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Introduction: Low-back pain causes sleep disorders, which impairs the quality of life (QOL) of patients. Sleep disorders are associated with lumbar spinal stenosis (LSS); however, the postoperative effects of LSS surgery on sleep disorders are unknown. This study aimed to assess sleep disorders in patients with LSS using wearable activity trackers and determine whether surgery improves sleep quality. Methods: A total of 39 patients scheduled for LSS surgery (mean age 71.1±8.7 years; 22 men and 17 women) were studied. Sleep disorders in the participants were objectively evaluated using a wearable Motionlogger Micro system. Sleep efficiency (SEf), mean active count (MAC), and wake after sleep onset (WASO) were measured before and 6 months following surgery. Furthermore, the patient-based outcomes of pain and QOL-related scores were measured and compared with those of healthy participants. The group with improved SEf following surgery was designated as “nonpoor sleepers,” whereas the group that did not exhibit improvements was designated as “poor sleepers.” The two groups were compared based on patient factors, patient-based questionnaires, and sleep disorder measurements. Results: The SEf and WASO were significantly worse in patients with LSS compared with healthy participants (P

Study Design Prospective cohort study (open-label, single-arm, and non-blinded). Purpose This study aims to determine the effects of systemic administration of tocilizumab, an anti-interleukin-6 (IL-6) receptor antibody on refractory low back pain and leg symptoms. Overview of Literature IL-6 overexpression is associated with neuropathic pain pathogenesis, which is potentially followed by chronic low back pain, including leg pain and numbness. This finding suggest that inhibition of IL-6 at the site of pain or in the transmission pathway could provide novel therapeutic targets for chronic low back pain. Methods This prospective, single-arm study included 11 patients (eight men; mean age, 62.7 years) with ≥3-months’ chronic pain history due to lumbar disease. Subcutaneous TCZ injections were administered twice, at a 2-week interval. We evaluated low back pain, leg pain, and leg numbness using numeric rating scales and the Oswestry Disability Index (ODI; baseline and 6 months postinjection); serum IL-6 and tumor necrosis factor-α levels (baseline and 1 month postinjection); and clinical adverse events. Results Intractable symptoms reduced after TCZ administration. Low back pain improved for 6 months. Improvements in leg pain and numbness peaked at 4 and 1 month, respectively. Improvements in ODI were significant at 1 month and peaked at 4 months. Serum IL-6 was increased at 1 month. IL-6 responders (i.e., patients with IL-6 increases >10 pg/mL) showed particularly significant improvements in leg pain at 2 weeks, 1 month, and 2 months compared with nonresponders. We observed no apparent adverse events. Conclusions Systemic TCZ administration improved symptoms effectively for 6 months, with peak improvements at 1–4 months and no adverse events. Changing serum IL-6 levels correlated with leg pain improvements; further studies are warranted to elucidate the mechanistic connections between lumbar disorders and inflammatory cytokines.

Abstract Treprostinil is a chemically stable analog of prostacyclin, and inhaled treprostinil was developed to deliver the effects directly to the pulmonary vasculature while minimizing systemic side effects. The objective of the study was to evaluate the efficacy on hemodynamics and exercise capacity, safety, and pharmacokinetics (PK) of inhaled treprostinil in Japanese patients with pulmonary arterial hypertension (PAH). Inhaled treprostinil was administered at three breaths (18 μg)/session four times daily, and the dose was gradually increased to a maximum of nine breaths (54 μg)/session. Endpoints included change in pulmonary vascular resistance index (PVRI) as primary, other efficacy parameters, safety, and PK. Seventeen PAH patients, the majority of whom (76.5%) had been receiving both an endothelin receptor antagonist (ERA) and a phosphodiesterase type‐5 (PDE5) inhibitor/soluble guanylate cyclase (sGC) stimulator, received inhaled treprostinil. At Week 12, PVRI statistically decreased by −39.4 ± 25.5% (95% confidence interval: −52.6 to −26.3). The most frequently reported adverse events related to treprostinil were headache, cough, throat irritation, and hot flush. Regarding PK, there were no notable differences in the geometric mean Cmax and AUClast between Japanese and non‐Japanese patients. Treatment with inhaled treprostinil using the dosing regimen approved in the United States resulted in significant improvement in hemodynamics, exercise capacity, and symptoms with a favorable tolerability and safety profile in Japanese patients. Inhaled treprostinil could be a valuable therapeutic option for Japanese patients with PAH, including those receiving a combination therapy with an ERA and a PDE5 inhibitor/sGC stimulator. Trial registration: JAPIC Clinical Trials Information [JapicCTI‐194651].

Pulmonary arterial hypertension (PAH) is a rare complication of ANCA-associated vasculitis (AAV). We report a 37-year-old man with PAH complicated by both AAV and SSc who presented with dyspnea, cardiac enlargement, positive myeloperoxidase (MPO)-ANCA, anti-centromere antibodies, proteinuria, and urinary casts. Elevated pulmonary arterial pressure (58/22/34 mmHg) and low PAWP (2 mmHg) were confirmed by right heart catheterization. Treatment with glucocorticoids (GC) decreased urinary protein and serum MPO-ANCA; however, PAH did not respond to GC. Therefore, a combination of beraprost, bosentan, and tadalafil was needed. The differences in responses to GC suggest that the pathophysiology of nephropathy is different from that of PAH. We considered that nephropathy was associated with AAV but that PAH was associated with SSc in the present case. We discuss the pathophysiology and treatment response of PAH complicated by AAV, referring to nine past cases.

