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Pazopanib is a multi-tyrosine kinase inhibitor that is used to treat advanced soft-tissue sarcoma, and its efficacy has been confirmed in several clinical trials, although no clinically useful biomarkers have been identified. In other cancers, the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the lymphocyte-to-monocyte ratio (LMR) are associated with chemotherapy response and prognosis. Therefore, we aimed to evaluate the associations of pazopanib response with NLR, PLR, and LMR among patients with advanced soft-tissue sarcoma. Data regarding NLR, PLR, and LMR were obtained for 25 patients who received pazopanib for soft-tissue sarcoma. The patients were categorized according to their values for NLR (≥3.8 vs.

Background/aim The presence of cancer stem cells (CSCs) contributes to metastasis, recurrence, and resistance to chemo/radiotherapy in hepatocellular carcinoma (HCC). The WNT signaling pathway is reportedly linked to the maintenance of stemness of CSCs. In the present study, in order to eliminate liver CSCs and improve the prognosis of patients with HCC, we explored whether small-molecule compounds targeting WNT signaling pathway suppress liver CSCs. Materials and methods The screening was performed using cell proliferation assay and reporter assay. We next investigated whether these compounds suppress liver CSC properties by using flow cytometric analysis and sphere-formation assays. A mouse xenograft model transplanted with CD44-positive HuH7 cells was used to examine the in vivo antitumor effect of IC-2. Results In HuH7 human HCC cells, 10 small-molecule compounds including novel derivatives, IC-2 and PN-3-13, suppressed cell viability and WNT signaling activity. Among them, IC-2 significantly reduced the CD44-positive population, also known as liver CSCs, and dramatically reduced the sphere-forming ability of both CD44-positive and CD44-negative HuH7 cells. Moreover, CSC marker-positive populations, namely CD90-positive HLF cells, CD133-positive HepG2 cells, and epithelial cell adhesion molecule-positive cells, were also reduced by IC-2 treatment. Finally, suppressive effects of IC-2 on liver CSCs were also observed in a xenograft model using CD44-positive HuH7 cells. Conclusion The novel derivative of small-molecule WNT inhibitor, IC-2, has the potential to suppress liver CSCs and can serve as a promising therapeutic agent to improve the prognosis of patients with HCC.

Background We reported the impact of joint diseases on modified health assessment questionnaire (MHAQ) scores determined using 2011 data from NinJa (National Database of Rheumatic Diseases by iR-net in Japan). The MHAQ score was significantly associated with disease in almost all joints and physical ability tended to become aggravated. We also developed a joint-weighted scoring system from odds ratios. Respective integer scores assigned to disease in bilateral and unilateral joints comprised shoulder, 4 and 2; elbow, 3 and 2; wrist, 2 and 2; hip, 0 and 3; knee, 3 and 2; ankle, 2 and 2; finger, 1 and 1. Statistical analyses indicated a cut-off at 3 points using this system (Ono K, et al., Modern Rheumatology, 2016). Objectives To validate the weighted scoring system using NinJa data from 2009 and 2014. Methods We analyzed data from 7,189 and 13,459 patients listed in the NinJa database during 2009 and 2014. The presence or absence of disease in each joint (swelling and/or tenderness were considered to indicate active disease) and whether the disease was bilateral or unilateral were investigated. We calculated joint scores for each patient using a weighted scoring system and then created ROC curves for each patient based on total scores. Results Patients in the 2009 and 2014 groups were aged 62.4±12.6 and 64.1±12.8 years, median DAS28 CRP values were 2.9 and 2.4, and total joint scores were 3.4 and 2.4 with a significant difference (p Conclusions Disease activity changed from moderate to low in the NinJa cohorts and the scoring system was validated for the years 2009 and 2014. The weighted scoring system appears useful to predict functional disability in a simpler way by examining each joint rather than changes in disease activity among patients with RA. References Ono K, et al., The impact of joint disease on the Modified Health Assessment Questionnaire scores in rheumatoid arthritis patients: A cross-sectional study the National Database of Rheumatic Diseases by iR-Net in Japan. Modern Rheumatology, 2016(4): 529–533. Disclosure of Interest None declared

[Purpose] This study was designed to examine the epidemiological background of Whiplash-associated disorders in Japanese adults and to investigate the psychological factors associated with prolonged treatment for Whiplash-associated disorders. [Subjects and Methods] An online survey was completed by 127,956 participants, of whom 4,164 had been involved in a traffic collision. A random sample of the collision participants (n=1,698) were provided with a secondary questionnaire. From the 974 (57.4%) participants who returned the questionnaire, 183 cases (intractable neck pain treated over a period of 6 months) and 333 controls (minor neck pain treated within 3 months) were selected. Among the control group, the psychological factors associated with prolonged treatment for Whiplash-associated disorders were investigated. [Results] Among the 4,164 collision participants, 1,571 (37.7%) had experienced Whiplash-associated disorders. The prevalence in the general population was 1.2% (1.3% in male and 1.0% in female). Significant differences were observed between the cases and controls for all psychological factors, although both groups had similar distributions of age and gender. [Conclusion] Poor psychological factors were associated with prolonged treatment for whiplash-associated disorders in Japanese adults. These psychological factors should be considered during the treatment of whiplash-associated disorders.

