to identify factors that affect union rate at the L-S junction. RESULTS Of the 327 patients, 47 (14.4%) had nonunion at the L-S junction. Union rate of the L-S junction at the single level, and at 2, 3, 4, 5, and more than 5 levels were 96.6%, 92.9%, 87.4%, 64.7%, 66.7%, and 58.0%, respectively. A significant difference of union rate was found between less than 4 levels and 4 or more levels of fusion (P < 0.05). The factors found by multivariate analysis to significantly affect union rate at the L-S junction were fusion length and fat content of paraspinal muscle. CONCLUSION The risk of nonunion at the L-S junction was found to increase significantly for more than 3 levels of fusion. We advise that additional stronger fixation is needed in such cases.

The ginsenoside Rg3 is known to have a protective effect against hyperglycemia, obesity and diabetes in vivo. In this study, we examined the effect of Rg3 on insulin signaling and glucose uptake in cultured L6 myotubes. Rg3 increased glucose uptake both in the basal and insulin-induced states of L6 myotubes. Consistent with the increase in glucose uptake, Rg3 stimulated the phosphorylation of IRS-1 and Akt. Interestingly, Rg3 dramatically increased IRS-1 protein levels, while the protein level of Akt was not affected. Rg3 regulated IRS-1 expression at the transcriptional level and also increased the level of GLUT4 mRNA. Treatment of ginsam, in which Rg3 is the major compound of ginsenosides, increased the IRS-1 protein levels in OLEFT rats. In addition, we found that this effect of Rg3 on insulin signaling was not mediated by the AMPK pathway. In conclusion, these results suggest that Rg3 improves insulin signaling and glucose uptake primarily by stimulating the expression of IRS-1 and GLUT4.

This multinational study was conducted to investigate the association between a mitochondrial DNA (mtDNA) T16189C polymorphism and type 2 diabetes in Asians. The mtDNA 16189C variant has been reported to be associated with insulin resistance and type 2 diabetes. However, a recent meta-analysis concluded that it is negatively associated with type 2 diabetes in Europids. Since the phenotype of an mtDNA mutant may be influenced by environmental factors and ethnic differences in the nuclear and mitochondrial genomes, we investigated the association between the 16189C variant and type 2 diabetes in Asians.The presence of the mtDNA 16189C variant was determined in 2,469 patients with type 2 diabetes and 1,205 non-diabetic individuals from Korea, Japan, Taiwan, Hong Kong and China. An additional meta-analysis including previously published Asian studies was performed. Since mtDNA nucleotide position 16189 is very close to the mtDNA origin of replication, we performed DNA-linked affinity chromatography and reverse-phase liquid chromatography/tandem mass spectrometry and chromatin immunoprecipitation to identify protein bound to the 16189 region.Analysis of participants from five Asian countries confirmed the association between the 16189C variant and type 2 diabetes [odds ratio (OR) 1.256, 95% CI 1.08-1.46, p=0.003]. Inclusion of data from three previously published Asian studies (type 2 diabetes n=3,283, controls n=2,176) in a meta-analysis showed similar results (OR 1.335, 95% CI 1.18-1.51, p=0.000003). Mitochondrial single-stranded DNA-binding protein (mtSSB) was identified as a candidate protein bound to the 16189 region. Chromatin immunoprecipitation in cybrid cells showed that mtSSB has a lower binding affinity for the 16189C variant than the wild-type sequence.The mtDNA 16189C variant is associated with an increased risk of type 2 diabetes in Asians.

Adipose tissue is a highly versatile system in which mitochondria in adipocytes undergo significant changes during active tissue remodelling. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is a mitochondrial protein and a known mitochondrial quality regulator. In this study, we investigated the role of BNIP3 in adipocytes, specifically under conditions of peroxisome proliferator-activated receptor-γ (PPARγ)-induced adipose tissue remodelling. The expression of BNIP3 was evaluated in 3T3-L1 adipocytes in vitro, C57BL/6 mice fed a high-fat diet and db/db mice in vivo. Mitochondrial bioenergetics was investigated in BNIP3-knockdown adipocytes after rosiglitazone treatment. A putative peroxisome proliferator hormone responsive element (PPRE) was characterised by promoter assay and electrophoretic mobility shift assay (EMSA). The protein BNIP3 was more abundant in brown adipose tissue than white adipose tissue. Furthermore, BNIP3 expression was upregulated by 3T3-L1 pre-adipocyte differentiation, starvation and rosiglitazone treatment. Conversely, BNIP3 expression in adipocytes decreased under various conditions associated with insulin resistance. This downregulation of BNIP3 was restored by rosiglitazone treatment. Knockdown of BNIP3 in adipocytes inhibited rosiglitazone-induced mitochondrial biogenesis and function, partially mediated by the 5′ AMP-activated protein kinase (AMPK)–peroxisome proliferator-activated receptor γ, co-activator 1 α (PGC1α) signalling pathway. Rosiglitazone treatment increased the transcription level of Bnip3 in the reporter assay and the presence of the PPRE site in the Bnip3 promoter was demonstrated by EMSA. The protein BNIP3 contributes to the improvement of mitochondrial bioenergetics that occurs on exposure to rosiglitazone. It may be a novel therapeutic target for restoring mitochondrial dysfunction under insulin-resistant conditions.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a critical regulator of carbohydrate and lipid metabolism, adipocyte differentiation and inflammatory response. Post-translational modification of PPARγ and its degradation involve several pathways, including the ubiquitin–proteasome system. Here, we identified F-box only protein 9 (FBXO9) as an E3 ubiquitin ligase of PPARγ. We screened interacting partners of PPARγ using immunoprecipitation and mass spectrometric analysis and identified FBXO9 as an E3 ubiquitin ligase of PPARγ. FBXO9 directly interacted with PPARγ through the activation function-1 domain and ligand-binding domain. FBXO9 decreased the protein stability of PPARγ through induction of ubiquitination. We found that the F-box motif of FBXO9 was required for its ubiquitination function. The activity of PPARγ was significantly decreased by FBXO9 overexpression. Furthermore, FBXO9 overexpression in 3T3-L1 adipocytes resulted in decreased levels of endogenous PPARγ and suppression of adipogenesis. These results suggest that FBXO9 is an important enzyme that regulates the stability and activity of PPARγ through ubiquitination.