Study Design Retrospective observational study. Purpose Lumbar spinal stenosis (LSS) has traditionally been evaluated morphologically, there is a paucity of literature on quantitative assessment of LSS. The purpose of this study was to investigate whether intraspinal diffusion tensor imaging (DTI) parameters such as apparent diffusion coefficient (ADC) and fractional anisotropy (FA) are useful for assessing LSS. Overview of Literature Quantitative assessment of LSS is challenging. Methods Study participants comprised five healthy volunteers (mean age, 27.2 years) and 27 patients with LSS (mean age, 58.4 years) who were individually assessed using 3.0 Tesla magnetic resonance imaging. Intraspinal ADC and FA values of 10 intervertebral discs from healthy volunteers and 52 intervertebral discs from LSS patients were measured. Also, intraspinal canal area, Schizas classification (A: normal, B: mild stenosis, C: severe stenosis) and correlations with symptoms were investigated. Clinical symptoms were checked for the presence of low back pain (LBP), intermittent claudication (IMC), and bladder and bowel dysfunction (BBD). Results Compared to healthy individuals, LSS patients had significantly lower ADC (p

Abstract This study examined the factors that inhibit the therapeutic effects of cognitive behavioral therapy (CBT) and clarify the adaptation judgment criteria of CBT. We included patients with chronic low back pain and allocated them to the adaptation (with visual analog scale [VAS] improvement) or non-adaptation group (without VAS improvement). The patients were analyzed using various psychological tests. CBT improved depressive symptoms and catastrophic thinking; however, they were not correlated with the VAS and did not directly affect low back pain improvement. The non-adaptation group showed an unexplainable/vague sense of anxiety; an excessive focus on searching for pain; a strong intimacy desire; a strong tendency of medical dependency; and fantasy or distortion of the actual experience, especially self-image. Moreover, the patients showed a low ability to objectively express or attribute meaning to pain due to poor language skills, attention-deficit hyperactivity disorder, and emotional value judgment. Individuals with the aforementioned characteristics of pre-CBT psychological tests should select a different treatment approach given the high poor-adaption possibility. Even patients with depressive or anxious symptoms are not necessarily adaptable for CBT. Therefore, pre-CBT tests for treatment suitability are necessary. Future studies should establish a protocol for psychotherapy suitable for the non-adaptation group.

Introduction: Mirogabalin should be equivalent to pregabalin, but with fewer incidences of adverse drug reactions (ADRs). To verify these benefits in actual clinical trials, our study investigated the frequency of ADRs and mirogabalin's analgesic effects during treatment of peripheral neuropathic pain. Methods: This study included 74 patients with lower limb pain. We surveyed patient reports of ADRs during the follow-up period as the primary endpoint and examined the visual analog scale (VAS) reported for lower limb pain as the secondary endpoint (before administration, and two and four weeks after administration). Results: The occurrence of ADR was 27.0%, like the frequency of ADRs in the clinical trials for other disorders. However, the discontinuation rate of administration was 10.8%, which was significantly lower than the frequency of ADR occurrences. When the analgesic effect was assessed, a significant decrease in the temporal change of VAS for lower limb pain was observed before administration, and two and four weeks after administration. Conclusions: In this study, the occurrence of ADRs reported by the patients was like the frequency of ADRs reported in the clinical trials for other disorders. When assessing the analgesic effect, the temporal change of VAS for lower limb pain was found to decrease significantly before administration, and two and four weeks after administration.

Study Design Observational study. Purpose To evaluate healthy volunteers and patients with spinal canal lesions using apparent diffusion coefficient (ADC) maps with diffusion-weighted imaging. Overview of Literature Decompression surgery for lumbar spinal stenosis (LSS) is selected on the basis of subjective assessment and cross-sectional magnetic resonance imaging (MRI). However, there is no objective standard for this procedure. Methods We performed 3T MRI in 10 healthy volunteers and 13 patients with LSS. The ADC values in the spinal canal were evaluated at 46 vertebrae (L4/5 and L5/S1 for each participant), and the reduced and conventional fields of view were compared. Results The ADC values were 2.72±0.12 at L4/5 in healthy volunteers, 2.76±0.19 at L5/S1 in healthy volunteers, 1.77±0.58 at L4/5 in patients with LSS, and 2.35±0.29 at L5/S1 in patients with LSS. The ADC value at L4/5 in patients with LSS was significantly lower than that at L5/S1 in patients with LSS and that at L4/5 and L5/S1 in healthy volunteers (p

