CD206+ M2-like macrophages protect against intervertebral disc degeneration partially by targeting R-spondin-2.

OBJECTIVE: This study aimed to explore the specific function of M2 macrophages in intervertebral disc degeneration (IDD). METHODS: Intervertebral disc (IVD) samples from normal (n = 4) and IDD (n = 6) patients were collected, and the expression of M2-polarized macrophage marker, CD206, was investigated using immunohistochemical staining. Nucleus pulposus cells (NPCs) in a TNF-α environment were obtained, and a mouse caudal IVD puncture model was established. Mice with Rheb deletions, specifically in the myeloid lineage, were generated and subjected to surgery-induced IDD. IDD-induced damage and cell apoptosis were measured using histological scoring, X-ray imaging, immunohistochemical staining, and TdT-mediated dUTP nick end labeling (TUNEL) assay. Finally, mice and NPCs were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in IDD. RESULTS: Accumulation of CD206 in human and mouse IDD tissues was detected. Rheb deletion in the myeloid lineage (RheBcKO) increased the number of CD206+ M2-like macrophages (mean difference 18.6% [15.7-21.6%], P < 0.001), decreased cell apoptosis (mean difference -15.6% [-8.9 to 22.2%], P = 0.001) and attenuated the IDD process in the mouse IDD model. NPCs treated with Rspo2 displayed increased extracellular matrix catabolism and apoptosis; co-culture with a conditioned medium derived from RheBcKO mice inhibited these changes. Anti-Rspo2 treatment in the mouse caudal IVD puncture model exerted protective effects against IDD. CONCLUSIONS: Promoting CD206+ M2-like macrophages could reduce Rspo2 secretion, thereby alleviating experimental IDD. Rheb deletion may help M2-polarized macrophages accumulate and attenuate experimental IDD partially by inhibiting Rspo2 production. Hence, M2-polarized macrophages and Rspo2 may serve as therapeutic targets for IDD.

Characteristics and potentials of stem cells derived from human degenerated nucleus pulposus: potential for regeneration of the intervertebral disc.

BACKGROUND: Eliminating the symptoms during treatment of intervertebral disc degeneration (IVDD) is only a temporary solution that does not cure the underlying cause. A biological method to treat this disorder may be possible by the newly discovered nucleus pulposus derived stem cells (NPDCs). However, the uncertain characteristics and potential of NPDCs calls for a comprehensive study. METHODS: In the present study, nucleus pulposus samples were obtained from 5 patients with IVDD undergoing discectomy procedure and NPDCs were harvested using fluorescence activated cell sorting (FACS) by the co-expression of GD2+ and Tie2+. After in vitro expansion, the properties of NPDCs were compared with those of bone marrow mesenchyme stem cells (BMSCs) from the same subjects. RESULTS: NPDCs performed similar properties in cell colony-forming ability, cell proliferation rate, cell cycle and stem cell gene expression similar to those of BMSCs. In addition, NPDCs could be differentiated into osteoblasts, adipocytes, and chondrocytes, and are found to be superior in chondrogenesis but inferior in adipocyte differentiation. CONCLUSIONS: NPDCs derived from the degenerated intervertebral disc still keep the regeneration ability similar to BMSCs. Besides, the superior capacity in chondrogenesis may provide a promising cell candidate for cell-based regenerative medicine and tissue engineering in IVDD.

Efficacy and safety of bone marrow-derived cell transplantation for spinal cord injury: a systematic review and meta-analysis of clinical trials.

PURPOSE: Bone marrow-derived cells (BMDCs) for clinical transplantation were carried out many years in treating spinal cord injury (SCI) without a clear conclusion. This study aimed to evaluate the safety and efficacy of BMDC transplantation in treatment of SCI patients. METHOD: Electronic databases, including PubMed, EMBASE, MEDLINE, and the Cochrane library, were searched to identify clinical therapeutic trials studying the application of BMDC transplantation in SCI. RESULTS: Overall the quality of the 24 studies was low, including one Grade I level of evidence, six Grade II levels, three Grade III levels, and 14 Grade IV levels. With a maximum of six-yr follow-up, the procedure-related complications were minor and temporary, without serious adverse events (p = 0, n = 594). AIS improvement rate was analyzed in favor of BMDCs 6.13 (95% CI, 3.0-12.51; p < 0.001). In patient with complete (AIS A) and chronic SCI, the application of cell transplantation numbers between n × (10(7) -10(8) ) seemed to be more beneficial (p < 0.05 for all groups). CONCLUSIONS: Based on short-medium terms following up, BMDC transplantation appears to be safe and valid in SCI patients, more effective in chronic and complete injury. Nonetheless, prospective, randomized trials in larger cohorts are still needed.

