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Abstract Background Muscle mass and phase angle (PhA) can be measured using multi-frequency bioelectrical impedance analysis (BIA). Osteoarthritis of the hip (OAhip) causes decreased muscle mass and PhA in the deformed lower limb. However, previous studies have not accounted for the influence of sex, and thus, the relationship between muscle mass, PhA, and motor function remains unclear. This study aimed to elucidate the relationship between PhA, an index of muscle mass and quality measured using BIA, and motor function during gait and standing in female patients with OAhip. Methods Muscle mass and PhA of patients with OAhip were measured using BIA. Motor function was evaluated using the Timed Up and Go test, ground reaction/weight, rate of force development/weight, and load ratio between the osteoarthritic (OA) and contralateral sides when standing up. The difference between the OA side and the contralateral lower limb was tested to clarify the characteristics of the deformed lower limb. The relationship between each motor function was determined using a partial correlation coefficient with age as a control variable and multiple regression analysis with each motor function as the dependent variable and age, OA-side muscle mass/body weight ratio, and PhA as independent variables. Results This study involved 60 patients with OAhip (age 65.6 ± 7.6 years, height 154.2 ± 6.0 cm, weight 56.8 ± 10.5 kg) scheduled for unilateral total hip arthroplasty. Muscle mass, PhA, and lower limb load ratio were significantly decreased in the lower limbs on the OA side. Furthermore, using a partial correlation coefficient with age as a control variable, PhA showed significant correlations with motor functions related to standing up and walking, and multiple regression analysis revealed that PhA was independently related to each motor function. Conclusions Evaluation and interventions that consider muscle quality rather than muscle mass are important.

Whole-body phase angle (PhA) is associated with motor function and geriatric diseases. However, it was unclear which parts of the upper- or lower-limb PhA were involved. This study investigated the differences in the PhA of the upper and lower extremities and their relationships with frailty, locomotive syndrome indices, and motor function in community-dwelling older adult participants. This study was a cross-sectional observational study. In 69 community-dwelling older adults, the PhA at each measurement site (whole body, upper limbs, and lower limbs), motor function, Kihon Checklist (KCL), and 25-Geriatric Locomotive Function Scale (GLFS-25) were measured. This study examined differences in each PhA and its relationship with motor function and geriatric diseases. Multiple regression analysis was performed using GLFS-25 as the dependent variable and sex and lower-limb PhA as independent variables. In this cohort (mean age: 72.3 ± 5.7 years; 18 males and 51 females), lower-limb PhA was significantly lower than upper-limb PhA. Unlike other PhAs, lower-limb PhA was related to grip strength, TUG, F/w, and GLFS-25. Multiple regression analysis showed that the lower-limb PhA was independently related to GLFS-25. Cellular health of the lower extremity is associated with gait, standing function, and indicators of locomotive syndrome.

Abstract The aim of this study was to analyze the 5-year natural course of frailty status assessed with the Kihon Checklist (KCL) and the risk factors of transition towards frailty in community-dwelling older adults. We used the data from the postal KCL survey conducted by the municipal government between 2011 and 2016. The sample of the current study consisted of 551 older adults (265 men and 286 women) aged 65–70 years in 2011. The median KCL score increased from 2 (interquartile range 1–3) in 2011 to 3 (1–5) in 2016 (p

Abstract Background Although pelvic incidence (PI) is a key morphologic parameter in assessing spinopelvic sagittal alignment, accurate measurements of PI become difficult in patients with severe hip dislocation or femoral head deformities. This study aimed to investigate the reliability of our novel morphologic parameters and the correlations with established sagittal spinopelvic parameters. Methods One hundred healthy volunteers (25 male and 75 female), with an average age of 38.9 years, were analysed. Whole-body alignment in the standing position was measured using a slot-scanning X-ray imager. We measured the established spinopelvic sagittal parameters and a novel parameter: the sacral incidence to pubis (SIP). The correlation coefficient of each parameter, regression equation of PI using SIP, and regression equation of lumbar lordosis (LL) using PI or SIP were obtained. The intraclass correlation coefficient (ICC) was calculated as an evaluation of the measurement reliability. Results Reliability analysis showed high intra- and inter-rater agreements in all the spinopelvic parameters, with ICCs > 0.9. The SIP and pelvic inclination angle (PIA) demonstrated strong correlation with PI (R = 0.96) and pelvic tilt (PT) (R = 0.92). PI could be predicted according to the regression equation: PI = − 9.92 + 0.905 * SIP (R = 0.9596, p

Abstract Background The anatomical sacral slope is considered as an anatomical pelvic parameter independent of femoral head centers for measurement of anatomical sacral slope and was previously described to strongly correlate with pelvic incidence on a two-dimensional examination of healthy subjects. However, the correlation between anatomical sacral slope and pelvic incidence was unclear in patients with developmental dysplasia of the hip. This study aimed to examine the correlation between anatomical sacral slope and other spinopelvic parameters by analyzing plain radiographs of female patients with developmental dysplasia of the hip. Methods Eighty-four women with developmental dysplasia of the hip were examined. Lumbar lordosis, thoracic kyphosis, pelvic incidence, sacral slope, and anatomical sacral slope (the angle formed by the straight line of the S1 superior endplate and a line at a right angle to the anterior pelvic plane) were determined by analyzing plain radiographs. The correlations were examined by Pearson’s correlation coefficients, and intra- and inter-rater intraclass correlation coefficients were evaluated for reliability. Results A strong correlation was observed between pelvic incidence and anatomical sacral slope (r = 0.725, p < 0.001). In addition, the correlation between anatomical sacral slope and lumbar lordosis was similar to that between pelvic incidence and lumbar lordosis (r = 0.661, p < 0.001, and r = 0.554, p < 0.001, respectively). The intra-rater intraclass correlation coefficient values were 0.869 and 0.824 for anatomical sacral slope and pelvic incidence, respectively. Furthermore, the inter-rater intraclass correlation coefficient values were 0.83 and 0.685 for anatomical sacral slope and pelvic incidence, respectively. Conclusions We observed that the strong correlation between anatomical sacral slope and pelvic incidence in patients with developmental dysplasia of the hip was equal to that in normal healthy subjects. The correlation between anatomical sacral slope and lumbar lordosis was equal to that between pelvic incidence and lumbar lordosis. Additionally, the intraclass correlation coefficient values for the anatomical sacral slope were slightly higher than those for pelvic incidence. Thus, we conclude that anatomical sacral slope can be considered as a helpful anatomical pelvic parameter that is a substitute for pelvic incidence not only in normal healthy subjects, but also in patients with developmental dysplasia of the hip.

