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BackgroundIncreasing biomedical studies have shown that the dysfunction of miRNAs is closely related with many human diseases. Identifying disease-associated miRNAs would contribute to the understanding of pathological mechanisms of diseases. Supervised learning-based computational methods have continuously been developed for miRNA-disease association predictions. Negative samples of experimentally-validated uncorrelated miRNA-disease pairs are required for these approaches, while they are not available due to lack of biomedical research interest. Existing methods mainly choose negative samples from the unlabelled ones randomly. Therefore, the selection of more reliable negative samples is of great importance for these methods to achieve satisfactory prediction results.ResultsIn this study, we propose a computational method termed as KR-NSSM which integrates two semi-supervised algorithms to select more reliable negative samples for miRNA-disease association predictions. Our method uses a refinedK-means algorithm for preliminary screening of likely negative and positive miRNA-disease samples. ARocchioclassification-based method is applied for further screening to receive more reliable negative and positive samples. We implement ablation tests in KR-NSSM and find that the combination of the two selection procedures would obtain more reliable negative samples for miRNA-disease association predictions. Comprehensive experiments based on fivefold cross-validations demonstrate improvements in prediction accuracy on six classic classifiers and five known miRNA-disease association prediction models when using negative samples chose by our method than by previous negative sample selection strategies. Moreover, 469 out of 1123 selected positive miRNA-disease associations by our method are confirmed by existing databases.ConclusionsOur experiments show that KR-NSSM can screen out more reliable negative samples from the unlabelled ones, which greatly improves the performance of supervised machine learning methods in miRNA-disease association predictions. We expect that KR-NSSM would be a useful tool in negative sample selection in biomedical research.

Increasing biomedical evidence has proved that the dysregulation of miRNAs is associated with human complex diseases. Identification of disease-related miRNAs is of great importance for disease prevention, diagnosis and remedy. To reduce the time and cost of biomedical experiments, there is a strong incentive to develop efficient computational methods to infer potential miRNA-disease associations. Although many computational approaches have been proposed to address this issue, the prediction accuracy needs to be further improved. In this study, we present a computational framework MKGAT to predict possible associations between miRNAs and diseases through graph attention networks (GATs) using dual Laplacian regularized least squares. We use GATs to learn embeddings of miRNAs and diseases on each layer from initial input features of known miRNA-disease associations, intra-miRNA similarities and intra-disease similarities. We then calculate kernel matrices of miRNAs and diseases based on Gaussian interaction profile (GIP) with the learned embeddings. We further fuse the kernel matrices of each layer and initial similarities with attention mechanism. Dual Laplacian regularized least squares are finally applied for new miRNA-disease association predictions with the fused miRNA and disease kernels. Compared with six state-of-the-art methods by 5-fold cross-validations, our method MKGAT receives the highest AUROC value of 0.9627 and AUPR value of 0.7372. We use MKGAT to predict related miRNAs for three cancers and discover that all the top 50 predicted results in the three diseases are confirmed by existing databases. The excellent performance indicates that MKGAT would be a useful computational tool for revealing disease-related miRNAs.

Objective To compare the pedicle morphology of nondystrophic scoliosis secondary to neurofibromatosis type 1 (ND-NF1) scoliosis secondary to neurofibromatosis type 1 (NF1-S) and adolescent idiopathic scoliosis (AIS) using computed tomography (CT) in a consistent classification system. Methods The transverse pedicle widths of cancellous and cortical channels were measured using preoperative spinal CT images (T1–L5) and then classified as having type A–E pedicles; type B, C, D, and E pedicles were regarded as abnormal. A subset of these patients, a postoperative CT was performed to evaluate the accuracy of pedicle screw placement. According to the perforation of the medial or lateral pedicle walls by the pedicle screw, the placement of screw was classified by a grade ranging from 0 to 3, and grades 2 and 3 were regarded as misplacement. Results In total, 3230 pedicles were measured and classified, and the incidence rate of abnormal pedicles in the ND-NF1 group was significantly greater than that of the AIS group (65.9% vs. 61.4%, P = 0.03). The misplacement rate in the ND-NF1 group was significantly greater than that in the AIS group (12.2% vs. 7.4%; P = 0.01), and in terms of the corresponding 1100 pedicles, the incidence rate of abnormal pedicles in the ND-NF1 group was higher than that in the AIS group (71.7% vs. 64.9%; P = 0.02). Conclusions The incidence rate of abnormal pedicles in patients with ND-NF1 is significantly greater than that of patients with AIS, and it may the reason for the higher misplacement rate of pedicle screws in patients with ND-NF1.

Multiparametric magnetic resonance imaging and targeted biopsy have been widely accepted as the most accurate technique to detect localize prostate cancer. It is a time-consuming and expensive option and may not be widely available in China, making ultrasound the first choice for the detection of prostate cancer. In this current retrospective study, the diagnostic values of enhanced transrectal ultrasound, contrast-enhanced transrectal ultrasound, and real-time sonoelastography were evaluated. Symptomatic 315 men older than 40 years with prostate-specific antigen level greater than 4.0 ng/mL, with abnormal digital rectal examinations, and with suspicious lesions for prostate cancer under enhanced transrectal ultrasound included in the study. Enhanced transrectal ultrasound was suspicious in all 315 men, with 189 of 315 men with prostate cancer according to the prostate biopsy report. Sonoelastography was suspicious in 294 of 315 men, with 166 of 315 men with prostate cancer according to the prostate biopsy report. Contrast-enhanced transrectal ultrasound was suspicious in 221 of 315 men, with 159 of 315 men with prostate cancer according to the prostate biopsy report. Real-time sonoelastography alone and contrast-enhanced transrectal ultrasound alone were missed in 27 (11%) and 39 (15%) lesions to report cancer through biopsies. Working area for enhanced transrectal ultrasound, real-time sonoelastography, and contrast-enhanced transrectal ultrasound for detection of prostate cancer were 0 to 1 diagnostic confidence, 0.11 to 0.895 diagnostic confidence, and 0.39 to 0.63 diagnostic confidence respectively. Real-time sonoelastography and contrast-enhanced transrectal ultrasound may improve the detection of prostate cancer in men with suspicious prostate lesions under enhanced transrectal ultrasound (Level of Evidence: III; Technical Efficacy Stage: 2).