Investigation of macrophage polarization in herniated nucleus pulposus of patients with lumbar intervertebral disc herniation.

Macrophage infiltration and polarization during lumbar intervertebral disc herniation (LDH) have attracted increased attention but their role remains unclear. To explore macrophage polarization in herniated nucleus pulposus (NP) tissue of patients with LDH and investigate the association between cell frequency and different clinical characteristics or symptoms, we conducted a retrospective study by analyzing NP tissue samples from 79 patients. Clinical features and symptoms, using the visual analog scale (VAS) and Oswestry disability index (ODI), were collected. The macrophage markers CD68, CCR7, CD163, and CD206; pro-inflammatory cytokine TNF-α; and anti-inflammatory factor IL-4 were analyzed by immunohistochemistry. The frequency of polarized macrophages and positivity rate of pro- and anti-inflammatory cytokines showed significant differences in some of clinical characteristics. Specifically, higher CCR7+ and TNF-α + proportions were identified in the high-intensity zone (HIZ) and the type of extrusion and sequestration NP tissue than in non-HIZ and protrude NP tissue. Higher CD206+ and IL-4+ proportion were detected in Modic changes. However, no differences in gender, age, smoking status, Pfirrmann grade, analgesic use, leg pain duration, and segments were found between groups. CD68+ , CCR7+ , and CD206+ cell proportions, and TNF-α and IL-4 showed positive associations with VAS scores preoperation. Associations between ODI and the macrophages markers were weak/insignificant. Our results indicated that macrophage polarization or macrophage-like cells contribute to LDH pathological features. Macrophage populations displaying significant associations with VAS score reflected continuous M1/M2 transition contributing to pain during LDH. These findings may contribute to enhanced/personalized pharmacological interventions for patients with LDH considering pain heterogeneity.

Influence of macrophage polarization in herniated nucleus pulposus tissue on clinical efficacy after lumbar discectomy.

Background: Low back pain or sciatic pain because of lumbar intervertebral disc herniation (LDH) is caused by mechanical compression and/or an inflammatory component on the nerve root. However, it is difficult to define to what extent each component contributes to the pain. This study attempted to explore the effects of macrophage polarization on clinical symptoms in patients experiencing LDH after surgery, and investigated the association between macrophage cell percentages and clinical efficacy. Methods: This study retrospectively harvested nucleus pulposus (NP) tissue samples from 117 patients. Clinical symptoms and efficacy using the visual analog scale (VAS) and Oswestry Disability Index (ODI) were evaluated at different time points preoperatively and postoperatively. CD68, CCR7, CD163, and CD206 were selected as macrophage phenotypic markers. Results: Seventy-six samples showed positive expression of macrophage markers in NP samples of patients with LDH, whereas 41 patients displayed negative results. No significant differences were detected between the two groups, involvement of several demographic data, and preoperative clinical findings. With respect to the macrophage-positive group, no significant correlation was detected between the positive rate of the four markers and the VAS score or ODI after surgery. However, patients with NP samples positive for CD68 and CCR7 expression showed significantly lower VAS scores 1 week after surgery compared with those in the negative group. Moreover, the improvement in VAS score showed a strong positive correlation with CD68- and CCR7-positive cell percentages. Conclusions: Our results indicated that pro-inflammatory M1 macrophages may be associated with the reduction of chronic pain after surgery. Therefore, these findings contribute to better personalized pharmacological interventions for patients with LDH, considering the heterogeneity of pain.

[Outcome prediction of single-period CO(2) laser therapy for vulvar condylomata acuminate].

