Circular RNA PDK1 targets miR-4731-5p to enhance TNXB expression in ligamentum flavum hypertrophy.

Hypertrophic ligamentum flavum (LF) is a main factor responsible for lumbar spinal stenosis (LSS); however, the exact mechanisms of the pathogenesis of these processes remain unknown. This study aimed to elucidate whether circular RNAs and microRNAs regulate the pathogenesis of LF and LSS, especially focusing on circPDK1 (hsa_circ_0057105), a circRNA targeting pyruvate dehydrogenase kinase 1 and differentially expressed in LF tissues between lumbar disk herniation and LSS patients. The circPDK1/miR-4731 and miR-4731/TNXB (Tenascin XB) interactions were predicted and validated by luciferase reporter assay. Colony formation, wound-healing, and MTT assays were used for estimating cell proliferation and migration. Protein expression levels were evaluated using Western blotting. TNXB expression was verified using immunohistochemistry (IHC). Overexpressing circPDK1 promoted the proliferation, migration, and expression of fibrosis-related protein (alpha smooth muscle actin (α-SMA), lysyl oxidase like 2 (LOXL2), Collagen I, matrix metalloproteinase-2 (MMP-2) and TNXB) in LF whereas miR-4731-5p showed opposite effects. The expression of TNXB was promoted by circPDK1; contrary results were observed with miR-4731-5p. Co-overexpression of miR-4731-5p partially reversed the proliferative and fibrosis-prompting effects of circPDK1 or TNXB. The circPDK1-miR-4731-TNXB pathway may be proposed as a regulatory axis in LF hypertrophy, which might shed light on in-depth research of LSS, as well as providing a novel therapeutic target for LF hypertrophy-induced LSS.

Optimizing Lumbar Pedicle Screw Trajectory Utilizing a 3D-Printed Drill Guide to Ensure Placement of Pedicle Screws Into Higher Density Bone May Improve Pedicle Screw Pullout Resistance.

BACKGROUND: Lower preoperative Hounsfield Unit (HU) values of vertebral body are associated with pedicle screw (PS) loosening after implantation with traditional trans-pedicular trajectory. However, the relationship between trajectory HU value and PS fixation quality remains unknown. This study aimed to investigate if 3-dimensionally (3D)-printed guider directed accurate implantation of pedicle screw could increase the anti-pulling properties of screws. METHODS: 3D models of cadaveric spines were reconstructed by using computed tomography image and PS trajectories were designed for both sides of vertebra. The designed trajectories were divided into high HU group and low HU group. PS implantation with 3D-printed screw guide can be in complementary shape with target vertebra. Throughout 3D finite element analysis and biomechanical tests, the pull-out strength of screws in high or low trajectory HU groups were compared. RESULTS: The HU value was 132 ± 13 (mean ± standard deviation) in low HU group and 189 ± 17 in high HU group. The distance between planned trajectories and actual trajectories was 1.69 ± 0.4 mm. Biomechanical tests showed that in the high trajectory HU group the pull-out strength of screws was 750.41 ± 80.65 N; compared with 655.83 ± 74.31 N in the low trajectory HU group, the difference was statistically significant. When simulated with the finite element method, the pull-out strength of low HU trajectory pedicle screws was lower than that of high HU trajectory pedicle screws. CONCLUSIONS: Preoperative computer-assisted trajectory design using a 3D-printed screw guide may direct more accurate implantation with optimal implantation trajectory, and may provide a new way to improve pedicle screw fixation.

A propensity-matched analysis of stereotactic body radiotherapy and sublobar resection for stage I non-small cell lung cancer in patients at high risk for lobectomy: the results in a Chinese population.