Keiko Yamada,1,2 Ko Matsudaira,3,4 Eizaburo Tanaka,1,5 Hiroyuki Oka,3 Junji Katsuhira,3,6 Hiroyasu Iso1 1Public Health, Department of Social Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 2Center for Pain Management, Osaka University Hospital, Suita, Osaka, 3Department of Medical Research and Management for Musculoskeletal Pain, 22nd Century Medical and Research Center, Faculty of Medicine, The University of Tokyo, Tokyo, 4Japan Labour Health & Welfare Organization, Tokyo, 5Hyogo Institute for Traumatic Stress, Kobe, 6Department of Prosthetics & Orthotics and Assistive Technology, Faculty of Medical Technology, Niigata University of Health and Welfare, Niigata, Japan Background: Responses to early-life adversity may differ by sex. We investigated the ­sex-specific impact of early-life adversity on chronic pain, chronic multisite pain, and somatizing tendency with chronic pain. Methods: We examined 4229 respondents aged 20–79 years who participated in the Pain Associated Cross-Sectional Epidemiological Survey in Japan. Outcomes were: 1) chronic pain prevalence, 2) multisite pain (≥3 sites) prevalence, and 3) multiple somatic symptoms (≥3 symptoms) among respondents with chronic pain related to the presence or absence of early-life adversity. Multivariable-adjusted odds ratios (ORs) were calculated with 95% confidence intervals using a logistic regression model including age, smoking status, exercise routine, sleep time, body mass index, household expenditure, and the full distribution of scores on the Mental Health Inventory-5. We further adjusted for pain intensity when we analyzed the data for respondents with chronic pain. Results: The prevalence of chronic pain was higher among respondents reporting the presence of early-life adversity compared with those reporting its absence, with multivariable ORs of 1.62 (1.22–2.15, p

To purpose of this study was to reveal the mean levels and positive proportion of serological markers related to rheumatoid arthritis, and clarify their relationship with osteoporosis and hand osteoarthritis (OA). A total of 1546 participants from the third survey of the research on osteoarthritis/osteoporosis against disability study were enrolled in the current study. Using participant blood samples, the levels of anti-cyclic citrullinated protein (CCP) antibody, rheumatoid factor (RF), matrix metalloproteinase-3 (MMP-3), C-reactive protein (CRP), and high-sensitivity CRP (hsCRP) were measured. Subjects with higher than normal levels were defined as being positive. Osteoporosis was defined according to the recommendations set by World Health Organization criteria in 1994. Radiographic hand OA was evaluated using the modified Kellgren–Lawrence (KL) scale. The positive proportion of anti-CCP antibody, RF, MMP-3, CRP, and hsCRP was 1.8, 7.1, 15.0, 6.7, and 6.4%, respectively. MMP-3 was associated with age, and was significantly higher in men than in women. Positive MMP-3 was not significantly related to osteoporosis or severe hand OA (KL grade ≥3) after adjustment for other factors including age, sex, and body mass index. The results from this study clarified the values and positive proportion of RA-related markers and revealed their relationship with osteoporosis and hand OA.

Juichi Tonosu,1 Hiroyuki Oka,2 Ko Matsudaira,2 Akiro Higashikawa,1 Hiroshi Okazaki,1 Sakae Tanaka3 1Department of Orthopedic Surgery, Kanto Rosai Hospital, Kawasaki, 2Department of Medical Research and Management for Musculoskeletal Pain, 22nd Century Medical and Research Center, 3Department of Orthopedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan Abstract: The objective of this study was to evaluate the relationship between magnetic resonance imaging (MRI) findings and previous low back pain (LBP) in participants without current LBP. Current LBP was defined as LBP during the past month. Previous LBP was defined as a history of medical consultation for LBP. Ninety-one participants without current LBP were included. Sagittal T2-weighted MRI was used to assess the intervertebral space from T12/L1 to L5/S1. These images were classified into five grades based on the Pfirrmann grading system. Furthermore, we evaluated the presence of disk bulging, high-intensity zone, and spondylolisthesis. We compared the MRI findings between groups with (27 participants) and without (64 participants) previous LBP without current LBP. Intraobserver and interobserver kappa values were evaluated. Participants had an average age of 34.9years; 47 were female and 44 were male; and their average body mass index was 21.8kg/m2. Compared to the group of participants without previous LBP, the group of participants with previous LBP had a significantly higher incidence of disk degeneration such as a Pfirrmann grade ≥3, disk bulging, and high-intensity zone in the analyses adjusted by age and sex. There were no significant differences in spondylolisthesis between the groups. An odds ratio of >10 was only found for Pfirrmann grade ≥3, ie, a Pfirrmann grade ≥3 was strongly associated with a history of previous LBP in participants without current LBP. Keywords: disk bulging, low back pain, magnetic resonance imaging, MRI, Pfirrmann grading, previous history, high-intensity zone

Incidental durotomy (ID) is a common intraoperative complication of spine surgery. It can lead to persistent cerebrospinal fluid leakage, which may cause serious complications, including severe headache, pseudomeningocele formation, nerve root entrapment, and intracranial hemorrhage. As a result, it contributes to higher healthcare costs and poor patient outcomes. The purpose of this study was to clarify the independent risk factors that can cause ID during posterior open spine surgery for degenerative diseases in adults. We conducted a prospective multicenter study of adult patients who underwent posterior open spine surgery for degenerative diseases at 10 participating hospitals from July 2010 to June 2013. A total of 4,652 consecutive patients were enrolled. We evaluated potential risk factors, including age, sex, body mass index, American Society of Anesthesiologists physical status classification, the presence of diabetes mellitus, the use of hemodialysis, smoking status, steroid intake, location of the surgery, type of operative procedure, and past surgical history in the operated area. A multivariate logistic regression analysis was performed to identify the risk factors associated with ID. The incidence of ID was 8.2% (380/4,652). Corrective vertebral osteotomy and revision surgery were identified as independent risk factors for ID, while cervical surgery and discectomy were identified as factors that independently protected against ID during posterior open spine surgery for degenerative diseases in adults. Therefore, we identified 2 independent risk factors for and 2 protective factors against ID. These results may contribute to making surgeons aware of the risk factors for ID and can be used to counsel patients on the risks and complications associated with open spine surgery.

