Clinical results of arthroscopic tight fibrous band release for adult moderate-to-severe gluteal fibrosis using anterior and posterior portals: a retrospective analysis of 118 consecutive cases.

BACKGROUND: To evaluate the clinical outcomes of arthroscopic tight fibrous band release in the treatment of adult moderate-to-severe gluteal fibrosis using anterior and posterior portals during mid-term follow-up. METHODS: The data of 138 patients (58 males, 80 females) aged between 18 and 42 years (mean, 28.6 years), presenting with bilateral moderate-to-severe gluteal fibrosis (GF) from October 2013 to August 2019, was retrospectively analyzed. All patients underwent arthroscopic tight fibrous band release using anterior and posterior portals with radiofrequency energy. Under arthroscopic guidance through the posterior portal, we debrided the fatty tissue overlying the contracted band of the gluteal muscle and excised the contracted bands using a radiofrequency device introduced through the anterior portal. The pre- and post-operative gluteal muscle contracture disability (GD) scale and the patient satisfaction rate were compared to evaluate the curative effect of the operation. RESULTS: The average operation time was 18 min (range, 10-30 min) and the average blood loss was 4 ml (range, 2-10 ml) for unilateral arthroscopic release. Two cases of post-operative minimal hematomas, 2 cases of bruising and 2 cases of local subcutaneous edema were observed as early complications and were cured by conservative treatment. After surgery, all incisions healed in stage I, and no other complications such as wound infection, nerve and blood vessel injury were detected. One hundred eighteen patients were followed up for 6 to 72 months (mean, 36 months). No lateral instability of the hip was observed and all patients returned to normal gait. The degree of adduction of the hip joint in all these 118 patients was significantly improved relative to their pre-operative conditions. One hundred fifteen patients (97.5%) were able to crouch with knees close to each other after surgery. One hundred fourteen patients (96.6%) were able to cross the affected leg completely without any support. The GD scale was improved from 55.5 ± 10.6 before operation to 90.1 ± 5.2 at the last follow-up (p < 0.05). The patient satisfaction rate was 95.8%. CONCLUSION: Arthroscopic tight fibrous band release using anterior and posterior portals is minimally invasive for adult moderate-to-severe gluteal fibrosis, with a high success rate, quick recovery after surgery and reliable medium-term effect.

Wip1 phosphatase deficiency impairs spatial learning and memory.

Spatial learning and memory are typically assessed to evaluate hippocampus-dependent cognitive and memory functions in vivo. Protein phosphorylation and dephosphorylation by kinases and phosphatases play critical roles in spatial learning and memory. Here we report that the Wip1 phosphatase is essential for spatial learning, with knockout mice lacking Wip1 phosphatase exhibiting dysfunctional spatial cognition. Aberrant phosphorylation of the Wip1 substrates p38, ATM, and p53 were observed in the hippocampi of Wip1-/- mice, but only p38 inhibition reversed impairments in long-term potentiation in Wip1-knockout mice. p38 inhibition consistently ameliorated the spatial learning dysfunction caused by Wip1 deficiency. Our results demonstrate that deletion of Wip1 phosphatase impairs hippocampus-dependent spatial learning and memory, with aberrant downstream p38 phosphorylation involved in this process and providing a potential therapeutic target.

Conformation of G-quadruplex Controlled by Click Reaction.

G-quadruplexes are non-canonical four stranded secondary structures possessing great biological importance. Controlling G-quadruplex conformation for further regulating biological processes is both exciting and challenging. In this study, we described a method for regulating G-quadruplex conformation by click chemistry for the first time. 8-ethynyl-2'-deoxyguanosine was synthesized and incorporated into a 12-nt telomere DNA sequence. Such a sequence, at first, formed mixed parallel/anti-parallel G-quadruplexes, while it changed to anti-parallel after reaction with azidobenzene. Meanwhile, the click reaction can give the sequence intense fluorescence.

Absence of the Adenosine A2A Receptor Confers Pulmonary Arterial Hypertension Through RhoA/ROCK Signaling Pathway in Mice.