Introduction: There are several reports about invasive muscle injury during posterior spinal surgery. However, few reports have evaluated the association between the clinical symptoms and changes in the physical properties of the psoas major after oblique lateral interbody fusion (OLIF). Therefore, the current study aimed to investigate the relationship between the clinical symptoms and changes in the psoas major muscle before and after OLIF. Methods: Twenty-seven patients who underwent single-level OLIF following the diagnosis of degenerative lumbar disease were included in the study. The cross-sectional areas (CSAs) of the psoas major on the approaching and contralateral sides were measured in the axial computed tomography view of the surgical intervertebral space preoperatively and postoperatively at 1 week and 3, 6, and 12 months. The preoperative and postoperative changes in the CSAs were compared. Muscle degeneration was evaluated using axial magnetic resonance images at the same level as that in the CSA evaluation preoperatively and at 12 months postoperatively. Additionally, the relationship between these parameters and postoperative lower limb symptoms was investigated. Results: Significant swelling of the psoas major on the approach side was observed 1 week postoperatively (p < 0.05). No postoperative muscle degeneration was observed. Three cases of paresthesia in the front of the thigh were observed, but no association was found with changes in CSA in any of the cases. Conclusions: The OLIF approach caused swelling of the psoas major 1 week postoperatively with no more muscle degeneration in the mid-term. Although numbness of the lower limbs was found in some cases, no association was found with changes in CSA. Our study findings suggest that the OLIF approach causes temporary injury or swelling of the psoas major, but the long-term damage to the muscle is not significant.

Abstract Background Lumbar spinal disease causes disabilities in performing daily activities. Operative treatments are aimed at pain relief and rapid return to routine activity. Patient-based outcome measures are used to evaluate pathologies and therapeutic effects associated with lumbar spinal disease. Nevertheless, it remains unknown as to how much such treatment improves activity levels. The purpose of the current study was to measure changes in activity levels before and after lumbar spinal surgery using a wearable activity tracker and to analyze the differences between results and patient-based outcomes. Methods Sixty patients who underwent lumbar surgery were studied. The physical activity of participants was objectively evaluated using a wearable Micro-Motion logger system (Actigraph). We measured the amount of activity before and at 1, 3, 6, and 12 months after the surgery to evaluate postoperative changes. The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire, Oswestry Disability Index, Roland-Morris Disability Questionnaire and visual analog scale were used to assess patient-based outcomes of pain and activities of daily living-related scores; we analyzed the relationships between scores and actual activity levels. Results The amount of actual activity decreased significantly 1 month after the surgery compared to that during the preoperative period, which then improved after 3 months postoperatively (p

Study Design Controlled laboratory study. Purpose This study aimed to evaluate the in vitro pharmacological activity of growth factors (GFs) in freeze-dried platelet-rich plasma (FD-PRP) after storage for 4 weeks. Overview of Literature Freshly prepared PRP is a rich source of many GFs. We reported that FD-PRP stored for 8 weeks accelerated bone union in a rat posterolateral fusion model equally well as fresh-PRP. However, the pharmacological activity of FD-PRP after long-term storage has not been shown in vitro. Methods Immediately after preparation, as well as 4 weeks after freeze-dried storage, the platelet count was measured. Human osteoblasts were treated with fresh-PRP and FD-PRP, respectively. Western blotting was used to assess the phosphorylation of the platelet-derived growth factor (PDGF) receptor (PDGFR) and its downstream target, extracellular signal-regulated kinase (ERK). The proliferation rates of osteoblasts were investigated by immunocytochemistry and MTT cell viability assays. Furthermore, we used western blotting to evaluate the effect of PDGFR knockdown on the phosphorylation of ERK stimulated with fresh-PRP and FD-PRP. Results Platelet counts in both the fresh-PRP and FD-PRP samples were approximately 10-fold higher than in peripheral blood samples. The phosphorylation and activation of the PDGFR and ERK were evenly induced by fresh-PRP and FD-PRP stimulation. Both freshPRP and FD-PRP significantly induced osteoblast proliferation in MTT cell viability assays. Furthermore, osteoblast PDGFR knockdown attenuated the downstream ERK activation by fresh PRP and FD-PRP. Conclusions We demonstrated the pharmacological activity of PDGF in FD-PRP in vitro after 4 weeks of storage.

Introduction: Leptomeningeal metastasis (LM) is known to demonstrate a very poor prognosis. The purpose of this study was to evaluate the prognostic factors in LM cases diagnosed by spinal magnetic resonance imaging (MRI). Methods: We retrospectively analyzed 19 patients with LM detected by spinal MRI between 2010 and 2017. Results: The primary tumors were breast carcinoma (n = 7), lung carcinoma (n = 6), lymphoma (n = 3), colorectal carcinoma (n = 2), and gastric carcinoma (n = 1). Thirteen patients exhibited preceding brain metastasis, and 11 of these exhibited metastasis in the posterior fossa. Ten patients exhibited limb paralysis. Performance status at diagnosis was 0-1 in 6 patients, 2 in 9 patients, and 3-4 in 4 patients. Testing of cerebrospinal fluid revealed malignant cells in 9 patients. On MRI, 11 patients demonstrated disseminated tumor lesions at the cervical cord level, 15 patients at the thoracic cord level, and 11 patients below the conus level. Eleven patients received radiation therapy, while intrathecal chemotherapy was performed in 9 patients. Univariate analysis revealed cervical cord level lesions, intrathecal chemotherapy, paralysis, and performance status as prognostic factors. Multivariate analysis identified existence of a cervical cord lesion as associated with a poor prognosis (hazards ratio (HR) 3.46, 95% confidence interval (CI) 1.12-12.2), while administration of intrathecal chemotherapy was associated with a good prognosis (HR 0.15, 95% CI 0.026-0.67). Conclusions: In LM patients, cervical cord level lesions are a negative factor for prognosis, and performance of intrathecal chemotherapy is a positive factor for prognosis.