Objectives To establish the normal values of spino-pelvic alignment and to clarify the effect of age-related changes using large, community-based cohorts. Methods In this study, data from 1461 participants (466 men, 995 women) were analyzed. On lateral standing radiographs, the following parameters were measured: thoracic kyphosis (TK), lumbar lordosis (LL), pelvic tilt (PT), pelvic incidence (PI), and C7 sagittal vertical axis (SVA). All values are expressed as the mean±standard deviation. The Spearman rank correlation coefficient was used to examine correlations between variables of spino-pelvic parameters. Finally, we analyzed the relationship between age and spino-pelvic parameters. Therefore, we entered values for the body mass index (BMI), SVA, TK, and PI-LL into a multiple regression model to adjust for potential confounding factors. Results The SVA, TK, and PT increased with age, and LL decreased with age. Regarding sex differences, the TK was statistically significantly larger in men than in women, and LL, PT, and PI were statistically significantly smaller in men than in women. Correlation coefficients between the SVA and TK, between the SVA and PI-LL, and between TK and PI-LL were none, strong, and weak, respectively. Results of multiple regression analysis between age and spino-pelvic parameters showed that the standardized partial regression coefficients for the SVA, TK, and PI-LL were 0.17, 0.30, and 0.23, respectively, in men and 0.29, 0.32, and 0.23, respectively, in women. Conclusions We found that all parameters were significantly associated with age in men and women. The SVA, TK, and PT increased with age, and LL decreased with age. Results of multiple regression analysis also demonstrated that the SVA, TK, and PI-LL are related to age. Indeed, the PI-LL value increased with age. In this study, a more excessive PI-LL mismatch was shown, indicating an increased risk of spinal malalignment. Differences in the absolute values of spino-pelvic parameters in each sex were small yet statistically significant. Thus, further study should be performed to corroborate this finding.

Background Although the occupational health field has identified psychosocial factors as risk factors for low back pain that causes disability, the association between disabling low back pain and psychosocial factors has not been examined adequately in Japanese hospital workers. Therefore, this study examined the association between low back pain, which interfered with work, and psychosocial factors in Japanese hospital workers. Method This cross-sectional study was conducted at a hospital in Japan. In total, 280 hospital workers were recruited from various occupational settings. Of these, 203 completed a self-administered questionnaire that included items concerning individual characteristics, severity of low back pain, fear-avoidance beliefs (Fear-Avoidance Beliefs Questionnaire), somatic symptoms (Somatic Symptom Scale-8), psychological distress (K6), workaholism, and work-related psychosocial factors (response rate: 72.5%). Logistic regression was used to explore risk factors associated with disabling low back pain. Results Of the 203 participants who completed questionnaires, 36 (17.7%) reported low back pain that interfered with their work. Multivariate analyses with individual factors and occupations adjusted for showed statistically significant associations between disabling low back pain and fear-avoidance beliefs (adjusted odds ratio [OR]: 2.619, 95% confidence interval [CI]: 1.003–6.538], somatic symptoms (OR: 4.034, 95% CI: 1.819–9.337), and interpersonal stress at work (OR: 2.619, 95% CI: 1.067–6.224). Conclusions Psychosocial factors, such as fear-avoidance beliefs, somatic symptoms, and interpersonal relationships at work, were important risk factors in low back pain that interfered with work in Japanese hospital workers. With respect to occupational health, consideration of psychosocial factors is required to reduce disability related to low back pain.

Objective This study aimed to establish sex- and age-dependent distributions of the cross sectional area and fatty infiltration ratio of paraspinal muscles, and to examine the correlation between paraspinal muscle degeneration and low back pain in the Japanese population. Methods In this cross-sectional study, data from 796 participants (241 men, 555 women; mean age, 63.5 years) were analyzed. The measurement of the cross sectional area and fatty infiltration ratio of the erector spinae and multifidus from the level of T12/L1 to L4/5 and psoas major at the level of T12/L1 was performed using axial T2-weighted magnetic resonance imaging. Multivariate logistic regression analysis was used to estimate the association between fatty infiltration of the paraspinal muscles and the prevalence of low back pain. Results The cross sectional area was larger in men than women, and tended to decrease with age, with the exception of the erector spinae at T12/L1 and L1/2 in women. The fatty infiltration ratio was lower in men than women, except for multifidus at T12/L1 in 70–79 year-olds and psoas major in those less than 50 years-old, and tended to increase with age. Logistic regression analysis adjusted for age, sex, and body mass index showed that the fatty infiltration ratio of the erector spinae at L1/2 and L2/3 was significantly associated with low back pain (L1/2 level: odds ratio, 1.05; 95% confidence interval, 1.005–1.104; L2/3 level: odds ratio, 1.05; 95% confidence interval, 1.001–1.113). Conclusion This study measured the cross sectional area and fatty infiltration ratio of paraspinal muscles in the Japanese population using magnetic resonance imaging, and demonstrated that the fatty infiltration ratio of the erector spinae in the upper lumbar spine was significantly associated with the presence of low back pain. The measurements could be used as reference values, which are important for future comparative studies.

In vitro mammalian cytogenetic tests detect chromosomal aberrations and are used for testing the genotoxicity of compounds. This study aimed to identify a supportive genomic biomarker could minimize the risk of misjudgments and aid appropriate decision making in genotoxicity testing. Human lymphoblastoid TK6 cells were treated with each of six DNA damage-inducing genotoxins (clastogens) or two genotoxins that do not cause DNA damage. Cells were exposed to each compound for 4 h, and gene expression was comprehensively examined using Affymetrix U133A microarrays. Toxicogenomic analysis revealed characteristic alterations in the expression of genes included in cyclin-dependent kinase inhibitor 1A (CDKN1A/p21)-centered network. The majority of genes included in this network were upregulated on treatment with DNA damage-inducing clastogens. The network, however, also included kinesin family member 20A (KIF20A) downregulated by treatment with all the DNA damage-inducing clastogens. Downregulation of KIF20A expression was successfully confirmed using additional DNA damage-inducing clastogens. Our analysis also demonstrated that nucleic acid constituents falsely downregulated the expression of KIF20A, possibly via p16 activation, independently of the CDKN1A signaling pathway. Our results indicate the potential of KIF20A as a supportive biomarker for clastogenicity judgment and possible mechanisms involved in KIF20A downregulation in DNA damage and non-DNA damage signaling networks.

