GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.

As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.

Impaired metabolism of oligodendrocyte progenitor cells and axons in demyelinated lesion and in the aged CNS.

The key pathology of multiple sclerosis (MS) comprises demyelination, axonal damage, and neuronal loss, and when MS develops into the progressive phase it is essentially untreatable. Identifying new targets in both axons and oligodendrocyte progenitor cells (OPCs) and rejuvenating the aged OPCs holds promise for this unmet medical need. We summarize here the recent evidence showing that mitochondria in both axons and OPCs are impaired, and lipid metabolism of OPCs within demyelinated lesion and in the aged CNS is disturbed. Given that emerging evidence shows that rewiring cellular metabolism regulates stem cell aging, to protect axons from degeneration and promote differentiation of OPCs, we propose that restoring the impaired metabolism of both OPCs and axons in the aged CNS in a synergistic way could be a promising strategy to enhance remyelination in the aged CNS, leading to novel drug-based approaches to treat the progressive phase of MS.

Raloxifene Protects Cisplatin-Induced Renal Injury in Mice via Inhibiting Oxidative Stress.

PURPOSE: Cisplatin is one of the most widely used antineoplastic drugs but has limited therapeutic effects due to nephrotoxicity. The aim of this study was to determine the possible renoprotective effect of the antioxidant raloxifene on cisplatin-induced nephrotoxicity in mice. MATERIALS AND METHODS: Cisplatin-induced acute renal injury was established in female C57 mice that were treated with saline (normal control) or raloxifene over a 7-day period. The body weight of the mice was recorded. Histopathological examinations of the kidney tissues were performed using H&E, PAS staining and TEM. The histomorphology of liver and other organs was observed by H&E staining. The serum levels of creatinine, blood urea nitrogen (BUN), alanine transaminase (ALT) and glutamic oxalacetic transaminase (AST) were analyzed by specific kits. Superoxide dismutase (SOD) and glutathione (GSH) activity, and the content of malondialdehyde (MDA) in the kidney, liver homogenates and HK-2 cells were measured by WST-8 and thiobarbituric acid colorimetric methods. Moreover, the mitochondrial structures of HK-2 cells were performed using TEM. The viability and proliferation of HK-2 cells were examined by CCK-8 and EdU incorporation assays. The mitochondrial membrane potential was measured by JC-1 fluorescence. RESULTS: Raloxifene significantly reduced the levels of serum creatinine, urea, ALT and AST in the cisplatin-treated mice, and alleviated cisplatin-induced renal and hepatic tissue injury. Furthermore, raloxifene also increased the activity of GSH and SOD in the renal tissues and HK-2 cells, and reduced MDA levels, thereby limiting oxidative stress in the kidney. CONCLUSION: Raloxifene protected against cisplatin-induced nephrotoxicity by activating the antioxidant system, along with alleviating liver damage. It should be considered as a potential adjuvant in cisplatin-based chemotherapeutic protocols.

Normal Basal Epithelial Cells Stimulate the Migration and Invasion of Prostate Cancer Cell RM-1 by TGF-ß1/STAT3 Axis in vitro.