Introduction: Limb muscle mass measurement using dual-energy X-ray absorptiometry (DXA) is considered the gold standard for the diagnosis of sarcopenia. Moreover, bioelectrical impedance analysis (BIA) is also recognized as a beneficial tool considering its high correlation with DXA. However, it remains to be elucidated whether DXA and BIA can accurately measure trunk lean mass. The aim of this study was to investigate the correlation between DXA and BIA measurements of trunk muscle mass and the cross-sectional area (CSA) of trunk muscles measured using magnetic resonance imaging (MRI) and to compare measures of trunk muscle mass obtained using DXA and BIA in patients with low back pain (LBP). Methods: In total, 65 patients participated in the study. The correlation between DXA and BIA measurements and the CSA of trunk and paraspinal muscles at the L4-5 level were calculated. In addition, the correlation between DXA and BIA measurements of trunk muscle mass and the differences between these two measurements were determined. Results: The correlation coefficient between DXA and BIA trunk muscle mass measurement and trunk muscle CSA was 0.74 and 0.56 for men and 0.69 and 0.44 for women, respectively. DXA and BIA measurement values showed a significantly moderate correlation with the CSA of the erector spinae (ES) and psoas major (PM). The multifidus (MF) CSA did not correlate with measurements of DXA and BIA in both men and women. Although DXA and BIA measurements were significantly correlated, a significant difference between these two measurements was found. BIA overestimated the trunk muscle mass significantly compared with DXA. Conclusions: Trunk muscle mass measured with DXA and BIA was correlated with the CSA of most trunk muscles. Although the measurement of DXA and BIA showed a high correlation, BIA overestimated trunk muscle mass compared with DXA. Both DXA and BIA are beneficial for measuring trunk muscle mass.

Introduction: Wearable accelerometers can be used to evaluate waking and sleeping movements. Although a correlation between accelerometer data captured at the wrist and waist has been reported, it has not been evaluated in patients with low back pain. Therefore, this study aimed to evaluate correlations between movement measured at the wrist and waist, using wearable accelerometers, in patients with low back pain. Methods: Twenty patients with chronic low back pain and 20 healthy volunteers were enrolled. Two identical accelerometers were simultaneously worn by each participant, one on the nondominant wrist and the other at the waist, for 1 week. We compared the mean number of active movements and mean total amount of movement between the wrist and the waist to evaluate daytime and sleep activities. During sleep, we also evaluated sleep efficiency and time awake after sleep onset. Results: In daytime activity, the mean number of active movements and mean total amount of movement was greater for the wrist than for the waist, and the amount of waist movements relative to wrist movements was significantly lower in patients with low back pain than in healthy volunteers (p < 0.05). Despite these differences, the mean number of active movements and mean total amount of movement at the wrist and waist were strongly correlated in both groups. During sleep, although there was no difference in either measured sleep efficiency at the wrist or waist or time awake after sleep onset, measurements were strongly correlated in both groups. Conclusions: A strong correlation between movement data at the wrist and waist during both daytime activities and sleep was identified in patients with low back pain. Therefore, a wearable accelerometer worn on the wrist can reliably measure the movement of patients with low back pain, simplifying data capture for clinical and research purposes and improving patient comfort.

Abstract Background Giant cell tumor is known to be a benign neoplasm that arises most commonly in the long bones, while cases in the spine are rare. Recently, denosumab, a monoclonal antibody that inhibits receptor activator of nuclear factor-kappa β ligand, has been used to treat patients with giant cell tumor. However, there are few reports of total en bloc spondylectomy being used for paravertebral giant cell tumor lesions following denosumab therapy. Case presentation Our patient was a 20-year-old Japanese woman with a 4-month history of lower back pain. A spinal computed tomography scan and magnetic resonance imaging of her lumbar spine revealed an osteolytic lesion involving the L3 vertebral body, and the tumor extended toward the left side of the paravertebral soft tissue and into the left pedicle. The lesion was diagnosed as a giant cell tumor by needle biopsy. Denosumab treatment calcified the paravertebral giant cell tumor lesion and the tumor vertebral body was removed completely by total en bloc spondylectomy. Conclusion This case report describes a patient with a paravertebral giant cell tumor who was successfully treated by preoperative denosumab injection followed by total en bloc spondylectomy.

We previously developed an in vivo site-specific transfection method using a suction device in mice; namely, a tissue suction-mediated transfection method (tissue suction method). The aim of this study was to apply the tissue suction method for cardiac gene transfer. Naked plasmid DNA (pDNA) was intravenously injected in mice, followed by direct suction on the beating heart by using a suction device made of polydimethylsiloxane. We first examined the effects of suction conditions on transgene expression and toxicity. Subsequently, we analyzed transgene-expressing cells and the transfected region of the heart. We found that heart suction induced transgene expression, and that -75 kPa and -90 kPa of suction achieved high transgene expression. In addition, the inner diameter of the suction device was correlated with transgene expression, but the pressure hold time did not change transgene expression. Although the tissue suction method at -75 kPa induced a transient increase in the serum cardiac toxicity markers at 6 h after transfection, these markers returned to normal at 24 h. The cardiac damage was also analyzed through the measurement of hypertrophic gene expression, but no significant differences were found. In addition, the cardiac function monitored by echocardiography remained normal at 11 days after transfection. Immunohistochemical analysis revealed that CD31-positive endothelial cells co-expressed the ZsGreen1-N1 reporter gene. In conclusion, the tissue suction method can achieve an efficient and safe gene transfer to the beating heart in mice.