The objective of the present longitudinal study was to clarify whether osteophytosis and joint space narrowing predict quality of life (QOL) decline using a longitudinal population-based cohort of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. The present study analyzed 1,525 participants who completed the radiographic examination at baseline and questionnaires regarding QOL at a 3-year follow-up (546 men and 979 women; mean age, 67.0 ± 11.0 years). This study examined the associations of osteophyte area (OPA) and minimum joint space width (mJSW) in the medial compartment of the knee at baseline with pain and physical functional disability measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). OPA and mJSW in the medial compartment of the knee were measured using a knee osteoarthritis (OA) computer-aided diagnosis system. Overall, OPA independently predicted physical functional disability after 3 years of follow-up. When analyzed in men and women separately, OPA, rather than mJSW, was an independent predictor for pain and physical functional disability after 3 years of follow-up in men. OPA, rather than mJSW, also predicted worsening of pain in men during the 3-year follow-up, whereas in women, mJSW, rather than OPA, predicted worsening of pain. In conclusion, the present longitudinal study using a large-scale population from the ROAD study found gender differences in the association of osteophytosis and joint space narrowing with pain and physical functional disability.

The present study aimed to investigate association of physical activities of daily living with the incidence of certified need of care in the national long-term care insurance (LTCI) system in elderly Japanese population-based cohorts.Of the 3,040 participants in the baseline examination, we enrolled 1,773 (699 men, 1,074 women) aged 65 years or older who were not certified as in need of care-level elderly at baseline. Participants were followed during an average of 4.0 years for incident certification of need of care in the LTCI system. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used assess function. Associated factors in the baseline examination with the occurrence were determined by multivariate Cox proportional hazards regression analysis. Receiver operating characteristic curve analysis was performed to evaluate cut-off values for discriminating between the occurrence and the non-occurrence group.All 17 items in the WOMAC function domain were significantly associated with the occurrence of certified need of care in the overall population. Cut-off values of the WOMAC function score that maximized the sum of sensitivity and specificity were around 4-6 in the overall population, in men, and in women. Multivariate Cox hazards regression analysis revealed that a WOMAC function score ≥4 was significantly associated with occurrence with the highest hazard ratio (HR) for occurrence after adjusting for confounders in the overall population (HR [95 % confidence interval (CI)] 2.54 [1.76-3.67]) and in women [HR (95 % CI) 3.13 (1.95-5.02)]. A WOMAC function score ≥5 was significantly associated with the highest HR for occurrence in men [HR (95 % CI) 1.88 (1.03-3.43)].Physical dysfunction in daily living is a predictor of the occurrence of certified need of care. Elderly men with a WOMAC function score ≥5 and women with a score ≥4 should undergo early intervention programs to prevent subsequent deterioration.

To examine the onset and resolution of pain and physical functional disability using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and their association with knee osteoarthritis (OA) in the longitudinal large-scale population of the nationwide cohort study, Research on Osteoarthritis/osteoporosis Against Disability (ROAD).Subjects from the ROAD study who had been recruited during 2005-2007 were followed up 3 years later. A total of 1,578 subjects completed the WOMAC questionnaire at baseline and follow up, and the onset and resolution rate of pain and physical functional disability were examined. We also examined the association of onset of pain and physical functional disability and their resolution with severity of knee OA as well as age, body-mass index and grip strength.After a 3.3-year follow-up, the onset rate of pain was 35.0% and 35.3% in men and women, respectively, and the onset rate of physical functional disability was 38% and 40%, respectively. Resolution rate of pain was 20.3% and 26.2% in men and women, respectively, and resolution rate of physical functional disability was 16% and 14% in men and women, respectively. Knee OA was significantly associated with onset and resolution of pain and physical functional disability in women, but there was no significant association of knee OA with onset of pain and resolution of physical functional disability in men.The present longitudinal study revealed the onset rate of pain and physical functional disability as well as their resolution, and their association with knee OA.

OBJECTIVES: This study aimed to estimate the prevalence, magnitude, and direction of the associations among disability, pain intensity, number of pain sites, and health-related quality of life (HRQoL) in patients reporting low back pain (LBP) as their primary pain. METHODS: In January 2009, an Internet survey was performed for randomly selected adults aged 20-79 years who were registered as Internet research volunteers. Of 20 044 respondents, individuals with LBP as the primary pain were analyzed for associations among disability, number of pain sites, and HRQoL. Factors associated with low HRQoL were examined using multiple logistic regression modeling. RESULTS: Of the 20 044 respondents, 25.2 % (n = 5060) reported LBP and 13.5 % (n = 2696) reported LBP as their primary pain. Among those with LBP as the primary pain, HRQoL decreased with increase in disability and number of pain sites. In multivariate analyses, disability [adjusted odds ratio (aOR), 2.93-4.58], number of pain sites (aOR, 1.42-6.12), pain intensity ≥7 (aOR, 1.88), and age ≥60 years (aOR, 1.55) were associated with low HRQoL. CONCLUSIONS: Approximately 13.5 % of patients reported LBP as their primary pain. Disability with absence from social activity and ≥7 pain sites were strongly associated with low HRQoL.

Self-efficacy, which is a belief to achieve a goal, is important for sufficient enhancement of physical ability of elderly people. For implementation of self-efficacy to assistive systems, it is necessary to subliminally change reference trajectories of the system within the range at which people cannot recognize the difference (just-noticeable difference: JND). This study clarified that elderly people have weaker position sense rather than young people when they are moved passively in relatively fast speed. New reference hip trajectories are computed to gradually extend hip flexion of human standing-up motion based on the measured JND.