Abstract Background Vertebroplasty with posterior spinal fusion (VP + PSF) is one of the most widely accepted surgical techniques for treating osteoporotic vertebral collapse (OVC). Nevertheless, the effect of the extent of fusion on surgical outcomes remains to be established. This study aimed to evaluate the surgical outcomes of short- versus long-segment VP + PSF for OVC with neurological impairment in thoracolumbar spine. Methods We retrospectively collected data from 133 patients (median age, 77 years; 42 men and 91 women) from 27 university hospitals and their affiliated hospitals. We divided patients into two groups: a short-segment fusion group (S group) with 2- or 3-segment fusion (87 patients) and a long-segment fusion group (L group) with 4- through 6-segment fusion (46 patients). Surgical invasion, clinical outcomes, local kyphosis angle (LKA), and complications were evaluated. Results No significant differences between the two groups were observed in terms of neurological recovery, pain scale scores, and complications. Surgical time was shorter and blood loss was less in the S group, whereas LKA at the final follow-up and correction loss were superior in the L group. Conclusion Although less invasiveness and validity of pain and neurological relief are secured by short-segment VP + PSF, surgeons should be cautious regarding correction loss.

Abstract Background and aim The pathophysiology of rheumatoid arthritis (RA) is characterized by excess production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) by neutrophils and macrophages in synovium. Additionally, these cytokines promote the production of reactive oxygen species (ROS), and increased production of matrix metalloproteinases (MMPs), including MMP-3, in synoviocytes that result in joint destruction. There is limited information on how proteolytic enzymes such as MMP-3 can be regulated. We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on RA and identified the relationship between the c-Jun N terminal kinase (JNK) pathway and MMP-3. We hypothesized that elucidating this relationship would lead to novel therapeutic approaches to RA treatment and management. Methods We investigated the effect of administering a low dose (1000 μM or less) of an antioxidant (NAC) to human rheumatoid fibroblast-like synoviocytes (MH7A cells). We also investigated the response of antioxidant genes such as nuclear factor erythroid -derived 2-related factor 2 (Nrf2) and Sequestosome 1 (p62). The influence of MMP-3 expression on the JNK pathway leading to joint destruction and the mechanisms underlying this relationship were investigated through primary dispersion culture cells collected from the synovial membranes of RA patients, consisting of rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS). Results Low-dose NAC (1000 μM) increased the expression of Nrf2 and phospho-p62 in MH7A cells, activating antioxidant genes, suppressing the expression of MMP-3, and inhibiting the phosphorylation of JNK. ROS, MMP-3 expression, and IL-6 was suppressed by administering 30 μM of SP600125 (a JNK inhibitor) in MH7A cells. Furthermore, the administration of SP600125 (30 μM) to RA-FLS suppressed MMP-3. Conclusions We demonstrated the existence of an MMP-3 suppression mechanism that utilizes the JNK pathway in RA-FLS. We consider that the JNK pathway could be a target for future RA therapies.

Abstract The growth cone is a specialized structure that forms at the tip of extending axons in developing and regenerating neurons. This structure is essential for accurate synaptogenesis at developmental stages, and is also involved in plasticity-dependent synaptogenesis and axon regeneration in the mature brain. Thus, understanding the molecular mechanisms utilized by growth cones is indispensable to understanding neuronal network formation and rearrangement. Phosphorylation is the most important and commonly utilized protein modification in signal transduction. We previously identified microtubule-associated protein 1B (MAP 1B) as the most frequently phosphorylated protein among ~ 1200 phosphorylated proteins. MAP 1B has more than 10 phosphorylation sites that were present more than 50 times among these 1200 proteins. Here, we produced phospho-specific antibodies against phosphorylated serines at positions 25 and 1201 of MAP 1B that specifically recognize growing axons both in cultured neurons and in vivo in various regions of the embryonic brain. Following sciatic nerve injury, immunoreactivity with each antibody increased compared to the sham operated group. Experiments with transected and sutured nerves revealed that regenerating axons were specifically recognized by these antibodies. These results suggest that these MAP 1B phosphorylation sites are specifically involved in axon growth and that phospho-specific antibodies against MAP 1B are useful markers of growing/regenerating axons.

Abstract Background It was previously reported that pelvises with developmental dysplasia of the hip are tilted anteriorly, which increases bony coverage of the femoral head. This study aimed to investigate the correlation between anatomical parameters of the pelvis such as pelvic incidence and anatomical pelvic tilt and functional parameters of the spine and pelvis such as tilt of the anterior pelvic plane. Methods We examined 84 female patients with bilateral developmental dysplasia of the hip who had undergone curved periacetabular osteotomy at author’s institution. Radiographs of the thoracic to lumbar spines and the pelvis were obtained in the standing position to measure spino-pelvic parameters before surgery. Morphological parameters of the acetabulum such as the anterior center-edge (CE) angle, posterior CE angle, lateral CE angle, and acetabular anteversion were measured using a preoperative three-dimensional pelvic model reconstructed from computed tomography images. Pearson’s correlation analysis was conducted to evaluate the relationship of these parameters. Results With regard to correlations between pelvic incidence (PI) and other parameters, the sacral slope (SS) value (r = 0.666) was the highest among functional parameters and the anatomical-SS value (r = 0.789) was the highest among morphological parameters. There were moderate correlations of the anterior pelvic plane angle (APPA) with pelvic tilt (PT) (r = − 0.594) and anatomical-PT (r = 0.646). With regard to correlations between spino-pelvic parameters and bony morphological parameters of the acetabulum, there was a moderate correlation between anatomical-PT and acetabular anteversion (AA) (r = 0.424). There were moderate correlations of APPA with the anterior CE angle (r = − 0.478), posterior CE angle (r = 0.432), and AA (r = 0.565). APPA had a stronger correlation with anatomical-PT (r = 0.646) than with AA. Conclusions The tilt of the pelvis may be more dependent on anatomical-PT, a morphological parameter of the pelvis, than the lateral CE angle, anterior CE angle, posterior CE angle, and acetabular anteversion on bony coverage of the acetabulum. This study is the first to investigate the correlation between functional parameters of the pelvis and spine and morphological parameters of the pelvis and acetabulum besides PI.