A number of studies have reported favorable surgical results for metastatic spinal tumors from various solid tumors. However, there are few data available on metastatic spinal cord compression (MSCC) from lung cancer despite its considerable frequency.The study aims to present the functional outcomes, survival time, and complications after surgical treatment for MSCC from non-small cell lung cancer (NSCLC).This is a longitudinal observational study.The study includes 50 patients who had neurologic deficit and underwent surgical treatment for MSCC from NSCLC.The Eastern Cooperative Oncology Group performance status (ECOG-PS), ambulatory status, overall survival, factors associated with survival time, and perioperative complications were analyzed.The postoperative changes of ECOG-PS and ambulatory status were assessed. The factors affecting postoperative ambulatory status were evaluated using logistic regression analysis. Survival time was calculated using the Kaplan-Meier method. To identify the prognostic factors, log-rank test and Cox hazards regression model were used for univariate and multivariate analyses, respectively. Major complications within postoperative 30 days and mortality rate were recorded.The study cohort consisted of 27 males and 23 females with a mean age of 58.0±11.3 years at the time of surgery. An ECOG-PS improvement by at least one grade was observed in 33 of 50 cases (66.0%). Among 39 patients who were not ambulatory before surgery, 23 patients (59.0%) regained ambulatory ability after surgery. Patients who were preoperatively ambulant and those who underwent surgery within 72 hours from neurologic deficit had an increased chance of postoperative ambulation. The median for overall survival after surgery was 5.2 months. Five prognostic factors were identified on univariate analysis: time from neurologic deficit, responsiveness to preoperative chemotherapy, postoperative chemotherapy, postoperative ECOG-PS, and postoperative ambulatory status. Multivariate analysis revealed that time to neurologic deficit (risk ratio [RR]: 2.28, p=.023), postoperative chemotherapy (RR: 6.58, p.001), and postoperative ECOG-PS (RR: 2.73, p=.040) were independent prognostic factors of survival time. Major complications developed in 34.0% of patients (17 of 50), and the 30-day mortality rate was 10.0% (5 of 50).Functional improvements were observed through surgical treatment even with relatively high complication rates for MSCC from NSCLC. Earlier surgical treatment could act as an adjuvant therapy for prolonging survival by improving functional status.

Objective Recently, the survival of patients with hepatocellular carcinoma (HCC) has been prolonged with improvements in various diagnostic tools and medical treatment modalities. Consequently, spine metastases from HCC are being diagnosed more frequently. The accurate prediction of prognosis plays a critical role in determining a patient's treatment plan, including surgery for patients with spinal metastases of HCC. We investigated the clinical features, surgical outcomes, and prognostic factors of HCC presenting with spine metastases, in patients who underwent surgery. Methods A retrospective review was conducted on 33 HCC patients who underwent 36 operations (three patients underwent surgical treatment twice) from February 2006 to December 2013. The median age of the patients was 56 years old (range, 28 to 71; male : female=30 : 3). Results Overall survival was not correlated with age, sex, level of metastases, preoperative Child-Pugh classification, preoperative ambulatory function, preoperative radiotherapy, type of operation, administration of Sorafenib, or the Tokuhashi scoring system. Only the Tomita scoring system was shown to be an independent prognostic factor for overall survival. Comparing the Child-Pugh classification and ambulatory ability, there were no statistically differences between patients pre- and post-operatively. Conclusion The Tomita scoring system represents a practicable and highly predictive prognostic tool. Even though surgical intervention may not restore ambulatory function, it should be considered to prevent deterioration of the patient's overall condition. Additionally, aggressive management may be needed if there is any ambulatory ability remaining.

Small ubiquitin-like modifier (SUMO)-specific proteases (SENPs) that reverse protein modification by SUMO are involved in the control of numerous cellular processes, including transcription, cell division, and cancer development. However, the physiological function of SENPs in energy metabolism remains unclear. Here, we investigated the role of SENP2 in fatty acid metabolism in C2C12 myotubes and in vivo. In C2C12 myotubes, treatment with saturated fatty acids, like palmitate, led to nuclear factor-κB–mediated increase in the expression of SENP2. This increase promoted the recruitment of peroxisome proliferator–activated receptor (PPAR)δ and PPARγ, through desumoylation of PPARs, to the promoters of the genes involved in fatty acid oxidation (FAO), such as carnitine-palmitoyl transferase-1 (CPT1b) and long-chain acyl-CoA synthetase 1 (ACSL1). In addition, SENP2 overexpression substantially increased FAO in C2C12 myotubes. Consistent with the cell culture system, muscle-specific SENP2 overexpression led to a marked increase in the mRNA levels of CPT1b and ACSL1 and thereby in FAO in the skeletal muscle, which ultimately alleviated high-fat diet–induced obesity and insulin resistance. Collectively, these data identify SENP2 as an important regulator of fatty acid metabolism in skeletal muscle and further implicate that muscle SENP2 could be a novel therapeutic target for the treatment of obesity-linked metabolic disorders.

Abnormally high levels of circulating free fatty acids can lead to pancreatic islet beta-cell dysfunction and apoptosis, contributing to beta-cell failure in Type 2 diabetes. The NAD(+)-dependent protein deacetylase Sirtuin-3 (SIRT3) has been implicated in Type 2 diabetes. In this study, we tested whether SIRT3 overexpression affects palmitate-induced beta-cell dysfunction in cells of line NIT1, which are derived from mouse pancreatic beta-cells. Two different lengths of SIRT3 were overexpressed: full length SIRT3 (SIRT3LF), which was preferentially targeted to mitochondria and partially to the nucleus, and its N-terminal truncated form (SIRT3SF), which was located in the nucleus and cytoplasm. Overexpression of SIRT3LF and SIRT3SF using an adenoviral system alleviated palmitate-induced lipotoxicity such as reduction of cell viability and mitogen-activated protein kinase (MAPK) activation. Chronic exposure to low concentrations of palmitate suppressed glucose-stimulated insulin secretion, but the suppression was effectively reversed by overexpression of SIRT3LF or SIRT3SF. The mRNA levels of the endoplasmic reticulum (ER) stress responsive genes ATF4, GRP94 and FKBP11 were increased by palmitate treatment, but the increases were completely inhibited by SIRT3LF overexpression and less effectively inhibited by SIRT3SF overexpression. This result suggests that overexpression of SIRT3 inhibits induction of ER stress by palmitate. Collectively, we conclude that overexpression of SIRT3 alleviates palmitate-induced beta-cell dysfunction.