BACKGROUND: To investigate the comparative effectiveness of stereotactic body radiotherapy (SBRT) and sublobar resection (SLR) in patients with stage I non-small cell lung cancer (NSCLC) considered to be high-risk lobectomy patients. METHODS: From January 2012 to December 2015, patients who underwent SBRT or SLR for clinical stage I NSCLC were examined retrospectively. Propensity score matching (PSM) was performed to reduce selection bias in SBRT and SLR patients. RESULTS: Data from 86 SBRT and 79 SLR patients was collected. Median follow-up periods of the SBRT and SLR groups were 32 and 37 months, respectively. Patients treated with SBRT exhibited significantly higher age, higher likelihood of being male, larger tumor diameter, lower forced expiratory volume in 1 second (FEV1), and poorer performance status compared with SLR patients. There were no significant differences between SBRT and SLR patients for 3-year overall survival (OS) (80.3% and 82.3%, P=0.405), cause-specific survival (CSS) (81.3% and 83.4%, P=0.383), and local control (LC) (89.7% and 86.0%, P=0.501). Forty-nine patients were identified from each group after performing PSM. After patients were matched for age, gender, performance status, tumor characteristics and pulmonary function, no significant differences were observed in 3-year OS (85.4% and 73.3%, P=0.649), CSS (87.2% and 74.9%, P=0.637) and LC (95.6% and 82.1%, P=0.055). Prevalence of significant adverse events (grade 3 or worse) was 0% and 10.2% in the matched SBRT and SLR groups (P=0.056), respectively. CONCLUSIONS: Disease control and survival in the SBRT patients was equivalent to that seen in SLR patients with stage I NSCLC considered high-risk lobectomy candidates. SBRT could therefore be an alternative option to SLR in treating patients with a high operative risk.

The compression of L5 nerve root, single or double sites?-radiographic graded signs, intra-operative detect technique and clinical outcomes.

BACKGROUND: The L5 nerve root could be compressed at both L4-5 and L5-S1 regions. If L5 nerve root has confirmed compression at L4-5 level and questionable compression at L5-S1 foramina, performing both surgeries at L4-5 and L5-S1 levels may induce unnecessary extra surgery on L5-S1; however, ignoring foraminal stenosis of L5/S1 may require re-exploration. METHODS: Two hundred seventeen patients with L5 nerve root compressed at L4-5 lateral access were performed with L4-5 decompression and interbody fusion. Lee et al. grade classification was used to assess the foraminal stenosis of L5-S1 preoperatively. Nerve root probe was designed and used to detect if there were foraminal stenosis at L5-S1 level that compressing the exiting L5 nerve root. Visual analog scale (VAS) of low back pain, leg pain and Oswestry Disability Index (ODI) were used to assess clinical outcomes. RESULTS: For all of 217 patients who underwent L4-5 surgery, L5-S1 foramina were preoperatively assessed as: grade 0: 125 cases, grade 1: 58 cases, grade 2: 23 cases, and grade 3: 11 cases. After intra-operative L5 nerve root detection, 11/11 patients with grade 3 radiographic foraminal stenosis, 6/23 (26.1%) with grade 2 and 2/58 (3.4%) who had grade 1 underwent L4-5 and L5-S1 transforaminal lumbar interbody fusion (TLIF), the others received only L4-5 TLIF. Compared to pre-operative baseline data, both L4-5 TLIF and L4-5 and L5-S1 TLIF groups had significant decreased VAS of low back pain and leg pain, and ODI at 3 and 24 months after operation. CONCLUSIONS: We suggested that our novel nerve root probe combined with pre-operative radiographic grade may be helpful to surgeons to identify the single or double compression of L5 nerve root and make a more precise surgical strategy to improve surgical outcome than the method depended on pre-operative radiographic grade alone.

The outcomes of percutaneous kyphoplasty in treatment of the secondary osteoporotic vertebral compression factures: a case-control study.

BACKGROUND: To investigate the outcomes of using percutaneous kyphoplasty in the treatment of the secondary osteoporotic vertebral compression fractures. METHODS: Eighty-one patients had the secondary single segmental osteoporotic vertebral compression fractures after the initial fractures and treated by percutaneous kyphoplasty were reviewed, 74 of them had minimum 2 years follow-up were included in this study. The 74 patients with primary osteoporotic vertebral compression fractures treated by percutaneous kyphoplasty at the same time period were matched as control group in 1:1 ratio. Visual Analogue Scales (VAS) and Oswestry Disability Index (ODI) were used to assess the back pain and functional outcomes. The kyphotic angulation (KA) and compression ratio (CR) of the fractured vertebra was measured too. RESULTS: Both the secondary fracture group and control group had significantly relieved back pain, improved functional outcomes, corrected KA and restored CR after operation, but no difference was found between two groups. CONCLUSIONS: Our findings suggest that percutaneous kyphoplasty is an effective and safe procedure for patients with secondary single segmental osteoporotic vertebral compression fractures; it can achieve similar clinical outcomes to the primary osteoporotic vertebral compression fractures.

