Comparison of the Japanese Orthopaedic Association (JOA) Score and Modified JOA (mJOA) Score for the Assessment of Cervical Myelopathy: A Multicenter Observational Study

Objectives

The Japanese Orthopaedic Association (JOA) score is widely used to assess the severity of clinical symptoms in patients with cervical compressive myelopathy, particularly in East Asian countries. In contrast, modified versions of the JOA score are currently accepted as the standard tool for assessment in Western countries. The objective of the present study is to compare these scales and clarify their differences and interchangeability and verify their validity by comparing them to other outcome measures.

Materials and Methods

Five institutions participated in this prospective multicenter observational study. The JOA and modified JOA (mJOA) proposed by Benzel were recorded preoperatively and at three months postoperatively in patients with cervical compressive myelopathy who underwent decompression surgery. Patient reported outcome (PRO) measures, including Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ), the Short Form-12 (SF-12) and the Neck Disability Index (NDI), were also recorded. The preoperative JOA score and mJOA score were compared to each other and the PRO values. A Bland-Altman analysis was performed to investigate their limits of agreement.

Results

A total of ninety-two patients were included. The correlation coefficient (Spearman’s rho) between the JOA and mJOA was 0.87. In contrast, the correlations between JOA/mJOA and the other PRO values were moderate (|rho| = 0.03 – 0.51). The correlation coefficient of the recovery rate between the JOA and mJOA was 0.75. The Bland-Altman analyses showed that limits of agreement were 3.6 to -1.2 for the total score, and 55.1% to -68.8% for the recovery rates.

Conclusions

In the present study, the JOA score and the mJOA score showed good correlation with each other in terms of their total scores and recovery rates. Previous studies using the JOA can be interpreted based on the mJOA; however it is not ideal to use them interchangeably. The validity of both scores was demonstrated by comparing these values to the PRO values.     

Sleep Deprivation Is Associated with Bicycle Accidents and Slip and Fall Injuries in Korean Adolescents

Objective

This study sought to evaluate associations between sleep time and bicycle accidents, falls under various circumstances, and dental injuries in adolescents.

Methods

A total of 61,696 participants ranging from 12 to 18 years of age who completed the Korea Youth Risk Behavior Web-based Survey (KYRBWS) in 2013 were enrolled in this study. Bicycle riding accidents were analyzed for 17,232 bicycle-riding participants. Data were collected regarding the weekday sleep duration for the most recent 7 days, which was categorized as < 5.5 h, 5.5–6.5 h, 6.5–7.5 h, or ≥ 7.5 h per day, and the incidence of bicycle accidents, slips and falls under various circumstances, and dental injuries in the most recent 12 months. Adjusted odds ratios (aORs) were calculated among sleep groups for bicycle accidents, slips and falls, and dental injuries using simple and multiple logistic regression analyses with complex sampling.

Results

Bicycle riding accidents and slips and falls in classrooms, corridors, the ground, toilets, stairs, and other unspecified situations showed positive correlations with sleep deprivation. Comparisons of groups with ≥ 7.5 h sleep, < 5.5 h, 5.5–6.5 h sleep, and 6.5–7.5 h sleep revealed increased associations with slips and falls under various circumstances. In particular, the aORs were higher in the groups with less sleep (aOR of the 5.5 h group > the 5.5–6.5 h group > the 6.5–7.5 h group). There was no significant relationship between sleep deprivation and dental injury.

Conclusions

This study demonstrated that sleep deprivation among Korean adolescents was associated with bicycle accidents and falls at home and school. Thus, adequate sleep may be needed to prevent accidents and falls.     

The Role of ARF6 in Biliary Atresia

Background & Aims

Altered extrahepatic bile ducts, gut, and cardiovascular anomalies constitute the variable phenotype of biliary atresia (BA).

Methods

To identify potential susceptibility loci, Caucasian children, normal (controls) and with BA (cases) at two US centers were compared at >550000 SNP loci. Systems biology analysis was carried out on the data. In order to validate a key gene identified in the analysis, biliary morphogenesis was evaluated in 2-5-day post-fertilization zebrafish embryos after morpholino-antisense oligonucleotide knockdown of the candidate gene ADP ribosylation factor-6 (ARF6, Mo-arf6).