BACKGROUND:Pulmonary arterial hypertension (PAH) is frequently complicated by sleep disordered breathing (SDB), and previous studies have largely focused on hypoxemic SDB. Even though nocturnal hypercapnia was shown to exacerbate pulmonary hypertension, the clinical significance of nocturnal hypercapnia among PAH patients has been scarcely investigated. METHOD:Seventeen patients with PAH were identified from 246 consecutive patients referred to Kyoto University Hospital for the evaluation of lung transplant registration from January 2010 to December 2017. Included in this study were 13 patients whose nocturnal transcutaneous carbon dioxide partial pressure (PtcCO2) monitoring data were available. Nocturnal hypercapnia was diagnosed according to the guidelines of the American Academy of Sleep Medicine. Associations of nocturnal PtcCO2 measurements with clinical features, the findings of right heart catheterization and pulmonary function parameters were evaluated. RESULTS:Nocturnal hypercapnia was diagnosed in six patients (46.2%), while no patient had daytime hypercapnia. Of note, nocturnal hypercapnia was found for 5 out of 6 patients with idiopathic PAH (83.3%). Mean nocturnal PtcCO2 levels correlated negatively with the percentage of predicted total lung capacity (TLC), and positively with cardiac output and cardiac index. CONCLUSION:Nocturnal hypercapnia was prevalent among advanced PAH patients who were waiting for lung transplantation, and associated with %TLC. Nocturnal hypercapnia was associated with the increase in cardiac output, which might potentially worsen pulmonary hypertension especially during sleep. Further studies are needed to investigate hemodynamics during sleep and to clarify whether nocturnal hypercapnia can be a therapeutic target for PAH patients.

Advanced gastric cancer with bone metastasis has a very poor prognosis with short median survival. To the best of our knowledge, no reports in literature have described extensive recovery of paralysis with multimodality treatment without surgery in these cases. This report describes the case of a 52-year-old severely paralyzed female patient with spinal metastasis from advanced gastric cancer. She was inoperable, owing to a large thrombus in the inferior vena cava; alternative multimodality treatments, including chemotherapy and radiotherapy, were administered. The paralysis and the bladder and rectal dysfunction improved considerably. In addition, the performance status (PS) and Frankel grade also improved dramatically, from 4 to 1 and grade B to D, respectively. At 1 year after initiation of treatment, she is ambulatory. Patients with poor PS are often offered palliative therapy. However, this case demonstrates that poor PS solely due to paralysis from spinal metastasis may necessitate multimodality treatment instead of palliative care.

Desmoplastic fibroma of the bone (DFB) is a notably rare, lytic, locally aggressive but nonmetastatic, primary benign bone tumor in patients less than 30 years old. As the recommended primary treatment for DFB, wide resection is preferred to curettage from the perspective of recurrence but wide resection of DFB in the pelvis such as in the acetabulum could result in greater functional loss, suggesting the need for conservative treatments. However, there is no report on long-term follow-up following conservative treatment for DFB. The present case involved a 21-year-old woman with right hip pain. Radiological evaluation revealed a massive lesion throughout the right ilium and acetabulum with partial osteolysis, cortical destruction, marginal sclerosis, slight pseudotrabeculation, and bone expansion. Open biopsy from the ilium showed the proliferation of spindle cells in an abundant collagenous matrix without atypia and mitosis, suggesting a diagnosis of DFB. Conservative treatment was selected considering the risk of greater functional loss following wide ilium resection. An evaluation 10 years after follow-up showed a partially sclerotic lesion of the ilium and the absence of pain. The current case demonstrates that conservative therapy may be effective even in some cases of aggressive DFB.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare inflammatory disorder with multiple phenotypes. The syndrome has identifiable radiologic characteristics that are the most important when making a diagnosis. X-rays of cases diagnosed with SAPHO syndrome reveal sclerotic lesions or mixed lytic and sclerotic lesions. Pure osteolytic lesions in SAPHO syndrome are rare, and to the best of our knowledge, no study has reported the radiologic change of purely osteolytic lesions to osteosclerotic lesions over time. Herein, we report on the case of a woman experiencing severe left thigh acute pain and having a medical history of palmoplantar pustulosis. Although SAPHO syndrome was suspected because of palmoplantar pustulosis, based on radiologic findings, bone metastasis of a malignant tumor or chronic bacterial osteomyelitis owing to a purely osteolytic lesion was suspected. However, needle biopsy revealed no malignancy and bacterial culture was negative, thus suggesting SAPHO syndrome. Nonsteroidal anti-inflammatory drugs, bisphosphonates, and corticosteroids were administered, which improved the left thigh pain. Furthermore, the radiologic change of osteolytic lesions to osteosclerotic lesions over time was confirmed, leading to the diagnosis of SAPHO syndrome. Our case demonstrates that knowledge of atypical radiologic findings is necessary to diagnose initial SAPHO syndrome.