The atherosclerotic plaque is characterized by narrowing of blood vessels and reduced blood flow leading to the insufficient blood supply to the brain. The hemodynamic changes caused by arterial stenosis increase the shearing force of the fibrous cap on the surface of the plaque, thereby reducing the stability of the plaque. Unstable plaques are more likely to promote angiogenesis and increase the risk of patients with cerebrovascular diseases. A timely understanding of the formation and stability of the arterial plaque can guide in taking targeted measures for reducing the risk of acute stroke in patients. It has been confirmed that nano-microbubbles can enter these plaques through the gaps in the patient’s vascular endothelial cells, thereby enhancing the acquisition of ultrasound information for plaque visualization. Therefore, we aim to investigate the diagnostic value of targeted nano-microbubbles for atherosclerotic plaques. This study constructed vascular endothelial growth factor receptor-2 (VEGFR-2) targeting antibody nano-microbubbles and compared its diagnostic value with that of blank nano-microbubbles for atherosclerotic plaques. Studies have found that VEGFR-2 targeting antibody nano-microbubbles can accurately detect the position of plaques. Its detection rate, sensitivity, and specificity for plaques are higher than those of blank nano-microbubbles. Similarly, the peak intensity and average transit time of VEGFR-2 targeting antibody nano-microbubbles were greater than those of blank nano-microbubbles. Therefore, we believe that the combination of VEGFR-2 antibody and nano-microbubbles can enhance the acquisition of ultrasound information on atherosclerotic plaque neovascularization, thereby improving the early diagnosis of unstable plaque.

Objective. In this paper, we study the role of the VHL gene in regulating the proliferation and apoptosis of renal cell carcinoma, as well as the safety and transfection efficiency of ultrasound microbubble gene transfection technology. Method. We use kidney cancer cell lines as an in vitro research object and apply ultrasound microbubble gene transfection technology to transfect the VHL gene into kidney cancer cell line (786-0). The proliferation and apoptosis of cells were measured to clarify the inhibitory effect of the VHL gene in renal cell carcinoma. After that, pEGFP-VHL was transfected using ultrasonic microbubble and liposome gene transfection techniques, respectively, and the transfection efficiency was measured by immunofluorescence. Results. Compared with untreated and 786-0 cells that are transfected with empty vector, the expression level of VHL gene mRNA in 786-0 cells that are transfected with pcDNA3.1-VHL was significantly increased, and the cell growth inhibition rate was significantly higher. The rate of apoptosis increased significantly. Transfection efficiency of the pEGFP-VHL gene after transfection of 786-0 cells for 48 h: control group 0, liposome group ( 35.55 ± 2.77 ) %, ultrasound microbubble group ( 18.27 ± 2.83 ) %, and two transfection methods on cells. There is no significant difference in the impact of vitality. Conclusion. VHL gene expression can significantly inhibit the proliferation ability of renal cancer cell line 786-0 and promote its apoptosis. VHL gene is a potential target for gene therapy of kidney cancer.

To our best knowledge, no study investigated the utility of the combination of high-frequency US and real-time shear wave elastography (RTSWE) in the evaluation of Achilles tendon (AT). Our study aimed to evaluate AT in patients with diabetic foot ulcers using high-frequency US and RTSWE. We retrospectively reviewed 100 patients who visited our hospital due to diabetes. Patients were divided into the study group (those with diabetic foot ulcers) and the control group (those without diabetic foot ulcers). Patients’ demographics, basic medical records, and laboratory tests were reviewed. High-frequency ultrasound and RTSWE were performed in both AT for all 100 patients. Young’s modulus was measured at the upper, middle, and lower parts of each AT by RTSWE. There were 50 patients with diabetic foot ulcers. Patients in the study group had older age, a higher incidence of insulin use, and a higher level of cholesterol than those in the control group. However, thickness and Young’s modulus of AT were comparable in two groups, when evaluated by the combination of high-frequency ultrasound and RTSWE. There was no significant difference in thickness and elastic modulus of AT in patients with and without diabetic foot ulcers when evaluated by the combination of high-frequency ultrasound and RTSWE.

Objective: In this study, we aimed to develop an amino-terminal fragment (ATF) peptide-targeted liposome carrying β-elemene (ATF24-PEG-Lipo-β-E) for targeted delivery into urokinase plasminogen activator receptor-overexpressing bladder cancer cells combined with cisplatin (DDP) for bladder cancer treatment. Methods: The liposomes were prepared by ethanol injection and high-pressure microjet homogenization. The liposomes were characterized, and the drug content, entrapment efficiency, and in vitro release were studied. The targeting efficiency was investigated using confocal microscopy, ultra-fast liquid chromatography, and an orthotopic bladder cancer model. The effects of ATF24-PEG-Lipo-β-E combined with DDP on cell viability and proliferation were evaluated by a Cell Counting Kit-8 (CCK-8) assay, a colony formation assay, and cell apoptosis and cell cycle analyses. The anticancer effects were evaluated in a KU-19-19 bladder cancer xenograft model. Results: ATF24-PEG-Lipo-β-E had small and uniform sizes (˜79 nm), high drug loading capacity (˜5.24 mg/mL), high entrapment efficiency (98.37 ± 0.95%), and exhibited sustained drug release behavior. ATF24-PEG-Lipo-β-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol (PEG)ylated β-elemene liposomes (PEG-Lipo-β-E). DDP, combined with ATF24-PEG-Lipo-β-E, exerted a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase, and these effects were dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways. Furthermore, the in vivo antitumor activity showed that the targeted liposomes effectively inhibited the growth of tumors, using the combined strategy. Conclusions: The present study provided an effective strategy for the targeted delivery of β-elemene (β-E) to bladder cancer, and a combined strategy for bladder cancer treatment.