OBJECTIVE: To evaluate the outcome of CO(2) laser treatment as primary therapy for vulvar condylomata acuminate and examine the risk factors and prediction model of single-period CO(2) laser treatment. METHODS: Between March 2009 and December 2010, a multicenter prospective study was conducted at three 3A hospitals of China (Peking Union Medical College Hospital, Zhejiang Women's Health Hospital & Tongji Hospital). All enrolled patients of vulvar condylomata acuminata received CO(2) laser vaporization as the primary therapy and had return visits at 1, 3 and 6 months individually after treatment. Therapeutic recurrence and side effects were recorded. Logistic regression was used to analyze the associations between demographic or clinical characteristics and the outcome of single-period CO(2) laser treatment and a prediction model was established subsequently. The optimal cutoff value of model was evaluated by area under the receiver operating characteristic curve (AUC ROC). RESULTS: A total of 160 patients completed a 6-month follow-up with a loss rate of 9.1% (16/176). And 131 patients (82%) were cured after the single-period CO(2) laser therapy with a total recovery rate of 94% (150/160). Side effects occurred in 50 (31%) patients with a complete self-recovery within 6 months. The most common side effects were local ulceration, pain and edema. No severe side effect was present. Large area of lesion (>8 cm(2)), vagina involved and unemployment were associated with the failure of single-period treatment while pain symptom was a protective factor of effectiveness. Age, marital status, symptom-free and vaginal involvement were not related with outcome. A prediction model was established as follows: Logit (P(0)) = -1.511+1.573X(1)+1.679X(2)+3.254X(3)-1.685X(4) (X(1)-X(4) representing area of lesion > 8 cm(2), vaginal involvement, unemployment and pain symptom respectively). The optimal cutoff value of P(0) was 0.35 with AUC ROC of 0.816 (P < 0.01). The sensitivity, specificity, positive predictive value and negative predictive value of model were 58.6%, 91.6%, 60.7% and 90.9% respectively. CONCLUSION: CO(2) laser is effective and safe therapy for vulvar condylomata acuminata. A prediction model has been proposed to predict the outcome of single-period CO(2) laser therapy in initially diagnosed patients. It may guide clinical decision-making.

M2 macrophage-conditioned medium inhibits intervertebral disc degeneration in a tumor necrosis factor-α-rich environment.

Inflammation is the primary pathological phenomenon associated with disc degeneration; the inflammatory cytokine tumor necrosis factor (TNF-α) plays a crucial role in this pathology. The anti-inflammatory and regenerative effects of M2 macrophages on nucleus pulposus cells (NPCs) in intervertebral disc degeneration (IDD) progression remain unknown. Here, M2 conditioned medium (M2CM) was harvested and purified from human acute monocytic leukaemia cell line (THP-1) cells and mouse peritoneal macrophages, respectively; it was used for culturing human NPCs and a mouse intervertebral disc (IVD) organ culture model. NPCs and IVD organ models were divided into three groups: group 1 treated with 10% fetal bovine serum (control); group 2 treated with 10 ng/ml TNF-α; and group 3 treated with 10 ng/ml TNF-α and M2CM (coculture group). After 2-14 days, cell proliferation, extracellular matrix synthesis, apoptosis, and NPC senescence were assessed. Cell proliferation was reduced in TNF-α-treated NPCs and inhibited in the M2CM co-culture treatment. Moreover, TNF-α treatment enhanced apoptosis, senescence, and expression of inflammatory factor-related genes, including interleukin-6, MMP-13, ADAMTS-4, and ADAMTS-5, whereas M2CM coculture significantly reversed these effects. In addition, co-culture with M2CM promoted aggrecan and collagen II synthesis, but reduced collagen Iα1 levels in TNF-α treatment groups. Using our established three-dimensional murine IVD organ culture model, we show that M2CM suppressed the inhibitory effect of TNF-α-rich environment. Therefore, co-culture with M2CM promotes cell proliferation and extracellular matrix synthesis and inhibits inflammation, apoptosis, and NPC senescence. This study highlights the therapeutic potential of M2CM for IDD.

Macrophage polarization regulates intervertebral disc degeneration by modulating cell proliferation, inflammation mediator secretion, and extracellular matrix metabolism.

Macrophage infiltration and polarization have been increasingly observed in intervertebral disc (IVD) degeneration (IDD). However, their biological roles in IDD are still unrevealed. We harvested conditioned media (CM) derived from a spectrum of macrophages induced from THP-1 cells, and examined how they affect nucleus pulposus cells (NPCs) in vitro, by studying cell proliferation, extracellular matrix (ECM) synthesis, and pro-inflammation expression; and in vivo by injection CM in a rat IDD model. Then, high-throughput sequencing was used to detect differentially expressed genes (DEGs). Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) networks were used to further analysis. Higher CCR7+ (M1 marker) and CD206+ (M2 marker) cell counts were found in the degenerated human IVD tissues as compared with the control. Furthermore, the cell co-culture model showed M1CM attenuated NPC proliferation, downregulated the expression of ECM anabolic genes encoding aggrecan and collagen IIα1, upregulated the expression of ECM catabolic genes encoding MMP-13, and inflammation-related genes encoding IL-1ß, IL-6, and IL-12, while M2CM showed contrasting trends. In IDD model, higher histological scores and lower disc height index were found following M1CM treatment, while M2CM exhibited opposite results. M1CM injection decreased ECM anabolic and increased ECM catabolic, as well as the upregulation of inflammation-related genes after 8 weeks treatment, while M2CM slowed down these trends. Finally, a total of 637 upregulated and 655 downregulated genes were detected in M1CM treated NPCs, and 975 upregulated genes and 930 downregulated genes in the M2CM groups. The top 30 GO terms were shown and the most significant KEGG pathway was cell cycle in both groups. Based on the PPI analysis, the five most significant hub genes were PLK1, KIF20A, RRM2, CDC20, and UBE2C in the M1CM groups and RRM2, CCNB1, CDC20, PLK1, and UBE2C in the M2CM groups. In conclusion, macrophage polarization exhibited diverse roles in IDD progression, with M1CM exacerbating cell proliferation suppression and IVD degeneration, while M2CM attenuated IDD development. These findings may facilitate the further elucidation of the role of macrophage polarization in IDD, and provide novel insights into the therapeutic potential of macrophages.