The in vitro mammalian cytogenetic tests monitor chromosomal aberrations in cultured mammalian cells to test the mutagenicity of compounds. Although these tests are especially useful for evaluating the potential clastogenic effects of chemicals, false positives associated with excessive toxicity occur frequently. There is a growing demand for mechanism-based assays to confirm positive results from cytogenetic tests. We hypothesized that a toxicogenomic approach that is based on gene expression profiles could be used to investigate mechanisms of genotoxicity. Human lymphoblastoid TK6 cells were treated with each of eight different genotoxins that included six DNA damaging compounds-mitomycin C, methyl methanesulfonate, ethyl methanesulfonate, cisplatin, etoposide, hydroxyurea-and two compounds that do not damage DNA-colchicine and adenine. Cells were exposed to each compound for 4h, and Affymetrix U133A microarrays were then used to comprehensively examine gene expression. A statistical analysis was used to select biomarker candidates, and 103 probes met our statistical criteria. Expression of cyclin-dependent kinase inhibitor 1A (CDKN1A)/p21 was ranked highest for discriminating DNA-damaging compounds. To further characterize the biological significance of alterations in gene expression, functional network analysis was performed with the 103 selected probes. Interestingly, a CDKN1A-centered interactome was identified as the most significant network. Together, these findings indicated that DNA-damaging compounds often induced changes in the expression of a large number of these 103 probes and that upregulation of CDKN1A was a common key feature of DNA damage stimuli. The utility of CDKN1A as a biomarker for assessing the genotoxicity of drug candidates was further evaluated; specifically, quantitative RT-PCR was used to assess the effects of 14 additional compounds-including DNA damaging genotoxins and genotoxins that do not damage DNA and five newly-synthesized drug candidates-on CDKN1A expression. In these assays, DNA damage-positive clastogens were clearly separated from DNA damage-negative compounds based on CDKN1A expression. In conclusion, CDKN1A may be a valuable biomarker for identifying DNA damage-inducing clastogens and as a follow-up assay for mammalian cytogenetic tests.

Study design Retrospective case series. Objective To clarify how preoperative global sagittal imbalance influences outcomes in patients with cervical compression myelopathy undergoing cervical laminoplasty. Summary of background data The influence of sagittal balance on outcomes of cervical laminoplasty remains uncertain. Methods The authors retrospectively reviewed data of 106 patients who underwent double-door cervical laminoplasty between 2004 and 2011 and investigated the influence of the C7 sagittal vertical axis (SVA) on outcome scores. Primary outcomes used were Japanese Orthopedic Association (JOA) scores, Numerical Rating Scale for neck or arm pain, the Short Form 36 Health Survey (physical and mental component summary scores ), and the Neck Disability Index (NDI). Results Ninety-two patients with complete data were eligible for inclusion. The preoperative C7 SVA was ≤5 cm in 64 patients (69.6%) and > 5 cm in 28 (30.4%). We compared each parameter by the magnitude of spinal sagittal balance (preoperative C7 SVA > 5 cm vs. C7 SVA ≤ 5 cm) after adjusting for age via the least square mean analysis because the average age was significantly higher in patients with C7 SVA > 5 cm. As for the radiographic parameters, both C2-7 SVA and C7 SVA were larger in patients when the C7 SVA was > 5 cm. Numerical Rating Scale for postoperative arm pain, postoperative JOA scores, and both pre- and postoperative physical component summary and NDI were worse in patients with C7 SVA > 5 cm; however, the JOA score recovery rate and changes in physical component summary and NDI were not significantly different. Conclusion Postoperative functional outcome scores were significantly lower in patients with C7 SVA > 5 cm, although the improvement after cervical laminoplasty was not greatly affected. The involvement of global sagittal balance and cervical regional alignment should be considered in evaluating surgical outcomes for patients undergoing cervical laminoplasty. Level of evidence 4.

Cross-sectional study. To determine the association between lumbar spondylolisthesis and low back pain and symptomatic lumbar spinal stenosis (LSS) in a population-based cohort. The basic epidemiology of lumbar spondylolisthesis is not well known. There is little information regarding the association between lumbar spondylolisthesis and clinical symptoms such as low back pain and LSS symptoms. This cross-sectional study included data from 938 participants (308 males, 630 females; mean age, 67.3 years; range, 40–93 years). Lumbar spondylolisthesis was defined as a slip of ≥5%. Diagnostic criteria for symptomatic LSS required the presence of both leg symptoms and radiographic LSS findings on magnetic resonance imaging. The prevalence of low back pain and symptomatic LSS was compared between those with or without spondylolisthesis. Furthermore, we determined the association between the amount of slippage and presence of symptomatic LSS. The prevalence of spondylolisthesis at any level was 15.8% in the total sample, 13.0% in males, and 17.1% in females; the prevalence was not significantly different between males and females (P = 0.09). In both, males and females, symptomatic LSS was related to spondylolisthesis [odds ratio (OR): 2.07; 95% CI: 1.20–3.44]; however, no such association was found for spondylolisthesis and presence of low back pain. The amount of slippage was not related to the presence of symptomatic LSS (P = 0.93). This population-based cohort study revealed that lumbar spondylolisthesis had a closer association with leg symptoms than with low back pain. There was a significant difference in the presence of symptomatic LSS between participants with and without spondylolisthesis. However, the amount of slippage was not related to the presence of symptomatic LSS. Level of Evidence: 3

Pain is a global public health problem with implications for both personal and social heath. Fear-avoidance beliefs (FABs) have been demonstrated to negatively impact and prolong pain in many Western countries, but little is known about the association between FABs and chronic pain (CP) in Asian countries, including Japan. We examined the relationship between FABs and CP in Japanese white-collar workers, a growing population with a high prevalence of CP.Questionnaires and company records were used to gather data from 433 Japanese white-collar workers. Data were related to experience of pain, participant sociodemographic/health/lifestyle characteristics, fear-avoidance beliefs [Tampa Scale for Kinesiophobia (TSK)], work-related psychosocial factors (Brief Job Stress Questionnaire), and depressive illness [Psychological Distress Scale (K6)]. Analysis of covariance and multilevel logistic regression modeling were used to analyze associations between the data while controlling for factors known to influence CP prevalence.Prevalence rate of CP was 11.1% (48 of 433 persons). Adjusted odds ratios for participants with CP significantly increased in participants with high TSK scores, even after adjusting for factors known to influence CP prevalence.We found a significant association between high TSK scores and CP in Japanese white-collar workers when controlling for other known factors that influence CP such as work-related psychosocial characteristics and depressive conditions. This finding suggests that FABs are independently associated with prevalence of CP.