Numerous evidence suggests that RhoA/Rho kinase (ROCK) signaling pathway plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH), but little is known about its effects on the development of PAH in mice with absence of the adenosine A2A receptor (A2AR). Eight A2AR knockout (KO) and 8 wild-type mice were used. Morphometric analysis of pulmonary arterioles included right ventricle/left ventricle plus ventricular septum (Fulton index), vessel wall thickness/total vascular diameter (WT%), and vessel wall area/total vascular area (WA%). The expression of RhoA and ROCK1 mRNA was determined by real-time polymerase chain reaction. The expression of RhoA, ROCK1, and phosphorylation of myosin phosphatase target subunit 1 proteins in pulmonary tissue was tested by Western blot. The position of ROCK1 protein was evaluated by immunohistochemistry. Compared with wild-type mice, A2AR KO mice displayed (1) increased Fulton index, WT%, and WA% (P < 0.01); (2) increased mRNA expression of RhoA and ROCK1 (each P < 0.05); (3) increased protein expression of RhoA, ROCK1, and phosphorylation of myosin phosphatase target subunit 1 (each P < 0.01); (4) increased location of ROCK1 protein in endothelial and smooth muscle cells of pulmonary artery, bronchial, and alveolar epithelial cells. Activation of RhoA/ROCK signaling pathway may cause pulmonary vascular constriction, pulmonary artery remodeling, and PAH in adenosine A2A receptor KO mice.

[Efficacy and safety of rh-endostatin combined with docetaxel in second-line or intolerant toxicity for first-line treatment in patients with advanced non-small cell lung cancer].

OBJECTIVE: To analyze the efficacy and safety of combination of rh-endostatin (Endostar) with docetaxel treatment on patients of non-small cell lung cancer (NSCLC) who presented PD or intolerable toxicity in/after first-line chemotherapy. METHODS: A randomized, double-blind, placebo-controlled and multi-center clinical trial was conducted. Patients with stage IIIB/IV of NSCLC experienced previous chemotherapy of one-regimen were screened for this trial. A total of 68 cases were included in this study. Single docetaxel and that combined with endostar were conducted in two arms. The response, time to progression (TTP) and adverse effects were observed in both arms. RESULTS: The objective response rate (ORR) and clinical benefit rate (CBR) were 0 and 62.5% in the combined arm, along with 0 and 53.3% in the single docetaxel arm, with a non-significant difference between the two groups (all P > 0.05), respectively. The median TTPs in the combined and single docetaxel arms were 2.63 and 2.07 months, respectively (P = 0.079). The median TTPs of the participants with progressive disease (PD) after first-line chemotherapy were 1.33 and 1.67 months in the combined and single docetaxel arms, respectively (P = 0.946). The median TTPs of the participants with intolerant adverse effects in first-line chemotherapy were 4.70 months and 3.17 months in the combined and single docetaxel arms, respectively (P = 0.070). The median TTPs of the patients with SD after 2 therapeutic cycles in the combined and single docetaxel arms were 6.23 months and 3.27 months, respectively (P = 0.040). The differences between two arms were non-significant in adverse, serious adverse and cardiovascular adverse effects (all P > 0.05). CONCLUSIONS: Endostar may prolong TTP in patients with advanced NSCLC benefited from docetaxel treatment without increased toxicities.

[The efficacy and adverse effects of individualized treatment for elderly patients with epidermal growth factor receptor wild-type non-small cell lung cancer under the guidance of molecular markers].

OBJECTIVE: To compare the efficacy and toxicity of chemotherapy under the guidance of molecular markers and with vinorelbine in elderly patients with epidermal growth factor receptor (EGFR) wild-type advanced non-small cell lung cancer (NSCLC). METHODS: A total of 86 elderly patients with pathologically-confirmed advanced NSCLC with EGFR wild-type were recruited between June 2010 to October 2012. There were 69 males and 17 females, aging from 70 to 83 years. They were divided randomly into 2 groups according to the proportion of 1: 1 by SPSS 16.0 software. The study group received chemotherapy (cisplatin, gemcitabine, paclitaxel, and pemetrexed ) under the guidance of molecular markers (excision repair cross-complementing 1 ERCC1, ribonucleotide reductase M1 RRM1, Class III beta-tubulin, thymidylate synthetase TS). The control group received vinorelbine 25 mg/m(2) days 1 and 8 with 21 days as a cycle. RESULTS: The progression-free survival (PFS) of the study group and the control group was 4.0 months (95%CI: 3.1-4.9) and 3.0 months (95% CI: 2.4-3.6 ) respectively, the difference being statistically significant (χ(2) = 4.750, P = 0.029). The objective response rate (ORR) was 23% (10/43) and 19% (8/43) (χ(2) = 0.281, P = 0.596), the disease control rate (DCR) was 79% (34/43) and 77% (33/43) (χ(2) = 0.068, P = 0.795), and the median overall survival (OS) was 8.3 months and 7.5 months (χ(2) = 0.756, P = 0.385), respectively; the differences being not significant. Adverse effects were similar between the study group and the control group. The most commonly seen adverse events were hematological toxicity, nausea, vomiting, fatigue, alopecia, joint and muscle pain. Most of the toxicity was of grade I and grade II. There was no treatment-related death. CONCLUSIONS: The PFS was prolonged in elderly patients with EGFR wild-type advanced NSCLC under the guidance of molecular markers, but there was no improvement in ORR, DCR and OS. Further studies are needed to evaluate the clinical significance of this treatment modality.