Undifferentiated pleomorphic sarcoma (UPS) is a high-grade, aggressive, soft tissue sarcoma that is often fatal. Although there are reports describing associations of sarcoma and skin lesions such as burns, radiation, and trauma, to our knowledge, UPS development in a keloid scar has not been reported. Herein, we present the case of a 76-year-old woman who had undergone surgery for endometrial cancer, 5 years before. She presented with a protruding lesion that was continuous to a keloid scar on the abdominal wall. The tumor appeared clinically malignant as it was protruding and doubled in size within three weeks, reaching approximately 6 × 6 × 2 cm. Since the tumor was diagnosed as UPS after pathological evaluation by needle biopsy, wide resection was performed. Intraoperatively, the tumor was apparently continuous to the keloid, protruding and pedunculated outside the body, and had not invaded the abdominal cavity. Histopathological examination of the resected tumor showed evidence of UPS and no suspicion of metastasis of endometrial cancer. No recurrence, metastases, or other complications were noted 6 months after surgery. The current case study reminds us that keloids may cause high-grade sarcoma such as UPS, and careful follow-up is required.

Introduction: Thus far, few reports have described the time series histological variations in injured paravertebral muscle tissues for long durations, considering the type of pain. The purpose of this study is to evaluate histological changes in injured paravertebral muscles and dominant nerves considering the type of pain. Methods: We used 59 eight-week-old male Sprague-Dawley rats. A 115-g weight was dropped from a height of 1 m on the right paravertebral muscle. Fluoro-Gold (FG), a sensory nerve tracer, was injected into this muscle. Hematoxylin and eosin (HE) staining and nerve growth factor (NGF) immunostaining of the muscle were performed for histological evaluation. L2 dorsal root ganglia (DRG) on both sides were resected, and immunohistochemical staining was performed for calcitonin gene-related peptide (CGRP, a pain-related neuropeptide) and for activating transcription factor 3 (ATF3, a neuron injury marker). Each examination was performed at 3 days, 1-3 weeks, and 6 weeks after injury. Results: HE staining of the paravertebral muscle indicated infiltration of inflammatory cells and the presence of granulation tissue in the injured part on the ipsilateral side at 3 days and 1 week after the injury. Fibroblasts and adipocytes were present at 2-3 weeks. At 6 weeks, the injured tissue was almost completely repaired. NGF was detected at 2-3 weeks post injury and appeared to colocalize with fibroblasts, but was not observed at 6 weeks post injury. The percentage of cells double-labeled with FG and CGRP in FG-positive cells of the primary muscle was significantly higher in the injured side at 3 days and 1-3 weeks post injury (P < 0.05). However, at 6 weeks, no significant difference was observed. No significant expression of ATF3 was observed. Conclusions: These results suggest that sensitization of the dominant nerve in the DRG, in which NGF may play an important role, can protract pain in injured muscles.

Study Design Cross-sectional observational study. Purpose To compare measurements of appendicular skeletal muscle mass (ASMM) and whole fat mass (WFM) obtained using dualenergy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) among patients with low back pain (LBP). Moreover, the study investigated the correlation between BIA-based ASMM and DXA-based bone mineral density (BMD). Overview of the Literature If reliable, BIA may be a useful alternative to DXA as a screening tool for sarcopenia and osteoporosis among patients with LBP. Methods Measurements were performed in 130 patients, including BMD of the lumbar spine and femoral neck. The correlation between DXA and BIA as well as between BIA-ASMM and BMD were evaluated. Results BIA and DXA were highly correlated in both male and female patients (r =0.73–0.90, p

Objective To validate the relationship between residual walking ability and monthly care cost as well as long-term care insurance (LTCI) certification level in elderly patients after surgical treatment for hip fractures in Japan. Methods Elderly patients aged >75 years who underwent surgical treatment for hip fractures in our hospital were included. The preand post-surgical (6-month) walking ability and LTCI certification and the presence or absence of dementia was determined from medical records and questionnaires. Walking ability was classified into 6 levels used in our daily medical practice. Based on these data, we correlated the relationship between walking ability and the LTCI certification level. Further, based on the official statistics pertaining to the average monthly costs per person at each LTCI certification level, we evaluated the relationship between walking ability and monthly care cost. Results A total of 105 cases (mean age, 80.2 years; 16 men; 39 patients with dementia) were included. The correlation between walking ability and average monthly cost per person as well as LTCI certification level at 6 months postoperatively (r=0.58) was demonstrated. The correlation was found in both groups with and without dementia. Conclusion The ability to walk reduced the cost of care in elderly patients who experienced hip fracture, regardless of the presence of dementia.