AIM: Basal epithelial cells are absent in distant prostate cancer. This study aimed to investigate whether basal epithelial cells could suppress migration and invasion of prostate cancer cells to become a new treatment strategy for prostate cancer. MAIN METHODS: Basal epithelial cells were identified by immunofluorescence with anti-p63. Wound healing assays or transwell assays were used to explore the effects of basal epithelial cells, TGF-ß1, SB431542 (inhibitor of TGF-ß type I receptor) or stattic (inhibitor of phosphorylated STAT3) on migration or invasion of mouse prostate cancer cell (RM-1). Concentration of TGF-ß1 was measured by ELISA assay. HE staining was used to investigate cell morphology. Immunocytochemistry with anti-p63 was used to identify basal epithelial cells. Levels of STAT3, p-STAT3 (Ser727) and proteins associated with EMT were measured with Western blot assay. Cell proliferation was measured with MTT or CCK8 assay. RESULTS: Normal basal epithelial cells acquired from mouse prostate were specific to anti-p63 and more than 90%. Basal epithelial cells and RM-1 could both secrete TGF-ß1. Basal epithelial cells and TGF-ß1 promoted the migration and invasion of RM-1 through changing the cell morphology and up-regulating expression of ZEB1, N-cadherin, vimentin, snail and p-STAT3 (Ser727), at the same time down-regulating E-cadherin of RM-1. SB431542 strongly suppressed migration, invasion as well as the expressions of EMT relevant proteins and p-STAT3 (Ser727) of co-cultured RM-1. In addition, stattic suppressed proliferation, migration and invasion of non-treated RM-1 and co-cultured RM-1. CONCLUSION: Our study suggests that normal basal epithelial cells might stimulate the migration and invasion of RM-1 by TGF-ß1/STAT3 axis which could be suppressed by inhibitor of TGF-ß receptor and inhibitor of p-STAT3. So, basal epithelial cells might not become a treatment strategy for prostate cancer, but our results could provide some researching references for other diseases which include basal epithelial cells such as prostatic intraepithelial neoplasia, prostatic hyperplasia, cervical cancer, or urinary bladder cancer.

Biological implications of PTEN upregulation and altered sodium/iodide symporter intracellular distribution in resveratrol-suppressed anaplastic thyroid cancer cells.

Objective: Anaplastic thyroid cancer/ATC is a highly aggressive malignancy with extremely poor prognosis. Resveratrol/Res promotes re-differentiation of cancer cells and exerts inhibitory effects on ATC cells. Sodium/iodide symporter/NIS and phosphate and tension homology deleted on chromsome ten/PTEN levels are positively correlated with the grade of thyroid cancer differentiation, while the impact of Res on them remain unknown. Materials and Methods: The patterns of NIS and PTEN expression and intracellular distribution in THJ-16T and THJ-21T ATC and Nthy-ori 3-1 normal thyroid cells and their relevance with Res-caused ATC suppression were investigated via multiple experimental methods. E-cadherin was cited as a re-differentiation biomarker of ATC cells. Results: MTT and EdU cell proliferation assays showed distinct growth suppression in ATC cells after Res treatment. TUNEL staining revealed extensive apoptosis of Res-treated THJ-16T and THJ-21T rather than Nthy-ori 3-1 cells. Western blotting, immunocytochemical/ICC and double-labeled immunofluorescent/IF staining showed increased PTEN levels accompanied with distinct NIS and PTEN nuclear co-translocation in Res-treated THJ-16T and THJ-21T cells. E-cadherin but not NIS appeared on the outer membrane. Conclusion: PTEN upregulation and the concurrent NIS and PTEN nuclear translocation in Res-suppressed ATC cells may indicate the better therapeutic outcome and would be a group of beneficial prognostic factors of ATCs.

[Application of guide combined with probing the internal wall of pedicle screw trajectory for subaxial cervical pedicle screw placement].