Unveiling the role of G-quadruplex structure in promoter region: Regulation of ABCA1 expression in macrophages possibly via NONO protein recruitment.

ABCA1 has been found to be critical for cholesterol efflux in macrophages. Understanding the mechanism regulating ABCA1 expression is important for the prevention and treatment of atherosclerosis. In the present study, a G-quadruplex (G4) structure was identified in the ABCA1 promoter region. This G4 was shown to be essential for ABCA1 transcription. Stabilizing the G4 by ligands surprisingly upregulated ABCA1 expression in macrophages. Knocking out the G4 remarkably reduced ABCA1 expression, and abolished the increase of ABCA1 expression induced by the G4 ligand. By pull-down assays, the protein NONO was identified as an ABCA1 G4 binder. Overexpression or repression of NONO significantly induced upregulation and downregulation of ABCA1 expression, respectively. ChIP and EMSA experiments showed that the G4 ligand promoted the binding between the ABCA1 G4 and NONO, which led to more recruitment of NONO to the promoter region and enhanced ABCA1 transcription. Finally, the G4 ligand was shown to significantly reduce the accumulation of cholesterol in macrophages. This study showed a new insight into the regulation of gene expression by G4, and provided a new molecular mechanism regulating ABCA1 expression in macrophages. Furthermore, the study showed a possible novel application of the G4 ligand: preventing and treating atherosclerosis.

Isolation of Hv-CRKP with co-production of three carbapenemases (blaKPC, blaOXA-181 or OXA-232, and blaNDM-1) and a virulence plasmid: a study from a Chinese tertiary hospital.

Background: The worldwide dissemination of K. pneumoniae isolates is a significant public health concern, as these organisms possess a unique capacity to acquire genetic elements encoding both resistance and hypervirulence. This study aims to investigate the epidemiological, resistance, and virulence characteristics of K. pneumoniae isolates that carry both virulence plasmids and blaOXA-48-like genes in a tertiary hospital in China. Methods: A total of 217 clinical isolates of carbapenem-resistant K. pneumoniae (CRKP) were collected between April 2020 and March 2022. The antimicrobial susceptibility test was conducted to evaluate the drug resistance profile. All isolates were screened for the presence of genes encoding carbapenemases (blaKPC, blaNDM, blaIMP, blaVIM, and blaOXA-48-like), ESBLs genes (blaCTX-M, blaSHV, blaTEM), and virulence plasmid pLVPK-borne genes (rmpA, rmpA2, iucA, iroB, and peg344) using polymerase chain reaction (PCR) amplification. Clonal lineages were assigned using multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). The plasmid incompatibility groups were identified using PCR-based replicon typing (PBRT). The transferability of carbapenemase-encoding plasmids and pLVPK-like virulence plasmids was assessed via conjugation. The plasmid location of rmpA2 was determined using S1-Pulsed Field Gel Electrophoresis (S1-PFGE) and southern blotting hybridization. The virulence potential of the isolates was assessed using the string test, capsular serotyping, serum killing assay and a Galleria mellonella larval infection model. Results: Of the 217 CRKP clinical isolates collected, 23% were identified as carrying blaOXA-48-like genes. All blaOXA-48-like isolates exhibited resistance to commonly used clinical antimicrobial agents, except for ceftazidime/avibactam, colistin, tigecycline, trimethoprim-sulfamethOXAzole, polymyxin B, and nitrofurantoin. The main common OXA-48-like carbapenemase enzymes were found to be blaOXA-181 and blaOXA-232. MLST and PFGE fingerprinting analysis revealed clonal transmission and plasmid transmission. OXA-48-like producing CRKP isolates mainly clustered in K64 ST11 and K47 ST15. Results of the string Test, serum killing assay (in vitro) and Galleria mellonella infection model (in vivo) indicated hypervirulence. PBRT showed that the blaOXA-181 and blaOXA-232 producing hypervirulent carbapenem-resistant Klebsiella pneumoniae (Hv-CRKP) were mainly carried on ColE-type, IncF, and IncX3. Eight clinical isolates of hv-CRKP were identified as carrying three carbapenem-resistant genes (blaKPC, blaOXA-181 or OXA-232, and blaNDM-1). Moreover, Southern blotting hybridization revealed that all eight isolates had a pLVPK-like virulent plasmid (138.9-216.9 kb) with an uneven number and size of plasmid. Conclusion: In our investigation, we have observed the emergence of hv-CRKP carrying blaOXA-48-like genes, which identified two genetic relationships: clonal transmission and plasmid transmission. PBRT analysis showed that these genes were mainly carried on ColE-type, IncF, and IncX3 plasmids. These isolates have been shown to be hypervirulent in vitro and in vivo. Additionally, eight clinical isolates of hv-CRKP were identified as carrying three carbapenem-resistant genes (blaKPC, blaOXA-181 or OXA-232, and blaNDM-1) and carrying a pLVPK-like virulent plasmid. Hence, our findings highlight the need for further investigation and active surveillance of hypervirulent OXA-48-like producing Hv-CRKP isolates to control their transmission.