Introduction: Osteoporosis can produce a persistent state of pain known as osteoporotic pain. One proposed mechanism of this pathology is increased calcitonin gene-related peptide (CGRP; a marker related to inflammatory pain) expression in the dorsal root ganglia (DRG) innervating osteoporotic vertebrae. Alternatively, a previous study revealed that axial loading caused osteoporotic pain in a rodent model of coccygeal vertebrae compression. Because this compression model is associated with trauma, additional mechanistic studies of osteoporotic pain in the absence of trauma are required. The current study aimed to evaluate the expression and relative distribution of transient receptor potential vanilloid 4 (TRPV4), a pain-related mechanoreceptor, in ovariectomized (OVX) osteoporotic rats. Methods: CGRP-immunoreactive (-ir) and TRPV4-ir DRG neurons innervating the L3 vertebrae of Sprague-Dawley rats were labeled with a neurotracer, FluoroGold. Intravertebral pH was also measured during the neurotracer procedure. TRPV4-ir/CGRP-ir FluoroGold-positive DRG neurons were quantified in sham control and OVX rats (n = 10, ea). The threshold for statistical significance was set at P < 0.05. Results: There was no statistical difference in the number of FluoroGold-positive DRG neurons between groups; however, there were significantly more CGRP-ir/TRPV4-ir FluoroGold-positive DRG neurons in the OVX group compared with the sham control group (P < 0.05) as well as the significantly increased molecular production of each peptide. Intravertebral pH was also lower in the OVX group compared with the sham control group (P < 0.05). Conclusion: Sensory neurons innervating osteoporotic vertebrae exhibited increased expression of co-localized CGRP and TRPV4 in OVX osteoporotic rats. Additionally, intravertebral pH was low in the vicinity osteoporotic vertebrae. Considering that TRPV4 is a mechanosensitive nociceptor that is activated in acidic environments, its upregulation may be associated with the pathology of osteoporotic pain derived from microinflammation involved in osteoporosis.

Introduction: Osteoporosis and sarcopenia are said to be similar disorders. However, few reports have described the effects of anti-osteoporosis drugs on muscle mass in clinical practice. Methods: We selected 150 postmenopausal women with osteoporosis treated by minodronate (osteoporosis medication [OM] group) and 50 postmenopausal women without osteoporosis who did not receive treatment (no osteoporosis [NO] group). The OM group was further divided into two treatment subgroups: a combination of monthly minodronate and daily activated vitamin D vs. monthly minodronate alone. We measured lumbar spine and femoral neck bone mineral density (BMD) with dual-energy X-ray absorptiometry and muscle mass of the upper limbs, lower limbs, and trunk with bioelectrical impedance analysis at baseline and after 6 months. Results: The OM and NO groups contained 130 and 37 patients, respectively (mean age: 73.9 ± 8.3 and 74.1 ± 10.0 years, respectively). In the OM group, lumbar spine BMD significantly increased after 6 months, while lower limb muscle mass significantly decreased. In the NO group, lumbar spine BMD and lower limb muscle mass did not significantly change after 6 months. In the OM group, BMD of the lumbar spine significantly increased but the lower limb muscle mass significantly decreased after 6 months relative to the NO group. In the combination therapy subgroup of the OM group muscle mass decreased significantly less than in the minodronate-alone subgroup. Conclusions: In postmenopausal women with osteoporosis, minodronate can increase BMD but cannot increase muscle mass. However, simultaneous use of activated vitamin D can suppress muscle mass decrease. The combination of activated vitamin D and minodronate may be useful for treating osteoporosis in postmenopausal women.

Introduction: Discogenic back pain remains poorly understood with respect to etiopathogenesis, despite being a considerable burden. We sought to examine the expression of vascular endothelial growth factor in injured intervertebral discs in rat caudal vertebrae. Methods: Forty-eight male Sprague Dawley rats were assigned to 2 groups according to disc puncture injury: puncture (n = 32) or non-puncture (n = 16). Disc puncture was performed percutaneously such that the incision would be in the primary plane of motion for the coccygeal discs 5-6, 6-7, and 7-8. A 26-gauge needle was used to puncture each disc 10 times. Punctured discs were examined histologically by hematoxylin and eosin staining at 1, 7, 14, and 28 days post-injury. Results: Vascular endothelial growth factor was localized immunohistochemically, and determined quantitatively using an enzyme-linked immunosorbent assay. Peak inflammation occurred on the 7th day post-injury, but tissue degeneration continued until day 28. Local expression of vascular endothelial growth factor tended to be highest in the annulus fibrosus on the 7th and 14th days after puncture injury. The level of vascular endothelial growth factor was highest 1-day post-injury, and then gradually decreased thereafter. Furthermore, vascular endothelial growth factor levels in the puncture group were significantly higher than those in the non-puncture control group (p < 0.05). Conclusions: We found increased expression of the inflammatory cytokine vascular endothelial growth factor in injured intervertebral discs, suggesting that vascular endothelial growth factor may be clinically important in discogenic back pain.