The p53 tumour suppressor has a key role in the control of cell growth and differentiation, and in the maintenance of genome integrity1,2. p53 is kept labile under normal conditions, but in response to stresses, such as DNA damage, it accumulates in the nucleus for induction of cell-cycle arrest, DNA repair or apoptosis. Mdm2 is an ubiquitin ligase that promotes p53 ubiquitination and degradation3,4,5. Mdm2 is also self-ubiquitinated and degraded. Here, we identified a novel cascade for the increase in p53 level in response to DNA damage. A new SUMO-specific protease, SUSP4, removed SUMO-1 from Mdm2 and this desumoylation led to promotion of Mdm2 self-ubiquitination, resulting in p53 stabilization. Moreover, SUSP4 competed with p53 for binding to Mdm2, also resulting in p53 stabilization. Overexpression of SUSP4 inhibited cell growth, whereas knockdown of susp4 by RNA interference (RNAi) promoted of cell growth. UV damage induced SUSP4 expression, leading to an increase in p53 levels in parallel with a decrease in Mdm2 levels. These findings establish a new mechanism for the elevation of cellular p53 levels in response to UV damage.

Retinoid X receptor alpha (RXRalpha) belongs to a family of ligand-activated transcription factors that regulate many aspects of metazoan life. Here we demonstrate that RXRalpha is a target substrate of a small ubiquitin-related modifier (SUMO)-specific protease, SUSP1, which is capable of controlling the transcriptional activity of RXRalpha. RXRalpha was modified by SUMO-1 in vivo as well as in vitro, and the Lys-108 residue within the IKPP sequence of RXRalpha AF-1 domain was identified as the major SUMO-1 acceptor site. Prevention of SUMO modification by Lys-to-Arg mutation led to an increase not only in the transcriptional activity of RXRalpha but also in the activity of its heterodimeric complex with retinoic acid receptor-alpha or peroxisome proliferator-activated receptor-gamma (PPARgamma). SUSP1 co-localized with RXRalpha in the nucleus and removed SUMO-1 from RXRalpha but not from androgen receptor or PPARgamma. Moreover, overexpression of SUSP1 caused an increase in the transcriptional activity of RXRalpha, whereas small hairpin RNA-mediated knockdown of endogenous SUSP1 led to a decrease in RXRalpha activity. These results suggest that SUSP1 plays an important role in the control of the transcriptional activity of RXRalpha and thus in the RXRalpha-mediated cellular processes.

To investigate the morphological characteristics of the axis of rheumatoid arthritis (RA) patients with atlantoaxial instability and to determine, by means of sagittal reconstructed computed tomography (CT), the suitability for atlantoaxial transarticular screw fixation. Twenty-seven patients, who had undergone reconstructed cervical spine CT scanning preoperatively and posterior atlantoaxial arthrodesis for atlantoaxial instability, were identified from a database for inclusion in this study. The isthmus height and internal height of the lateral mass of the axis were measured using digital imaging software. The mean isthmus height and internal height of the lateral mass of the axis in RA patients (n=14) were significantly lower than in non-RA patients (n=13) (P

A lumbar total disc replacement (TDR) is believed to be a promising substitute in the surgical treatment for lumbar degenerative disc disease. The purpose of this study is to report the clinical and radiographic outcomes of 36 consecutive patients who underwent lumbar TDR using ProDisc II, and the factors associated with a better clinical outcome after a 2-year minimum follow-up. At the time of the latest follow-up, the success rate was 94% of 36 patients according to the criteria of the US Food and Drug Administration. Of the 10 patients unable to work preoperatively, 7 patients returned to work. Moreover, mean score on the visual analog scale for low back and leg pain improved significantly from 7.5 and 4.7 to 3.0 and 1.2, respectively (P

A lumbar total disc replacement (TDR) is a type of motion-preserving surgery, which aims to restore and maintain the normal range of motion (ROM) and the sagittal balance of the spine. However, little is known regarding how the spinopelvic alignment and ROM of the lumbar spine are influenced by the lumbar TDR with ProDisc. This study retrospectively analyzed the sagittal alignment and ROM of the lumbar spine in 26 consecutive patients who had undergone the TDR with ProDisc with a minimum follow-up of 24 months. A standing lateral radiograph, which included the femoral heads and dynamic flexion-extension lateral radiographs of the spine were taken before surgery and at the follow-up visit. The radiological parameters included the sacral tilt, the pelvic tilt, and the lumbar lordosis. The segmental lordosis and ROM were also measured at each operative level. Nineteen patients underwent a single-level TDR and 7 patients underwent a double-level TDR. The mean lumbar lordosis increased significantly from 30.5 degrees to 40.8 degrees in all patients who underwent TDR without any significant changes in the sacral tilt and pelvic tilt at the latest follow-up (P

Objective— There is still debate as to whether antiatherosclerotic effect of PPARγ ligands is dependant on PPARγ gene itself or some other pathway. Methods and Results— To investigate the effect of PPARγ gene modulation on neointima formation after balloon injury, we delivered adenoviral vectors expressing the wild-type (WT) dominant negative (DN) PPARγ, or a control gene (β-galactosidase [BG]) into carotid artery after balloon injury in rosiglitazone (a PPARγ ligand)-treated (R+) (3 mg/kg/d) and nontreated (R−) rats. Two weeks after gene delivery, in both R+ and R− animals, the PPARγ-WT gene transfer showed a significantly lower intima-media ratio (IMR) than control group. Moreover, the delivery of a PPARγ-DN form showed the highest IMR (in R+WT, 0.51±0.15; R+BG, 0.89±0.14; R+DN, 1.20±0.18, P P Conclusions— In vivo transfer of the PPARγ-WT gene was found to inhibit smooth muscle proliferation, sustain apoptosis, and reduce neointima formation after balloon injury irrespective of rosiglitazone treatment. These results indicate that PPARγ overexpression itself has a protective role against restenosis after balloon injury.