Prediction of MRI findings including disc injury and posterior ligamentous complex injury in neurologically intact thoracolumbar burst fractures by the parameters of vertebral body damage on CT scan.

OBJECTIVE: To formulate radiological indexes based on CT for further MRI examination to detect posterior ligamentous complex injury (PLC) or disc injury in thoracolumbar burst fractures without neurological deficit in the emergent setting. MATERIALS AND METHODS: Patients with a single thoracolumbar burst fracture and no neurological deficit were included into this study. Radiological indexes on CT included canal compromise (CC), anterior and posterior vertebral height ratio (PVH and AVH ratio), local kyphosis (LK) and regional kyphosis (RK). PLC and disc injury were assessed on MRI. Statistical analysis was performed to identify the predictive power for radiological indexes for any MRI findings either or both disc and PLC injury. RESULTS: Eighty-four patients were included in this study. According to MRI, patients with no PLC and disc injury were allocated into MRI finding negative group, others were defined as positive group. There was no significant difference in AVH ratio, PVH ratio and RK between these two groups. The CC and LK were significant higher in positive group than that in negative group (p < 0.001).The areas under receiver operating characteristic curve were 0.826 and 0.893 for CC and LK respectively and without significant difference. The best thresholds for CC and LK were 0.19 (sensitivity: 69.4%; specificity: 87.5%) and 14.00° (sensitivity: 83.3%; specificity: 83.3%), respectively. CONCLUSION: The presence of CC > 0.19 and/or LK > 14.00° on CT scan can predict MRI findings including PLC and disc injury. These thresholds may be the guideline for MRI examination in patients with neurologically intact thoracolumbar burst fracture in the emergent condition.

The role of cage height on the flexibility and load sharing of lumbar spine after lumbar interbody fusion with unilateral and bilateral instrumentation: a biomechanical study.

BACKGROUND: One- and two-level lumbar interbody fusion with unilateral instrumentation is as effective as that with bilateral instrumentation. The height of the interbody cage influences the operated segment stability and the fusion technique success. The purpose of this research was to determine the effect of the fusion cage height (i.e. long and short) on both the stability (based on flexibility measures) and load sharing of the unilateral and bilateral instrumented transforaminal lumbar interbody fusion (TLIF) technique. METHODS: The flexibility and load sharing tests were performed on seven human lumbar spines. Different configurations combining a long or short cage with a unilateral, bilateral, or no posterior fixation were used to stabilize the operated segment. Two sets of modular cages were designed for each type of test to simulate the long and short cages. During the flexibility test, a pure-moment load of 7.5 Nm was applied. The range of motion (ROM) was recorded for flexion-extension, lateral bending, and axial rotation. During the load sharing test, an axial-compression load of 400 N was applied. The load bearing of the cages was recorded using a cage-embedded load cell. RESULTS: When the fusion cage height decreased 2 mm, the segment flexibility with unilateral fixation showed a significant increase in the ROM for flexion-extension, lateral bending, and axial rotation of 74.9, 83.8, and 175.2% (P < 0.01), respectively. In contrast, for bilateral fixation, the height decrease resulted in no significant change in ROM for flexion-extension (P = 0.686), lateral bending (P = 0.698), and axial rotation (P = 0.133). Using a short fusion cage, the load bearing decreased in 17.1, 21.5, and 54.1% (P < 0.05) for the cage alone, unilateral, and bilateral fixation, respectively. CONCLUSIONS: A cage longer than the intervertebral space should be chosen to increase the stability and intervertebral graft load borne when performing TLIF with unilateral instrumentation.

Hypertrophy and Fibrosis of the Ligamentum Flavum in Lumbar Spinal Stenosis is Associated With Increased Expression of LPA and LPAR1.

