LncRNA RP11-59J16.2 aggravates apoptosis and increases tau phosphorylation by targeting MCM2 in AD.

Alzheimer's disease (AD) is a degenerative disease of central nervous system with unclear pathogenesis, accounting for 60%-70% of dementia cases. Long noncoding RNAs (LncRNAs) play an important function in the development of AD. This study aims to explore the role of differentially expressed lncRNAs in AD patients' serum in the pathogenesis of AD. Microarray analysis was performed in the serum of AD patients and healthy controls to establish lncRNAs and mRNAs expression profiles. GO analysis and KEGG pathway analysis revealed that G1/S transition of mitotic cell cycle might be involved in the development of AD. The result showed that RP11-59J16.2 was up-regulated and MCM2 was down-regulated in serum of AD patients. SH-SY5Y cells were treated with Aß 1-42 to establish AD cell model. Dual luciferase reporter gene analysis verified that RP11-59J16.2 could directly interact with 3'UTR of MCM2 and further regulate the expression of MCM2. Inhibition of RP11-59J16.2 or overexpression of MCM2, CCK-8 assay and Annexin V FITC/PI apoptosis assay kit results showed that RP11-59J16.2 could reduce cell viability, aggravate apoptosis and increase Tau phosphorylation in AD cell model by inhibiting MCM2. In short, our study revealed a novel lncRNA RP11-59J16.2 that could promote neuronal apoptosis and increase Tau phosphorylation by regulating MCM2 in AD model, and indicated that lncRNA RP11-59J16.2 might be a potential target molecule for AD development.

Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy.

BACKGROUND: Genetic variation at the PTK2B locus encoding the protein Pyk2 influences Alzheimer's disease risk. Neurons express Pyk2 and the protein is required for Amyloid-ß (Aß) peptide driven deficits of synaptic function and memory in mouse models, but Pyk2 deletion has minimal effect on neuro-inflammation. Previous in vitro data suggested that Pyk2 activity might enhance GSK3ß-dependent Tau phosphorylation and be required for tauopathy. Here, we examine the influence of Pyk2 on Tau phosphorylation and associated pathology. METHODS: The effect of Pyk2 on Tau phosphorylation was examined in cultured Hek cells through protein over-expression and in iPSC-derived human neurons through pharmacological Pyk2 inhibition. PS19 mice overexpressing the P301S mutant of human Tau were employed as an in vivo model of tauopathy. Phenotypes of PS19 mice with a targeted deletion of Pyk2 expression were compared with PS19 mice with intact Pyk2 expression. Phenotypes examined included Tau phosphorylation, Tau accumulation, synapse loss, gliosis, proteomic profiling and behavior. RESULTS: Over-expression experiments from Hek293T cells indicated that Pyk2 contributed to Tau phosphorylation, while iPSC-derived human neuronal cultures with endogenous protein levels supported the opposite conclusion. In vivo, multiple phenotypes of PS19 were exacerbated by Pyk2 deletion. In Pyk2-null PS19 mice, Tau phosphorylation and accumulation increased, mouse survival decreased, spatial memory was impaired and hippocampal C1q deposition increased relative to PS19 littermate controls. Proteomic profiles of Pyk2-null mouse brain revealed that several protein kinases known to interact with Tau are regulated by Pyk2. Endogenous Pyk2 suppresses LKB1 and p38 MAPK activity, validating one potential pathway contributing to increased Tau pathology. CONCLUSIONS: The absence of Pyk2 results in greater mutant Tau-dependent phenotypes in PS19 mice, in part via increased LKB1 and MAPK activity. These data suggest that in AD, while Pyk2 activity mediates Aß-driven deficits, Pyk2 suppresses Tau-related phenotypes.

Comparison between gravity drainage group and suction drainage group after cervical laminoplasty: a retrospective STROBE-compliant cohort study.