OBJECTIVE: To investigate the skill and evaluate the accuracy for application of guide combined with probing the internal wall of pedicle screw trajectory for subaxial cervical pedicle screw placement. METHODS: Subaxial cervical pedicle screw was inserted in 11 patients by the guide combined with probing the internal wall of pedicle screw trajectory from January 2014 to October 2016, including 7 males and 4 females with an average age of 48.1 years(ranged 32 to 63 years). There were 4 cases with cervical spondylotic myelopathy, 4 with fracture and dislocation of cervical vertebrae, 1 with cervical cord injury without fracture and dislocation, and 2 with atlantoaxialfracture and dislocation. The target pedicle's diameter, optimal entry point, sagittal angle and cross-sectional angle were measured by CT before operation. During operation, the pedicle screw inserted angle was controlled by a guide with a self-designed protractor and probed the internal wall of pedicle screw trajectory as medial safety margin of insertion screw. The accuracy of cervical pedicle screw was evaluated by CT with classification of four grades and assessed whether there was injury of spine cord or vertebral artery postoperatively. RESULTS: Seventy-one cervical pedicle screws were placed among 11 patients, and no one had been found with clinical manifestations of injury of spine cord (or nerve root) or vertebral artery after operation. According to postoperative CT scan for evaluating the grade of screw position, 52 screws were in grade 0, 13 in grade 1, 4 in grade 2, 2 in grade 3, and 91% (65/71) located in good position. In total, 6 screws were incorreted in placement, and 4 cases of them broke medial wall and 2 cases broke lateral wall. CONCLUSIONS: The method of probing the internal wall of pedicle screw trajectory for subaxial cervical pedicle screw placement is safe and reliable, but the studying curve is long. Probing the internal wall of pedicle screw trajectory and controlling the insertion angle by guide with a protractor are key points of this technology.

Development of an on-line source-tagged model for sulfate, nitrate and ammonium: A modeling study for highly polluted periods in Shanghai, China.

An on-line source-tagged model coupled with an air quality model (Nested Air Quality Prediction Model System, NAQPMS) was applied to estimate source contributions of primary and secondary sulfate, nitrate and ammonium (SNA) during a representative winter period in Shanghai. This source-tagged model system could simultaneously track spatial and temporal sources of SNA, which were apportioned to their respective primary precursors in a simulation run. The results indicate that in the study period, local emissions in Shanghai accounted for over 20% of SNA contributions and that Jiangsu and Shandong were the two major non-local sources. In particular, non-local emissions had higher contributions during recorded pollution periods. This suggests that the transportation of pollutants plays a key role in air pollution in Shanghai. The temporal contributions show that the emissions from the "current day" (emission contribution from the current day during which the model was simulating) contributed 60%-70% of the sulfate and ammonium concentrations but only 10%-20% of the nitrate concentration, while the previous days' contributions increased during the recorded pollution periods. Emissions that were released within three days contributed over 85% averagely for SNA in January 2013. To evaluate the source-tagged model system, the results were compared by sensitivity analysis (emission perturbation of -30%) and backward trajectory analysis. The consistency of the comparison results indicated that the source-tagged model system can track sources of SNA with reasonable accuracy.

Promotive effects of bone morphogenetic protein 2 on angiogenesis in hepatocarcinoma via multiple signal pathways.

The effects of Bone morphogenetic protein 2 (BMP-2) on the angiogenesis of hepatocellular carcinoma have not yet been observed and its molecular mechanisms is not clear. We first constructed the recombinant lentivirus vectors expressing small hairpin RNA against BMP-2 gene (LV-SH-BMP2) and the recombinant lentivirus vectors over-expressing BMP-2 (overexpression-LV-BMP2), and then the two recombinant lentivirus vectors were respectively transfected into Hep G2 cells. The Hep G2 cells transfected with LV-SH-BMP2 or overexpression-LV-BMP2 were respectively co-cultured with human umbilical vein endothelial cells (HUVECs) to observe the effects of BMP-2 on HUVECs. The effect of BMP-2 on tumor microvessel density (MVD) was examined. The abilities of proliferation, migration and angiogenesis were significantly inhibited in the HUVECs co-cultured with BMP-2 knockdown Hep G2 (all P < 0.05), but significantly enhanced in the HUVECs co-cultured with BMP-2 overexpression Hep G2 (all P < 0.05). MVD was significantly increased in overexpression-LV-BMP2-transfected Hep G2 tumor, but decreased in LV-SH-BMP2-transfected Hep G2 tumors. The protein expressions of VEGF, p-P38, p-ERK, p-AKT, p-m-TOR were significantly increased after BMP-2 over-expression, or significantly decreased after BMP-2 knockdown (all P < 0.05). These results reveal that BMP-2 can enhance HUVEC proliferation, migration and angiogenesis through P38, ERK and Akt/m-TOR pathway.