Abstract Background This study was conducted to determine gender differences in the relationship between extracurricular sports activities (ECSA) and low back pain (LBP) in children and adolescents. Methods In a cohort analysis of a 6-year birth cohort annual survey, students were followed from the fourth to sixth grades of elementary school (E4–E6; 9–12 years old) through the first to third grades of junior high school (J1–J3; 12–15 years old). All students completed annual questionnaires on ECSA and LBP. The odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the association strength between ECSA and LBP. We also calculated the population attributable fraction (PAF), which was defined as the proportion of students with ECSA-related LBP among all students with LBP. Results ECSA was significantly associated with LBP only in grade J3 among boys (OR: 2.00, 95% CI: 1.47–2.71). On the other hand, among girls, ECSA was significantly associated with LBP in grades E5 (OR: 1.48, 95% CI: 1.00–2.20), E6 (OR: 1.91, 95% CI: 1.33–2.75), and J3 (OR: 1.81, 95% CI: 1.26–2.61). Among boys, PAF was similar in all grades (range, 10–16%), whereas among girls, the PAF varied (− 11 to 29%) and was significantly higher in girls than in boys in grades E5 (19.0% vs. 1.1%, P

Abstract Background We assessed the morphological differences in the knee joint related to knee rotation angle in patients with hip dysplasia. These results may explain the anatomy of the knee in patients with hip dysplasia and aid in planning knee surgery. Methods We enrolled 73 women (146 legs, 35.6 ± 9.0 years) with bilateral hip dysplasia and 45 healthy women (90 legs, 49.0 ± 18.9 years) without lumbago, knee symptoms, or osteoarthritic findings of the knee or spine on plain radiographs. We examined the parameters affecting knee rotation angle, such as the condylar twist angle and femoral condyle measurements with a three-dimensional bone model using the correlation coefficients of each parameter. Results The condylar twist angle and the length of the posterior part of the lateral femoral condyle were statistically positively correlated with knee rotation angle in both the normal (condylar twist angle: r = 0.286, p = 0.007, posterolateral: r = 0.429, p

Abstract Background Sagittal spinal balance and standing posture are affected by pelvic morphology, especially pelvic incidence (PI). However, it is not difficult to identify the hip center because of overlap of the pelvis, image contrast, and soft tissue artifacts. Measurements of PI are not always suitable in all patients, especially those with osteoarthritis of the hip joint whose femoral head is nonspherical, subluxed, or dislocated. We measured PI, pelvic tilt (PT), and sacral slope (SS) as anatomical parameters using a novel three-dimensional measurement in order to compare the pelvic morphology between normal, healthy men and women. Methods In this cross-sectional study, we evaluated 108 Japanese subjects (55 men, 53 women) without low back or knee pain. We used the three-dimensional pelvis model adjusted to the anterior pelvic plane and measured the pelvic parameters. The subjects were stratified by age ( 0.87. Conclusions We found a strong correlation between PI and anatomical-SS in men and women. This novel measurement concept may be useful to estimate PI from anatomical-SS because the measurements of PI are not always suitable in all patients, especially those with osteoarthritis of the hip joint whose femoral head is not spherical or whose femoral head is subluxed or dislocated. This is the first report to describe the relationship between PI, anatomical-PT, and anatomical-SS as morphologic parameters with a high interclass correlation coefficient for intraobserver and interobserver reliabilities.

Study Design Retrospective case series. Purpose To investigate the oncological outcomes, including distant relapse, after en bloc spondylectomy (EBS) for spinal metastases in patients with a minimum of 2-year follow-up. Overview of Literature Although EBS has been reported to be locally curative and extend survival in select patients with spinal metastases, detailed reports regarding the control of distant relapse after EBS are lacking. Methods We conducted a retrospective review of 18 consecutive patients (median age at EBS, 62 years; range, 40–77 years) who underwent EBS for spinal metastases between 1991 and 2015. The primary cancer sites included the kidney (n=7), thyroid (n=4), liver (n=3), and other locations (n=4). Survival rates were estimated using the Kaplan–Meier method, and groups were compared using the log-rank method. Results The median operative time and intraoperative blood loss were 767.5 minutes and 2,375 g, respectively. Twelve patients (66.7%) experienced perioperative complications. Five patients (27.8%) experienced local recurrence of the tumor at a median of 12.5 months after EBS, four of which had a positive resection margin status. Thirteen patients (72.2%) experienced distant relapse at a median of 21 months after EBS. The estimated median survival period after distant relapse was 20 months (95% confidence interval, 0.71–39.29 months). No association was found between resection margin status and distant relapse. Overall, the 2-year, 5-year, and 10-year survival rates after EBS were 72.2%, 48.8%, and 27.1%, respectively. Importantly, the era in which EBS was performed did not impact the oncological outcomes. Conclusions Our results suggest that EBS by itself, even if margin-free, cannot prevent further dissemination, which occurred in >70% of patients at a median of 21 months after EBS. These results should be considered and conveyed to patients for clinical decision-making.

Abstract Background To date, there have been little published data on surgical outcomes for patients with PD with thoracolumbar OVF. We conducted a retrospective multicenter study of registry data to investigate the outcomes of fusion surgery for patients with Parkinson’s disease (PD) with osteoporotic vertebral fracture (OVF) in the thoracolumbar junction. Methods Retrospectively registered data were collected from 27 universities and their affiliated hospitals in Japan. In total, 26 patients with PD (mean age, 76 years; 3 men and 23 women) with thoracolumbar OVF who underwent spinal fusion with a minimum of 2 years of follow-up were included (PD group). Surgical invasion, perioperative complications, radiographic sagittal alignment, mechanical failure (MF) related to instrumentation, and clinical outcomes were evaluated. A control group of 296 non-PD patients (non-PD group) matched for age, sex, distribution of surgical procedures, number of fused segments, and follow-up period were used for comparison. Results The PD group showed higher rates of perioperative complications (p