OBJECTIVES: A retrospective study was conducted to compare gravity drainage and suction drainage after cervical laminoplasty. PATIENTS AND METHODS: A total of 375 patients who underwent laminoplasty between January 2011 and December 2015 were engaged in this analysis. We investigated the patients' basic characteristics, drainage characteristics and postoperative complications. RESULTS: During the initial 24 h after laminoplasty, the drainage volume in the suction drainage group was 177.31 ± 92.02 mL, and the drainage volume in the gravity drainage group was 133.33 ± 92.40 mL. The drainage volume showed significant difference (p < 0.01). The total drainage volume was 357.49 ± 195.16 mL and 250.16 ± 27.44 mL in the suction drainage group and gravity drainage group, respectively. The total drainage volume between the two groups was statistically different (p = 0.03). The postoperative Hb was significantly different between the gravity group and suction group on the first day after the operation (108.37 ± 23.92 mL vs. 87.32 ± 21.53 mL, p = 0.02). The number of patients required blood transfusion was significantly different between the two groups as well (p = 0.04). Two cases had symptomatic epidural hematomas (SEH) after laminoplaty. However, the occurrence of SEH among the two groups was not different significantly. Twelve patients had surgical site infection (SSI). Of these 12, nine had applied gravity drainage and three suction drainage. The rate of SSI was similar between the two groups (p = 0.71). CONCLUSION: The initial 24 h' drainage volume and the total drainage volume increased significantly in the suction drainage group. The postoperative Hb was lower in the suction group than the gravity drainage group the first postoperative day. More patients needed blood transfusion if suction drainage was performed. The application of suction drainage cannot decrease the incidence of SSI and SEH after laminoplasty. Gravity drainage is recommended for laminoplasty.

Simultaneous metabolomics and proteomics analysis of plasma-derived extracellular vesicles.

Extracellular vesicles (EVs) are nanoscale vesicles with a phospholipid bilayer. In the past few decades, EVs have gained more and more attention, which is attributed to their important roles in cell-to-cell communication. They are regarded as promising sources for disease biomarkers and have been explored for applications in early-stage diagnostics, monitoring of disease status, therapeutics and drug delivery. Nevertheless, EVs are a heterogeneous group of vesicles, and include two predominant classes: exosomes and microvesicles. The origins of these vesicles are diverse, which determines their differences in features and functions. To study the diversity of these EV subpopulations, it is essential to elucidate their compositions including proteins, metabolites, etc. Here, we presented a tandem extraction method to obtain metabolites and proteins from the same batch of EVs simultaneously, enabling a multi-omics differential analysis of exosomes and microvesicles in human plasma. As a result, we found 112 different proteins and 50 different metabolites between exosomes and microvesicles, demonstrating the diversity of these EV subpopulations. Furthermore, compared with human plasma, these two major classes of EVs showed distinct metabolome features, which indicated the necessity of analysing the metabolites derived from EVs to obtain a more comprehensive profile of the plasma metabolome, and the potential of EVs as important sources for biomarker screening.

A new urinary exosome enrichment method by a combination of ultrafiltration and TiO2 nanoparticles.

Exosomes are small membrane-bound vesicles secreted by most cell types and play an important role in cell-to-cell communication. Increasing evidence shows that exosomal proteins in urine may be used as novel biomarkers for certain diseases. Purified urinary exosomes are necessary for downstream studies and application development. However, conventional methods for exosome isolation and enrichment are technically challenging and time-consuming. Poor specificity, low recovery and instrumental dependence also limit the use of these methods. It is particularly urgent to develop a rapid and efficient extraction method for basic research and clinical application. Particularly, urine is a dilute solution system with relatively low abundance of exosomes, due to which the isolation of urinary exosome requires more efficient technology. Here, we propose a new strategy for facile exosome isolation from human urine by utilizing the ultrafiltration technique and the specific interaction of TiO2 with the phosphate groups on the lipid bilayer of exosomes. Downstream characterization and proteomic analysis indicate that high-quality exosomes can be obtained from human urine by this ultrafiltration-TiO2 series method in 20 minutes, and 91.5% exosomes with an intact structure are captured from urine by this method. Moreover, 1874 protein groups have been identified through LC-MS. The results show that the protein identification of our method is 23% higher at least than those obtained by conventional strategies. We also identified 30 differential proteins by comparing the urinary exosomes from healthy male and female volunteers. These proteins are related to biological processes, such as lipid metabolism, fatty acid metabolism and nucleotide metabolism. Our analysis reveals that combining conventional ultrafiltration and TiO2-based isolation is ideal to overcome the inherent limitations of identification of exosome proteins derived from urine, and yield highly pure exosome components for downstream proteomic analysis.