[Bone substitutes augmentation combined with internal fixation versus internal fixation alone in treating proximal femoral fractures in the elderly: a meta-analysis].

OBJECTIVE: To systematically review the effectiveness of bone substitute augmentation combined with internal fixation versus internal fixation alone in treating proximal femoral fractures in the elderly. METHODS: Subject term and keywords were searched from Pubmed, Cochrane databases and CNKI from database foundation to August 2015. Randomized controlled studies and qusi-randomized controlled studies on bone substitutes augmentation combined with internal fixation versus internal fixation alone for the treatment of proximal femoral fractures in the elderly were chosen. Postoperative re-displacement, re-operation rate, complications (infection and bone ununion), functional outcome, quality of life scores and muscle strength were seen as outcome indicators. Enumeration data were statistical analyzed by risk difference and 95% confidence interval. Measurement data were analyzed by standardized mean difference and 95% confidence interval. If the same measurement data were evaluated by different standards in different studies, standardized mean differences and 95% confidence interval were used. The methods of statistical analysis were used by Cochrane databases. RESULTS: Eleven RCTs (677 patients) were included. Meta-analysis results indicated that bone substitutes augmentation combined with internal fixation occurred fewer re-displacement [SMD = -0.75, 95% CI (-1.03, -0.47)] and obtained better function [SMD = 0.40, 95% CI (0.20, 0.59)]. While there were no significant differences in reoperation rate [RD = 0.02, 95% CI (-0.05, -0.09)], pain at 1 week after operation [MD = -1.79, 95% CI (-13.55, -9.96)], pain ranged from 6 to 8 weeks [MD = -7.24, 95% CI (-20.07, -5.59)], postoperative pain at 12 weeks [MD = -0.32, 95% CI (-4.9, -3.55)], muscle strength [MD = 1.25, 95% CI (-6.98, -9.48)], bone ununion [RD = 0.02, 95% CI (-0.01, -0.05)] and postoperative complications [MD = 0.01, 95% CI (-0.03, -0.04)]. CONCLUSION: Compared with single internal fixation, bone substitutes augmentation combined with internal fixation for the treatment of proximal femoral fractures in the elderly less occur re-displacement and could obtain better functional recovery.

[A Numerical Study of Typical Heavy Air Pollution Episode of PM2.5 in Shanghai].

To analyze the characteristics and formation mechanism of a heavy air pollution episode in Shanghai City from January 23th to January 24th, 2013, the observed data of PM2.5 concentration and ground meteorological data and the WRF-Chem model were collected. The analysis revealed that the synoptic necessary mechanism of the heavy air pollution episode could be characterized by the following patterns: Accompanied with weak cold front activities, the city experienced weak winds (i. e. stable atmosphere) at first and then northerly winds (i. e. pollutant transport process ), causing the continuous increase and maintaining of pollutant concentration. The detailed results are shown as follows: Firstly, the stable atmosphere circulation pattern which lasted for 10 hours was not good for air pollution dispersion, as a result, local PM2.5 concentrations continued to increase and reached severe pollution level and the high concentrations maintained for 7 hours caused by the stable boundary layer (e. g. static surface winds and low level temperature inversion) during nighttime, and the average PM2.5 concentrations during the stable weather process was 172.4 µg · m⁻³. Secondly, the dispersion condition was slightly improved later on with the arrival of a weak cold front, the upstream pollution transportation occurred at the same time, leading to further increase of PM2.5 concentration (up to 280 µg · m⁻³), and the average PM2.5 concentration during the upstream transportation process was 213.6 µg · m⁻³. Numerical simulation with the WRF-Chem model showed that, average contribution of upstream transportation to local PM2.5 concentrations during the episode was 23% . Among them, the contribution during the stable weather and upstream transportation stage was 17.2% and 32.2% . Our results suggested that there were significant differences in the contribution of upstream transportation to the local PM2.5 concentration of Shanghai due to variation of weather conditions. Therefore, the government can design effective emission control strategy in advance taking pollution weather forecasting into account.