Abstract Background The inclination of the medial compartment of the proximal tibia (MCT) is assumed to be a critical factor for varus alignment in advanced knee osteoarthritis (OA). This study was aimed at investigating; (1) whether the inclination of MCT is aligned parallel to the ground under weight-bearing (WB) conditions; (2) whether this is associated with the change in alignment and the relative position between the bones; and (3) whether the tibia or femur mainly contributes to the changes. Methods We examined 102 knees (84 women, 18 men; mean 75 years). A three-dimensional (3D) assessment system was applied on biplanar whole lower extremity radiographies using 3D-to-2D image registration technique. The evaluation parameters were 1) MCT angle, 2) femorotibial angle (FTA), 3) medial-lateral femoral location to the tibia (M-L femoral location), 4) WB line passing point, and 5) tibial position to WB line (tibial position) and 6) femoral postion to WB line (femoral position). Each parameter was evaluated in non-WB and WB conditions, and the differences (Δ-parameters). Results MCT angle in the world coordinate system was larger than that in the tibial coordinate system (p

Atypical femoral fracture is a low-energy stress fracture in the subtrochanteric region or the femoral shaft and is a complication of the long-term use of bisphosphonates. Histopathological findings of atypical femoral fractures have not been clarified. Herein, we report the case of a 61-year-old woman who fell while walking, which prompted her to visit our facility. She had a 7-year history of alendronate use to treat osteoporosis. A radiograph showed an atypical subtrochanteric femoral fracture, following which she underwent a primary surgery, where an intramedullary femoral nail was used. Implant breakage was discovered 8 weeks after the primary surgery. The patient underwent a revision surgery in which the entry point for the revised intramedullary hole was created to prevent varus position. The lag screw was successfully inserted into the center of the femoral head. Cancellous bone, isolated from the right ilium, was autogenously implanted into the fracture site. Fracture healing was promoted using low-intensity pulse ultrasonography. Callus formation was detected on a radiograph, and full weight-bearing was advised 12 weeks after the revision surgery. The fracture had healed completely at 13 months after the revision surgery. The patient was able to walk without support and could independently perform activities of daily life. Laboratory findings suggested that the concentrations of her bone formation markers were normal, while those of bone resorption markers were elevated. Iliac bone histomorphometry did not reveal severely suppressed bone turnover. In the cortex of fracture site, the lacunar density was markedly lower than the osteocyte density, and microcracks were detected, suggesting impaired osteocyte function and a low potential for fracture healing. This case is notable because it helps to clarify the histopathological findings of atypical femoral fractures.

Background: Previous studies have reported associations between nonalcoholic fatty liver disease, periodontitis, and obesity. Serum immunoglobulin G (IgG) antibody titer against Porphyromonas gingivalis, a major pathogen of periodontitis, is an established indicator of periodontal infection. However, the relationship between the antibody titer and liver enzyme levels has not been clarified yet. A study in the elderly was needed to evaluate the effect of long-term persistent bacterial infection on liver function. The objective of this study was to investigate the association between liver function and infection by P. gingivalis, and the effect of obesity on the association. Methods: A cross-sectional study was conducted in adult outpatients visiting Sado General Hospital, in Niigata Prefecture, Japan, from 2008 to 2010. The final participants included 192 men and 196 women (mean age 68.1 years). Multivariable logistic regression analyses were performed to assess the association between the serum IgG antibody titer and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamine transferase (GGT) levels. Results: In women, serum IgG antibody titers against P. gingivalis was associated with elevated ALT, but not with AST or GGT, independent of covariates (p = 0.015). No significant association was found between the antibody titer and the elevated liver enzymes in men. The effect of obesity on the relationship between antibody titer and liver enzyme levels was not statistically significant. Conclusions: A cross-sectional analysis of adult outpatients suggested an association between P. gingivalis infection and ALT levels in women. The effect of obesity on this association was not statistically significant.

Forefoot deformities are common among patients with rheumatoid arthritis (RA). Herein, we describe a case of intractable ulceration on the dorsomedial aspect of the right 5th digit, secondary to forefoot deformity, in a 76-year-old woman with a 35-year history of RA. The ulcer was due to a persistent subcutaneous infection. Although the infection was controllable with antibiotics, there was concern of relapse because of the abnormal pressure on the skin due to an overlap of the 4th and 5th digits. We proceeded with surgical correction of the forefoot alignment, including shortening oblique osteotomy of metatarsals 2 through 5, rather than amputation of the 5th digit. Following surgery, targeted antibiotic treatment was provided. The postoperative course was unremarkable, and the patient recovered weight-bearing function without recurrence of pain or ulceration. Forefoot realignment is a feasible option that should be considered for treating intractable foot pain and ulceration secondary to long-lasting RA.

Abstract Background Humans support their bodies exclusively by vertical balance in bipedal locomotion, and the body, especially the lower extremity, generally changes with age. Sex and body constitution are assumed to be associated with lower extremity alignment, but this association remains to be elucidated. This study sought to clarify this association in healthy, elderly, non-obese humans in a Japanese population. Methods The present study investigated 55 healthy volunteers (mean age: 70 ± 6 years). A 3D extremity alignment system was applied under weight-bearing conditions on biplane long lower extremities X-rays using a 3D-to-2D image registration technique. The evaluation parameters included 3D hip-knee-ankle angle (3DHKA) alignment in the coronal (coronal alignment) and sagittal planes (sagittal alignment) and rotational alignment between the femur and tibia. The influences of sex and body constitution on all the alignment were analyzed. Results Multiple linear regression analysis with the dependent variable of each alignment showed that sex was the dominant factor for coronal and rotational alignment (coronal: p

Abstract Background We previously described that the anteroposterior (AP) axis of the tibia is approximately perpendicular to the transverse axis of the anterior pelvic plane (APP) in the standing position in healthy subjects. The purpose of this study was to investigate the rotational alignment between the APP and clinical epicondylar axis and the AP axis of the tibia relative to pelvic coordination in the standing position in normal subjects and in women with developmental dysplasia of the hip (DDH) to aid decision making for surgeons in the alignment of implants in total hip or knee arthroplasty. Methods This study included 77 Japanese women. Twenty-nine in the DDH group underwent curved periacetabular osteotomy; 48 women without lumbago and knee pain were included in the normal group. Femoral neck anteversion (FNA), condylar twist angle, and knee rotation angle were measured in femoral coordination. The angle between the femoral neck axis and clinical epicondylar axis (CEA) was measured, the transverse axis of the APP was also measured, and the angle between the AP axis of the tibia and transverse axis of the APP was calculated. Results There was a moderate negative correlation between FNA and CEA relative to the APP. This finding indicated a trend towards greater FNA leading to more internal rotation. Knee rotation angle (KRA) relative to the APP was 1.65° ± 5.58° in the normal group and − 2.65° ± 7.57° in the DDH group. This finding indicated that the tibia AP axis was approximately perpendicular to the APP in the standing position both in the normal and DDH groups. Conclusion We found that the tibia AP axis was at approximately a right angle to the transverse axis of the APP in the standing position in both the normal and DDH groups, while the KRA was different in the normal and DDH groups. These findings may prove helpful for positional alignment investigations needed for implantation in total hip or knee arthroplasty and gait analysis.