ObjectivesLow back pain (LBP) is a common cause of disability among nursing personnel. Although many studies regarding the risk factors for LBP among nursing staff have focused on the physical load at work, multidimensional assessments of risk factors are essential to identify appropriate preventive strategies. We aimed to investigate the association of multidimensional factors (individual, physical, psychological and occupational) with disabling LBP among nursing personnel in Japan.DesignObservational study with comparative cross-sectional design.SettingData were collected using the self-administered questionnaire at a tertiary medical centre.ParticipantsAfter excluding participants with missing variables, 718 nursing personnel were included in the analysis.Outcome measuresA self-administered questionnaire assessed individual characteristics, rotating night shift data, severity of LBP, previous episode of LBP, sleep problem, kinesiophobia (Tampa Scale for Kinesiophobia), depressive condition (K6), physical flexibility and frequency of lifting at work. A logistic regression model was used to evaluate the factors associated with disabling LBP (LBP interfering with work) among nursing personnel.ResultsOf all participants, 110 (15.3%) reported having disabling LBP. The multivariable logistic regression analysis after adjustment for several confounding factors showed that kinesiophobia (highest tertile, adjusted OR (aOR): 6.13, 95% CI : 3.34 to 11.27), previous episode of LBP (aOR: 4.31, 95% CI: 1.50 to 12.41) and insomnia (aOR: 1.66, 95% CI: 1.05 to 2.62) were significantly associated with disabling LBP.ConclusionsThe present study indicated that kinesiophobia, a previous episode of LBP, and sleep problems were associated with disabling LBP among nursing personnel. In the future, workplace interventions considering assessments of these factors may reduce the incidence of disabling LBP in nursing staff, although further prospective studies are needed.

Objectives: To determine standard reference values for isometric knee extension force using a cohort of Japanese type 2 diabetic patients without diabetic polyneuropathy. Methods: Patient data were collected from the Multicenter Survey of the Isometric Lower Extremity Strength in Type 2 Diabetes study and compared with previously published data of healthy control subjects. In total, we enrolled 898 patients with type 2 diabetes aged 30–87 years, who did not have diabetic polyneuropathy. The control group included 510 healthy subjects aged 30–88 years. Maximum isometric knee extension force (KEF) values were obtained by using a hand-held dynamometer with belt stabilization. In addition, KEF (kgf) was adjusted for bodyweight (kg) to calculate %KEF. Results: KEF and %KEF decreased with age in both patients with diabetes and healthy control subjects. The mean values of KEF and %KEF in patients with diabetes were reduced by 9.7% and 20.8%, respectively, in males, and by 11.6% and 23.0%, respectively, in females compared to the values in healthy control subjects. Conclusion: KEF and %KEF in patients with type 2 diabetes without diabetic polyneuropathy may reduce by approximately 10% and 20%, respectively, compared to these values in healthy control subjects. This study provides reference values for isometric KEF with respect to sex in a population covering a wide age range.

Low back pain (LBP) is a common major health problem. Fear-avoidance beliefs are thought to be an important risk factor for chronic LBP. This study investigated factors associated with the Fear-Avoidance Beliefs Questionnaire (FABQ) scores of Japanese adults who experienced LBP. We focused on the association of FABQ scores with medical advice to rest and the experience of seeing family members and/or significant others with disabling LBP.In February 2011, 1,063,083 adults aged 20-79 years who had registered as internet-based research volunteers were randomly selected and invited to participate in a questionnaire survey. The data from 52,650 respondents who had experienced LBP were analyzed. Multiple linear regression analysis was used to examine the association between FABQ physical activity scores and the advice for respondents with LBP to rest, the experience of seeing others with disabling LBP, and other personal and LBP factors.After controlling for age, sex, and lifetime and current LBP disability grades, the experience of seeing others with disabling LBP (regression coefficient β = 0.94), rest advice (β = 0.91), history of chronic LBP (β = 0.78), radiating pain below the knee (β = 0.44), and workers' compensation (β = 0.51) were associated with higher FABQ physical activity scores. Conversely, regular exercise (β = -0.89) and LBP attributed to sports (β = -0.76) were associated with lower FABQ physical activity scores.The association between rest advice and higher fear-avoidance beliefs supports the recent treatment guidelines that emphasize continuation of daily activities.cross-sectional study.

Background Although poor standing posture is a known cause of low back pain, the mechanisms involved are unclear. The aim of this study was to clarify the kinetic and posture angle features of standing posture that might influence low back pain. Methods Sixty-seven young men were enrolled in this cross-sectional case-control study and were categorized according to whether they did or did not have low back pain. Habitual standing posture was assessed in each group, using a three-dimensional motion analysis system, force plates, and a spinal mouse. Kinetic and posture angle factors were compared between participants with and without low back pain. The relationship between specific features of standing posture and low back pain was analyzed using logistic regression. Results The intervertebral disc compressive force and the low back moment were significantly greater in the group with low back pain than in the group without low back pain. The intervertebral disc compressive force was the factor most strongly associated with low back pain during static standing. Conclusions Logistic regression analysis identified intervertebral disc compressive force as an independent variable associated with low back pain. This finding suggests that increased intervertebral disc compressive force may promote development of low back pain in standing posture.