[Strategy by stages for preventing respiratory complications of acute cervical spinal cord injury].

OBJECTIVE: To investigate clinical effects of strategy by stages for preventing respiratory complications of patients with acute cervical spinal cord injury (ACSCI). METHODS: From September 2009 to May 2013,the clinical data of 91 patients with ACSCI underwent surgery were retrospectively analyzed. Among the patients, 42 patients were divided into in-stages group, including 30 males and 12 females with an average age of 50 years old (ranged 28 to 76) which were treated with strategy by stages for preventing respiratory complications; others 49 patients which were not treated with the strategy regarded as control group, including 38 males and 11 females with an average age of 47 years old (ranged 30 to 77). All of them had definite history of trauma, and were admitted to orthopaedics within 48 h after trauma. In in-stages group, respiratory muscle strength training, high-dose ambroxol using and other treatment were performed to prevent respiratory complilcations according to preoperative, intraoperative and postoperative stage. While in control group, there were no systematic and effective measures utilized. Chi-square test was used to evaluate the difference for respiratory complications rate, the rate of tracheostomy or intubation and mortality caused by the respiratory complications between two groups. RESULTS: Ten patients developed with respiratory complications in in-stages group (7 patients with pneumonia, 1 with atelectasis and 2 with respiratory failure), among which 3 patients underwent tracheostomy or intubation. In control group, 24 patients developed with respiratory complilcations (15 with pneumonia,3 with atelectasis and 6 with respiratory failure), among which 11 patients underwent tracheostomy or intubation. There was significant difference between two groups (χ2 = 6.12, 4.07; P = 0.013, 0.044). Five patients died because of respiratory complications, one case were in in-stages group and 4 in control group. There was significant difference between two groups (χ2 = l.39, P = 0.238). CONCLUSION: The strategy by stages is an effective method for preventing respiratory complications of ACSCI and can reduce the respiratory complications rate and improve the prognosis of respiratory complications.

Fascia and Primo Vascular System.

The anatomical basis for the concept of acupuncture points/meridians in traditional Chinese medicine (TCM) has not been resolved. This paper reviews the fascia research progress and the relationship among acupuncture points/meridians, primo vascular system (PVS), and fascia. Fascia is as a covering, with common origins of layers of the fascial system despite diverse names for individual parts. Fascia assists gliding and fluid flow and holds memory and is highly innervated. Fascia is intimately involved with nourishment of all cells of the body, including those of disease and cancer. The human body's fascia network may be the physical substrate represented by the meridians of TCM. The PVS is a newly found circulatory system; recent increased interest has led to new research and new discoveries in the anatomical and functional aspects of the PVS. The fasciology theory provides new insights into the physiological effects of acupuncture needling on basic cellular mechanisms including connective tissue mechanotransduction and regeneration. This view represents a theoretical basis and means for applying modern biomedical research to examining TCM principles and therapies, and it favors a holistic approach to diagnosis and treatment.

[Research on the reliability of the Akagi line as a reference axis to guide for rotational alignment of the proximal tibial component in total knee arthroplasty].

OBJECTIVE: To study on the reliability of the Akagi line as a reference axis to guide for rotational alignment of the proximal tibial component in total knee arthroplasty (TKA) the rotational alignment reference bony landmarks of the proximal tibial component on magnetic resonance image (MRI) were measured. METHODS: From January 2010 to December 2013, 80 normal knees of Chinese volunteers including 35 males and 45 females with an average age of (35.4±6.1) years were reviewed. The images of the knees were obtained by MRI. The surgical epicondylar axis (STEA) was identified in the femoral transverse sections and then was projected to the side of tibia, forming the SETA'. A line connecting the medial border of the patellar tendon and the middle of the posterior cruciate ligament insertion (Akagi line) and its vertical line (AK), as well as a line connecting the medial 1/3 of the patellar tendon and the middle of the posterior cruciate ligament insertion and its vertical line (AP), were identified in the tibial transverse sections. The angles were measured between the AK, AP and STEA'. RESULTS: The angle between AK and STEA' was (0.59±2.07)°, and there was no significant difference between the two lines (t=-2.54, P=0.13). The mean angle between AP and STEA' was (3.21±2.04)°, and there was a significant difference between the two lines (t=14.05, P<0.05). There was a significant difference between the AK and AP (t=-11.68, P<0.05). CONCLUSION: The reliability of the Akagi line as a reference axis to guide for rotational alignment of the proximal tibial component in TKA is good.