Abstract Background We previously reported that the clinical epicondylar axis (CEA) was approximately parallel to the transverse axis of the anterior pelvic plane (APP) in the standing position in normal subjects. The purpose of this study was to investigate the rotational alignment between APP in the standing position and the anteroposterior (AP) axis of the tibia relative to pelvic coordination in normal subjects. Methods This study included 68 healthy Japanese, 24 males and 44 females, without lumbago and knee pain. Femoral neck anteversion (FNA), condylar twist angle, and knee rotation angle were measured in femoral coordination. The angle between the femoral neck axis and CEA transverse axis of APP was also measured, and the angle between the AP axis of the tibia and the transverse axis of APP was calculated. The mean value of knee rotation angle was 0.23° and 2.06° in male and female subjects, respectively. Results There was a moderate positive correlation between FNA and the femoral axis angle relative to the transverse axis of APP. The knee rotation angle relative to APP was 0.33° and 1.56° in male and female subjects, respectively, and the tibia AP axis was approximately perpendicular to the transverse axis of APP in the standing position. Regarding validation, we obtained high interclass correlation coefficients for both intraobserver and interobserver reliability. Conclusion We found that the knee rotation angle was almost 0° and that the tibia AP axis was approximately perpendicular to the CEA. The tibia AP axis was also approximately perpendicular to the transverse axis of the APP in standing position.

Abstract Porhyromonas gingivalis, a causative bacterium of periodontitis, is implicated in the etiology of rheumatoid arthritis (RA), mainly because of expressing peptidyl arginine deiminase (PAD) that generates RA-related autoantigens. However, compared with other periodontopathic bacteria, the precise role of P. gingivalis in RA is largely unknown. We found that orally administered P. gingivalis changed the gut microbiome with concomitant elevation of serum endotoxin and inflammatory markers, and impairment of the gut barrier function. Based on findings showing a relationship between gut microbiota and RA, we investigated whether the change of gut microbiota induced by P. gingivalis and Prevotella intermedia, another periodontopathic bacterium without PAD, is associated with collagen-induced arthritis (CIA). DBA/1J mice were orally administered with or without bacteria followed by induction of CIA. P. gingivalis, but not P. intermedia, administration significantly aggravated arthritis with increased interleukin-17 levels in sera and culture supernatants, increased Th17 cell proportions among mesenteric lymphocytes, and a significant change in the gut microbiome. However, P. gingivalis administration did not elevate the level of anti-citrullinated protein antibody. These results suggest a unique role of P. gingivalis in the link between periodontitis and RA by affecting the gut immune system and the gut microbiota composition.

Abstract Background A solitary fibrous tumour (SFT) is an unusual neoplasm typically found in soft tissues. Although SFTs can arise in the bones, they very rarely arise in the vertebral arch. Here, we describe a case of a SFT that arose in the vertebral arch of the first lumbar (L1) spinal vertebrae and mimicked osteosarcoma. Case presentation A 49-year-old woman presented with a 2-month history of lower back pain and a lumbar region mass. Magnetic resonance imaging demonstrated a heterogeneously enhanced mass in the L1 vertebral arch. The patient received neoadjuvant chemotherapy, followed by a surgical procedure comprising an anterior spinal fusion and en bloc resection. Histologically, our initial diagnosis was osteosarcoma. The postoperative course was uneventful, and the patient received adjuvant chemotherapy. However, the tumour metastasised to the lung 5 years after the first surgery, and a second surgery was performed for lung tumour resection. The histology of the metastatic lung tumour appeared similar to that of the malignant SFT, and the specimen from the first surgery was re-examined. Immunohistochemically, the tumour was positive for STAT6. Reverse transcription-polymerase chain reaction revealed a NAB2-STAT6 fusion gene, thus confirming our final diagnosis of malignant SFT. The patient died of disease progression 8 years after the first surgery; however, there was no evidence of local recurrence. Conclusions Malignant SFT in the vertebral arch is extremely rare and very difficult to distinguish histologically an osteoid from lace-like collagen. STAT6 immunostaining is useful for distinguishing malignant SFTs from other neoplasms. Although it is difficult to completely resect a SFT arising from the spine, we demonstrated the feasibility of an en bloc resection of spinal tumours arising from posterior elements, without local recurrence.

Purpose: This study aimed to investigate radiographic outcomes after posterior spinal fusion (PSF) for pediatric patients younger than 10 years with upper cervical disorders. Methods: Thirteen patients (mean age at surgery, 5.9 years; range, 1 to 9 years) who underwent PSF with a minimum of 2 years of follow-up (mean, 5.8 years) were included. Diagnoses were atlanto-axial instability due to congenital disorders for 11 patients and atlanto-axial rotatory fixation for 2 patients. The fusion area was occipito-cervical for 7 patients and C1/2 for 6 patients. PSF was performed using rigid screw-rod constructs for 6 patients and conventional techniques for 7 patients. Ten patients required halo immobilization after surgery. Fusion status, perioperative complications, radiographic alignment, and range of motion (ROM) from C2 to C7 were evaluated. Results: Twelve patients successfully achieved bony fusion (fusion rate, 92%), but complications occurred in 5 patients. Regarding radiographic measures (preoperative/postoperative/final follow-up), the mean atlanto-dental interval was significantly reduced (8.0 mm/2.7 mm/3.5 mm) and the C2-7 ROM was increased (from 49.4 degrees to 66.0 degrees) at the final follow-up (both comparisons, p