Background and Purpose: RAS mutations limit the effectiveness of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in combination with chemotherapy for metastatic colorectal cancer (mCRC) patients. Therefore, new cell death forms have focused on identifying indirect targets to inhibit Ras-induced oncogenesis. Recently, emerging evidence has shown the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Methods: KRAS mutant CRC cell HCT116 and Lovo were treated with cetuximab and β-elemene, a bioactive compound isolated from Chinese herb Curcumae Rhizoma. Ferroptosis and epithelial-mesenchymal transformation (EMT) were detected in vitro and in vivo. Orthotopic CRC animal model were established and the tumor growth was monitored by IVIS bioluminescence imaging. Tumor tissues were collected to determine ferroptosis effect and the expression of EMT markers after the treatment. Results: CCK-8 assay showed that synergetic effect was obtained when 125 µg/ml β-elemene was combined with 25 µg/ml cetuximab in KRAS mutant CRC cells. AV/PI staining suggested a non-apoptotic mode of cell death after the treatment with β-elemene and cetuximab. In vitro, β-elemene in combination with cetuximab was shown to induce iron-dependent reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, upregulation of HO-1 and transferrin, and downregulation of negative regulatory proteins for ferroptosis (GPX4, SLC7A11, FTH1, glutaminase, and SLC40A1) in KRAS mutant CRC cells. Meanwhile, combinative treatment of β-elemene and cetuximab inhibited cell migration and decreased the expression of mesenchymal markers (Vimentin, N-cadherin, Slug, Snail and MMP-9), but promoted the expression of epithelial marker E-cadherin. Moreover, ferroptosis inhibitors but not other cell death suppressors abrogated the effect of β-elemene in combination with cetuximab on KRAS mutant CRC cells. In vivo, co-treatment with β-elemene and cetuximab inhibited KRAS mutant tumor growth and lymph nodes metastases. Conclusions: Our data for the first time suggest that the natural product β-elemene is a new ferroptosis inducer and combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant CRC cells by inducing ferroptosis and inhibiting EMT, which will hopefully provide a prospective strategy for CRC patients with RAS mutations.

Genetic diagnosis is a promising approach because several single-nucleotide polymorphisms (SNPs) associated with adolescent idiopathic scoliosis (AIS) progression have been reported. We review the predictive value of SNPs in curve progression of adolescent idiopathic scoliosis.We reviewed DNA-based prognostic testing to predict curve progression. Then, the multiple polymorphisms in loci related to AIS progression were also reviewed, and we elucidated the predictive value of SNPs from four functional perspectives, including endocrine metabolism, neuromuscular system, cartilage and extracellular matrix, enzymes, and cytokines.The ScoliScores were less successful predictors than expected, and the weak power of predictive SNPs might account for its failure. Susceptibility loci in ESR1, ESR2, GPER, and IGF1, which related to endocrine metabolism, have been reported to predict AIS progression. Neuromuscular imbalance might be a potential mechanism of scoliosis, and SNPs in LBX1, NTF3, and SOCS3 have been reported to predict the curve progression of AIS. Susceptibility loci in SOX9, MATN1, AJAP1, MMP9, and TIMP2, which are related to cartilage and extracellular matrix, are also potentially related to AIS progression. Enzymes and cytokines play essential roles in regulating bone metabolism and embryonic development. SNPs in BNC2, SLC39A8, TGFB1, IL-6, IL-17RC, and CHD7 were suggested as predictive loci for AIS curve progression.Many promising SNPs have been identified to predict the curve progression of AIS. However, conflicting results from replication studies and different ethnic groups hamper their reliability. Convincing SNPs from multiethnic populations and functional verification are needed.

Colorectal cancer (CRC) is among the most prevalent cancers. Long non-coding RNAs (lncRNAs) are important participant in various cancers. Based on the literature, lncRNA RASSF8-AS1 inhibits laryngeal squamous cell carcinoma (LSCC) malignant progression. However, the role of RASSF8-AS1 in CRC remains unclear.This study centered on uncovering the role of RASSF8-AS1 and its related regulatory mechanisms in CRC cells.RT-qPCR and western blot were performed to examine the expression of target genes. Functional assays were conducted to determine the effect of target genes on the migration and invasion of CRC cells. Mechanism assays were also carried out to figure out the specific downstream mechanisms of RASSF8-AS1. In vivo assays were also involved.The expression of RASSF8-AS1 and RASSF8 was positively correlated in CRC, and the two genes were down-regulated in CRC cells and tissues. Moreover, CRC cell invasion and migration as well as xenograft CRC tumor growth suppressed by RASSF8-AS1 overexpression were entirely recovered by RASSF8 knockdown or partially rescued by miR-33a-5p augment. As for the downstream mechanism, RASSF8-AS1 sponged miR-33a-5p to up-regulate RASSF8, or recruited HNRNPC to stabilize RASSF8 mRNA.RASSF8-AS1 modulates miR-33a-5p/HNRNPC/RASSF8 axis to further impede CRC cell invasion and migration.The research data is confidential.

The purpose of this study was to evaluate computed tomography (CT) doses in child examinees at different ages throughout the Shanghai metropolitan area. The head and body CT dose indices (CTDIs) of 50 CT scanners were tested by phantom measurements using standard imaging protocols. The values of CTDIw, CTDIvol and dose length product (DLP) were calculated and saved in a table along with the parameters of routine head and chest scans for different age groups of children and adults. The effective doses were estimated from the K-factors by age and DLP. The CTDIvol, DLP and effective dose for multi-detector row CT (MDCT) in children during routine head scans were larger than those for single-detector row CT (SDCT) and dual-detector row CT (DDCT). The CTDIvol, DLP and effective dose for MDCT and DDCT in children during routine chest scans were lower than those for SDCT. Radiation risks are higher for children in CT examinations compared to adults.