[Clinical observation on the modified external fixation with splints for double fractures of forearm in children].

OBJECTIVE: To explore the advantages of conservative treatment for trauma of children,and evaluate effect of external fixation for the treatment of double fractures of forearm. METHODS: From June 2007 to June 2008, 52 patients with double fractures of forearm were treated with manipulative reduction and modified external fixation by splints. Among them, 33 males and 19 females,the age was from 4 to 15 years with an average of 8.6 years. The course of disease was from 1 hour to 7 days. All patients had a definite history of trauma, and pre-treatment X-ray film showed double fracture of ulna and radius. RESULTS: All patients were followed up from 6 to 14 months with an average of 9.4 months. All fractures healed and the healing time was from 4 to 8 weeks with an average of 6 weeks. The clinical effect was evaluated according to Berton criteria, 37 cases obtained excellent result, 15 good. CONCLUSION: Strict choose indication of conservative treatment can obtain satisfied effect in treating double fractures of forearm in children. The method has advantages of safe operation, less injury, cheap expense, which can well obtain functional rehabilitation of patients.

[Surgical treatment of displaced intra-articular fractures of the calcaneus in elderly patients].

OBJECTIVE: To study the clinical effects of surgical treatment of displaced intra-articular fractures of the calcaneus in elderly patients, and to discuss the operative indications. METHODS: From January 2000 to December 2007, 24 elderly patients with 26 fractures underwent open reduction and internal fixation for a displaced intra-articular fracture of calcaneus, which included 18 feet of 18 males and 8 feet of 6 female, with an average age of 67 years (range, 60 to 75 years). According to Sanders classification based on CT scanning, 13 fractures were rated as type II, 12 as type III and 1 as type IV. Böhler angle and Gissane angle were measured preoperatively and postoperatively and foot function was assessed with Maryland foot score system. RESULTS: Twenty-four cases with 26 feet were followed up for an average of 18.4 months (range, 12 to 26 months). Mean Böhler angle was (10.4 +/- 8.2) degrees preoperatively and (27.8 +/- 7.4) degrees postoperatively and mean Gissane angle was (136.5 +/- 10.3) degrees preoperatively and (124.3 +/- 4.2) degrees postoperatively. The difference between preoperative and postoperative values was found with statistically significant (P < 0.05). The results were excellent in 5 feet, good in 16 feet, fair in 4 feet and poor in 1 foot. There were 3 cases of wound necerosis, 2 cases of wound infection, 1 case of sural nerve injury and 6 cases of posttraumatic subtalar arthritis complications. CONCLUSION: Good clinical result could be obtained with surgical treatment in elderly patients with displaced intra-articular fractures of the calcaneus. Open reduction appears to be an acceptable method of treatment for displaced calcaneal fractures in elderly patients if they have good general conditions.

(4S)-Benzyl 4-isopropyl-5-oxo-1,3-oxazolidine-3-carboxyl-ate.

In the crystal structure of the title compound, C(14)H(17)NO(4), obtained by the reaction of N-benzoxycarbonyl-l-valine, paraformaldehyde and 4-methyl-benzene-sulfonic acid, mol-ecules are linked by C-H⋯O hydrogen bonds, generating linear chains parallel to the a axis. C-H⋯π inter-actions of stacked benzene rings also provide stability for the crystal structure.