Resistin is thought to be an important link between obesity and insulin resistance. It has been suggested that genetic polymorphism in the promoter of resistin gene is a determinant of resistin mRNA expression and possibly associated with obesity and insulin resistance. In this study, we investigated the association between the genotype of resistin promoter and its plasma concentrations. We examined g.-537A>C and g.-420C>G polymorphisms in the resistin promoter and measured plasma resistin concentrations in Korean subjects with or without Type 2 diabetes. We also did haplotype-based promoter activity assays and the gel electrophoretic mobility shift assay. The −420G and the −537A alleles, which were in linkage disequilibrium, were associated with higher plasma resistin concentrations. Individuals with haplotype A-G (−537A and −420G) had significantly higher plasma resistin concentrations than the others. Haplotype A-G had modestly increased promoter activity compared to the other haplotypes. Electrophoretic mobility shift assay showed that the −420G allele is specific for binding of nuclear proteins from adipocytes and monocytes. However, none of the two polymorphisms were associated with Type 2 diabetes or obesity in our study subjects. Polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans.

Novel bioactive and biodegradable glass ceramics with high mechanical strength in the (50-x/2)CaO · SiO2xB2O3 (4.2 ≤ x ≤ 17.2) system were investigated. The systems consisted of three phases: monoclinic wollastonite, calcium metaborate, and amorphous borosilicate matrix. The glass ceramics containing 4.2 mol% and 8.4 mol% B2O3 showed high bulk density and a dense microstructure. Mechanical strengths of the glass ceramics were higher than those of other bioactive ceramics: high compressive strength (2813 MPa), bending strength of 212 MPa, and fracture toughness of 3.12 MPa · m1/2. The glass-ceramic formed apatite layer on their surface in the simulated body fluid and showed significant biodegradation. The degree of apatite formation in the glass ceramics depended on the calcium metaborate content and borosilicate glassy matrix. Additional calcium metaborate and borosilicate glassy matrix increased the apatite formation rate on the surface. It might be likely that calcium metaborate causes supersaturation of Ca ions, for its high solubility in SBF and the water-reactive borosilicate glassy matrix formed SiOH groups on the surface to provide nucleation sites for apatite formation. Also, through in vitro test for the biocompatibility of the CaOSiO2B2O3 glass ceramics, no cytotoxicity of the glass ceramics were found. The results on bioactivity and noncytotoxicity indicated that glass ceramics in the (50-x/2)CaO · SiO2xB2O3 (4.2 ≤ x ≤ 17.2) system could be useful as a biodegradable bone replacement material. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 79–89, 2004

We studied the outcome of expansive laminoplasty in 37 patients with cervical spondylotic myelopathy. Patients were divided into two groups according to the recovery rate (RR) - a 'good' group ( n=19), and a 'fair' group ( n=18). Patients in the good group showed a greater pre-operative Japanese Orthopaedic Association (JOA) score, a greater compression ratio, and a larger Pavlov ratio ( P0.05). The presence of high signal intensity on MRI proved to be of no prognostic importance.

Myristoylated alanine-rich C kinase substrate (MARCKS) translocates from the cytosol to the plasma membrane while mononucleated myoblasts fuse to form multinucleated myotubes. Here, we show that protein phosphatase-1-mediated dephosphorylation of MARCKS largely influences its subcellular localization and the fusion process. Treatment with okadaic acid or tautomycin, which are potent inhibitors of protein phosphatases and cell fusion, was found to reversibly block the MARCKS translocation. Moreover, the dephosphorylating activity against MARCKS markedly increased during myogenesis, and this increase was closely correlated with the membrane fusion of the cells. In addition, protein phosphatase-1 was identified as a major enzyme that is responsible for dephosphorylation of MARCKS. Furthermore, a mutation preventing MARCKS phosphorylation and thus facilitating MARCKS translocation resulted in promotion of the cell fusion. In contrast, overexpression of MARCKS carrying a mutation that blocks myristoylation and thus prevents the MARCKS translocation impaired the myoblast fusion. Together with the fact that MARCKS regulates the cytoskeleton dynamics by crosslinking the actin filaments in the plasma membrane and that myoblast fusion accompanies massive cytoskeleton reorganization, these results suggest that protein phosphatase-1-mediated MARCKS localization at the membrane is required for the fusion of embryonic muscle cells.

The sintering behavior of calcium pyrophosphate (CPP, Ca2P2O7)-doped beta-tricalcium phosphate [TCP, Ca3(PO4)2], prepared by solid state reaction, was investigated in-situ, using dilatometry. Pure beta-TCP undergoes phase transition to alpha-TCP at about 1200 degrees C; hence pure beta-TCP ceramics should be sintered bclow 1200 degrees C. Pure beta-TCP sintered body can achieve a relative density of only 86% when sintered at 1150 degrees C. However, the addition of CPP in the range of 0.5-3 wt% delays phasc transition of beta-TCP and enables sintering of beta-TCP at 1200 degrees C without a phase transformation to alpha-TCP. Due to this effect of CPP added to TCP, CPP-doped beta-TCP ceramics with relative density over 95% could be obtained when sintered at 1200 degrees C for 2 h.

Bone marrow (BM) has been considered as a reservoir of stem/progenitor cells which are able to differentiate into ectodermal, endodermal, and mesodermal origins in vitro as well as in vivo. Following adequate stimulation, such as granulocyte stimulating factor (G-CSF) or AMD3100, BM resident stem/progenitor cells (BMSPCs) can be mobilized to peripheral blood. Several host-related factors are known to participate in this mobilization process. In fact, a significant number of donors are resistant to G-CSF induced mobilization protocols. AMD3100 is currently used in combination with G-CSF. However, information regarding host-related factors which may influence the AMD3100 directed mobilization is extremely limited. In this study, we were to get some more knowledge on the host-related factors that affect the efficiency of AMD3100 induced mobilization by employing in vivo mobilization experiments. As a result, we found that C57BL/6J mice are more sensitive to AMD3100 but less sensitive to G-CSF which promotes the proliferation of BMSPCs. We excluded S1P as one of the host related factor which influences AMD3100 directed mobilization because pre-treatment of S1P receptor antagonist FTY720 did not inhibit BMSPC mobilization. Further in vitro experiments revealed that BALB/c mice, compared to C57BL/6J mice, have less BMSPCs which migrate in response to host related factors such as sphingosine-1-phosphate (S1P) and to CXCL12. We conclude that AMD3100-directed mobilization depends on the number of BMSPCs rather than on the host-related factors. These results suggest that the combination of AMD3100 and G-CSF is co-operative and is optimal for the mobilization of BMSPCs.