[Effect of ginsenoside Rg1 on the spatial learning-memory ability in dementia rats after transplanted with bone marrow mesenchymal stem cells].

OBJECTIVE: To study the effect and mechanism of ginsenoside Rg1 on the spatial learning-memory ability in rats with Alzheimer's disease after transplanted with bone marrow mesenchymal stem cells (BMSCs). METHODS: Using digital randomization table method, seventy-five male SD rats were divided into the bilateral FF transection model group (as the model group: ambi-hippocampal fimbria-fomix transected), the sham-operative control group (the SOC group: receiving the same modeling process as the model group, but without ambi-hippocampal fimbria-fomix transected), the ginsenoside Rg1 treatment group (as the treatment group: Two weeks after modeling ginsenoside Rg1 was peritoneally injected at the dose of 5 mg/kg, once daily for four weeks in total), the BMSCs transplanted treatment group [as the control group: Two weeks after modeling every rat received transplantation of BMSCs (10 microL, 1 x 10(6) cells)], and the ginsenoside Rg1 + BMSCs treatment group (as the combination group: They received both transplantation of BMSCs and peritoneal injection of ginsenoside Rgl). The spatial learning-memory ability of rats was detected by Morris water maze and the escape latency (s) was recorded, mRNA expression of nerve growth factor (NGF) was detected using Real-time PCR. RESULTS: Six weeks after the hippocampal fimbria-fomix (FF) transection, the escape latency o feach medication group was obviously shorter than that of the model group, and the spatial learning-memory ability of dementia rats was somewhat improved. The spatial learning-memory ability of rats in the combination group was (29.95 +/- 2.03) and the mRNA expression level of NGF was (1.13 +/- 0.15), better than those in the BMSCs group (44.36 +/- 1.43, 0.78 +/- 0.09, P<0.05). CONCLUSIONS: Ginsenoside Rg1 could strengthen the spatial learning-memory ability in dementia rats after transplanted with BMSCs. Its mechanism might be possibly correlated with up-regulating mRNA expression of NGF in basal forebrain after BMSCs transplantation.

Resina Draconis Reduces Acute Liver Injury and Promotes Liver Regeneration after 2/3 Partial Hepatectomy in Mice.