Cervical endometriosis: clinical character and management experience in a 27-year span.

OBJECTIVE: The purpose of this study was to analyze the clinicopathologic characters and explore the possible cause of cervical endometriosis. STUDY DESIGN: By retrospective review, among 13,566 cases of endometriosis that had been treated in our hospital, 33 cases of pathologically proven cervical endometriosis were extracted. RESULTS: Of 33 cases, 17 women had abnormal vaginal bleeding or visible cervical lesions; the other 16 women had no obvious clinical manifestations but were diagnosed retrospectively on histopathologic reports. Vaginal delivery or curettage procedures had occurred in 84.8% of patients. Only 2 patients had undergone cervical surgery of cryotherapy or electric excision. Seven cases were misdiagnosed before final surgery with the primary suspicion of cervical myoma, inflammatory cyst, cervical polyp, uterine submucous myoma, melanoma or melanin mole, and cervical cancer. Surgical treatment was performed for all symptomatic patients. No recurrence was seen. CONCLUSION: Cervical endometriosis should be distinguished from other benign or malignant cervical lesions. Surgical excision is suggested for symptomatic patients.

Plastic repair for a case with synpolydactyly.

On March 23, 2010, we successfully treated a boy with synpolydactyly who had a total of 31 fingers and toes. Although there was bone syndactyly both the hands of the boy, one-step correction of four extremities was successful, this operation lasted 5 h and 20 min and intraoperative bleeding was about 50 ml. Skin grafting was successful after operation and all incisions healed well. The appearance and function of hands and feet were satisfactory.

Pharmacokinetics of depside salts from Salvia miltiorrhiza in healthy Chinese volunteers: A randomized, open-label, single-dose study.

BACKGROUND: Depside salts from Salvia miltiorrhiza, with active components of lithospermic acid B (LSB), rosmarinic acid (RA), and lithospermic acid (LA), are a multicomponent drug marketed in China for the treatment of coronary heart disease. OBJECTIVES: The aims of this study were to determine the concentrations of LSB, RA, and LA in human plasma and urine, and to compare the pharmacokinetic properties of depside salts from S miltiorrhiza in healthy Chinese volunteers. METHODS: A randomized, open-label, single-dose study was conducted in healthy Chinese volunteers. Participants were randomly assigned to receive a single intravenous infusion of 100 or 200 mg of depside salts from S miltiorrhiza. Blood was collected through a venous cannula prior to study drug administration (0 min) and at 10, 20, 30, 60, 65, 70, 80, and 90 minutes and 2, 3, 4, 6, 8, 12, and 24 hours after study drug administration. Urine samples were taken before study drug administration (0) and at 0 to 12 and 12 to 24 hours after study drug administration. LSB, RA, and LA concentrations in serum and urine were analyzed by an LC-MS/MS method. Tolerability was determined by clinical assessment; vital signs (ie, blood pressure, heart rate, breathing rate, body temperature) monitoring at baseline and at the end of the study, clinical laboratory tests (ie, hematology, blood biochemistry, hepatic function, renal function, urinalysis), 12-lead ECG measurements, and physical examinations at baseline and after completion of the study. RESULTS: Twelve Chinese volunteers (6 males, 6 females; mean [SD] age, 25.2 [3.8] years; mean height, 165.7 [8.9] cm; mean body mass index, 21.6 [2.5] kg/m(2)) were enrolled in the study. Peak plasma concentrations of LSB, RA and LA were observed at 0.3 to 1 hour following the 1-hour intravenous infusion, with respective mean (SD) Cmax of 4925 (1861), 174 (61), and 361 (101) ng/mL for the 100-mg dose and 10,285 (2259), 308 (77), and 674 (85) ng/mL for the 200-mg dose. The AUClast values for LSB, RA, and LA were 4537 (1265), 129 (28), and 1229 (330) ng/mL/h, respectively, for the 100-mg dose and 10,426 (2589), 260 (53), and 2792 (729) ng/mL/h for the 200-mg dose. No significant difference in pharmacokinetic parameters was observed between male and female subjects. Three metabolites were found in the plasma with low concentrations. The urinary excretion recoveries of LSB, RA, and LA were 0.58% (0.42%), 25.21% (20.61%), and 10.02% (7.72%) for the 100-mg dose and 0.38% (0.18%), 20.11% (10.50%), and 6.34% (3.20%) for the 200-mg dose. No adverse events were reported by the subjects or found by the investigators in the analysis of vital signs, 12-lead ECG measurements, physical examinations, or clinical laboratory tests. CONCLUSIONS: Following single intravenous infusion of 100 or 200 mg of depside salts from S miltiorrhiza to healthy Chinese subjects, no statistical differences in pharmacokinetic parameters were observed between males and females. The 2 doses of depside salts from S miltiorrhiza were clinically well tolerated during the study.