Results

Among 39 and 24 cases at centers 1 and 2, respectively, and 1907 controls, which clustered together on principal component analysis, the SNPs rs3126184 and rs10140366 in a 3’ flanking enhancer region for ARF6 demonstrated higher minor allele frequencies (MAF) in each cohort, and 63 combined cases, compared with controls (0.286 vs. 0.131, P = 5.94x10^-7, OR 2.66; 0.286 vs. 0.13, P = 5.57x10^-7, OR 2.66). Significance was enhanced in 77 total cases, which included 14 additional BA genotyped at rs3126184 only (p = 1.58x10^-2, OR = 2.66). Pathway analysis of the 1000 top-ranked SNPs in CHP cases revealed enrichment of genes for EGF regulators (p<1 x10^-7), ERK/MAPK and CREB canonical pathways (p<1 x10^-34), and functional networks for cellular development and proliferation (p<1 x10^-45), further supporting the role of EGFR-ARF6 signaling in BA. In zebrafish embryos, Mo-arf6 injection resulted in a sparse intrahepatic biliary network, several biliary epithelial cell defects, and poor bile excretion to the gall bladder compared with uninjected embryos. Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with Mo-arf6 at lower doses of each agent and rescued with arf6 mRNA.

Conclusions

The BA-associated SNPs identify a chromosome 14q21.3 susceptibility locus encompassing the ARF6 gene. arf6 knockdown in zebrafish implicates early biliary dysgenesis as a basis for BA, and also suggests a role for EGFR signaling in BA pathogenesis.     

Optimal Route for Human Umbilical Cord Blood-Derived Mesenchymal Stem Cell Transplantation to Protect Against Neonatal Hyperoxic Lung Injury: Gene Expression Profiles and Histopathology

The aim of this study was to determine the optimal route of mesenchymal stem cell (MSC) transplantation. To this end, gene expression profiling was performed to compare the effects of intratracheal (IT) versus intravenous (IV) MSC administration. Furthermore, the therapeutic efficacy of each route to protect against neonatal hyperoxic lung injury was also determined. Newborn Sprague-Dawley rats were exposed to hyperoxia (90% oxygen) from birth for 14 days. Human umbilical cord blood-derived MSCs labeling with PKH26 were transplanted through either the IT (5×10⁵) or IV (2×10⁶) route at postnatal day (P) 5. At P14, lungs were harvested for histological, biochemical and microarray analyses. Hyperoxic conditions induced an increase in the mean linear intercept and mean alveolar volume (MAV), indicative of impaired alveolarization. The number of ED-1 positive cells was significantly decreased by both IT and IV transplantations. However, IT administration of MSCs resulted in a greater decrease in MAV and ED-1 positive cells compared to IV administration. Moreover, the number of TUNEL-positive cells was significantly decreased in the IT group, but not in the IV group. Although the IT group received only one fourth of the number of MSCs that the IV group did, a significantly higher number of donor cell-derived red PKH 26 positivity were recovered in the IT group. Hyperoxic conditions induced the up regulation of genes associated with the inflammatory response, such as macrophage inflammatory protein-1 α, tumor necrosis factor-α and inter leukin-6; genes associated with cell death, such as p53 and caspases; and genes associated with fibrosis, such as connective tissue growth factor. In contrast, hyperoxic conditions induced the dwon-regulation of vascular endothelial growth factor and hepatocyte growth factor. These hyperoxia-induced changes in gene expression were decreased in the IT group, but not in the IV group. Thus, local IT MSC transplantation was more effective than systemic IV MSC administration in protecting against neonatal hyperoxic lung injury.     

Hepatitis B virus X increases immune cell recruitment by induction of chemokine SDF-1

Hepatitis B virus X protein is a major factor in the HBV-induced disease developments. Stromal cell-derived factor-1 is a small cytokine that is strongly chemotactic for lymphocytes. We explored the role of HBx on recruitment of HBV-induced virus-nonspecific immune cells into liver. Immune cell recruitment and SDF-1 expression level significantly increased in livers of HBx-transgenic mice and X-box binding protein-1 significantly increased SDF-1 gene expression. Finally, we confirmed that immune cell recruitment into liver tissues of HBx-TG mice was diminished by a chemokine receptor antagonist. Therefore, HBx increases ER stress-dependent SDF-1 expression and induces HBV-induced immune cell recruitment into liver.     