Background: Cervical Spondylotic radiculopathy (CSR) is the most common spinal degenerative disease. Its clinical manifestations are pain and numbness in the neck and arm and limitation of neck movement, which greatly affects the life and work of patients. Acupuncture and electroacupuncture are commonly used in China, the efficacy of acupuncture has been confirmed. Existing evidence shows that electroacupuncture seems to be better than acupuncture, but there is a lack of clinical research to directly compare the two. Methods: This is a prospective randomized controlled trial to compare the efficacy of electroacupuncture and acupuncture in the treatment of CSR and to explore the safety and potential mechanism of electroacupuncture in the treatment of CSR. Approved by the Clinical Research Ethics Committee of our hospital, the patients are randomly divided into an experimental group (electroacupuncture group) or control group (acupuncture group). The patients are followed up for 30 days after 4 weeks of treatment. Observation indexes included VAS score, Neck Disability Index, Yasuhisa Tanaka 20 Score Scale, adverse reactions and so on. Finally, the data will be analyzed by SPSS 18.0 software. Discussion: This study will directly compare the advantages and disadvantages of electroacupuncture and acupuncture in the treatment of CSR. The results of this study will help to guide patients with CSR to choose appropriate treatment. Trial registration: OSF Registration number: DOI 10.17605/OSF.IO/9MKPN

The aim of the study was to determine if multiple intraspinal anomalies increase the risk of scoliosis correction compared to the normal intraspinal condition or 1 or 2 intraspinal anomalies in congenital scoliosis (CS) and whether correction for multiple intraspinal anomalies need to be performed with preliminary neurosurgical intervention before scoliosis correction. A total of 318 consecutive CS patients who underwent corrective surgery without preliminary neurosurgical intervention at a single institution from 2008 to 2016 were retrospectively reviewed, with a minimum of 2 years of follow-up. The patients were divided into 3 groups according to different intraspinal conditions. In the normal group (N group; n = 196), patients did not have intraspinal anomalies. In the abnormal group (A group; n = 93), patients had 1 or 2 intraspinal anomalies. In the multiple anomaly group (M group; n = 29), patients had 3 or more intraspinal anomalies including syringomyelia, split cord malformation [SCM], tethered cord, low conus, intraspinal mass, Chiari malformation or/and arachnoid cyst. The occurrence of complications as well as perioperative and radiographic data were analyzed. The incidence rate of multiple intraspinal anomalies in CS patients was 9.1% (29/318). No significant difference was observed in the perioperative outcomes or radiographic parameters at the final follow-up. There were no significant differences among the 3 groups in the total, major or neurological complication rates (all P > .05). Two patients (1 in the N group and 1 in the A group) experienced transient neurological complications, whereas no patient experienced permanent neurological deficits during surgery or follow-up. To our knowledge, the current study reported the largest cohort of intraspinal anomalies in patients with CS that has been reported in the literature. The results of our study demonstrated that patients with congenital scoliosis associated with intraspinal anomalies, even multiple intraspinal anomalies that coexist with more complex intraspinal pathologies, may safely and effectively achieve scoliosis correction without preliminary neurological intervention. More complex intraspinal pathologies do not seem to increase the risk of neurosurgical complications during corrective surgery.

Purpose To evaluate the relationship between the DNA mismatch repair (MMR) status and histone lysine‐specific demethylase 6A (KDM6A) on the prognosis of colorectal cancer (CRC). Methods About 594 patients with CRC from The Cancer Genome Atlas (TCGA) were enrolled in this retrospective study. Subsequently, a series of different classification tests for MMR status, cancer types, and target gene expression was conducted. Results After filtering out the KDMs group of genes, we selected KDM6A as the target gene. A significant difference in the performance of KDM6A in tumor and normal tissues were confirmed. Our results showed a lower KDM6A expression, lower KDM6A exon expression, and higher KDM6A DNA methylation than their corresponding normal tissues in colon adenocarcinoma (COAD). Notably, the main MMR genes were highly expressed in tumor tissues than normal tissues both in COAD and rectum adenocarcinoma (READ). Moreover, proficient DNA mismatch repair (pMMR) was found to be an important poor prognostic factor in COAD (p = 0.0064) and the low KDM6A expression was an important factor for poor prognosis in READ (p = 0.0217). Based on these results, we consequently relate MMR status with KDM6A expression in predicting the prognosis of patients with CRC. Moreover, patients with pMMR exhibited a low KDM6A expression in COAD (p = 0.0250). Samples were divided into two groups based on the KDM6A expression. Interestingly, the group with low KDM6A expression showed no difference between pMMR and deficient DNA mismatch repair (dMMR) in prognosis, whereas the group with high KDM6A expression was closely related to MMR status in OS (p = 0.0082). Besides, COAD patients with high KDM6A expression and pMMR status had poor OS (p = 0.0082). Conclusions The KDM6A/MMR classification‐based subtypes of low KDM6A expression/READ, high KDM6A expression/pMMR, and COAD/pMMR were associated with poor prognosis. This classification can be a novel prognostic approach in CRC., The KDM6A/MMR classification based subtypes of low KDM6A expression/READ, high KDM6A expression/pMMR, and COAD/pMMR were associated with poor prognosis. This classification could more accurately stratify CRC patients as per the prognostic performance.

Ferroptosis, a novel form of programmed cell death, is characterized by iron-dependent lipid peroxidation and has been shown to be involved in multiple diseases, including cancer. Stimulating ferroptosis in cancer cells may be a potential strategy for cancer therapy. Therefore, ferroptosis-inducing drugs are attracting more attention for cancer treatment. Here, we showed that erianin, a natural product isolated from Dendrobium chrysotoxum Lindl, exerted its anticancer activity by inducing cell death and inhibiting cell migration in lung cancer cells. Subsequently, we demonstrated for the first time that erianin induced ferroptotic cell death in lung cancer cells, which was accompanied by ROS accumulation, lipid peroxidation, and GSH depletion. The ferroptosis inhibitors Fer-1 and Lip-1 but not Z-VAD-FMK, CQ, or necrostatin-1 rescued erianin-induced cell death, indicating that ferroptosis contributed to erianin-induced cell death. Furthermore, we demonstrated that Ca2+/CaM signaling was a critical mediator of erianin-induced ferroptosis and that blockade of this signaling significantly rescued cell death induced by erianin treatment by suppressing ferroptosis. Taken together, our data suggest that the natural product erianin exerts its anticancer effects by inducing Ca2+/CaM-dependent ferroptosis and inhibiting cell migration, and erianin will hopefully serve as a prospective compound for lung cancer treatment.