Purpose: Anatomical sacral slope (a-SS), a pelvic anatomical parameter that does not require the center of the femoral head, strongly correlates with pelvic incidence (PI) during three-dimensional measurements in normal subjects. Sagittal alignment of spinal and pelvic parameters is typically evaluated using two-dimensional radiographs; however, the relationship between a-SS and PI has not been evaluated using radiographs. This study aimed to evaluate the correlation between a-SS and other spinal and pelvic parameters using radiographs. Methods: We evaluated 144 healthy women. Using sagittal radiographs, we measured lumbar lordosis (LL), thoracic kyphosis, PI, SS, pelvic tilt, and a-SS, which were defined as the angle between the superior end plate of S1 and a line perpendicular to the anterior pelvic plane. Pearson coefficients were used to determine correlations, and intraobserver and interobserver intraclass correlation coefficients (ICCs) were used for validation. Results: There was a strong correlation between PI and a-SS ( r = 0.756). Moreover, correlations between a-SS and LL and between PI and LL were similar ( r = 0.661 and r = 0.554, respectively). The intraobserver ICCs were 0.884 for a-SS and 0.840 for PI. The interobserver ICCs were 0.856 for a-SS and 0.653 for PI. Conclusion: a-SS was strongly correlated with PI. The correlation between a-SS and LL was equivalent to the correlation between PI and LL. Moreover, the ICC for a-SS was larger than that of PI. This study suggests that a-SS is a useful new pelvic anatomical parameter that can be used instead of PI.

The natural history of asymptomatic retroperitoneal schwannomas is poorly understood. This study aimed at investigating the natural history of incidental retroperitoneal schwannomas. The medical charts and imaging studies of 22 asymptomatic patients under observation for at least 12 months for retroperitoneal schwannomas were reviewed. The duration of follow-up ranged between 13 and 176 months (mean 48 months). In the 22 patients managed by the "wait and see" approach, the average tumor size at initial presentation was 51 mm, which increased to 57 mm at final follow-up. During the final follow-up, 2 patients required surgical treatment for tumor enlargement, while the remaining patients remained asymptomatic without surgery. The average growth rate of the tumors was 1.9 mm/year (range: -1.9 to 8.7 mm/year). The majority of asymptomatic retroperitoneal schwannomas demonstrate minimal growth and may be suitable for management with the "wait and see" approach.

Background/Aims: Evidence on modifiable factors associated with cognitive impairment in Japanese patients is scarce. This study aimed to determine modifiable factors for cognitive impairment in a Japanese hospital-based population. Methods: Subjects of this cross-sectional study were 1,143 patients of Sado General Hospital (Niigata, Japan) registered in the Project in Sado for Total Health (PROST) between June 2008 and September 2014. We assessed disease history, body mass index (BMI), leisure time physical activity, walking time, smoking and drinking habits, and consumption of vegetables, fruits, and green tea as predictors, with cognitive impairment defined by the Mini-Mental State Examination (score Results: The mean subject age was 68.9 years, and the prevalence of cognitive impairment was 21.5%. Multivariate analysis revealed that age (p Conclusions: Modifiable factors, such as low BMI, low fruit consumption, and low green tea consumption, are associated with cognitive impairment. Longitudinal studies will be needed to confirm these findings.

Background/Aims: We aimed to determine whether the concentration of serum C-reactive protein (CRP) is associated with cognitive function in an adult Japanese population. Methods: Participants of this cross-sectional study were from a subgroup of the Project in Sado for Total Health (PROST; n = 454; mean age, 70.5 years). The cognitive state was evaluated using the Mini-Mental State Examination (MMSE), and those with an MMSE score APOE allele. Results: Of the 454 participants, 94 (20.7%) were cognitively declined. Relative to the lowest (first) quartile of CRP concentration, adjusted ORs were 1.29 (95% CI 0.61-2.75) for the second, 1.78 (95% CI 0.82-3.86) for the third, and 3.05 (95% CI 1.45-6.42) for the highest (fourth) quartiles (p for trend = 0.018). When data were stratified by sex, the association between CRP concentration and cognitive decline was observed only in women. Conclusion: Our findings suggest an association between higher CRP concentration and lower cognitive function. Chronic inflammation may affect cognitive function in adults, in particular women.

Bone modeling is a biological process of bone formation that adapts bone size and shape to mechanical loads, especially during childhood and adolescence. Bone modeling in cortical bone can be easily detected using sequential radiographic images, while its assessment in trabecular bone is challenging. Here, we performed histomorphometric analysis in 21 bone specimens from biopsies collected during hip arthroplasty, and we proposed the criteria for histologically identifying an active modeling-based bone formation, which we call a “forming minimodeling structure” (FMiS). Evidence of FMiSs was found in 9 of 20 specimens (45%). In histomorphometric analysis, bone volume was significant higher in specimens displaying FMiSs compared with the specimens without these structures (BV/TV, 31.7 ± 10.2 vs. 23.1 ± 3.9%; p

INTRODUCTION:Posterior tibial slope (PTS) and sagittal alignment are important factors in the etiology of knee osteoarthritis and knee surgery. Clinically, sagittal alignment, which indicates flexion contracture of the knee, contributes to knee function in weight-bearing (WB) conditions. PTS and sagittal alignment under WB conditions in varus osteoarthritic knees are presumed to affect each other, but their association remains unclear. In this study, we aimed to clarify the association. MATERIAL AND METHODS:In total, 140 osteoarthritic varus knees were investigated. Under WB conditions, a three-dimensional (3D) alignment assessment system was applied via biplanar long-leg X-rays, using 3D-to-2D image registration technique. The evaluation parameters were as follows: 1) 3D mechanical flexion angle (3DMFA) in regards to sagittal alignment, 2) passing point in the WB line (PP), and 3) medial and lateral PTS. RESULTS:The medial and lateral PTS showed a positive correlation with 3DMFA and PP, respectively (medial PTS-3DMFA, p = 0.001; medial PTS-PP, p < 0.0001; lateral PTS-3DMFA, p < 0.0001; lateral PTS-PP, p = 0.002). The flexion contracture group with 3DMFA >5° demonstrated greater PTS than non-flexion contracture group (medial PTS, p = 0.006; lateral PTS, p = 0.006). CONCLUSIONS:Both medial and lateral PTS were correlated with sagittal alignment under WB conditions and were larger in the flexion contracture group. This finding can explain the function to take the load articular surface parallel to the ground for holding the balance in WB conditions in the sagittal plane for osteoarthritic knees. Moreover, surgeons may be required to decrease the PTS during knee arthroplasty to restore full extension in knees of patients with fixed flexion contracture.