AIM: To investigate the protective effects and possible mechanisms of action of resina draconis (RD) on acute liver injury and liver regeneration after 2/3 partial hepatectomy (PH) in mice. METHODS: 2/3 PH was used to induce acute liver injury. Mice were divided into three groups: sham, vehicle + 2/3 PH, and RD + 2/3 PH. Resina draconis was administered intragastrically after 2/3 PH into the RD + 2/3 PH group, and the same volume of vehicle (1% sodium carboxymethyl cellulose) was injected into the vehicle + 2/3 PH group and sham group mice. The index of liver to body weight (ILBW) and proliferating cell nuclear antigen (PCNA) were assayed to evaluate liver regeneration. Blood and liver tissues were collected for serological and western blotting analysis. RESULTS: Resina draconis protected against 2/3 PH-induced acute severe liver injury and promoted liver regeneration as shown by significantly increased ILBW compared with that of controls. 2/3 PH increased serum AST and ALT levels, which were significantly decreased by RD treatment, while 2/3 PH decreased serum TP and ALB, which were increased by RD treatment. In the RD + 2/3 PH group, PCNA expression was significantly increased compared with the 2/3 PH group. Further, hepatocyte growth factor (HGF), TNFα, and EGFR levels were increased in the RD group at postoperative days 2 and 4 compared with the those in the 2/3 PH group. CONCLUSION: Our results suggest that RD ameliorates acute hepatic injury and promotes liver cell proliferation, liver weight restoration, and liver function after 2/3 PH, probably via HGF, TNFα, and EGFR signaling.

Loss of surface EWI-2 on CD9 null oocytes.

CD9, a member of the tetraspanin family, associates with a variety of other proteins to form the tetraspanin web. CD9 forms direct and relatively stable associations with the immunoglobulin superfamily proteins EWI-2 and EWI-F. Deletion of the Cd9 gene results in female infertility since Cd9 null mice produce oocytes that fail to fuse. It is thought that the absence of CD9 causes the inability of the oocytes to fuse. In this study, we report that the expression level of EWI-2 on the Cd9(-/-) oocyte surface is <10% of the wild-type level. Hence, the severe reduction in EWI-2 activity may be responsible for the loss of fusion ability. An entirely different mutant of CD9, not a deletion but a depalmitoylated construct, does not affect in vivo female fertility suggesting that the palmitate modification of CD9 is not essential for its putative fusion function. Additionally, the level of EWI-2 on the surface of the oocytes from these females was comparable to the EWI-2 level on wild-type oocytes. We also found that soluble, recombinant EWI-2 binds preferentially to acrosome-reacted sperm but the bound EWI-2 does not inhibit sperm-oocyte fusion. Overall, the results indicate that deletion of CD9, which is known to have multiple associations, may have pleiotropic effects on function that will require further dissection.

Comparing the efficacy of concurrent EGFR-TKI and whole-brain radiotherapy vs EGFR-TKI alone as a first-line therapy for advanced EGFR-mutated non-small-cell lung cancer with brain metastases: a retrospective cohort study.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is a global public health problem, and brain is a common metastatic site in advanced NSCLC. Currently, whole-brain radiotherapy (WBRT) remains a major treatment for brain metastases, while EGFR-tyrosine kinase inhibitor (TKI) is the standard treatment for advanced NSCLC harboring EGFR mutations, which is also effective for brain metastases. However, whether EGFR-TKIs plus radiotherapy is superior to EGFR-TKIs alone for the treatment of advanced EGFR-mutant NSCLS with brain metastases remains controversial. This study aimed to compare the efficacy of concurrent EGFR-TKIs and WBRT vs EGFR-TKI alone in a retrospective cohort of advanced EGFR-mutant NSCLS with brain metastases. PATIENTS AND METHODS: The medical records of 104 treatment-naïve, advanced EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed, and there were 56 patients undergoing concurrent EGFR-TKI and WBRT, and 48 patients given EGFR-TKI alone, including 20 cases with salvage WBRT upon brain metastasis progression. The survival prognosis was compared between the two cohorts. RESULTS: The baseline clinicopathologic factors were balanced between the two cohorts. After a median follow-up of 23 months, 35.6% of the study subjects survived. Concurrent EGFR-TKI and WBRT significantly improved the median intracranial PFS (iPFS) compared with EGFR-TKI alone (17.7 vs 11.0 months, P=0.015); however, no significant difference was seen in median overall survival between the two cohorts (28.1 vs 24.0 months, P=0.756). In addition, the median iPFS was found to significantly vary in the number of brain metastases (≤3 vs>3 metastases: 18.0 vs 12.5 months, P=0.044). Subgroup analysis showed that concurrent EGFR-TKI and WBRT improved median iPFS compared with EGFR-TKI alone in patients with more than three brain metastases (P=0.001); however, no significant difference was observed between the two regimens in patients with three or less brain metastases (P=0.526). CONCLUSION: Our data demonstrate that concurrent EGFR-TKI and WBRT achieves longer iPFS than EGFR-TKI alone in advanced EGFR-mutant NSCLC with brain metastases. In advanced EGFR-mutant NSCLC with three or less brain metastases, EGFR-TKI alone may be an option as a first-line therapy.