A cDNA encoding an ubiquitin-specific processing protease, UBP109, in rat skeletal muscle was cloned and its product was characterized. Northern analysis revealed that UBP109 mRNA is highly expressed in testis and spleen, compared with other tissues. Furthermore, in situ hybridization showed that the level of UBP109 mRNA in liver, spinal cord and brain dramatically changed during embryonic development, indicating that the expression of UBP109 mRNA is developmentally regulated. UBP109 was expressed in Escherichia coli and purified to apparent homogeneity using a 125I-labelled ubiquitin-peptide fusion as a substrate. The purified enzyme cleaved at the C-terminus of the ubiquitin moiety in natural and engineered fusions irrespective of their sizes. UBP109 also released free ubiquitin from poly-His-tagged penta-ubiquitin. Moreover, it released free ubiquitin from poly-ubiquitinated protein conjugates of rabbit reticulocytes. In addition, UBP109 localized to both the cytoplasm and the nucleus and, among three putative nuclear localization sequences, only the one located near the C-terminus is responsible for nuclear localization. These results suggest that UBP109 may play an important role in generation of free ubiquitin from its precursors and its recycling from poly-ubiquitinated protein conjugates, and hence in regulation of ubiquitin-mediated cellular processes, particularly related to embryonic development.

The peroxisome proliferator-activated receptor γ (PPARγ) is a central regulator of adipogenesis and modulates glucose and lipid metabolism. In this study, herpesvirus-associated ubiquitin-specific protease (HAUSP) was isolated as a binding partner of PPARγ. Both endogenous and exogenous PPARγ associated with HAUSP in co-immunoprecipitation analysis. HAUSP, but not the catalytically inactive HAUSP C223S mutant, increased the stability of both endogenous and exogenous PPARγ through its deubiquitinating activity. Site-directed mutagenesis experiments showed that the Lys(462) residue of PPARγ is critical for ubiquitination. HBX 41,108, a specific inhibitor of HAUSP, abolished the increase in PPARγ stability induced by HAUSP. In addition, knockdown of endogenous HAUSP using siRNA decreased PPARγ protein levels. HAUSP enhanced the transcriptional activity of both exogenous and endogenous PPARγ in luciferase activity assays. Quantitative RT-PCR analysis showed that HAUSP increased the transcript levels of PPARγ target genes in HepG2 cells, resulting in the enhanced uptake of glucose and fatty acids, and vice versa, upon siRNA knockdown of HAUSP. In vivo analysis using adenoviruses confirmed that HAUSP, but not the HAUSP C223S mutant, decreased blood glucose and triglyceride levels, which are associated with the increased expression of endogenous PPARγ and lipid accumulation in the liver. Our results demonstrate that the stability and activity of PPARγ are modulated by the deubiquitinating activity of HAUSP, which may be a target for the development of anti-diabetic drugs.

The successful islet transplantation, for the treatment of type 1 diabetes, depends on the quantity and the quality of transplanted islets. Previously, it has reported that the significant loss of isolated islet mass could be prevented by sphingolipid metabolite, sphinogosine 1-phophate (S1P). This study was performed to elucidate whether the beneficial effects of S1P maintaining isolated pancreatic islets ex vivo are mimicked by modulation of intracellular S1P. We tested the in vitro effect of various agents that modulate intracellular S1P levels in insulinoma cell lines and isolated islets to compare their anti-apoptotic effects with that of S1P. As results, we discovered that 4-deoxypyridoxine (DOP), which inhibits the degradation of intracellular S1P by inhibiting S1P lyase (SPL) activity, minimized the chemically induced apoptosis of insulinoma cell lines as S1P did. Also, supplementation of DOP in the culture media protected the regression of isolated islets that have been maintained ex vivo at least for 18 h providing the evidence of increasing viability of isolated islets with DOP, which impaired SPL activity. In conclusion, these results suggest that the application of SPL inhibitors could be considered as a supplement for the maintenance of viable islets isolated from donor sources in the process of islet transplantation.

A retrospective case series.To compare the surgical outcomes of open-door and French-door cervical laminoplasty for decompressing multilevel cervical spinal cord compressions.Cervical laminoplasty is an effective method for decompressing multilevel cervical spinal cord compressions. Laminoplasty is usually classified as an open-door or French-door technique, but it is still unclear whether laminoplasty affects cervical alignment and clinical outcomes.Fifty-one patients underwent cervical laminoplasty over a 2-year period for cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, or for a mixed-type condition. The following criteria were evaluated and compared retrospectively for open-door laminoplasty (group A) and French-door laminoplasty (group B): Nurick grades, Japanese Orthopedic Association (JOA) scores, neck disability index, and visual analog scale scores for axial neck pain and radiating pain. During radiologic evaluations, changes in cervical lordotic angles and range of motion were measured at C2-C7.Postoperatively, radiating pain improved significantly in both groups (P0.05), but axial neck pain was more severe in both groups at last follow-up than preoperatively (P0.05). Mean neurological improvement was 12.5% according to Nurick grades and 28% according to JOA scores in all study subjects. In particular, the mean Nurick grades showed significant improvement in group A (P0.05), and the recovery rate was higher in group A than in group B according to Nurick grades (23.5% vs. 6.3%; P0.05) and JOA scores (44.4% vs. 13%; P0.05). In contrast, radiologically, cervical lordotic angle and range of motion were more significantly decreased in group B (P0.05).Although open-door and French-door laminoplasty techniques were found to be effective for treating cervical compressive myelopathy, the open-door technique seems to be superior with respect to clinical and radiologic outcomes.