Background Previous studies have reported that rod composition and diameter, as well as the correction technique are key factors associated with thoracic kyphosis (TK) restoration. However, few study has analyzed the correlation between screw density and TK restoration in hypokyphotic adolescent idiopathic scoliosis (AIS). Methods Fifty-seven thoracic AIS patients with preoperative TK

Objective A meta-analysis was performed to compare incidence rates of radiographic and surgical proximal junctional kyphosis (PJK) between upper thoracic (UT) and lower thoracic (LT) vertebrae as site of upper instrumented vertebrae (UIV) endpoints for long fusion surgery in adult spinal deformity (ASD). Methods MEDLINE, Embase, and Cochrane Library databases were searched for English-language articles that addressed UT versus LT fixation strategies. The division of the UT and LT groups was based on UIV. Two reviewers independently assessed the quality of the studies using the Newcastle-Ottawa Scale. Data on incidence rates of radiographic and surgical PJK were extracted from the included studies. RevMan 5.3 was used for data pooling and analysis. Results Ten retrospective studies comprising 1230 patients were included. Pooled data on radiographic PJK were available in 9 studies comprising 1032 patients, and total radiographic PJK rate was 32.2%. Pooled data on surgical PJK were available in 6 studies comprising 732 patients, and total surgical PJK rate was 6.7%. Decreased radiographic PJK (95% confidence interval, 0.49–0.85; P = 0.002; I 2 = 48%) and surgical PJK (95% confidence interval, 0.18–0.76; P = 0.007; I 2 = 22%) were found in the UT group. Conclusions Radiographic PJK is a very common complication of long fusion surgery in adult spinal deformity with an incidence rate of 32.2%. Surgical PJK has an incidence rate of 6.7% and should be seriously considered. The pooled results indicate that choosing UT vertebrae as the site of UIV could decrease the incidence rates of radiographic and surgical PJK.

Objective To compare perioperative, radiographic, and Scoliosis Research Society-22 (SRS-22) outcomes of consecutive, interval, and skipped pedicle screw techniques in patients with moderate Lenke type 1 adolescent idiopathic scoliosis (AIS). Methods We retrospectively reviewed 65 consecutive moderate Lenke type 1 AIS patients at a single institution using all-pedicle screw constructs, with a minimum of 2 years of follow-up. In the consecutive group (C group, n = 22), pedicle screws were instrumented at consecutive levels bilaterally. In the interval group (I group, n = 18), pedicle screws were placed at every level on the concave side while skipping levels on the convex side. In the skipped group (S group, n = 25), pedicle screws were instrumented by skipping levels bilaterally. Perioperative, radiographic, and SRS-22 measurements were analyzed with a 1-way analysis of variance. Results No significant differences were found in length of hospital stay, fused levels, coronal correction, and SRS-22 scores among the 3 groups. Increased surgery time was found in the C group compared with the I and S groups ( P = 0.001 and P = 0.005, respectively). Decreased blood loss and blood transfusions were found in the S group compared with the C group ( P = 0.04 and P = 0.047, respectively). Decreased implant costs were found in the S group compared with the C and I groups ( P P = 0.03, respectively). Conclusions Consecutive, interval, and skipped pedicle screw techniques all provide satisfactory deformity correction and SRS-22 outcomes with few complications. With better perioperative outcomes, interval and skipped pedicle screw techniques are the more cost-effective options for patients with moderate Lenke type 1 AIS.

Objective: This study aimed to develop a new polyethylene glycol (PEG)ylated β-elemene liposome (PEG-Lipo-β-E) and evaluate its characterization, pharmacokinetics, antitumor effects and safety in vitro and in vivo. Methods: The liposomes were prepared by ethanol injection and high-pressure micro-jet homogenization. Characterization of the liposomes was conducted, and drug content, entrapment efficiency (EE), in vitro release and stability were studied by ultra-fast liquid chromatography (UFLC) and a liquid surface method. Blood was drawn from rats to establish the pharmacokinetic parameters. The anticancer effect was evaluated in a KU-19-19 bladder cancer xenograft model. Histological analyses were performed to evaluate safety. Results: The PEG-Lipo-β-E showed good stability and was characterized as 83.31 ± 0.181 nm in size, 0.279 ± 0.004 in polydispersity index (PDI), −21.4 ± 1.06 mV in zeta potential, 6.65 ± 0.02 in pH, 5.024 ± 0.107 mg/mL in β-elemene (β-E) content, and 95.53 ± 1.712% in average EE. The Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) indicated the formation of PEG-Lipo-β-E. Compared to elemene injection, PEG-Lipo-β-E demonstrated a 1.75-fold decrease in clearance, a 1.62-fold increase in half-life, and a 1.76-fold increase in area under the concentration-time curves (AUCs) from 0 hour to 1.5 hours (P < 0.05). PEG-Lipo-β-E also showed an enhanced anticancer effect in vivo. Histological analyses showed that there was no evidence of toxicity to the heart, kidney, liver, lung or spleen. Conclusions: The present study demonstrates PEG-Lipo-β-E as a new formulation with ease of preparation, high EE, good stability, improved bioavailability and antitumor effects.

Objective To compare bony spur resection (BR) with bony spur nonresection (BN) treatment in patients with congenital scoliosis and type I split cord malformation. Methods Patients with congenital scoliosis and type I split cord malformation who underwent corrective surgery in a single institution from 2008 to 2015 were retrospectively evaluated. Patients were divided into 2 groups according to whether BR was performed or not: the BR group included 12 patients, and the BN group included 20 patients. Complications and perioperative and radiographic data were recorded and compared. Results The study included 32 patients. Mean age at surgery was 14.3 years, and average follow-up period was 2.8 years. There were no statistically significant differences in correction rate of the major curve or other radiographic parameters at final follow-up. Preoperative concerns (6.8 vs. 5.8, P = 0.006), operative times (508.5 minutes vs. 311.3 minutes, P = 0.009), blood loss (1433.3 mL vs. 1015.8 mL, P = 0.064), and hospital charges ($22,387.80 vs. $15,706.8, P = 0.032) were lower in the BN group than in the BR group. Total and major complication rates were higher in the BR group than in the BN group, even though there were no statistically significant differences (58.3% vs. 30.0% and 8.3% vs. 5.0%, respectively). Conclusions In patients with congenital scoliosis and type I split cord malformation, not resecting the bony spur can achieve satisfactory radiographic and clinical outcomes with potentially fewer complications.