Co-culturing nucleus pulposus mesenchymal stem cells with notochordal cell-rich nucleus pulposus explants attenuates tumor necrosis factor-α-induced senescence.

BACKGROUND: Cell therapy for the treatment of intervertebral disc degeneration (IDD) faces serious barriers since tissue-specific adult cells such as nucleus pulposus cells (NPCs) have limited proliferative ability and poor regenerative potential; in addition, it is difficult for exogenous adult stem cells to survive the harsh environment of the degenerated intervertebral disc. Endogenous repair by nucleus pulposus mesenchymal stem cells (NPMSCs) has recently shown promising regenerative potential for the treatment of IDD. Notochordal cells (NCs) and NC-conditioned medium (NCCM) have been proven to possess regenerative ability for the treatment of IDD, but this approach is limited by the isolation and passaging of NCs. Our previous study demonstrated that modified notochordal cell-rich nucleus pulposus (NC-rich NP) has potential for the repair of IDD. However, whether this can protect NPMSCs during IDD has not been evaluated. METHODS: In the current study, tumor necrosis factor (TNF)-α was used to mimic the inflammatory environment of IDD. Human NPMSCs were cocultured with NC-rich NP explants from healthy rabbit lumbar spine with or without TNF-α. Cell proliferation and senescence were analyzed to investigate the effect of NC-rich NP explants on TNF-α-treated NPMSCs. The expression of mRNA encoding proteins related to matrix macromolecules (such as aggrecan, Sox-9, collagen Iα, and collagen IIα), markers related to the nucleus pulposus cell phenotype (including CA12, FOXF1, PAX1, and HIF-1α), and senescence markers (such as p16, p21, and p53), senescence-associated proinflammatory cytokines (IL-6), and extracellular proteases (MMP-13, ADAMTS-5) was assessed. The protein expression of CA12 and collagen II was also evaluated. RESULTS: After a 7-day treatment, the NC-rich NP explant was found to enhance cell proliferation, decrease cellular senescence, promote glycosaminoglycan (GAG), collagen II, and CA12 production, upregulate the expression of extracellular matrix (ECM)-related genes (collagen I, collagen II, SOX9, and ACAN), and enhance the expression of nucleus pulposus cell (NPC) markers (HIF-1α, FOXF1, PAX1, and CA12). CONCLUSION: Modified NC-rich NP explants can attenuate TNF-α-induced degeneration and senescence of NPMSCs in vitro. Our findings provide new insights into the therapeutic potential of NC-rich NP for the treatment of IDD.

[Analysis of clinical outcomes of simplified treatment of lumbar spondylolisthesis with adjacent segment degeneration by MAST Quadrant].

OBJECTIVE: To explore the method and clinical effect of MAST Quadrant for lumbar spondylolisthesis with adjacent segment degeneration. METHODS: From April 2014 to January 2016, 36 cases of lumbar spondylolisthesis with adjacent segment degeneration were treated by MAST Quadrant(target nerve decompression and transforaminal lumbar interbody fusion or articulationes zygapophysiales fusion by unilateral fixation with MAST Quadrant). Twenty-three cases were degenerative lumbar spondylolisthesis and 13 cases were isthmic lumbar spondylolisthesis. According to Meyerding grade of spondylolisthesis, 16 cases were grade I, 17 cases were grade II, and 3 cases were grade III. Visual analogue score (VAS), Oswesty Disability Index (ODI) and JOA score were used to evaluate the clinical outcome. RESULTS: The amount of intraoperative bleeding was 230 to 480 ml with an average of 340 ml and the amount of postoperative blood loss was 15 to 80 ml with an average of 43 ml. Operative time was 176 to 240 min with an average of 193 min; X-ray exposure time was 2 to 6 s with an average of 3.6 s. Two cases were complicated with dural tear without nerve injury during operation. Thirty cases were followed up from 12 to 17 months with an average of 15.2 months. VAS scores for preoperative, 5 days, 3 months after surgery were 7.6±1.7, 1.9±0.4, 0.8±0.4 respectively, and there was significant difference before and after operation(P<0.05). The ODI scores for preoperative and 3 months after surgery were 35.9±1.2 and 3.7±0.7 respectively, and there was significant difference before and after operation(P<0.05). JOA scores for preoperative, 5 days, 1 months, 3 months after surgery were 13.2±0.4, 24.4±0.4, 27.4±0.1, 27.9±0.5 respectively, and there was significant difference before and after operation(P<0.05). CONCLUSIONS: MAST Quadrant can be applied to treat lumbar spondylolisthesis with adjacent segment degeneration, and the minimally invasive sugical technique is a safe and effective method, with the advantage of simple operation, fast recovery.