To understand the neural mechanisms underlying the therapeutic effects of crossing nerve transfer for brachial plexus injuries in human patients, we investigated the cortical responses after crossing nerve transfer in mice using conventional and tomographic optical imaging. The distal cut ends of the left median and ulnar nerves were connected to the central cut ends of the right median and ulnar nerves with a sciatic nerve graft at 8 weeks of age. Eight weeks after the operation, the responses in the primary somatosensory cortex (S1) elicited by vibratory stimulation applied to the left forepaw were visualized based on activity-dependent flavoprotein fluorescence changes. In untreated mice, the cortical responses to left forepaw stimulation were mainly observed in the right S1. In mice with nerve crossing transfer, cortical responses to left forepaw stimulation were observed in the left S1 together with clear cortical responses in the right S1. We expected that the right S1 responses in the untreated mice were produced by thalamic inputs to layer IV, whereas those in the operated mice were mediated by callosal inputs from the left S1 to layer II/III of the right S1. To confirm this hypothesis, we performed tomographic imaging of flavoprotein fluorescence responses by macroconfocal microscopy. Flavoprotein fluorescence responses in layer IV were dominant compared to those in layer II/III in untreated mice. In contrast, responses in layer II/III were dominant compared to those in layer IV in operated mice. The peak latency of the cortical responses in the operated mice was longer than that in the untreated mice. These results confirmed our expectation that drastic reorganization in the cortical circuits was induced after crossing nerve transfer in mice.

Instability after total knee arthroplasty is a critical problem. The purpose of this study was to clarify the stability of implanted knees during walking by comparing differences in dynamic instability during knee acceleration between individuals with or without previously experienced subjective instability, as measured by self-reported questionnaire.We examined 92 knees with medial pivot implants. Mean patient age and follow-up duration were 78.4 years and 32.8 months, respectively. An accelerometer was used to investigate the accelerations along three axes; that is, vertical (VT), mediolateral (ML), and anteroposterior (AP) directions in 3-dimensional (3D) space. The analysis in the stance phase and gait cycle was performed by: (1) root mean square (RMS) values of acceleration and (2) frequency domain analysis using fast Fourier transformation (FFT). A self-reported knee instability score was used for the subjective feeling of instability.A total of 76 knees did not feel unstable (group 0), but 16 knees felt unstable (group 1) in patients during activities of daily living. Regarding the RMS, there were no differences in each direction between the groups. For FFT, the cumulative amplitude in the frequency < 30 Hz also showed no significant differences in all directions between the groups during the stance phase (VT, p = 0.335; ML, p = 0.219; AP, p = 0.523) or gait cycle (VT, p = 0.077; ML, p = 0.082; AP, p = 0.499).Gait analysis based on the acceleration data showed that there were no between-group differences in objective dynamic instability during acceleration of the knee, with or without reports of previously experienced subjective instability, as assessed by the self-reported questionnaire.

Vibratory and joint position sensations are usually impaired simultaneously and afferents for both sensations ascend the dorsal columns. There are a few evidences that the central pathways in the spinal cord for position and vibratory sensations are not identical. In this study, we examined the clinical features of patients with sensory impairments of vibratory and joint position sensations. According to 43 evaluated patients' results, the dissociation between an intact vibratory sensation and impaired joint position sensation may be important for the diagnosis of spinal disorders. We also report three cases of patients with spinal ataxia caused by sensory impairments and who show the dissociation between an impaired joint position sensation and an intact vibratory sensation. The combination of intact vibration sensation and impaired joint position sensation may suggest a dorsal column lesion in the spinal cord.

BACKGROUND:We recently reported that tranexamic acid (TXA) evokes pain in rats by inhibiting γ-aminobutyric acid and glycine receptors on neurons in the spinal dorsal horn. Although TXA is commonly used to reduce perioperative blood loss during various surgeries, its potential to induce intraoperative nociception, thereby increasing the need for more analgesics during surgery, has not been investigated. Therefore, this study aimed to investigate whether TXA evokes pain and increases the need for a higher infusion rate of remifentanil in patients undergoing surgery for adolescent idiopathic scoliosis (AIS). METHODS:Data were collected from patients with AIS who underwent posterior spinal fusion surgery from January 2008 to December 2015. All surgical procedures were performed under total intravenous anesthesia with propofol and remifentanil, by the same team of orthopedic surgeons and anesthesiologists at a single institution. Patients in the TXA group were administered TXA (loading and maintenance doses, 1000 mg and 100 mg/h) whereas those in the control group were not. Our primary outcome was the infusion rate of the intraoperative opioid analgesic remifentanil. RESULTS:The final analysis was based on data collected from 33 and 30 patients in the control and TXA groups, respectively. No differences were observed in the demographic data or the hemodynamic parameters between the two groups of patients. In the TXA group, the durations of surgery and anesthesia were shorter, intravascular fluid volume and total blood loss were lower, and the doses of fentanyl and ketamine administered were higher than they were in the control group (P < 0.05 for all). The mean infusion rate of intraoperative remifentanil was significantly higher in the TXA group than in the control group (control group: 0.23 ± 0.04 μg/kg/min; TXA group: 0.28 ± 0.12 μg/kg/min; P = 0.014). CONCLUSIONS:Patients who received TXA during the AIS surgery required a higher infusion rate of remifentanil, indicating that TXA evoked pain during the surgery.

Plasma D-dimer level is clinically useful for diagnosing patients with suspected deep vein thrombosis (DVT). However, the cut-off value for the D-dimer level remains controversial and undetermined with regard to total hip arthroplasty (THA). The objective of this study was to estimate the efficacy of an age- and D-dimer-based index for diagnosing DVTs in asymptomatic cases before THA. We enrolled 224 patients with no symptoms associated with DVT before THA. All the patients underwent ultrasonography, and the plasma D-dimer level was recorded about 1 month preoperatively. The optimal cut-off value was calculated using multiple logistic regression and receiver operating curve analyses. DVTs were detected in 13 patients (5.8%) using ultrasonography. Multiple logistic regression analysis demonstrated that age (odds ratio [OR]: 1.13; p = 0.007) and D-dimer value (OR: 1.74; p = 0.003) were related to the existence of preoperative DVT. A DVT index (0.12 × age + 0.45 × the D-dimer value) of 8.15 was the most reasonable cut-off value according to the receiver operating curve analysis. This value caused 100% sensitivity and 70.1% specificity, with an area under the curve (AUC) of 0.905 (range, 0.836-0.975). For age and D-dimer value, the AUCs were 0.828 (0.749-0.907) and 0.716 (0.522-0.910), respectively. This study demonstrated that age and D-dimer index can be useful in screening patients for DVTs before THA. This DVT index is also easy to calculate and may be clinically significant.