STUDY DESIGN: Histologic, immunohistochemical (IHC), and enzyme-linked immunosorbent assay analysis of the human ligamentum flavum (LF). OBJECTIVE: The purpose of this study was to determine the level of expression of lysophosphatidic acid (LPA) in the LF from lumbar spinal stenosis (LSS) patients and to analyze the relationship among LPA, LPA receptors (LPARs), and LF hypertrophy. SUMMARY OF BACKGROUND DATA: LF hypertrophy and fibrosis are important causes of LSS. LPA is involved in the fibrotic process in multiple organ systems. Therefore, we hypothesized that LPA and its receptors might also play a role in degeneration of the LF in LSS patients. METHODS: Forty-one LF samples were enrolled in this study. The thickness of the LF was measured by magnetic resonance imaging. Histologic analysis using hematoxylin and eosin and Masson trichrome stain was performed for each LF to evaluate the architecture of the extracellular matrix. The content of LPA and connective tissue growth factor (CTGF) in LF samples was analyzed using enzyme-linked immunosorbent assay. The expression of LPAR1 was determined by IHC. RESULTS: Degeneration of the LF was characterized by an increase in disorganized elastic fibers and fibrotic transformation by extracellular collagen deposition. The thickness of the LF and the concentration of LPA and CTGF in the hypertrophic LF group were significantly higher than the control group. Furthermore, the LPA and CTGF concentrations had a positive correlation with the LF thickness (r=0.91, P<0.001 and r=0.943, P<0.001, respectively). On the basis of IHC analysis, the expression of LPAR1 was increased in the hypertrophy group. CONCLUSIONS: The increased expression of LPA and LPAR1 is associated with the fibrosis and hypertrophy of the LF in patients with LSS. Further study on the mechanism underlying LF fibrosis may lead to new therapies for LF hypertrophy and fibrosis.

C-Met as a Molecular Marker for Esophageal Squamous Cell Carcinoma and Its Association with Clinical Outcome.

BACKGROUND: Epidermal growth factor receptor (EGFR), c-Met, and human epidermal growth factor receptor 2 (HER2) are overexpressed in a variety of human cancers, and may serve as biomarkers for disease prognosis. We examined whether high expression of these molecular markers correlates with poor disease prognosis in esophageal squamous cell cancer (ESCC). MATERIALS AND METHODS: Expression of EGFR, c-Met, and HER2 protein was detected by immunohistochemistry (IHC) in 180 paraffin-embedded tissue samples from stage IIB-IIIC ESCC patients. The overall survival (OS) rates were calculated according to the Kaplan-Meier method, and the log-rank test was used to evaluate differences between survival curves. The Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: The median survival of all patients was 46 months. There was no significant difference in OS in terms of HER2 and EGFR status (P = 0.177 and P=0.061, respectively). However, there was a significant difference in OS between c-Met high expression patients and c-Met low expression or negative patients (median: 41.9 months vs. 56.7 months; P = 0.001). Multivariate analysis also showed that, of the covariates analyzed, c-Met high expression was the only prognostic factor for OS (HR: 0.459 [95 % confidence interval: 0.287-0.733]; P = 0.001). Patients with ESCC that had concurrent overexpression of EGFR and c-Met had significantly worse survival than ESCC that displayed overexpression of either EGFR or c-Met individually or that did not have overexpression of either protein (P=0.000). CONCLUSIONS: Overexpression of HER2 and EGFR individually is not significantly associated with poor prognosis in ESCC. High expression of c-Met may be indicative of a poorer prognosis in ESCC. In order to promote efficient and rapid development of therapeutic methods in ESCC, further studies are necessary to explore the role of c-Met.

A phase II study of Endostatin in combination with paclitaxel, carboplatin, and radiotherapy in patients with unresectable locally advanced non-small cell lung cancer.