Polyphenol‐solubility alters amyloid fibril formation of α‐synuclein

Amyloid fibril formation is associated with various amyloidoses, including neurodegenerative diseases such as Alzheimer''s and Parkinson''s diseases. Amyloid fibrils form above the solubility of amyloidogenic proteins or peptides upon breaking supersaturation, followed by a nucleation and elongation mechanism, which is similar to the crystallization of solutes. Many additives, including salts, detergents, and natural compounds, promote or inhibit amyloid formation. However, the underlying mechanisms of the opposing effects are unclear. We examined the effects of two polyphenols, that is, epigallocatechin gallate (EGCG) and kaempferol‐7─O─glycoside (KG), with high and low solubilities, respectively, on the amyloid formation of α‐synuclein (αSN). EGCG and KG inhibited and promoted amyloid formation of αSN, respectively, when monitored by thioflavin T (ThT) fluorescence or transmission electron microscopy (TEM). Nuclear magnetic resonance (NMR) analysis revealed that, although interactions of αSN with soluble EGCG increased the solubility of αSN, thus inhibiting amyloid formation, interactions of αSN with insoluble KG reduced the solubility of αSN, thereby promoting amyloid formation. Our study suggests that opposing effects of polyphenols on amyloid formation of proteins and peptides can be interpreted based on the solubility of polyphenols.     

Chromocentre integrity and epigenetic marks

The epigenetic modification of histones dictates the formation of euchromatin and heterochromatin domains. We studied the effects of a deficiency of histone methyltransferase, SUV39h, and trichostatin A-dependent hyperacetylation on the structural stability of centromeric clusters, called chromocentres. We did not observe the expected disintegration of chromocentres, but both SUV39h deficiency and hyperacetylation in SUV39h+/+ cells induced the re-positioning of chromocentres closer to the nuclear periphery. Conversely, TSA treatment of SUV39h?/? cells re-established normal nuclear radial positioning of chromocentres. This structural re-arrangement was likely caused by several epigenetic events at centromeric heterochromatin. In particular, reciprocal exchanges between H3K9me1, H3K9me2, H3K9me3, DNA methylation, and HP1 protein levels influenced chromocentre nuclear composition. For example, H3K9me1 likely substituted for the function of H3K9me3 in chromocentre nuclear arrangement and compaction. Our results illustrate the important and interchangeable roles of epigenetic marks for chromocentre integrity. Therefore, we propose a model for epigenetic regulation of nuclear stability of centromeric heterochromatin in the mouse genome.     

c-Cbl-mediated degradation of TRAIL receptors is responsible for the development of the early phase of TRAIL resistance

We previously reported two modes of development of acquired TRAIL resistance: early phase and late phase [1]. In these studies, we observed that greater Akt activity and the expression of Bcl-xL were related mainly to the late phase of acquired TRAIL resistance.Recently we became aware of a possible mechanism of early phase TRAIL resistance development through internalization and degradation of TRAIL receptors (DR4 and DR5). Our current studies demonstrate that TRAIL receptors rapidly diminish at the membrane as well as the cytoplasm within 4 h after TRAIL exposure, but recover completely after one or two days. Our studies also reveal that Cbl, a ubiquitously expressed cytoplasmic adaptor protein, is responsible for the rapid degradation of TRAIL receptors; Cbl binds to them and induces monoubiquitination of these receptors concurrent with their degeneration soon after TRAIL exposure, creating the early phase of acquired TRAIL resistance.     

Synthesis of aminoquinazoline derivatives and their antiproliferative activities against melanoma cell line

The synthesis of a novel series of aminoquinazoline derivatives 1a–r and their antiproliferative activities against A375 human melanoma cell line were described. Among them, six compounds showed superior antiproliferative activities to Sorafenib as a reference compound. In particular, the representative compound 1q bearing chromen-4-one moiety exhibited excellent antiproliferative activity (IC₅₀ = 0.006 μM) and good selectivity over HS27 fibroblast cell line.