The purpose of this study is to assess the present situation about the overal performance quality of CT scanners from Second Level 2nd Class hospitals and private hospitals in Shanghai. The test and evaluation methods refer to Specification for Quality Assurance Test for Computed Tomography X-ray Scanners (GB 17589—2011). A total of 62 CT scanners from 59 hospitals were tested. The mean value of high-contrast resolution was 6.8 lp/cm, low contrast detectability was 2.4, CT number of water was 3.0 HU, noise was 0.43% and uniformity was 2.3 HU. In quality control tests, 20 of 62 CT scanners were qualified, and the percent of pass was only 32%. The equipment aging and lack of preventive maintenance were main reasons for performance degradation of CT scanners.

To explore the prevalence and distribution of abnormal vertebral pedicles in scoliosis secondary to neurofibromatosis type 1 (NF1-S) and to compare the abnormal vertebrae pedicles between dystrophic and nondystrophic scoliosis.Using computed tomography images, we carefully measured 2652 vertebral pedicles from 56 patients with NF1-S with dystrophic scoliosis and 22 patients with NF1-S with nondystrophic scoliosis. Pedicle morphology was classified as follows: type A, a cancellous channel of4 mm; type B, a cancellous channel of 2 to 4 mm; type C, a cancellous channel of2 mm with an entirely cortical channel of ≥2 mm; type D, a cortical channel of2 mm; or type E, absent pedicle. Types B, C, D, and E were defined as abnormal.The total prevalence of abnormal vertebral pedicles in patients with NF1-S was as high as 67%, with type B comprising 39%, type C comprising 22%, type D comprising 4%, and type E comprising 2%. A significantly greater rate of abnormal pedicles was found in dystrophic scoliosis compared with nondystrophic scoliosis (70% vs. 59%, P0.0001). The upper thoracic spine (87%) is the most concentrated region of abnormal pedicles compared with the lower thoracic (73%) and lumbar spine (34%).There is a significantly high prevalence of abnormal pedicles in patients with NF1-S and an increased rate of abnormal pedicles in dystrophic scoliosis compared with nondystrophic ones. The described pedicle classification system could serve as an objective tool to guide preoperative assessment.

Background The correlation between implant density and deformity correction has not yet led to a precise conclusion in adolescent idiopathic scoliosis (AIS). The aim of this study was to evaluate the effects of low density (LD) and high density (HD) pedicle screw instrumentation in terms of the clinical, radiological and Scoliosis Research Society (SRS)-22 outcomes in Lenke 1 AIS. Methods We retrospectively reviewed 62 consecutive Lenke 1 AIS patients who underwent posterior spinal arthrodesis using all-pedicle screw instrumentation with a minimum follow-up of 24 months. The implant density was defined as the number of screws per spinal level fused. Patients were then divided into two groups according to the average implant density for the entire study. The LD group (n = 28) had fewer than 1.61 screws per level, while the HD group (n = 34) had more than 1.61 screws per level. The radiographs were analysed preoperatively, postoperatively and at final follow-up. The perioperative and SRS-22 outcomes were also assessed. Independent sample t tests were used between the two groups. Results Comparisons between the two groups showed no significant differences in the correction of the main thoracic curve and thoracic kyphosis, blood transfusion, hospital stay, and SRS-22 scores. Compared with the HD group, there was a decreased operating time (278.4 vs. 331.0 min, p = 0.004) and decreased blood loss (823.6 vs. 1010.9 ml, p = 0.048), pedicle screws needed (15.1 vs. 19.6, p

Background Radiological outcomes between anterior and posterior approach in Lenke 5C curves were still controversial. Meta-analysis on published articles to compare fusion segments and radiological outcomes between the two surgical approaches was performed. Methods Electronic database was conducted for searching studies concerning the anterior versus posterior approach in Lenke 5C curves. After quality assessment, data of means, standard deviations, and sample sizes were extracted. RevMan 5.3 was adopted for data analysis. Results Seven case-control studies involving 308 Lenke 5C AIS patients were identified in the meta-analysis. No significant differences were noted in correction rate of thoracolumbar/lumbar curve (95 % CI −6.02 to 4.32, P = 0.75) and incidence of proximal junctional kyphosis (95 % CI 0.12 to 7.19, P = 0.94) of final follow-up, in change values of thoracolumbar/lumbar curve (95 % CI −3.28 to 7.19, P = 0.46) and thoracic kyphosis (95 % CI −4.10 to 0.13, P = 0.07). The anterior approach represented a significant shorter fusion segments compared to posterior approach (95 % CI −1.72 to −0.71, P

To investigate the reconstruction of thumb II-III degree defect by big toe wrap-around flap combined with second toe proximal interphalangeal joint.Between May 2004 to July 2012, 25 cases with thumbs II-III degree defects were treated. The ipsilateral big toe wrap-around flap combined with second toe proximal interphalangeal joint was designed to reconstruct the thumb defects based on the thumb size on the healthy side. The distal end of hallux was covered by flap at tibial side. The wound at the fibula side was covered by skin graft and flap. The bone defect at the second toe was filled with remnant hallux or iliac bone.All the 25 reconstructed thumbs survived completely. The patients were followed up for 6-26 months without any joint degeneration. According to the finger reconstruction functional criterion publicized by China Medical Association, the finger function was assessed as excellent in 10 case, good in 11 cases, poor in 4 cases. Joint necrosis happened in 2 cases and bone malunion in 2 cases. The 4 cases received dead bone debridement and iliac bone graft. No malfunction occurred in the donor site.Our surgical method is a currently effective way to reconstruct II-III degree thumb defects. Satisfactory functional and cosmetic results can be achieved both in donor site and recipient site.