Comparative Study of Percutaneous Sacroiliac Screw with or without TiRobot Assistance for Treating Pelvic Posterior Ring Fractures.

OBJECTIVES: To analyze the curative effect of TiRobot surgical robotic navigation and location system-assisted percutaneous sacroiliac screw fixation and percutaneous sacroiliac screw by traditional fluoroscopy, and to summarize the safety and benefits of TiRobot. METHODS: A total of 91 patients with pelvic posterior ring fractures from December 2015 to February 2018 were included in this study. According to the surgical methods selected by the patients, the patients were divided into a TiRobot surgical robotic navigation and location system group (TiRobot group) and a percutaneous sacroiliac screw fixation group (traditional group). Statistical indicators included the number of sacroiliac screws, the time of planning the sacroiliac screw path, fluoroscopy frequency, fluoroscopy time, operation time, length of incision, blood loss, anesthesia time, the healing process of skin incisions, and fracture healing time. Fracture reduction was evaluated according to the maximum displacement degree at the inlet and outlet view X-ray or CT. Matta standard was used to evaluate fracture reduction. At the last follow-up, the Majeed function system was used to evaluate the function. RESULTS: All patients were followed up for 8 to 32 months. A total of 66 sacroiliac screws were implanted in the TiRobot group. A total of 43 sacroiliac screws were implanted in the traditional group. There were statistically significant differences in terms of fluoroscopy frequency, fluoroscopy time, operation time, incision length, anesthesia time, and blood loss between the two groups; the TiRobot group was superior to the traditional group. The healing time of the TiRobot group and the traditional group was 4.61 ± 0.68 months (range, 3.5-6.3 months) and 4.56 ± 0.78 months (range, 3.4-6.2 months), respectively, and there was no statistical difference. Postoperatively, by Matta standard, the overall excellent and good rate of fracture reduction was 89.28% and 88.57%, respectively. At the last follow-up, by Majeed function score, the overall excellent and good rate was 91.07% and 91.43%. There was no statistical difference between the two groups. CONCLUSION: Sacroiliac screw implantation assisted by TiRobot to treat the posterior pelvic ring fractures has the characteristics of less trauma, shorter operation time, and less blood loss. TiRobot has the characteristics of high safety and accuracy and has great clinical application value.

Paeoniflorin attenuates impairment of spatial learning and hippocampal long-term potentiation in mice subjected to chronic unpredictable mild stress.

RATIONALE AND OBJECTIVE: Paeoniflorin has been reported to exhibit antidepressant-like effects in several animal model depression; and it also exerts a neuroprotective effect. In the present study, we investigated the effects of paeoniflorin administration on depression-like behaviors and cognitive abilities in mice subjected to chronic unpredictable mild stress (CUMS), an animal model associated with depressive disorders and cognitive deficits. METHODS: We administered paeoniflorin (20 mg/kg), which is the main active constituent extracted from Paeonia lactiflora Pall. and exerts multiple pharmacological actions, to CUMS mice. Subsequently, animals were subjected to tests of depression-like behavior including the sucrose preference test, the forced swimming test and the tail suspension test. The Morris water maze (MWM) task was applied to evaluate learning and memory capacity. Hippocampal CA1 long-term potentiation (LTP) was recorded. Dendritic spine density and the expression levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) in the hippocampus were also investigated. RESULTS: The administration of paeoniflorin protected against CUMS-induced depression-like behavior. Paeoniflorin also improved the performance of CUMS mice in the MWM. The impairment of hippocampal CA1 LTP caused by CUMS was also reversed. Furthermore, paeoniflorin administration prevented decreases in dendritic spine density and in the expression of BDNF and PSD95 in the hippocampus of CUMS mice. CONCLUSION: Our observations suggest that paeoniflorin is a potential antidepressant that protects against cognitive impairment in depression.

Biomechanical Analysis of a Novel Intercalary Prosthesis for Humeral Diaphyseal Segmental Defect Reconstruction.