Background Mutations in the coding sequence of SCN5A, which encodes the cardiac Na+ channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias. Methods and Results We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild‐type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity. Conclusions Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.

BACKGROUND:Bedridden patients are at risk of osteoporosis and fractures, although the long-term bone metabolic processes in these patients are poorly understood. Therefore, we aimed to determine how long-term bed confinement affects bone metabolism. METHODS:This study included 36 patients who had been bedridden from birth due to severe immobility. Bone mineral density and bone metabolism markers were compared to the bedridden period in all study patients. Changes in the bone metabolism markers during a follow-up of 12 years were studied in 17 patients aged

The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.

We developed a new estimation system using rapid prototyping technology that focuses on the relationship between the architecture and mechanical properties of trabecular bone. The system uses three-dimensional acrylic resin models of trabecular bone constructed from micro-CT data to predict the mechanical properties of trabecular bone. We used this method to clarify the relationship between loading orientation and bone fragility in the vertebral trabecular bone of ovariectomized (OVX) rats. Twenty 6-week-old female Wistar rats were randomly divided into two groups (OVX and normal groups). Five rats from each group were killed at 3 and 6 weeks following operations and the L4 vertebra was removed. Bone specimens from both groups were scanned using a micro-CT system. Subsequently, resin models of the bone were fabricated at 60× magnification from the micro-CT data sets using laser stereolithography. The resin models were subjected to compressive testing in three orthogonal orientations corresponding to the craniocaudal, mediolateral, and anteroposterior anatomic axes. The results showed that the elastic modulus and ultimate stress were lower in the models of OVX rats than in the normal rats, the mechanical properties of trabecular bone structure from OVX rats deteriorated with increasing time postoperatively, and the elastic moduli in the mediolateral and anteroposterior axes were especially reduced relative to the decrease in the craniocaudal axis in the OVX rats.

The morbidity associated with idiopathic osteonecrosis of the femoral head (ION) is increasing. The primary goal of treatment for ION is to prevent collapse of the femoral head. With the exception of hip arthroplasties, current joint-preserving surgeries for ION require long-term reduction of the load placed on the hip joint. To allow these patients to return quickly to their daily and social activities, we have developed a novel extra-articular device that reduces the weight-bearing of the hip joint. In this study, we evaluated the load-bearing function and the range of motion of a hip joint equipped with the extra-articular device. To demonstrate load reduction on the hip joint with this device, we measured the contact pressure on the femoral head surface and the principal strain on the coxal bone during static loading conditions, which simulated the various phases of human gait. The range of motion of the hip joint with the device was measured using an electro-goniometer. The extra-articular device remarkably reduced the contact pressure on the hip joint, with some restriction in hip flexion. Our novel extra-articular device appears to be a promising tool to secure reductions in the weight-bearing function of the hip joint, and will be applicable to new bone regeneration therapies.

Over 7000 patients are suffering from osteonecrosis of the femoral head annually in Japan. The patients have to undergo surgical treatments if the femoral head collapsed. The mechanism of femoral head collapse is still unclear, although morphological and mechanical changes in the necrotic hard bones or the reparative soft tissues have been believed to cause this collapse. We analyzed three-dimensional morphological and mechanical changes in the metaphyseal cancellous bone during bone regeneration after traumatic osteonecrosis of young rat femoral head using a micro-CT. Morphological indices and apparent modulus were calculated based on parallel plate model and finite element model, respectively. Bone volume, trabecular thickness, and apparent modulus initially decreased on day 7 after osteonecrosis, and they gradually increased during regenerating process. These findings indicate that the structural rigidity of cancellous bone in the regenerative area transiently decreases after osteonecrosis. These changes possibly induce femoral head collapse. The reparative area should be a target to treat osteonecrosis of the femoral head.

Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P = 0.0004, OR 3.08, 95%CI 1.67-5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A(I334V), VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A(I334V) (1031±111 ms versus 932±182 ms, P = 0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A(I334V). Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A(I334V) genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A(I334V) in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA.

Avulsion of spinal nerve roots in the brachial plexus (BP) can be repaired by crossing nerve transfer via a nerve graft to connect injured nerve ends to the BP contralateral to the lesioned side. Sensory recovery in these patients suggests that the contralateral primary somatosensory cortex (S1) is activated by afferent inputs that bypassed to the contralateral BP. To confirm this hypothesis, the present study visualized cortical activity after crossing nerve transfer in mice through the use of transcranial flavoprotein fluorescence imaging. In naïve mice, vibratory stimuli applied to the forepaw elicited localized fluorescence responses in the S1 contralateral to the stimulated side, with almost no activity in the ipsilateral S1. Four weeks after crossing nerve transfer, forepaw stimulation in the injured and repaired side resulted in cortical responses only in the S1 ipsilateral to the stimulated side. At eight weeks after crossing nerve transfer, forepaw stimulation resulted in S1 cortical responses of both hemispheres. These cortical responses were abolished by cutting the nerve graft used for repair. Exposure of the ipsilateral S1 to blue laser light suppressed cortical responses in the ipsilateral S1, as well as in the contralateral S1, suggesting that ipsilateral responses propagated to the contralateral S1 via cortico-cortical pathways. Direct high-frequency stimulation of the ipsilateral S1 in combination with forepaw stimulation acutely induced S1 bilateral cortical representation of the forepaw area in naïve mice. Cortical responses in the contralateral S1 after crossing nerve transfer were reduced in cortex-restricted heterotypic GluN1 (NMDAR1) knockout mice. Functional bilateral cortical representation was not clearly observed in genetically manipulated mice with impaired cortico-cortical pathways between S1 of both hemispheres. Taken together, these findings strongly suggest that activity-dependent potentiation of cortico-cortical pathways has a critical role for sensory recovery in patients after crossing nerve transfer.