To explore the effectiveness of the free anastomosis cutaneous nerve double arterialized venous flap graft in repairing finger defect.Between May 2010 and May 2013, 39 patients with finger defect were treated. There were 27 males and 12 females with an average age of 31 years (range, 17-45 years). The injury to admission time was 30-90 minutes (mean, 60 minutes). The causes included mechanical injury in 23 cases, crush injury in 11 cases, and other injury in 5 cases. The thumb was involved in 13 cases, the index finger in 11 cases, the middle finger in 9 cases, the ring finger in 4 cases, and the little finger in 2 cases. Skin soft tissue defect ranged from 2 cm x 1 cm to 4 cm x 2 cm. Of them, 22 cases had tendon injury, 17 cases had tendon and phalanx injuries. The size of free anastomosis cutaneous nerve double arterialized venous flap ranged from 2.5 cm x 1.5 cm to 4.5 cm x 2.5 cm. The donor site was directly sutured.Tension blister and swelling were observed at distal flap in 5 cases at 3-5 days after operation and were cured after symptomatic treatment; the other 34 flaps survived, and wound healed by first intention. Primary healing at donor site was obtained. The patients were followed up 6-12 months (mean, 9 months). The flap appearance and texture were good with two-point discrimination of 6-9 mm (mean, 7.5 mm). According to the upper extremity function evaluation criteria issued by the Hand Surgery Society of Chinese Medical Association, the results were excellent in 35 cases and good in 4 cases.The free anastomosis cutaneous nerve double arterial ized venous flap not only can ensure the flap blood supply, but also can obviously improve the sensory function of the flap, which greatly reduces the risk of postoperative flap atrophy, and can achieved satisfactory effectiveness.

Vasoactive intestinal peptide (VIP) released from some neurons and T cells affects T cell migration, cytokine generation, and other functions by binding to constitutively expressed type 1 G protein-coupled receptor (VPAC1) or activation-induced type 2 G protein-coupled receptor (VPAC2). Recently, a short-deletion (SD) splice variant of mouse VPAC2 that lacks 14 amino acids at the end of the last transmembrane domain has been identified in T cells and shown to resemble wild-type (WT) VPAC2 in affinity of VIP binding but to differ by lack of signaling of T cell adenylyl cyclase, migration, and IL-2 secretion. As Th2 cells are the principal source of immune VIP and have the greatest functional responses to VIP, the differences in signals transduced by WT and SD VPAC2 were studied in VPAC2–low D10G4.1 model Th2 cell transfectants individually expressing the respective types of VPAC2 equally. WT and SD VPAC2 Th2 cell transfectants secreted equal amounts of VIP. WT VPAC2 transfectants generated more IL-4 than did SD VPAC2 transfectants, and this increment was dependent on endogenous VIP. Exogenous VIP further increased IL-4 production by WT VPAC2 transfectants but decreased IL-4 production by SD VPAC2 transfectants. Cotransfection of the two constructs diminished VIP enhancement of IL-4 production seen with WT VPAC2 alone by preventing increases in nuclear levels of the requisite transcription factors c-Maf and Jun B. Thus the ratio of two forms of T cell VPAC2 determines the net effect of VIP on IL-4 generation by activated Th2 cells.

The vasoactive intestinal peptide (VIP) and its G protein-coupled receptors VPAC1 and VPAC2 prominently mediate diverse physiological functions in the neural, endocrine, and immune systems. A deletion variant of mouse VPAC2 has been identified in immune cells that lacks amino acids 367-380 at the carboxyl-terminal end of the seventh transmembrane domain. When expressed at equivalent levels in a human Jurkat T cell line, which has very low endogenous expression of human VPAC1 and VPAC2, wild-type and deletion-variant VPAC2 bound the same amount of 125I-VIP with similar affinity. Unlike wild-type VPAC2, however, deletion-variant VPAC2 did not transduce VIP-elicited increases in intracellular concentration of cyclic AMP, chemotaxis, or suppression of generation of interleukin-2. Natural deletion of part of the last transmembrane domain of VPAC2 thus abrogates signaling functions without apparent alterations of expression or ligand binding.

The aim of this study was to assess the effect of naringenin on osteoclastogenesis and titanium particle-induced osteolysis. Osteolysis from wear-induced particles and aseptic loosening are the most frequent late complications of total joint arthroplasty leading to revision of the prosthesis. Osteolysis during aseptic loosening is most likely due to increased bone resorption by osteoclasts. Through in vitro studies, we demonstrated that naringenin, a naturally occurring flavanone in grapefruit and tomatoes, exerts potent inhibitory effects on the ligand of the receptor activator of nuclear factor-κB (RANKL)-induced osteoclastogenesis and revealed that the mechanism of action of naringenin, which inhibited osteoclastogenesis by suppression of the p38 signaling pathway. Through in vivo studies, we proved that naringenin attenuated titanium particle-induced osteolysis in a mouse calvarial model. In general, we demonstrated that naringenin inhibited osteoclastogenesis via suppression of p38 signaling in vitro and attenuated titanium particle-induced osteolysis in vivo. This study also suggested that naringenin has significant potential for the treatment of osteolysis-related diseases caused by excessive osteoclast formation and activity.

The medullary raphé contains two subtypes of chemosensitive neuron: one that is stimulated by acidosis and another that is inhibited. Both types of neuron are putative chemoreceptors, proposed to act in opposite ways to modulate respiratory output and other pH sensitive brain functions. In this review, we will discuss the cellular properties of these chemosensitive raphé neurons when studied in vitro using brain slices and primary dissociated cell culture. Quantification of chemosensitivity of raphé neurons indicates that they are highly sensitive to small changes in extracellular pH (pH(o)) between 7.2 and 7.6. Stimulation by acidosis occurs only in the specific phenotypic subset of neurons within the raphé that are serotonergic. These serotonergic neurons also have other properties consistent with a specialized role in chemoreception. Homologous serotonergic neurons are present within the ventrolateral medulla (VLM), and may have contributed to localization of respiratory chemoreception to that region. Chemosensitivity of raphé neurons increases in the postnatal period in rats, in parallel with development of respiratory chemoreception in vivo. An abnormality of serotonergic neurons of the ventral medulla has been identified in victims of sudden infant death syndrome (SIDS). The cellular properties of serotonergic raphé neurons suggest that they play a role in the CNS response to hypercapnia, and that they may contribute to interactions between the sleep/wake cycle and respiratory control.