Transdural Approach to Resection of Intraspinal Extradural Ventral Cysts in the Lumbar Spine.

BACKGROUND: Intraspinal extradural ventral cysts in the lumbar spine can cause back pain and neurological deficits of the lower extremities. For the resection of this type of space-occupying lesion, the transdural approach has not been reported in the literature. CASE DESCRIPTION: A 66-year-old man presented, suffering from progressive radiation pain of his bilateral lower extremities. Imaging examination revealed a cystic lesion in ventral side of lumbar spinal canal. We conducted the excision of the cyst with the transdural approach. The symptoms of the patient disappeared immediately after the operation and recurrence of the symptoms has not been observed in the 3-month follow-up. CONCLUSIONS: This operation approach is safe and effective. Compared with the previous surgical approach reported in the literature, by this approach surgeons could achieve less injury, shorter operation time, and the same surgical outcomes in the short term. Therefore, we would like to present this approach to provide an alternative to deal with similar lesions.

Risk factors of postoperative low back pain for low-grade isthmic spondylolisthesis: a retrospective study.

OBJECTIVE: To investigate the risk factors of postoperative low back pain (LBP) following posterior lumbar interbody fusion (PLIF) surgery for low-grade isthmic spondylolisthesis (IS). METHODS: This retrospective study enrolled patients with IS that underwent PLIF between January 2011 and January 2016. Demographic, clinical, surgical and radiological characteristics were analysed to determine associations between these characteristics and LBP as measured using a visual analogue scale (VAS) pain score. RESULTS: A total of 192 patients were enrolled in the study. The mean VAS pain score of LBP decreased significantly after surgery. The mean preoperative VAS pain score was significantly greater in patients with symptoms of ≤3 years duration compared with those with symptoms lasting >3 years. The postoperative VAS pain score was significantly lower in patients with grade 1 slippage compared with those with grade 2 slippage. There was a significant correlation between preoperative to postoperative change of VAS pain score and postoperative disc height (r = 0.99). CONCLUSION: PLIF significantly improved LBP in patients with low-grade IS, although patients still reported some postoperative LBP. The grade of slippage was a risk factor for postoperative LBP. Restoring the disc height appeared to improve LBP.

Risk Factors of Postoperative Sacroiliac Joint Pain for Posterior Lumbar Surgery: ≥2-Year Follow-up Retrospective Study.

PURPOSE: A retrospective study was conducted to clarify the risk factors of postoperative sacroiliac joint pain (SIJP) for posterior open lumbar surgery. PATIENTS AND METHODS: A total of 472 patients who underwent posterior lumbar surgery between January 2011 and December 2014 were included in this analysis. We recorded basic characteristics, surgical characteristics, and SIJP information for each patient. RESULTS: The incidence of postoperative SIJP is 13.8% in our study. Comparison of the incidence of SIJP between diskectomy and posterior lumbar interbody fusion indicated that SIJP incidence tended to be higher in posterior lumbar interbody fusion patients (P = 0.029). Compared with the single-segment group, SIJP occurred more frequently in the multiple operative segments group (P = 0.025). Comparing the incidence of SIJP among different types of lumbar diseases, SIJP incidence is significantly higher in the lumbar stenosis group (P = 0035). CONCLUSION: Lumbar fusion surgery and multiple operative segments are interdependent risk factors for the postoperative SIJP. The incidence of postoperative SIJP also increases in patients with lumbar stenosis compared with lumbar disk herniation and lumbar spondylolisthesis.

Risk Factors of Postoperative Low Back Pain for Low-Grade Degenerative Spondylolisthesis: An At Least 2-Year Follow-Up Retrospective Study.

OBJECTIVE: A retrospective study was conducted to clarify the risk factors of postoperative low back pain (LBP) for low-grade degenerative spondylolisthesis. PATIENTS AND METHODS: A total of 239 patients who underwent posterior lumbar fusion between January 2011 and January 2015 were included in this analysis. We investigated patient characteristics, surgical characteristics, and radiographic characteristics. RESULTS: The mean visual analog scale (VAS) score of LBP decreased dramatically after the operation. The mean preoperative VAS score was greater in patients with severe lumbar multifidus (LM) intramuscular adipose tissue (IMAT). The postoperative VAS score was dramatically lower in patients with shorter symptom duration. Postoperative LBP disappeared more often in patients with shorter symptom duration. LBP VAS changing showed significant differences in different symptom duration groups and LM IMAT groups. CONCLUSIONS: LM IMAT and symptom duration were risk factors for postoperative LBP. Patients with severe LM IMAT reported more severe LBP before the operation. Postoperative LBP disappeared more often in patients with shorter symptom duration.