OBJECTIVE: To study the biomechanical properties of a novel modular intercalary prosthesis for humeral diaphyseal segmental defect reconstruction, to establish valid finite element humerus and prosthesis models, and to analyze the biomechanical differences in modular intercalary prostheses with or without plate fixation. METHODS: Three groups were set up to compare the performance of the prosthesis: intact humerus, humerus-prosthesis and humerus-prosthesis-plate. The models of the three groups were transferred to finite element software. Boundary conditions, material properties, and mesh generation were set up for both the prosthesis and the humerus. In addition, 100 N or 2 N.m torsion was loaded to the elbow joint surface with the glenohumeral joint surface fixed. Humeral finite element models were established according to CT scans of the cadaveric bone; reverse engineering software Geomagic was used in this procedure. Components of prosthetic models were established using 3-D modeling software Solidworks. To verify the finite element models, the in vitro tests were simulated using a mechanical testing machine (Bionix; MTS Systems Corporation, USA). Starting with a 50 N preload, the specimen was subjected to 5 times tensile (300 N) and torsional (5 N.m) strength; interval time was 30 min to allow full recovery for the next specimen load. Axial tensile and torsional loads were applied to the elbow joint surface to simulate lifting heavy objects or twisting something, with the glenohumeral joint surface fixed. RESULTS: Stress distribution on the humerus did not change its tendency notably after reconstruction by intercalary prosthesis whether with or without a plate. The special design which included a plate and prosthesis effectively diminished stress on the stem where aseptic loosening often takes place. Stress distribution major concentrate upon two stems without plate addition, maximum stress on proximal and distal stem respectively diminish 27.37% and 13.23% under tension, 10.66% and 11.16% under torsion after plate allied. CONCLUSION: The novel intercalary prosthesis has excellent ability to reconstruct humeral diaphyseal defects. The accessory fixation system, which included a plate and prosthesis, improved the rigidity of anti-tension and anti-torsion, and diminished the risk of prosthetic loosening and dislocation. A finite element analysis is a kind of convenient and practicable method to be used as the confirmation of experimental biomechanics study.

The association between clinical prognostic factors and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer patients: a retrospective assessment of 94 cases with EGFR mutations.

OBJECTIVE: This study aimed to examine the association of clinical prognostic factors with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer (NSCLC) patients. METHODS: The demographic and clinical characteristics of 94 patients with stage IV NSCLC were retrospectively reviewed, and the association between clinical factors and EGFR-TKIs efficacy was evaluated. RESULTS: Of the 94 stage IV NSCLC patients enrolled in this study, a 74.5% objective response rate (ORR) and 97.9% disease control rate (DCR) were observed for EGFR-TKIs treatment, and a higher ORR was seen in patients with 0 and 1 ECOG scores than those with 2 or greater scores (P = 0.049). The subjects had a median PFS of 11 months and a median OS of 31 months after EGFR-TKIs treatment. ECOG score and timing of targeted therapy were factors affecting PFS, and ECOG score, smoking status and brain metastasis were factors affecting OS. In addition, ECOG score was an independent prognostic factor for PFS in stage IV NSCLC patients, and the patients with EGFR 19del mutation had a longer PFS than those with exon 21 L855R mutation (P = 0.003), while ECOG score and brain metastasis were independent prognostic factors for OS. CONCLUSIONS: The results of this study demonstrate that EGFR-TKI therapy results in survival benefits for EGFR-mutant advanced NSCLC patients, regardless of gender, smoking history, pathologic type, type of EGFR mutations, brain metastasis and timing of targeted therapy. ECOG score is an independent prognostic factor for PFS, and ECOG score and brain metastasis are independent prognostic factors for OS in advanced NSCLC patients.

A novel isoflavone profiling method based on UPLC-PDA-ESI-MS.

A novel non-targeted isoflavone profiling method was developed using the diagnostic fragment-ion-based extension strategy, based on ultra-high performance liquid chromatography coupled with photo-diode array detector and electrospray ionization-mass spectrometry (UPLC-PDA-ESI-MS). 16 types of isoflavones were obtained in positive mode, but only 12 were obtained in negative mode due to the absence of precursor ions. Malonyldaidzin and malonylgenistin glycosylated at the 4'-O position or malonylated at the 4″-O position of glucose were indicated by their retention behavior and fragmentation pattern. Three possible quantification methods in one run based on UPLC-PDA and UPLC-ESI-MS were validated and compared, suggesting that methods based on UPLC-ESI-MS possess remarkable selectivity and sensitivity. Impermissible quantitative deviations induced by the linearity calibration with 400-fold dynamic range was observed for the first time and was recalibrated with a 20-fold dynamic range. These results suggest that isoflavones and their stereoisomers can be simultaneously determined by positive-ion UPLC-ESI-MS in soymilk.