This meta-analysis evaluated preoperative aspiration culture for diagnosing prosthetic joint infection (PJI) in total hip arthroplasty (THA) and total knee arthroplasty (TKA). The pooled sensitivity and specificity were 0.72 (95% confidence interval, 0.65 to 0.78) and 0.95 (0.93 to 0.97), respectively. Subgroup analyses revealed nonsignificant worse diagnostic performance for THA than for TKA (sensitivity, 0.70 versus 0.78; specificity, 0.94 versus 0.96). Preoperative aspiration culture has moderate to high sensitivity and very high specificity for diagnosing PJI.

Purpose: We have shown previously that the 88 kDa glycoprotein PC cell–derived growth factor (PCDGF/GP88) is expressed and acts as an autocrine growth factor in human multiple myeloma cells. The present study investigates whether PCDGF/GP88 expression in multiple myeloma cells leads to the development of resistance to dexamethasone, a conventional drug for multiple myeloma patients. Experimental Design: PCDGF functions and signaling pathways in dexamethasone-induced apoptosis were studied using a representative dexamethasone-sensitive multiple myeloma cell line ARP-1. The effect of PCDGF/GP88 was further confirmed in PCDGF/GP88–overexpressed ARP-1 cells. Results: Dexamethasone inhibits cell growth and induces apoptosis in a time- and dose-dependent fashion. Exogenous addition of PCDGF/GP88 to the ARP-1 cells prevented dexamethasone-induced apoptosis as examined by flow cytometry analysis and poly(ADP-ribose)polymerase cleavage assay. Signaling studies showed that mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and nuclear factor-κB were involved in the antiapoptotic effect of PCDGF/GP88. Overexpression of PCDGF/GP88 in ARP-1 cells rendered the cells refractory to dexamethasone-mediated apoptosis, enhanced their ability to form colonies in soft agar, and to form tumors in vivo without any change in glucocorticoid receptor expression and function. Conclusion: These data suggest that expression of PCDGF/GP88 confers resistance to dexamethasone and increase tumorigenesis of multiple myeloma cells in mouse xenografts. Our data here also raises the possibility of PCDGF/GP88 as a potential therapeutic target for dexamethasone-resistant multiple myeloma.

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are distinctive mediators of immune cellular proliferation, survival and functions, which are present at highly active concentrations in blood, lymph, and tissue corridors of lymphocyte traffic [Moolenaar et al., 1997; Spiegel et al., 1998]. In the immune system, dendritic cells, macrophages, mast cells, and platelets are the principal sources of LPA and S1P. Each type of immune cell expresses a characteristic profile of one or more of the nine Edg-family G protein-coupled receptors (GPCRs) selective for either S1P or LPA, which is controlled developmentally and by diverse stimuli (Table I) [Goetzl et al., 2000; Chun et al., 2002]. S1P and, often less effectively, LPA are chemotactic for many types of immune cells, including T-cells, B-cells, dendritic cells, and NK cells at their normal ambient tissue levels of 3–300 nM [Zheng et al., 2000, 2001; Graeler et al., 2002; Idzko et al., 2002; Kveberg et al., 2002]. At blood and lymph concentrations of over 0.3–3 μM, however, S1P but not LPA nearly completely inhibits lymphocyte migration to chemokines and other stimuli, and suppresses less profoundly lymphocyte proliferation and secretion of some cytokines [Graeler et al., 2002; Dorsam et al., 2003]. That expression of LPA and S1P GPCRs in thymus is restricted to the last phases of development indicates possible roles in terminal differentiation and emigration of CD4 and CD8 T-cells, which remain to be elucidated definitively. As there are numerous and often redundant stimuli of T-cell migration and distinct immunological functions, but fewer specific suppressive influences, the immunoregulatory activities of S1P and its GPCRs are the principal focus of current interest. The potential importance of these immunoregulatory effects is emphasized by their magnitude and involvement in development, tissue distribution, and activities of lymphocytes. Some of the recent excitement in this field is also attributable to the strong possibility of discovering unique classes of immunoactive drugs that target S1P GPCRs. Newly established mouse genetic models of altered expression of T-cell S1P GPCRs and novel functional anti-S1P R monoclonal antibodies now have provided systems and reagents for analyzing further the separate immune contributions of each of the predominant T-cell S1P GPCRs. The results of such studies also may permit accurate predictions of the immune effects of individual S1P GPCR-selective agonists and antagonists. TABLE I Immune Cell Expression of mRNAs Encoding LPA and S1P GPCRs*

Multiple myeloma (MM) is a clonal B-cell neoplasm. PC cell-derived growth factor (PCDGF) is a M(r) 88,000 glycoprotein growth factor. Our objective was to investigate the expression, function, and signaling pathways of PCDGF in human MM.PCDGF expression, function, and signaling pathways in human MM were studies using two human MM cell lines: ARP-1 and RPMI 8226. In addition, PCDGF expression in MM patients was examined using 13 human bone marrow biopsy samples.PCDGF mRNA and protein expression was detected in human MM cell lines such as ARP-1 and RPMI 8226. PCDGF added exogenously stimulated cell growth and sustained cell survival of both ARP-1 and RPMI 8226 cells in a dose- and time-dependent fashion. Conversely, treatment with neutralizing anti-PCDGF antibody inhibited the growth of RPMI 8226 cells suggesting that PCDGF acts as an autocrine growth factor for MM cells. Studies of signal transduction pathways showed PCDGF stimulated mitogen-activated protein kinase and phosphatidylinositol 3'-kinase pathways but not the Janus-activated kinase-signal transducer and activator of transcription pathway. Immunohistochemical analysis of bone marrow smears obtained from MM patients indicated that PCDGF expression was associated with myeloma cells from MM patients and correlated with the presence of MM disease.These data suggest that PCDGF is an autocrine growth factor in the cell growth and survival of human MM cells, and may be a potential candidate as a biomarker of MM cells.