Aim To examine the incidence of certified need of care in the national long-term care insurance (LTCI) system, and to determine its risk factors in the elderly of Japanese population-based cohorts of the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study. Methods Of the 3040 participants in the baseline examination of the ROAD study, we enrolled 1773 (699 men, 1074 women) aged 65 years or older who were not certified as in need of care level elderly at baseline. Participants were followed for incident certification of need of care in the LTCI system. Associated factors in the baseline examination with occurrence were determined by multivariate Cox proportional hazards regression analysis. Muscle dysfunction was defined in accordance with the European Working Group on Sarcopenia in Older People algorithm for screening sarcopenia. Results A total of 54 men and 115 women were certified as in need of care level elderly during the average 4.0-year follow up. The incidence was 2.0 and 2.5 per 100 person-years in men and women, respectively. Identified risk factors were region, age, body mass index

The prevalence of radiographic cervical ossification of the posterior longitudinal ligament (OPLL) in 1,562 Japanese from a population-based cohort was 1.9 %. The presence of OPLL showed a significant association with the femoral neck bone mineral density (BMD), presence of diffuse idiopathic skeletal hyperostosis (DISH) and plasma pentosidine levels. Only one new case of radiographic OPLL was detected, but OPLL progressed in all affected subjects.The purpose of this study was to clarify the prevalence and progression of radiographic OPLL and the associated factors, using the population-based cohort Research on Osteoarthritis/osteoporosis Against Disability (ROAD).In the ROAD study, 1,690 participants underwent X-ray examination of the entire spine and both knees. Radiographic OPLL, lumbar spondylosis, knee osteoarthritis and DISH were diagnosed by a single, well-experienced orthopaedic surgeon. An interviewer-administered questionnaire and tests for anthropometric measurements were administered, and the BMDs of the lumbar spine and proximal femur were determined. A new OPLL case was considered if heterotopic ossification in the posterior longitudinal ligament was absent at baseline but present during follow-up. Progression was defined as an increase in the maximum length or width of the ossification at follow-up over that at baseline.Radiographic OPLL was detected in 30 (17 men, 13 women) of 1,562 individuals who underwent X-ray examination of the cervical spine (prevalence = 1.9 %). Its prevalence was significantly higher in men than in women (p = 0.007), but no association with age was observed. In a logistic regression analysis, OPLL showed a significant association with the femoral neck BMD, presence of DISH and plasma pentosidine levels. Only one new case of radiographic OPLL was detected, but OPLL progressed in all affected subjects.This population-based study clarified the prevalence of radiographic OPLL in the Japanese population as well as its progression. OPLL showed significant association with plasma pentosidine levels, BMD and DISH.

Intra-articular (IA) injection of hyaluronic acid (HA) has been shown to relieve osteoarthritis (OA)-related pain and improve joint structure within a 1-year period. We examined the mid-term (2-year) efficacy of IA–HA in Japanese subjects by using a large-scale population-based cohort of the Research on Osteoarthritis/Osteoporosis Against Disability study. We performed a nested case control study of 60 case control pairs matched for age (within 1 year), sex, Kellgren and Lawrence grade, and history of knee pain. The mean follow-up period after IA–HA series was 2.9 years in case patients. We examined the association of IA–HA with knee radiographic severity and knee pain. To estimate radiographic severity of OA, six distinct features—joint space area and the minimum joint space width at medial and lateral sides, osteophyte area, and tibiofemoral angle—were measured using a fully automatic computer-assisted program. Comparison of the radiographic parameters between case patients and controls showed that the medial and lateral joint space areas were significantly bigger in case patients than in controls. After constructing a multivariate logistic regression model to examine the correlation of knee pain, IA–HA, and radiographic features, we found that unlike radiographic features, IA–HA was protectively associated with the presence of pain. IA–HA might effectively improve joint structure and relieve pain in patients with knee OA.

Assessments of serum 25-hydroxyvitamin D levels in 1,683 Japanese from a population-based cohort revealed prevalences of vitamin D insufficiency and deficiency were 81.3 and 1.2%, respectively. Vitamin D deficiency was significantly associated with female sex, examined month, current smoking, lack of regular walking, higher intact parathyroid hormone (iPTH), and poor daily vitamin D intake.To clarify the characteristics of subjects with vitamin D insufficiency and deficiency among men and women in the general Japanese population.We initiated research on osteoarthritis/osteoporosis against disability (ROAD), a large-scale population-based cohort study, in 2005-2007. Blood examination was performed to measure serum 25-hydroxyvitamin D (25D) and iPTH levels and biochemical markers of bone turnover in 1,683 participants (595 men, 1,088 women). Participants completed an interviewer-administered questionnaire, measurements of bone mineral density, and x-ray examination. Vitamin D deficiency and insufficiency were defined by serum 25D levels10 and ≥10 but30 ng/mL, respectively.The prevalence of vitamin D insufficiency and deficiency was 81.3 and 1.2%, respectively. Multinominal logistic regression analyses using potentially confounding variables revealed vitamin D insufficiency was significantly associated with age (+1 year, relative risk ratio, 0.98; 95% confidence interval, 0.96-0.99), gender (women vs. men, 2.28; 1.59-3.30), residing areas (coastal area vs. mountainous area, 0.58; 0.41-0.81), examined month (October, November, December vs. January, 0.51; 0.34-0.76), and serum levels of iPTH (+1 pg/mL, 1.02; 1.01-1.03). Vitamin D deficiency was significantly characterised by female sex (20.5; 3.1-136.7), examined month (0.28; 0.09-0.95), current smoking habit (6.39; 1.78-23.0), lack of regular outside walking (3.96; 1.34-11.7), higher iPTH (1.02; 1.01-1.03) and poor daily vitamin D intake (+10 μg/day, 0.48; 0.24-0.93).A high prevalence of vitamin D insufficiency and a low prevalence of vitamin D deficiency were found in Japanese men and women, and the characteristics of vitamin D status were clarified.

We report herein a case of adenocarcinoma arising from short-segment Barrett's esophagus (SSBE) in a 36-year-old man. An elevated tumor was found at the esophagogastric junction, and a histological evaluation of the biopsy specimen led to a diagnosis of adenocarcinoma. The tumor was found to be confined to the mucosa surrounding the SSBE, and endoscopic submucosal dissection was done without complications. Histological examination of the resected specimen showed that the adenocarcinoma had also invaded the muscularis mucosae and provided evidence of lymphovascular invasion. Additional surgical resection and regional lymph node dissection were therefore carried out; however, no lymph node metastasis was found. Adenocarcinoma arising from Barrett's mucosa is rare in young patients, especially in Japan, and this case is therefore particularly noteworthy.