Study design Retrospective patient data collection and investigator survey. Purpose To investigate patterns of opioid treatment for pain caused by spinal disorders in Korea. Overview of literature Opioid analgesic prescription and adequacy of consumption measures in Korea have markedly increased in the past decade, suggesting changing patterns in pain management practice; however, there is lack of integrated data specific to Korean population. Methods Patient data were collected from medical records at 34 university hospitals in Korea. Outpatients receiving opioids for pain caused by spinal disorders were included in the study. Treatment patterns, including opioid types, doses, treatment duration, outcomes, and adverse drug reactions (ADRs), were evaluated. Investigators were interviewed on their perceptions of opioid use for spinal disorders. Results Among 2,468 analyzed cases, spinal stenosis (42.8%) was the most common presentation, followed by disc herniation (24.2%) and vertebral fracture (17.5%). In addition, a greater proportion of patients experienced severe pain (73.9%) rather than moderate (19.9%) or mild (0.7%) pain. Oxycodone (51.9%) and fentanyl (50.8%) were the most frequently prescribed opioids; most patients were prescribed relatively low doses. The median duration of opioid treatment was 84 days. Pain relief was superior in patients with longer treatment duration (≥2 months) or with nociceptive pain than in those with shorter treatment duration or with neuropathic or mixed-type pain. ADRs were observed in 8.6% of cases. According to the investigators' survey, "excellent analgesic effect" was a perceived advantage of opioids, while safety concerns were a disadvantage. Conclusions Opioid usage patterns in patients with spinal disorders are in alignment with international guidelines for spinal pain management. Future prospective studies may address the suitability of opioids for spinal pain treatment by using appropriate objective measurement tools.

STUDY DESIGN Prospective observational study. PURPOSE To introduce the techniques and present the surgical outcomes of mini-open anterior lumbar interbody fusion (ALIF) at the most caudal segments of the spine combined with lateral lumbar interbody fusion (LLIF) for the correction of adult spinal deformity. OVERVIEW OF LITERATURE Although LLIF is increasingly used to correct adult spinal deformity, the correction of sagittal plane deformity with LLIF alone is reportedly suboptimal. METHODS Thirty-two consecutive patients with adult spinal deformity underwent LLIF combined with mini-open ALIF at the L5-S1 or L4-S1 levels followed by 2-stage posterior fixation. ALIF was performed for a mean 1.3 levels and LLIF for a mean 2.7 levels. Then, percutaneous fixation was performed in 11 patients (percutaneous group), open correction with facetectomy with or without laminectomy in 16 (open group), and additional pedicle subtraction osteotomy (PSO) in 5 (PSO group). Spinopelvic parameters were compared preoperatively and postoperatively. Hospitalization data and clinical outcomes were recorded. RESULTS No major medical complications developed, and clinical outcomes improved postoperatively in all groups. The mean postoperative segmental lordosis was greater after ALIF (17.5°±5.5°) than after LLIF (8.1°±5.3°, p

A retrospective comparative study.To present the results of thoracoscopic surgery in the treatment of adolescent idiopathic scoliosis (AIS) and to compare the results of thoracoscopic surgery with those of posterior surgery.Although racoscopic scoliosis correction has attracted attention since the early 2000s, its use has declined gradually, whereas posterior surgery using pedicle screws has become popular. Few studies have compared thoracoscopic surgery with posterior pedicle screw fixation for single thoracic AIS correction.Sixty-five patients with Lenke type-1 AIS were included and followed up for a minimum of 24 months. Forty-two patients underwent thoracoscopic surgery (thoracoscopic group) and 23 patients underwent posterior surgery (posterior group). Radiographic outcomes, including the correction rate and loss of correction, perioperative morbidities, and complications, were compared.Both groups were similar in terms of the preoperative baseline data. Although the correction rate of major thoracic curve was similar, the posterior group had a tendency to have a greater correction rate (72% vs. 66%). A loss of correction was significantly greater in the thoracoscopic group. The thoracoscopic group had a longer operation time and less intraoperative blood loss, with a lower transfusion rate than the posterior group. There was no difference at the last follow-up in terms of pain score and satisfaction. Five implant failures (12%) occurred in the thoracoscopic group and none in the posterior group. There were 3 patients with significant pulmonary complications necessitating active treatments in the thoracoscopic group.Despite its advantages, thoracoscopic surgery is losing its place in the surgical correction of AIS because of the frequent perioperative pulmonary complications and fixation problems compared with posterior pedicle screw fixation. Nevertheless, it can be utilized in selected cases particularly in cases of patient's strong demand for minimally invasive surgery.

Current strategies to accelerate hematopoietic reconstitution after transplantation include transplantation of greater numbers of hematopoietic stem/progenitor cells (HSPCs) or ex vivo expansion of harvested HSPCs before transplant. However, the number of cells available for transplantation is usually low, and strategies to expand HSPCs and maintain equivalent engraftment capability ex vivo are limited. We noted that activated granulocyte-derived cationic peptides positively primed responsiveness of HSPCs to a CXCL12 gradient. Accordingly, we noted that accelerated homing/engraftment of β-defensin-2, a well-known antimicrobial cationic peptide, primed bone marrow nucleated cells (BMNCs) compared to normal BMNCs after transplantation into lethally irradiated recipients. We envision that small cationic peptides, which primarily possess antimicrobial functions and are harmless to mammalian cells, could be applied to prime HSPCs before transplantation. This novel approach would be particularly important in cord blood transplantation, where the number of HSPCs available for transplantation is usually limited.