BACKGROUND: Endostatin inhibits the pro-angiogenic action of basic fibroblast growth factor and vascular endothelial growth factor in different human cancers. This study assessed the efficacy of endostatin combined with concurrent chemoradiotherapy of non-small cell lung cancer (NSCLC). METHODS: Nineteen patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-l, and adequate organ function were treated with 60-66 Gy thoracic radiation therapy over 30-33 fractions concurrent with weekly 7.5 mg/m(2) endostatin for 14 days, 50 mg/m(2) paclitaxel, and 2 mg/mL/min carboplatin over 30 min. Patients were then treated with 7.5 mg/m(2) endostatin for 14 days, 150 mg/m(2) paclitaxel, and 5 mg/mL/min carboplatin every 3 weeks for 2 cycles as the consolidation treatment. The objective response rate was recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. RESULTS: Six patients were unable to complete the consolidation treatment (4 pulmonary toxicity, 1 tracheoesophageal fistulae, and 1 progressive disease). Seventeen patients were included for data analysis. Specifically, one (5.9%) patient had a complete response and 12 (70.6%) had a partial response, whereas two patients had stable disease and the other two had disease progression. The overall response rate was 76% (95% confidence interval [CI], 51%-97%). The median progression-free survival was 10 months (95% CI, 7.6-12.3 months), and the median overall survival was 14 months (95% CI, 10.7-17.2 months). Early 10 patients who completed the treatment regimen showed that four patients experienced grade III pulmonary toxicity a few months after chemoradiotherapy, leading to the early closure of the trial according to the study design. CONCLUSIONS: The result of concurrent endostatin treatment with chemoradiotherapy in locally advanced unresectable NSCLC did not meet the goal per study design with unacceptable toxicity. The real impact of endostatin as the first-line treatment combined with chemoradiotherapy on the survival of NSCLC patients remains to be determined. (NCT 01158144).

Effect of a New Annular Incision on Biomechanical Properties of the Intervertebral Disc.

OBJECTIVE: To compare the biomechanical properties of a novel annular incision technique, an oblique incision made approximately 60° to the spinal column, with the traditional transverse and longitudinal annular slit incision in an ex vivo sheep lumbar spine model. METHODS: Sixteen sheep lumbar spines were used for the current ex vivo biomechanical comparative study. Functional spine unit (FSU) specimens composed of two vertebrae and one disc in the middle was cut from the whole lumbar spine. Annular slit incisions of 5 mm were made in different directions with a 15-blade knife at the intervertebral disc, following which partial discectomy was performed to produce the following groups: control with no incision, transverse slit, longitudinal slit and oblique slit groups. The specimens were then subjected to flexion-extension, lateral bending, axial rotation and compression tests. RESULTS: As expected, the control group showed the least range of motion (ROM) in the flexion-extension test. The oblique slit group showed a trend toward a smaller ROM than the transverse and longitudinal groups in 1, 2, 3 and 5 Nm flexion-extension tests; these differences were not statistically significant (P > 0.05). In addition, the transverse (5.80° ± 0.20°), longitudinal (5.77° ± 0.67°) and oblique (5.47° ± 0.43°) slit groups showed a significantly larger ROM than the control group (3.22° ± 0.28°) in 2 Nm lateral bending tests (P < 0.05). Compared with the transverse and longitudinal groups, the oblique group also showed a trend toward a smaller ROM in lateral bending tests (P > 0.05). Following increments in the axial torsion force, the ROM was greater in all four experimental groups than the ROM with 1 Nm axial torsion. Furthermore, a significantly smaller axial rotational ROM was found in the oblique than the transverse group for 1 and 5 Nm force (P < 0.05). With increase in the axial force to 5 Nm, the ROM in the oblique slit group (4.71° ± 0.52°) was significantly smaller than that in the transverse group (7.25° ± 0.46°, P < 0.05), but not significantly different from that of the longitudinal slit group (5.84° ± 0.23°, P > 0.05). Comparable ultimate loads to failure were found in the oblique, transverse and longitudinal groups; the highest ultimate load to failure being in the control group (P > 0.05). CONCLUSION: The novel oblique slit annular incision to the intervertebral disc showed a trend toward better biomechanical properties than the traditional transverse and longitudinal slit incisions.

Beta1 integrin inhibits apoptosis induced by cyclic stretch in annulus fibrosus cells via ERK1/2 MAPK pathway.