Risk Factors of Postoperative Low Back Pain for Lumbar Spine Disease.

PURPOSE: A retrospective study was conducted to clarify the risk factors of postoperative low back pain (LBP) for lumbar spine disease. PATIENTS AND METHODS: A total of 401 patients who underwent lumbar operation between January 2011 and December 2011 were included in this analysis. We investigated patient characteristics and surgical approaches and also compared the radiographic characteristics. RESULTS: The mean visual analogue scale (VAS) score decreased dramatically after the operation. The mean preoperative VAS score was greater in patients underwent posterior lumbar interbody fusion (PLIF) with longer duration of symptoms, longer operation time, and severe lumbar multifidus (LM) intramuscular adipose tissue (IMAT). The preoperative VAS score was dramatically lower in patients with lumbar herniation. The postoperative VAS score was dramatically lower in patients who underwent PLIF with longer operation time and mild LM IMAT. Postoperative LBP disappeared more often in patients who underwent PLIF with longer operation times. The number of operative levels and type of lumbar spine disease also were associated with postoperative LBP. CONCLUSION: Type of surgery, operation time, number of operative level, and type of disease were risk factors for the postoperative LBP. Patients underwent PLIF with shorter symptom duration, longer operation time severe LM IMAT, and lumber spondylolisthesis reported more severe LBP before the operation. Patients underwent discectomy with shorter operation times.

Predictors of Surgical Outcome in Acute Spinal Cord Injury Patients with Cervical Ossification of the Posterior Longitudinal Ligament.

OBJECTIVE: A retrospective study was conducted to clarify the predictors of the operation results for ossification of the posterior longitudinal ligament (OPLL) patients with acute spinal cord injury (SCI). Detailed analyses of surgical outcomes of OPLL patients with SCI have been rare because most surveys have aimed to investigate OPLL or SCI, but not both. PATIENTS AND METHODS: A total of 36 patients who underwent operation for OPLL between January 2011 and December 2011 were included in this analysis. We investigated the patients' characteristics and surgical approaches and compared the radiographic characteristics of OPLL patients with SCI. RESULTS: The mean modified Japanese Orthopaedic Association (mJOA) score improved dramatically after operation (P = 0.006). The mean preoperative mJOA score was greater in patients with Nurick 3 than in patients with Nurick 4 and 5 (P = 0.041). The preoperative mJOA score was dramatically lower in patients caused by traffic accident and in patients with segmental OPLL lesion (P < 0.05). The postoperative mJOA score was dramatically lower in patients with continuous OPLL lesion than in the segmental OPLL lesion (P = 0.028). Changing in mJOA score was significantly different between the patients with high-intensity zone (HIZ) and without HIZ on magnetic resonance imaging. CONCLUSIONS: HIZ on magnetic resonance imaging was significantly related to the surgical outcomes, which should be highlighted in the preoperative communication with patients. Patients with lower Nirick grade and segmental OPLL would show better symptom before the operation. In addition, SCI caused by slipping or falling showed better symptoms before the operation. Patients with segmental OPLL should show better resolution of symptoms after the operation.

Predictors of surgical outcome in ossification of the posterior longitudinal ligament.

STUDY DESIGN: A retrospective study. OBJECTIVE: To clarify the predictors of the operation results for ossification of the posterior longitudinal ligament (OPLL). SUMMARY OF BACKGROUND DATA: Detailed analyses of surgical outcomes of OPLL have been rare because most survey aimed to investigate cervical spondylotic myelopathy. METHODS: All patients who underwent cervical operation for OPLL between January 2011 and December 2011 were included in this analysis. We investigated the patients' characteristics and surgical approaches, and compared the radiographical characteristics of OPLL. RESULTS: The mean mJOA score improved from 8.312 ± 3.021 points preoperatively to 11.24 ± 3.43 points at 24 months after operation (P<0.001). The average change in mJOA score was significantly greater in patients with a higher Nirik score than in those with lower Nirik scores (P<0.0001). The average change in mJOA score was also significantly different in patients with trauma history (P<0.0001). The average recovery ratio was 42 ± 26.3% in young patients and 30 ± 31.6% in the group older than 50 years (P=0.012). The average recovery ratio in patients with acute and chronic symptoms was 48 ± 22.9% and 26 ± 33.9%, respectively. There was great difference between the two groups. CONCLUSION: OPLL patients with myelopathy would receive good result after the operation. Age and symptom duration are related to the surgical outcomes. Patients with lower Nirick grade and without trauma history would receive better results before and after the operation.