Background Comparatively little is known about the relation between the sagittal vertical axis and clinical outcome in cases of degenerative lumbar spondylolisthesis. The objective of this study was to determine whether lumbar sagittal balance affects clinical outcomes after posterior interbody fusion. This series suggests that consideration of sagittal balance during posterior interbody fusion for degenerative spondylolisthesis can yield high levels of patient satisfaction and restore spinal balance Methods A retrospective study of clinical outcomes and a radiological review was performed on 18 patients with one or two level degenerative spondylolisthesis. Patients were divided into two groups: the patients without improvement in pelvic tilt, postoperatively (Group A; n = 10) and the patients with improvement in pelvic tilt postoperatively (Group B; n = 8). Pre- and postoperative clinical outcome surveys were administered to determine Visual Analogue Pain Scores (VAS) and Oswestry disability index (ODI). In addition, we evaluated full spine radiographic films for pelvic tilt (PT), sacral slope (SS), pelvic incidence (PI), thoracic kyphosis (TK), lumbar lordosis (LL), sacrofemoral distance (SFD), and sacro C7 plumb line distance (SC7D) Results All 18 patients underwent surgery principally for the relief of radicular leg pain and back pain. In groups A and B, mean preoperative VAS were 6.85 and 6.81, respectively, and these improved to 3.20 and 1.63 at last follow-up. Mean preoperative ODI were 43.2 and 50.4, respectively, and these improved to 23.6 and 18.9 at last follow-up. In spinopelvic parameters, no significant difference was found between preoperative and follow up variables except PT in Group A. However, significant difference was found between the preoperative and follows up values of PT, SS, TK, LL, and SFD/SC7D in Group B. Between parameters of group A and B, there is borderline significance on preoperative PT, preoperative LL and last follow up SS. Correlation analysis revealed the VAS improvements in Group A were significantly related to postoperative lumbar lordosis (Pearson's coefficient = -0.829; p = 0.003). Similarly, ODI improvements were also associated with postoperative lumbar lordosis (Pearson's coefficient = -0.700; p = 0.024). However, in Group B, VAS and ODI improvements were not found to be related to postoperative lumbar lordosis and to spinopelvic parameters. Conclusion In the current series, patients improving PT after fusion were found to achieve good clinical outcomes in degenerative spondylolisthesis. Overall, our findings show that it is important to quantify sagittal spinopelvic parameters and promote sagittal balance when performing lumbar fusion for degenerative spondylolisthesis.

Thoracic ossification of the ligamentum flavum (OLF), a main cause of thoracic myelopathy, is an uncommon disease entity. It is seen mostly in East Asia, although the majority of reports have issued from Japan. In the present study, the clinical features and prognostic factors of thoracic OLF were examined in a large number of Korean patients.Data from 51 consecutive patients who underwent decompressive laminectomy with or without fusion for thoracic OLF between 1998 and 2008 were retrospectively analyzed. Patients were evaluated pre- and postoperatively using the modified Japanese Orthopedic Association (JOA) scale (maximum total score of 11). Patient age, sex, preoperative symptoms, duration of initial symptoms, number of involved segments, duration of follow-up, presence of dural adhesion (dural tearing), intramedullary high signal intensity, morphological classification of OLF (axial or sagittal), coexisting disease, and fusion or no fusion were also evaluated. Surgical outcomes were assessed using JOA recovery rate/outcome scores, and patient satisfaction grades and prognostic factors were analyzed.There were 18 men and 33 women with a mean age of 60.9 years (range 38-80 years). A mean preoperative JOA score of 5.5 improved to a mean score of 7.4 at the last follow-up (mean 52 months after surgery). The mean duration of the initial symptoms was 34.5 months (range 0.1-240 months) prior to surgery. The most common symptoms were motor dysfunction (80%); sensory deficit (67%); and pain, numbness, and claudication (59%) in the lower extremities. Knee hyperreflexia appeared in 69% of the patients. There were a total of 130 ossified segments, and the mean number of segments per patient was 2.6. Ninety-two (71%) of 130 segments were located below T-8. Recovery outcomes were good (18 patients), fair (16 patients), unchanged (11 patients), or worse (6 patients). Thirty-one patients (61%) were satisfied with their operations. Patients with a beak type of OLF on sagittal MR images experienced a higher recovery rate and a better satisfaction grade than did those with a round OLF. The patients with higher preoperative JOA scores demonstrated significantly higher JOA scores postoperatively (p0.001), and the preoperative JOA score had a significant correlation with the recovery rate in patients exhibiting mainly motor dysfunction (p = 0.040, r = 0.330).Of the thoracic OLF studies published to date, the present analysis involves the largest Korean population. The most common symptoms of thoracic OLF were motor dysfunction and sensory deficit in the lower extremities, although pain, numbness, and claudication were observed in some patients and were notably accompanied by knee hyperreflexia. At a minimum of 2 years after surgery for thoracic OLF, operative outcomes were generally good, and the prognostic factors affecting good surgical outcomes included a beak type of OLF and a preoperative JOA score6.

The main goal of total disc replacement (TDR) is to preserve motion. Despite reports of good clinical outcomes, various degrees of heterotopic ossification after TDR have been reported. The purpose of this study was to investigate the prevalence and its clinical relevance of heterotopic ossification. We evaluated 65 consecutive patients (82 segments) with mean follow-up duration of 45 months (range, 12–88 months). Two kinds of prosthesis, ProDisc® for 75 segments (91.5%) and CHARITETM for seven segments (8.5%), were used. Patients with heterotopic ossification were compared with those without heterotopic ossification with regard to segmental flexion–extension ROM, VAS and ODI. We analysed the occurrence site by nine zones. Heterotopic ossification was detected in 25 out of 82 segments (30.5%) at a mean follow-up of 17 months. According to McAfee’s classification, there was Class-I heterotopic ossification in eight segments (9.8%), Class-II in 12 segments (14.6%), and Class-III in five segments (6.1%). There was no Class-IV heterotopic ossification. There were no significant differences in the segmental ROM, VAS and ODI between the patients with Class-I or Class-II heterotopic ossification and those without heterotopic ossification The segmental ROM in the patients with Class-III heterotopic ossification was significantly decreased compared with the patients without heterotopic ossification (p = 0.018). But VAS and ODI were not significantly different compared with those of patients with no heterotopic ossification. Most heterotopic ossification (82.5%) was detected in the anterior and posterior aspects. In conclusion, most of the heterotopic ossification (Classes I and II) did not affect segmental ROM and clinical outcomes such as pain or function. In Class-III heterotopic ossification segmental ROM was decreased, but it did not affect clinical outcomes.