Low back pain is associated with intervertebral disc degeneration (IVDD) due to cellular loss through apoptosis. Mechanical factors play an important role in maintaining the survival of the annulus fibrosus (AF) cells and the deposition of extracellular matrix. However, the mechanisms that excessive mechanical forces lead to AF cell apoptosis are not clear. The present study was to look for how AF cells sense mechanical changes. In vivo experiments, the involvement of mechanoreceptors in apoptosis was examined by RT-PCR and/or immunoblotting in the lumbar spine of rats subjected to unbalanced dynamic and static forces. In vitro experiments, we investigated apoptotic signaling pathways in untransfected and transfected AF cells with the lentivirus vector for rat ß1 integrin overexpression after cyclic stretch. Apoptosis in AF cells was assessed using flow cytometry, Hoechst 33258 nuclear staining. Western blotting was used to analyze expression of ß1 integrin and caspase-3 and ERK1/2 MAPK signaling molecules. In the rat IVDD model, unbalanced dynamic and static forces induced apoptosis of disc cells, which corresponded to decreased expression of ß1 integrin. Cyclic stretch-induced apoptosis in rat AF cells correlated with the activation of caspase-3 and with decreased levels of ß1 integrin and the phosphorylation levels of ERK1/2 activation level. However, the overexpression of ß1 integrin in AF cells ameliorated cyclic stretch-induced apoptosis and decreased caspase-3 activation. Furthermore, ERK1/2-specific inhibitor promotes apoptosis in vector ß1-infected AF cells. These results suggest that the disruption of ß1 integrin signaling may underlie disc cell apoptosis induced by mechanical stress. Further work is necessary to fully elucidate the pathophysiological mechanisms that underlie IVDD caused by unbalanced dynamic and static forces.

Epidermal growth factor receptor protein overexpression and gene amplification are associated with aggressive biological behaviors of esophageal squamous cell carcinoma.

Alterations of the epidermal growth factor receptor (EGFR), including overexpression or gene mutations, contribute to the malignant transformation of human epithelial cells. The aim of this study was to assess EGFR overexpression or gene amplification in esophageal squamous cell carcinoma (ESCC) tissue samples and investigate their correlations with biological behaviors. Tissue specimens from 56 patients with surgically resected ESCC were obtained for immunohistochemical analysis of EGFR expression and fluorescence in situ hybridization analysis of EGFR amplification. The data were statistically analyzed to determine the associations with patient clinicopathological and survival data. EGFR was overexpressed in 30 of the 56 (53.6%) ESCC samples and was associated with poor tumor differentiation (P=0.047). EGFR amplification was detected in 13 cases (23.2%) and was associated with advanced pathological stage (P=0.042) and tumor lymph node metastasis (P=0.002). The univariate analysis identified no association between EGFR overexpression and the overall survival (OS) of the patients. By contrast, EGFR amplification predicted ESCC prognosis (P=0.031), while the multivariate analysis revealed a marginal statistical significance for the association between EGFR amplification and OS (P=0.056). EGFR overexpression and increased EGFR copy number were common events in ESCC and contributed to malignant biological behaviors, including tumor dedifferentiation and lymph node metastasis. EGFR amplification may therefore be useful in predicting OS in patients with ESCC.

Oxygen-glucose deprivation regulates BACE1 expression through induction of autophagy in Neuro-2a/APP695 cells.

Our previous findings have demonstrated that autophagy regulation can alleviate the decline of learning and memory by eliminating deposition of extracellular beta-amyloid peptide (Aß) in the brain after stroke, but the exact mechanism is unclear. It is presumed that the regulation of beta-site APP-cleaving enzyme 1 (BACE1), the rate-limiting enzyme in metabolism of Aß, would be a key site. Neuro-2a/amyloid precursor protein 695 (APP695) cell models of cerebral ischemia were established by oxygen-glucose deprivation to investigate the effects of Rapamycin (an autophagy inducer) or 3-methyladenine (an autophagy inhibitor) on the expression of BACE1. Either oxygen-glucose deprivation or Rapamycin down-regulated the expression of BACE1 while 3-methyladenine up-regulated BACE1 expression. These results confirm that oxygen-glucose deprivation down-regulates BACE1 expression in Neuro-2a/APP695 cells through the introduction of autophagy.

Clinical significance of gefitinib antitumor activity in patients with lung adenocarcinoma.