Minimally invasive procedure reduces adjacent segment degeneration and disease: New benefit-based global meta-analysis.

OBJECTIVE: Adjacent segment pathology (ASP) is a common complication presenting in patients with axial pain and dysfunction, requiring treatment or follow-up surgery. However, whether minimally invasive surgery (MIS), including MIS transforaminal / posterior lumbar interbody fusion (MIS-TLIF/PLIF) decreases the incidence rate of ASP remains unknown. The aim of this meta-analysis was to compare the incidence rate of ASP in patients undergoing MIS versus open procedures. METHODS: This systematic review was undertaken by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. We searched electronic databases, including PubMed, EMBASE, SinoMed, and the Cochrane Library, without language restrictions, to identify clinical trials comparing MIS to open procedures. The results retrieved were last updated on June 15, 2016. RESULTS: Overall, 9 trials comprising 770 patients were included in the study; the quality of the studies included 4 moderate and 5 low-quality studies. The pooled data analysis demonstrated low heterogeneity between the trials and a significantly lower ASP incidence rate in patients who underwent MIS procedure, compared with those who underwent open procedure (p = 0.0001). Single-level lumbar interbody fusion was performed in 6 trials of 408 patients and we found a lower ASP incidence rate in MIS group, compared with those who underwent open surgery (p = 0.002). Moreover, the pooled data analysis showed a significant reduction in the incidence rate of adjacent segment disease (ASDis) (p = 0.0003) and adjacent segment degeneration (ASDeg) (p = 0.0002) for both procedures, favoring MIS procedure. Subgroup analyses showed no difference in follow-up durations between the procedures (p = 0.93). CONCLUSION: Therefore, we conclude that MIS-TLIF/PLIF can reduce the incidence rate of ASDis and ASDeg, compared with open surgery. Although the subgroup analysis did not indicate a difference in follow-up duration between the two procedures, larger-scale, well-designed clinical trials with extensive follow-up are needed to confirm and update the findings of this analysis.

* Coculture with Partial Digestion Notochordal Cell-Rich Nucleus Pulposus Tissue Activates Degenerative Human Nucleus Pulposus Cells.

Recent studies suggested that notochordal cells (NCs) and NC-conditioned medium (NCCM) can stimulate cell viability and matrix production of nucleus pulposus cells (NPCs). However, the potential of notochordal cell-rich nucleus pulposus (NRNP) incorporating the native environment of the intervertebral disc (IVD) has not been evaluated. The objective of this study was to develop an optimal NRNP model and test whether it can allow a significant level of NPC activation in vitro. Rabbit NRNP explants were divided into three groups according to different digestion time: digestion NRNP of 8 h, partial digestion NRNP of 2 h, and natural NRNP. Cell viability and NC phenotype were compared between these groups after 14 days of incubation. The products of the selected partial digestion NRNP group were then cocultured with human degenerated NPCs for 14 days. NPC viability, cell proliferation and senescence, the production of glycosaminoglycan (GAG) found in extracellular matrix, and NP matrix production by NPCs were assessed. The results showed that coculturing with partial digestion NRNP significantly improved the cell proliferation, cell senescence, and disc matrix gene expression of NPCs compared with those in the monoculture group. In addition, GAG/DNA ratio in the coculture group increased significantly, while the level of collagen II protein remained unchanged. In this study, we demonstrated that partial digestion NRNP may show a promising potential for NPC regeneration in IVD tissue engineering.

Oral Bioavailability and Mass Balance Studies of a Novel Anti-arrhythmic Agent Sulcardine Sulfate in Sprague-Dawley Rats and Beagle Dogs.