Aggrecan variable number of tandem repeat polymorphism and lumbar disc degeneration: a meta-analysis.

STUDY DESIGN: Data on the association between the ACAN (encoded for aggrecan core protein) variable number of tandem repeat (VNTR) polymorphism and lumbar disc degeneration are conflicting, so we performed a meta-analysis. OBJECTIVE: Aggrecan is involved in the shock absorbing function of the lumbar disc; we performed a meta-analysis to assess the association between ACAN VNTR and lumbar degeneration. SUMMARY OF BACKGROUND DATA: To perform a meta-analysis, we searched for studies published until September 2012, using electronic databases (PubMed, EMBASE, and China National Knowledge Infrastructure). Eight studies involving 965 cases of lumbar disc degeneration and 982 control subjects were identified. METHODS: Assessment for eligibility and extraction of data were performed by 2 independent investigators. We extracted allele frequency for each study. We calculated the pooled odds ratios (ORs) and 95% confidence intervals (CI) to assess the strength of the association between the ACAN VNTR polymorphism and lumbar disc degeneration risk. RESULTS: Results from the allele model suggested an increased risk of lumbar disc degeneration for the shorter alleles carriers compared with the normal alleles and longer alleles (OR = 1.54, 95% CI: 1.04-2.30, P = 0.03). In subgroup analysis by ethnicity, significant increased risks were found among Asians with shorter alleles (OR=1.65, 95% CI: 1.17-2.33, P = 0.004). CONCLUSION: Our results suggest an increased risk of shorter alleles compared with normal alleles and longer alleles against lumbar disc degeneration among populations especially among Asian descent. Such association may not be statistically significant in European populations.

Effect of focal mild hypothermia on expression of MMP-9, TIMP-1, Tau-1 and ß-APP in rats with cerebral ischaemia/reperfusion injury.

PRIMARY OBJECTIVE: Following stroke, hypothermia is reported to reduce both cellular and extracellular damage. This study aimed to examine the effects of focal mild hypothermia on proteins associated with both extracellular (matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of MMP-9 (TIMP-1)) and cellular damage (Tau-1 and ß-amyloid precursor protein (ß-APP)) to characterize the protective effects of hypothermia. METHODS AND PROCEDURES: Male Wistar rats received ischaemic damage using a transient, focal ischaemia/reperfusion model. Afterwards, one group (HT) received 6 hours of focal mild hypothermia (33 °C) applied to the head, while another remained at normal temperature (NT). The brains were collected at 6, 12, 24, 48 and 72 hours after hypothermia to measure infarct volume ratio and to detect cells immunopositive for MMP-9, TIMP-1, Tau-1 and ß-APP, while neurological deficits were examined separately after 2 weeks. MAIN OUTCOMES AND RESULTS: Focal mild hypothermia had no effect on infarct volume ratio but expression of MMP-9, TIMP-1 Tau-1 and ß-APP was decreased. Furthermore, neurological function in the HT group was better than in the NT group. CONCLUSIONS: Focal mild hypothermia has protective effects on cerebral ischaemia-reperfusion injury characterized by decreased expression of MMP-9, TIMP-1, Tau-1 and ß-APP, along with improvement of neurological function despite no changes in infarct volume.

Association of ADAMTS5 gene polymorphisms with osteoarthritis in Chinese Han population: a community-based case-control study.