Non-small cell lung cancer is a subtype of adenocarcinoma, which has previously shown positive responses to gefitinib. The aim of the current study was to determine a clinical profile of gefitinib-induced disease controls for patients with lung adenocarcinoma. Retrospective evaluation of the clinical characteristics of 52 lung adenocarcinoma patients, enrolled at the Zhejiang Cancer Hospital (Hangzhou, China) between October 2004 and August 2008, was undertaken. All patients received gefitinib (250 mg/day orally) until disease progression or until an unacceptable toxicity was observed. Of the 52 patients, complete response (CR) and partial response (PR) rates were 23.1% (12/52) and 57.7% (30/52), respectively. An additional 19.2% (10/52) of patients demonstrated stable disease (SD) after three months of treatment with gefitinib. Disease control was observed in the primary lesion, and tumor metastasis to the lungs, brain, adrenal glands, pleura, peritoneum, pericardium, bone and lymph nodes was identified. The one-year progression-free survival (PFS) and overall survival (OS) rates were 74.8 and 78.0%, respectively. Multivariate analysis revealed that female patients were associated with significantly longer survival times when compared with males (hazard ratio, 0.077; 95% confidence interval [CI], 0.007-0.083; P=0.035). One-year PFS and OS rates in CR, PR and SD patients were 77.8, 73.9 and 33.3%, and 89.2, 79.8 and 33.7%, respectively, although neither difference was identified to be statistically significant. In addition, the median OS of SD patients was 12 months (95% CI, 7.2-16.8 months). Brain metastasis was the major site of disease progression (23.1%). Gefitinib treatment for patients with lung adenocarcinoma showed a marked long-term survival benefit, even in SD patients. However, further studies are required to analyze the efficacy of gefitinib in penetrating the blood-brain barrier in order to prolong PFS in patients with lung adenocarcinoma.

Glycogen synthase kinase-3 regulates production of amyloid-ß peptides and tau phosphorylation in diabetic rat brain.

The pathogenesis of diabetic neurological complications is not fully understood. Diabetes mellitus (DM) and Alzheimer's disease (AD) are characterized by amyloid deposits. Glycogen synthase kinase-3 (GSK-3) plays an important role in the pathogenesis of AD and DM. Here we tried to investigate the production of amyloid-ß peptides (A ß) and phosphorylation of microtubule-associated protein tau in DM rats and elucidate the role of GSK-3 and Akt (protein kinase B, PKB) in these processes. Streptozotocin injection-induced DM rats displayed an increased GSK-3 activity, decreased activity and expression of Akt. And A ß 40 and A ß 42 were found overproduced and the microtubule-associated protein tau was hyperphosphorylated in the hippocampus. Furthermore, selective inhibition of GSK-3 by lithium could attenuate the conditions of A ß overproduction and tau hyperphosphorylation. Taken together, our studies suggest that GSK-3 regulates both the production of A ß and the phosphorylation of tau in rat brain and may therefore contribute to DM caused AD-like neurological defects.

Bilateral decompression using a unilateral pedicle construct for lumbar stenosis.

PURPOSE: To determine the effectiveness of bilateral decompression via a unilateral approach using unilateral pedicle screw fixation for two-level lumbar stenosis with instability. METHODS: Between October 2006 and October 2010, 98 patients (61 men and 37 women) who had reached the three-year follow-up interval were treated with unilateral pedicle screw fixation at the authors' institution. All patients underwent two-level transforaminal lumbar interbody fusion (TLIF), and the mean age was 59.6 years (range, 40-72). Visual analog scale (VAS) scores and Oswestry Disability Index (ODI) were used to assess the pre-operative and postoperative clinical results. Fusion status, the disc space height, and the whole lumbar lordotic angle were analysed for the radiological evaluation. RESULTS: The ODI scores decreased significantly in both early and late follow-up evaluations and the visual analog scale (VAS) score demonstrated significant improvement in late follow-up (P < 0.01). The disc space height (P < 0.05) and the whole lumbar lordotic angle (P < 0.05) were increased at the final follow-up. Successful fusion was achieved in all patients. CONCLUSION: Bilateral decompression via a unilateral approach using unilateral pedicle screw fixation for two-level lumbar stenosis with instability, which can maintain the lumbar lordosis and the disc space height, is an effective and less invasive method than with bilateral constructs.

Unilateral versus bilateral instrumented transforaminal lumbar interbody fusion in two-level degenerative lumbar disorders: a prospective randomised study.