BACKGROUND AND OBJECTIVES: Sulcardine sulfate is a newly developed candidate drug used to control arrhythmias. The aim of this research was to investigate the pharmacokinetics, bioavailability and excretion characteristics of sulcardine in animals. METHODS: Sprague-Dawley rats were orally and intravenously given sulcardine at 20 and 40 mg/kg. Beagle dogs were also orally and intravenously dosed at 10 mg/kg. Both [3H]-labeled sulcardine and unlabeled sulcardine were given to rats. Feces, urine and bile were collected at 0-72 h for mass balance study. The contents of unlabeled sulcardine and radioactivity in samples were determined by a validated LC-MS/MS method and by liquid scintillation counting, separately. RESULTS: Sulcardine was rapidly eliminated in rats after dosing. The oral bioavailability was 34-35 % in rats, while a higher exposure was observed in dogs (bioavailability = 62.7 %). More than 90 % of dosed sulcardine was recovered, and approximately 20-40 % of the dose excreted into urine as the original form, and the remaining was found in feces and bile, most of which (about 40 %) was transformed into metabolites. No difference was observed between sexes. Metabolism may occur to a large extent after oral administration in rats but to a smaller extent in dogs. CONCLUSIONS: Sulcardine was extensively absorbed in both rats and dogs after oral administration. The mass balance data indicated that sulcardine was widely metabolized in rats after oral administration.

Proportion of Uterine Malignant Tumors in Patients with Laparoscopic Myomectomy: A National Multicenter Study in China.

BACKGROUND: The Food and Drug Administration recently announced that the use of morcellation may cause fibroids or pelvic dissemination and metastasis of uterine sarcoma; therefore, the use of morcellation is limited in the USA. A large sample study is necessary to assess the proportion of uterine malignant tumors found in patients with laparoscopic myomectomy. METHODS: A national multicenter study was performed in China. From 2002 to 2014, 33,723 cases were retrospectively selected. We calculated the prevalence and recorded the clinical characteristics of the patients with malignancy after morcellation application. A total of 62 cases were finally pathologically confirmed as malignant postoperatively. Additionally, the medical records of the 62 patients were analyzed in details. RESULTS: The proportion of postoperative malignancy after morcellation application was 0.18% (62/33,723) for patients who underwent laparoscopic myomectomy. Nearly 62.9% (39/62) of patients had demonstrated blood flow signals in the uterine fibroids before surgery. And, 23 (37.1%) patients showed rapid growth at the final preoperative ultrasound. With respect to the pathological types, 38 (61.3%) patients had detectable endometrial stromal sarcoma, 13 (21.0%) had detectable uterine leiomyosarcoma, only 3 (3.2%) had detectable carcinosarcoma, and 5 (8.1%) patients with leiomyoma had an undetermined malignant potential. CONCLUSIONS: The proportion of malignancy is low after using morcellation in patients who undergo laparoscopic myomectomy. Patients with fast-growing uterine fibroids and abnormal ultrasonic tumor blood flow should be considered for malignant potential, and morcellation should be avoided.

[Study on the early liver metastasis forecast of colorectal neoplasms].

OBJECTIVE: To obtain some effective objective markers used to predict the early liver metastasis of colorectal tumor, the relationship of liver metastasis of colorectal tumor with associate detection three markers such as CK20mRNA, CD44v6 and VEGF was studied. METHODS: The expression of CK20mRNA in patrol venous blood from 30 colorectal cancer patients was detected by fluorescent quantitative RT-PCR, and the results of CD44v6 and VEGF in colorectal cancer tissue were determined by means of immunohistochemistry, and then compared with those in control groups. RESULTS: The rate of positive expression of CK20mRNA in colorectal cancer patients' patrol venous blood was obviously superior to the level of benign pathological changes controls (P < 0.01), and significantly higher than that of normal controls (P < 0.01). The rate of positive expression of CD44v6 and VEGF in colorectal tumor tissue was distinctly superior to the level of benign pathological controls, and remarkable higher than that of normal controls (P < 0.01). The positive expression of liver metastasis was also clearly higher than that of no liver metastasis (P < 0.05). The rate of positive expression of CK20mRNA in patrol venous blood was evidently correlated to the expression of CD44v6 and VEGF in tumor tissue (r(1) = 0.933, r(2) = 0.906, P < 0.05). The results of associate detection of CK20mRNA, CD44v6 and VEGF were closely related to the incidence of liver metastasis. CONCLUSIONS: If combined detecting these markers of CK20mRNA, CD44v6 and VEGF to forecast liver metastasis of colorectal tumor, the sensitivity and specialty of prediction will be improved, there were highly clinical values in predicting in early diagnosis liver metastasis of colorectal tumor.

Full-Endoscopic Procedures Versus Traditional Discectomy Surgery for Discectomy: A Systematic Review and Meta-analysis of Current Global Clinical Trials.