Aggrecanase-2 (ADAMTS5) is reported to play essential roles in the pathophysiology of osteoarthritis (OA). To explore the relationship between ADAMTS5 gene polymorphisms and primary OA, we conducted a community-based case-control study. A total of 732 community residents aged 40-84 years participated in the community-based study in Northeast China. After taking physical examination and radiographic examination, 420 persons of the residents were diagnosed OA (216 women and 204 men). The other 312 individuals without any symptoms of osteoarthritis or signs in the radiographs (156 women and 156 men) were considered as healthy controls. After obtaining the DNA of patients and control group, genotypes of the ADAMTS5 gene polymorphisms were determined by polymerase chain reaction (PCR) followed by restriction enzyme digestion (HAEIII for P692L in exon 7 and BSRBI for R614H in exon 5). The numbers of patients with different OA subtypes were also calculated. The genotype and allele frequency of for the exon 5C/T BSRBI polymorphism was significantly different between OA patients and control individuals (P = 0.001, OR = 0.701, 95% CI = 0.569-0.863). This difference was more obvious in cervical OA patients (P = 0.001, OR = 0.664, 95% CI = 0.521-0.847). The mutation type of exon 5C/T BSRBI polymorphism would be a protective factor for OA especially for cervical OA. Our results suggest that the ADAMTS5 gene polymorphisms may contribute to the susceptibility of osteoarthritis in the Chinese Han population.

MATN3 gene polymorphism is associated with osteoarthritis in Chinese Han population: a community-based case-control study.

BACKGROUND: The matrilin, especially matrilin-3 (MATN3), are reported to play important roles in the pathophysiology of osteoarthritis (OA). To explore the relationship between MATN3 SNP6 (rs8176070) and primary OA, we conducted a community-based case-control study. METHODS: A total of 732 community residents aged 40-84 years participated in the community-based study in Northeast China. After taking physical and radiographic examinations, 420 of the residents were diagnosed OA (216 women and 204 men). The other 312 individuals without any symptoms of osteoarthritis or signs in the radiographs (156 women and 156 men) were considered as healthy controls. After obtaining the DNA of case and control groups, genotypes of the MATN3 SNP6 were determined by polymerase chain reaction followed by restriction enzyme digestion. The numbers of patients with different OA subtypes were also calculated. RESULTS: The distribution of genotypes and alleles of the MATN3 SNP6 between OA patients and controls was different significantly. The BB carrier tends to be associated with the increased osteoarthritis (P = 0.025, OR = 1.724, 95% CI = 1.071-2.77), especially the knee osteoarthritis (P = 0.021, OR = 2.402, 95% CI = 1.141-5.060) and lumber osteoarthritis (P = 0.020, OR = 1.880, 95% CI = 1.103-3.204). Bb carrier increased hand osteoarthritis risk (P = 0.002, OR = 5.380, 95% CI = 1.828-15.835). The B allele might have an effect on the increased knee osteoarthritis (P = 0.000, OR = 3.143, 95% CI = 2.283-4.328). CONCLUSION: These findings suggest that the MATN3 gene polymorphism might be associated with osteoarthritis in the Chinese Han population.

Association between α1-antichymotrypsin signal peptide -15A/T polymorphism and the risk of Alzheimer's disease: a meta-analysis.

No consensus has been recently reached at the relationship between the α1-antichymotrypsin (ACT) signal peptide -15A/T polymorphism and Alzheimer's disease (AD) risk. Thus, our study aimed to better assess this association by performing a meta-analysis, including 4,212 cases and 4,039 controls from 29 studies. Odds ratios (ORs) with the 95% confidence interval (CI) were used to assess the strength of relationship between ACT -15A/T polymorphism and AD risk. Overall, a borderline statistically significant association was detected under recessive model comparison in all subjects (AA vs. AT+TT: OR 1.12, 95% CI 1.01-1.25, P = 0.04). But in subgroup analysis by ethnicity, no significant association was found in Caucasians, Asians, or Africans. Moreover, after exclusion of one study which affect the heterogeneity, the ACT A allele and AA genotype were statistically associated with late-onset AD (LOAD) risk (AA vs. TT: OR 1.25, 95% CI 1.06-1.48, P = 0.007, A vs. T: OR 1.12, 95% CI 1.03-1.21, P = 0.008), especially in Caucasians. In conclusion, our study suggests that the common α1-antichymotrypsin signal peptide -15A/T polymorphism may not be a major risk factor for AD. However, the polymorphism is capable of increasing LOAD risk.