PURPOSE: The aim of this study was to analyse the clinical and radiological outcomes of unilateral versus bilateral instrumented TLIF in two-level degenerative lumbar disorders. METHODS: A prospective randomised clinical study was performed from January 2008 to May 2011. Sixty-eight consecutive patients with severe low back pain and radicular pain were divided randomly into the unilateral (n = 33) or bilateral (n = 35) pedicle screw fixation group based on a random number list. Operative time, blood loss, duration of hospital stay, fusion rate, complication rate and implant costs were recorded and analysed statistically. Visual analog scale (VAS) scores, Oswestry Disability Index (ODI), and SF-36 were used to assess the preoperative and postoperative clinical results in the two groups. RESULTS: No differences were observed between the two groups with respect to demographic data. The patients of the two groups had significant improvement in functional outcome compared to preoperatively. There was no significant difference comparing fusion rate, complication rate and duration of hospital stay between the two groups at postoperative follow-up (P > 0.05). However, compared with the bilateral pedicle screw group, a significant decrease occurred in operative time, blood loss and implant costs in the unilateral group. CONCLUSION: Two-level unilateral instrumented TLIF is an effective and safe method with reduced operative time and blood loss for multiple-level lumbar diseases. But it is imperative that the larger cage should be appropriately positioned to support the contralateral part of the anterior column by crossing the midline of the vertebral body.

Quantitative T2 mapping to characterize the process of intervertebral disc degeneration in a rabbit model.

BACKGROUND: To investigate the potential of T2 mapping for characterizing the process of intervertebral disc degeneration (IDD) in a rabbit model. METHODS: Thirty-five rabbits underwent an annular stab to the L4/5 discs (L5/6 discs served as internal normal controls). Degenerative changes were graded according to the modified Thompson classification and quantified in T2 respectively at pre-operation, 1, 3, 6, 12 and 24 weeks postoperatively. After MRI analysis, expression analysis of aggrecan and type II collagen gene in nucleus pulposus (NP) was performed using real time polymerase chain reaction (real-time PCR). The longitudinal changes in NP T2 and gene expressions were studied by repeated measures and ANOVA, linear regression was performed for their correlations through the process of IDD. The reliability analysis of method of measurement of NP T2 was also performed. RESULTS: There was a strong inverse correlation between NP T2 and Thompson grades (r = -0.85). The decline of L4/5 NP T2 through 24 weeks was nonlinear, the most significant decrease was observed in 3 weeks postoperatively (P<0.05). The tendency was confirmed at gene expression levels. NP T2 correlated strongly with aggrecan (R² = 0.85, P<0.01) and type II collagen (R² = 0.78, P<0.01) gene expressions. The intraclass correlation coefficients for interobserver and intraobserver reliability were 0.963 and 0.977 respectively. CONCLUSIONS: NP T2 correlates well with aggrecan and type II collagen gene expressions. T2 mapping could act as a sensitive, noninvasive tool for quantitatively characterizing the process of IDD in longitudinal study, help better understanding of the pathophysiology of IDD, assist us to detect the degenerative cascade, and develop a T2-based quantification scale for evaluation of IDD and efficacy of therapeutic interventions.

3-N-butylphthalide (NBP) attenuates the amyloid-ß-induced inflammatory responses in cultured astrocytes via the nuclear factor-κB signaling pathway.

BACKGROUND/AIMS: Activation of astrocytes is a common feature of Alzheimer's disease (AD). Proinflammatory molecules produced by activated astrocytes contribute to neuronal damage in AD. Moreover, dl-3-n-butylphthalide (NBP) has been reported to attenuate astroglial activation and exert neuroprotective effects in AD transgenic mice. However, the mechanism by which NBP inhibits activated astrocytes is poorly understood. METHODS: In this study, the primary astrocytes were obtained from the cerebral cortices of 1-day-old Sprague-Dawley rats. The levels of GFAP, COX-2, NF-κB, and IκBα were examined by Western blotting and the levels of TNF-α and IL-6 were determined by ELISA. RESULTS: NBP inhibited the amyloid-ß (Aß)-induced activation of astrocytes and the up-regulation of proinflammatory molecules. Importantly, NBP markedly suppressed Aß-induced IκBα degradation and nuclear factor-κB (NF-κB) translocation. CONCLUSION: Our results suggest that NBP attenuates Aß-induced activation of astrocytes and neuroinflammation via inhibition of the NF-κB signaling pathway.