BACKGROUND: Traditional discectomy surgery (TDS) provides good or excellent results in clinical surgical discectomy but may induce neural adhesion, spinal structural damage, instability, and other complications. The potential advantages of full-endoscopic (FE) procedures over standard TDS include less blood loss, less postoperative pain, shorter hospitalization, and an earlier return to work. However, more evidence is needed to support this new technology in clinical applications. OBJECTIVE: The aim of this systematic review and meta-analysis was to compare the safety and efficacy of FE and TDS. STUDY DESIGN: Comprehensive systematic review and meta-analysis of the literature. METHODS: Electronic databases, including PubMed, EMBASE, SinoMed, and Cochrane Library, were searched to identify clinical therapeutic trials comparing FE to TDS for discectomy. RESULTS: Six trials comprising 730 patients were included, and the overall quality of the literature was moderate, including 4 Grade I levels of evidence (4 randomized controlled trials, [RCTs]) and 2 Grade II levels (2 non-RCTs). The pooled data revealed no difference in reoperation rates between FE and TDS (P = 0.94), but the complication rate was significantly lower in the FE group (3.86%) than in the TDS group (11.4%). Perioperative parameters (operation time, blood loss, hospitalization time, and return to work days) were significantly lower in the FE group (P < 0.05 for all groups using either score). Postoperative pain and neurology score assessments were conducted at 4 different time points at 3 months, 6 months, 12 months, and 24 months. Significant differences were detected in the following: lumbar North American Spine Society (NASS) pain at 6 months (P = 0.008); cervical NASS neurology at 6 months (P = 0.03); visual analog scale (VAS) score in leg at 3 months (P < 0.001); VAS score in arm at 24 months (P = 0.002); VAS score in neck at 3 months, 6 months, and 12 months after therapy (P = 0.003, P = 0.004, P = 0.01); and VAS score in neck at 3 months and 6 months (P = 0.01, P = 0.004). Moreover, the pooled data revealed no statistically significant differences in improvements in the Oswestry disability index (ODI), instability (X-ray), and Hilibrand criteria (P > 0.05 for all groups). LIMITATIONS: Only 6 studies were included, 4 of which had the same authors. Between-study heterogeneity due to differences in socioeconomic factors, nutrition, and matching criteria is difficult to avoid. CONCLUSIONS: Based on this meta-analysis of 24 months of clinical results, we conclude that the FE procedure is as effective as TDS but has the additional benefits of lower complication rates and superior perioperative parameters. In addition, patients may experience less pain with FE techniques due to a smaller incision and less operative injury. However, large-volume, well-designed RCTs with extensive follow-up are needed to confirm and update the findings of this analysis.

BMP7-Based Functionalized Self-Assembling Peptides Protect Nucleus Pulposus-Derived Stem Cells From Apoptosis In Vitro.

Tissue engineering has shown great success in the treatment of intervertebral disk degeneration (IVDD) in the past decade. However, the adverse and harsh microenvironment associated in the intervertebral disks remains a great obstacle for the survival of transplanted cells. Although increasing numbers of new materials have been created or modified to overcome this hurdle, a new effective strategy of biological therapy is still required. In this study, bone morphogenic protein 7 (BMP7)-based functionalized self-assembling peptides were developed by conjugating a bioactive motif from BMP-7 (RKPS) onto the C-terminal of the peptide RADARADARADARADA (RADA16-I) at a ratio of 1:1 to form a new RADARKPS peptide. Human nucleus pulposus-derived stem cells (NPDCs) were cultured in the presence of RADA-RKPS or RADA16-I in an apoptosis-promoting environment that was induced by tumor necrosis factor-alpha, and cells were cultured with RADA16-I in normal medium that served as the control group. After 48 h of apoptosis induction, the viability, proliferation, apoptosis rate, and expression of apoptosis-related genes of NPDCs in the different groups were evaluated, and the differentiation of NPDCs toward nucleus pulposus-like cells was tested. The results showed that the RADA-RKPS peptide could significantly protect the survival and proliferation of NPDCs. In addition, the application of RADA-RKPS decreased the rate of cell apoptosis, as detected by TUNEL-positive staining. Furthermore, our in vitro study confirmed the apoptosis-protecting effects of RADA-RKPS peptides, which significantly reduced the BAX/BCL-2 ratio of NPDCs and upregulated the gene expression of collagen II a1, aggrecan, and Sox-9 after 48 h of apoptosis induction. Collectively, these lines of evidence suggest that RADA-RKPS peptides confer a protective effect to NPDCs in an apoptosis environment, suggesting their potential application in the development of new biological treatment strategies for IVDD.