Reduced Circulating Levels of miR-433 and miR-133b Are Potential Biomarkers for Parkinson's Disease.

Aberrant expression of microRNA (miRNA) in tissues may lead to altered level in circulation. Considerable evidence has suggested that miRNA deregulation is involved in the pathogenesis of Parkinson's disease (PD). In this study, we screened a set of PD-associated miRNAs and aimed to identify differentially expressed miRNAs in plasma of PD patients and to evaluate their potentiality to serve as PD biomarkers. A total of 95 subjects consisting of 46 sporadic PD cases and 49 controls were recruited. Plasma levels of six miRNAs including miR-433, miR-133b, miR-34b, miR-34c, miR-153, and miR-7 were evaluated using reverse transcribed quantitative PCR, among which we found that miR-34c and miR-7 were below detection limit under our condition. The results showed that levels of circulating miR-433 (P = 0.003) and miR-133b (P = 0.006), but not miR-34b and miR-153, were reduced in PD patients. miR-433 and miR-133b were strongly correlated in both control and PD groups (rs = 0.87 and 0.85, respectively). The correlation between miR-34b and miR-153 expressions was significantly reduced (P < 0.05) in the PD group. Although miR-433 and miR-133b were likely to be functionally complimentary as suggested by Pathway and Gene Ontology analyses, these two miRNAs per se might not be sufficient to predict PD. No correlation was observed between the four miRNAs and age or severity of disease. Collectively, our results demonstrate that circulating miR-433 and miR-133b are significantly altered in PD and may serve as PD biomarkers.

[The effect of rotational alignment of the femoral components on the patellofemoral biomechanics in total knee arthroplasty].

OBJECTIVE: To study the effect of rotational alignment of the femoral components on the patellofemoral biomechanics in total knee arthroplasty (TKA) demonstrated on autopsy specimens, as the guide for surgeons to choose the correct reference axis for rotational alignment of the femoral components and to reduce the patellofemoral joint complications. METHODS: Select 9 frozen fresh human cadaver knees without gross deformities or instabilities and mount specimens on a patellofemoral joint testing jig connected to a Model 8501 Instron machine (Instron Corporation, Canton, MA). The study simulated the action of squatting from the standing position with the foot firmly planted. Standard TKA was performed in each specimen by the same senior surgeon using Nexgen LPS total knee system (Zimmer Corporation, Warsaw Indiana). Alter rotational alignment of the femoral components referenced to the transepicondylar axis and the Whiteside's line respectively. Measure biomechanics of the patellofemoral joints using Fuji prescale film at 30 degrees , 60 degrees , 90 degrees , 120 degrees of knee flexion respectively. The digital values were obtained by the handheld pressure measurement systems (FPD-305E, FPD-306E) and Autocad software. RESULTS: The rotational alignment of the femoral components paralleled to the transepicondylar axis had the best results of the peak value of the patellofemoral contact pressure (P < 0.05). There were no statistically significant differences in patellofemoral contact area (P > 0.05). But the patellofemoral contact area had the close correlations to the angles of the knee flexion and the specimens. CONCLUSIONS: Rotational alignment of the femoral components has a great influence on the patellofemoral contact pressure in total knee arthroplasty. It is reliable for surgeons to choose the transepicondylar axis as the reference axis to rotate femoral components.

Wip1 phosphatase modulates both long-term potentiation and long-term depression through the dephosphorylation of CaMKII.

Synaptic plasticity is an important mechanism that underlies learning and cognition. Protein phosphorylation by kinases and dephosphorylation by phosphatases play critical roles in the activity-dependent alteration of synaptic plasticity. In this study, we report that Wip1, a protein phosphatase, is essential for long-term potentiation (LTP) and long-term depression (LTD) processes. Wip1-deletion suppresses LTP and enhances LTD in the hippocampus CA1 area. Wip1 deficiency-induced aberrant elevation of CaMKII T286/287 and T305 phosphorylation underlies these dysfunctions. Moreover, we showed that Wip1 modulates CaMKII dephosphorylation. Wip1(-/-) mice exhibit abnormal GluR1 membrane expression, which could be reversed by the application of a CaMKII inhibitor, indicating that Wip1/CaMKII signaling is crucial for synaptic plasticity. Together, our results demonstrate that Wip1 phosphatase plays a vital role in regulating hippocampal synaptic plasticity by modulating the phosphorylation of CaMKII.