Patellar fracture is one of the most challenging complications of total knee arthroplasty, but relatively, little is known about it in patients with rheumatoid arthritis. We retrospectively analyzed 329 total knee arthroplasties performed in 230 female patients with rheumatoid arthritis to identify the incidence and risk factors for postoperative patellar fractures. The mean age was 61.8 years, and the mean follow-up period was 6.2 years. Patellar resurfacing was performed in all cases. Five postoperative patellar fractures (1.51%) were identified, and a thin residual patellar thickness and the use of posterior-stabilizing components were identified as significant risk factors, although the number of fractures was small in both groups. There was also tendency of higher age and greater joint line change observed in patients with fracture compared with those without fracture.

Low back pain (LBP) is a common and major health problem. Although it is known that psychosocial factors are important predictors of LBP outcome, some factors, including financial compensation, have not been fully studied in Japan. This cross-sectional study aimed to examine the association between LBP compensation (workers' compensation and automobile insurance claims) and lifetime experience of chronic LBP and back pain disability (chronic disabling LBP) in a Japanese adult population.In February 2011, 1,063,083 adults aged 20-79 years registered as Internet research volunteers were invited to complete an online questionnaire. We analyzed the data from 52,650 respondents who had ever experienced LBP. Multiple logistic regression analysis was used to examine the association between LBP compensation and lifetime experience of chronic disabling LBP, adjusting for age, sex, smoking habits, educational level, cause of LBP, history of radiating pain below the knee, and history of low back surgery.Among the respondents, 2,039 (3.9 %) had experienced chronic disabling LBP. The prevalence of a history of receiving workers' compensation or automobile insurance claims was 1.1 % for each. In multiple logistic regression, the odds of chronic disabling LBP were significantly higher among those who received LBP-related compensation (workers' compensation or automobile insurance claims) compared with respondents who did not receive compensation.The prevalence of compensated LBP was low. However, a history of compensated LBP was significantly associated with experiencing chronic disabling LBP.

A few cohort studies have determined which patients with lumbar spinal stenosis are likely to need surgery because of the deterioration of symptoms. However, there are still insufficient data regarding the management of lumbar spinal stenosis due to lack of prognostic factors associated with the need for surgery. The purpose of this study was to identify the prognostic factors associated with the need for surgical treatment in patients with lumbar spinal stenosis.Patients with lumbar spinal stenosis from our hospital and related facilities were enrolled. Eligibility criteria were as follows: age 50-85 years and the patient's conditions met the definition of lumbar spinal stenosis; the presence of neurogenic intermittent claudication caused by numbness and/or pain in the lower limbs; and magnetic resonance imaging-confirmed symptomatic LSS. We followed 274 patients (151 men; mean age, 71 ± 7.4 years) for 3 years to identify prognostic factors. We used a multivariate logistic regression model to investigate the association between the indication for surgical treatment (within 3 years) and age, sex, complications, depression, illness duration, the presence of cauda equina symptoms, and the presence of degenerative spondylolisthesis/scoliosis.In the survey conducted 3 years after treatment, 185 patients responded (follow-up rate 67.5%). In 82 patients, surgery was performed during the follow-up period. The multivariate logistic regression model showed that the presence of cauda equina symptoms and the presence of degenerative spondylolisthesis/scoliosis were significantly associated with the indication for surgical treatment within 3 years.This study showed that the presence of cauda equina symptoms and degenerative spondylolisthesis/scoliosis were prognostic factors associated with the indication for surgery in patients with lumbar spinal stenosis.

OBJECTIVE:The purpose of this study was to evaluate the relations between the degree of encroachment, measured as the cross-sectional area of the dural sac, and low back pain in a large population. METHODS:In this cross-sectional study, data from 802 participants (247 men, 555 women; mean age, 63.5 years) were analyzed. The measurement of the cross-sectional area of the dural sac from the level of L1/2 to L4/5 was taken using axial T2-weighted images. The minimum cross-sectional area was defined as the cross-sectional area of the dural sac at the most constricted level in the examined spine. Participants were divided into three groups according to minimum cross-sectional area measurement quartiles (less than the first quartile, between the first and third quartiles, and greater than the third quartile). A multivariate logistic regression analysis was used to estimate the association between the minimum cross-sectional area and the prevalence of low back pain. RESULTS:The mean minimum cross-sectional area was 117.3 mm2 (men: 114.4 mm2; women: 118.6 mm2). A logistic regression analysis adjusted for age, sex, body mass index, and other confounding factors, including disc degeneration, showed that a narrow minimum cross-sectional area (smaller than the first quartile) was significantly associated with low back pain (odds ratio, 1.78; 95% confidence interval, 1.13-2.80 compared to the wide minimum cross-sectional area group: minimum cross-sectional area greater than the third quartile measured). CONCLUSION:This study showed that a narrow dural sac cross-sectional area was significantly associated with the presence of low back pain after adjustment for age, sex, and body mass index. Further investigations that include additional radiographic findings and psychological factors will continue to elucidate the causes of low back pain.

Risk of knee osteoarthritis (OA) was assessed in a population-based case-control study of Japanese men. The study covered three health districts in Wakayama and Osaka prefectures, Japan. Subjects were male individuals >or=45 years old diagnosed radiographically with knee OA, and who did not display any established causes of secondary OA. Controls selected randomly from the general population were individually matched to cases for age, sex, and residential district. Subjects were interviewed using structured questionnaires to determine medical history, physical activity, socio-economic factors, and occupation. Interviews were obtained from 37 cases and 37 controls. In univariate analysis, heaviest weight in the past and physical work such as factory, construction, agricultural, or fishery work as the principal occupation significantly raised the risk of male knee OA (P