STUDY DESIGN: Retrospective study. PURPOSE: To investigate whether intersegmental compression can affect the results of threedimensional correction for idiopathic scoliosis. OVERVIEW OF LITERATURE: Intersegmental compression is usually performed to increase the correction rate and enhance kyphosis restoration. However, it is presumed that the risk of decompensation is increased. METHODS: Twenty-seven patients with idiopathic scoliosis who were corrected thoracoscopically were divided into two groups: a compression group and a non-compression group. Thoracic and lumbar scoliotic Cobb angles were measured pre-operatively, one week postoperatively, and at last follow-up. Changes in thoracic kyphosis and in sagittal and coronal balance were compared. RESULTS: The average correction rates for thoracic scoliotic curves were 70.3% and 58.8% in the compression and non-compression groups, respectively (p=0.023), at 1 week postoperatively. However, these changed to 62.6% and 58.1% at the final follow-up visit (p=0.381). Thoracic kyphosis increased by 37.4% in the compression group and 20.9% in the non-compression group at 1 week postoperatively (p=0.435). Finally, thoracic kyphosis increased by 59.9% and 42.6%(p=0.473), respectively, at final follow-up. Axial rotation was corrected by 45.3% and 24.7% in the compression and non-compression groups, respectively (p=0.214). There were no significant differences in postoperative changes in coronal and sagittal balance between the two groups. CONCLUSIONS: Three-dimensional correction by intersegmental compression tended to produce better results, especially during the early postoperative period. However, at final follow-up, no significant differences were observed between the two groups in terms of three-dimensional correction. Thus, we conclude that intersegmental compression is not always necessary for thoracoscopic scoliosis correction.

The biological response of fetal rat calvarial cells on a TiO2 nanotubular surface (Ti-NT) was evaluated by cell viability assay, alkaline phosphatase (ALP) activity and reverse transcription polymerase chain reaction (RT-PCR) analysis. The cell viability assay showed no significant difference between the Ti-NT and smooth titanium surfaces (Ti-S). Ti-NT had better cellular responses with regard to the ALP activity and bone-associated markers, such as bone sialoprotein and osteocalcin mRNA than Ti-S. These results suggest that Ti-NT stimulate the differentiation into osteoblasts of fetal rat calvarial cells, potentially contributing to rapid osseointegration.

Study Design. Prospective, randomized, double blind, clinical study. Objective. To compare the hemostatic and electrolyte effects of 2 commonly administered hydroxyethyl starches (HES) in patients undergoing posterior lumbar interbody fusion (PLIF). Summary of Background Data. HES are commonly administered colloid solutions to restore and maintain intravascular volume before transfusion is initiated. However, infusion of HES itself can impair coagulation. HES-induced coagulopathy could be a serious problem in PLIF which involves continuous bone bleeding and oozing. Voluven (Fresenius Kabi, Germany), previously regarded as the least coagulopathic due to its low molecular weight (MW) and degree of substitution (DS), is a saline-based HES. Hextend (Biotime, United States) is a new type of HES with physiologic pH and balanced electrolytes, including calcium, which is beneficial to coagulation. Studies comparing the coagulopathy of Hextend and Voluven are rare. Therefore, coagulation, pH/electrolyte changes, and blood loss using Hextend and Voluven in patients undergoing PLIF were compared. Methods. Fifty-four patients scheduled for PLIF involving 3 vertebrae or less were randomly assigned to the Voluven or the Hextend group. Of each solution 15 mL/kg was administered during surgery. Blood loss, coagulation, and electrolyte profiles were checked before infusion and 5 minutes, 3 hours, and 24 hours after the end of infusion. Results. The Hextend group showed slightly better electrolyte balance, however, more coagulation impairment and postoperative transfusion (37% vs. 11%) compared with the Voluven group. The effect of Hextend on coagulation lasted until 24 hours after infusion. Conclusion. If coagulopathy is a concern during PLIF, then, a HES with low MW/DS in a saline-based medium (Voluven) may be a better alternative than a HES with high MW/DS in a balanced salt medium (Hextend).

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor regulating inflammation, atherosclerosis, insulin sensitivity and adipogenesis. Recently, it has been discovered that modification by the small ubiquitin-like modifier (SUMO) plays an important role in PPARgamma activity. In the present study, we investigated the effect of sumoylation on the antiatherogenic property of PPARgamma. PPARgamma-K107R sumoylation mutant, PPARgamma-wild type (WT) and control genes were transfected on vascular smooth muscle cells (VSMCs) to compare their effect on the proliferation and migration. Adenoviral vectors expressing the PPARgamma-K107R, PPARgamma-WT or control gene were delivered into the carotid arteries of rats after balloon injury. The PPARgamma-K107R increased the transcriptional activity of peroxisome proliferator response element (PPRE) and had a more potent transcriptional repression activity on the inducible nitric oxide synthase (iNOS) promoter as compared to the other sumoylation mutants or WT. PPARgamma-K107R or WT gene transfer inhibited VSMCs proliferation and migration to a greater extent than the control. The PPARgamma-K107R had more potent activity than PPARgamma-WT in this regard. PPARgamma-K107R or WT transfer showed a significantly lower intima-media ratio (IMR) than the control after balloon injury in rats. Again, the delivery of the PPARgamma-K107R decreased IMR further compared to PPARgamma-WT. In addition, the PPARgamma-K107R transfer showed a lower proliferation index and a higher apoptotic index than PPARgamma-WT. In conclusion, the PPARgamma sumoylation mutant K107R strongly inhibited VSMCs proliferation and migration, sustained apoptosis, and reduced neointimal formation after balloon injury. These results indicate that desumoylation at K107 in PPARgamma might play an important role against atherosclerosis.

Oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus and in diabetic vascular complications. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, improve insulin sensitivity and are currently used for the treatment of type 2 diabetes mellitus. Here, we show that TZD prevents oxidative stress-induced insulin resistance in human skeletal muscle cells, as indicated by the increase in insulin-stimulated glucose uptake and insulin signaling. Importantly, TZD-mediated activation of PPARgamma induces gene expression of glutathione peroxidase 3 (GPx3), which reduces extracellular H(2)O(2) levels causing insulin resistance in skeletal muscle cells. Inhibition of GPx3 expression prevents the antioxidant effects of TZDs on insulin action in oxidative stress-induced insulin-resistant cells, suggesting that GPx3 is required for the regulation of PPARgamma-mediated antioxidant effects. Furthermore, reduced plasma GPx3 levels were found in patients with type 2 diabetes mellitus and in db/db/DIO mice. Collectively, these results suggest that the antioxidant effect of PPARgamma is exclusively mediated by GPx3 and further imply that GPx3 may be a therapeutic target for insulin resistance and diabetes mellitus.