Introduction: Failed spinal fusion surgery sometimes requires salvage surgery when symptomatic, especially with postsurgical decrease in intervertebral disc height followed by foraminal stenosis. For such cases, an anterior approach to lumbar lateral interbody fusion (LLIF) provides safe, direct access to the pathological disc space and a potential improvement in the fusion rate. One LLIF approach, oblique lateral interbody fusion (OLIF), targets the oblique lateral window of the intervertebral discs to achieve successful lateral interbody fusion. The current technical note describes spinal revision surgery using the OLIF procedure. Technical Note: The subjects were patients with leg pain and/or lower back pain derived from decreased intervertebral height followed by foraminal stenosis due to failed spinal fusion surgery. These patients underwent additional OLIF surgery and posterior fusion with no additional posterior direct decompression. Their outcomes were evaluated using the Japanese Orthopaedic Association (JOA) scores at baseline and final follow-up. Bony union was also evaluated using computed tomography images at final follow-up. Six subjects were evaluated, with two representative cases described in detail. Four patients had an adjacent segment disorder, and the other two patients had pseudarthrosis due to postoperative infection. The mean JOA score improved from 5.7 ± 5.4 to 21.2 ± 2.3, with a mean recovery rate of 65.0%. All cases showed intervertebral bony union. Conclusions: We introduced a salvage strategy for failed posterior spine fusion surgery cases using the OLIF procedure. Patients effectively achieved recovered intervertebral and foraminal height with no additional posterior direct decompression.

Introduction: Oblique lateral interbody fusion (OLIF) can achieve recovery of lumbar lordosis (LL) in minimally invasive manner. The current study aimed to evaluate the location of lateral intervertebral cages during OLIF in terms of LL correction. Methods: The subjects were patients who underwent OLIF for lumbar degenerative diseases, including lumbar spinal stenosis, spondylolisthesis, and discogenic low back pain. Their clinical outcome was evaluated using visual analogue scale on lower back pain (LBP), leg pain and numbness. The following parameters were retrospectively evaluated on plain radiographic images and computed tomography scans before and at 1 year after OLIF: the intervertebral height, vertebral translation, and sagittal angle. The cage position was defined by equally dividing the caudal endplate into five zones (I to V), and its association with segmental lordosis restoration was analyzed. Subjects were also evaluated for a postoperative endplate injury. Results: Eighty patients (121 fused levels) with lumbar degeneration who underwent OLIF were included. There were no significant specific distribution in preoperative disc pathology such as disc angle, height, and translation. After OLIF, sagittal alignment was improved with an average correction angle of 3.8º at the instrumented segments in a level-independent fashion. All cases showed significant improvement in clinical outcomes, and had improvement in the radiological parameters (P

Study DesignAn experimental animal study.PurposeTo evaluate effects of anti-vascular endothelial growth factor (VEGF) on the content and distribution of the calcitonin gene-related peptide (CGRP) in the dorsal ganglia in a rat model.Overview of LiteratureIncreased expression of VEGF in degenerative disc disease increases the levels of inflammatory cytokines and nerve ingrowth into the damaged discs. In animal models, increased levels of VEGF can persist for up to 2 weeks after an injury.MethodsThrough abdominal surgery, the dorsal root ganglia (DRG) innervating L5/L6 intervertebral disc were labeled (FluoroGold neurotracer) in 24, 8-week old Sprague Dawley rats. The rats were randomly allocated to three groups of eight rats each. The anti-VEGF group underwent L5/6 intervertebral disc puncture using a 26-gauge needle, intradiscal injection of 33.3 µg of the pegaptanib sodium, a VEGF165 aptamer. The control-puncture group underwent disc puncture and intradiscal injection of 10 µL saline solution, and the sham-surgery group underwent labeling but no disc puncture. Two rats in each group were sacrificed on postoperative days 1, 7, 14, and 28 after surgery. L1–L6 DRGs were harvested, sectioned, and immunostained to detect the content and distribution of CGRP.ResultsCompared with the control, the percentage of CGRP-positive cells was lower in the anti-VEGF group (p

Study DesignObservational study.PurposeTo assess the correlation among inflammatory cytokine expression levels, degree of intervertebral disk (IVD) degeneration, and predominant clinical symptoms observed in degenerative disk disease (DDD).Overview of LiteratureLow back pain (LBP) is associated with inflammatory cytokine expression levels, including those of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and nerve growth factor (NGF). However, the association between cytokine expression levels and the physiological mechanisms of disk degeneration and clinical pain remain controversial.MethodsUsing the enzyme-linked immunosorbent assay, TNF-α, IL-6, and NGF expression levels were analyzed in 58 IVD samples that were harvested from patients with lumbar DDD. Patient samples were grouped according to the degree of IVD degeneration using the Pfirrmann grading system and magnetic resonance imaging, and the correlations between the disease groups and each cytokine expression level were assessed. In addition, on the basis of their predominant preoperative symptoms, the patients were assigned to either an LBP or leg pain group to determine the correlation among these disease manifestations and individual cytokine expression levels.ResultsA gradual increase in TNF-α (R=0.391) and IL-6 (R=0.388) expression levels correlated with the degree of IVD degeneration, whereas NGF (R=0.164) expression levels exhibited a minimal decrease with disease progression. Regarding the predominant clinical manifestation, only the LBP group exhibited a significant increase in TNF-α expression levels (p=0.002).ConclusionsThese results suggested that TNF-α and IL-6 play an important role in the pathophysiology of IVD degeneration at any stage, whereas NGF plays an important role during the early disease stages. Moreover, because TNF-α expression levels were significantly high in the LBP group, we propose that they are involved in LBP onset or progression.

Study DesignControlled laboratory study.PurposeThis study aimed to evaluate the efficacy of platelet-rich plasma (PRP) stored at room temperature (RT), frozen, or after freeze-drying.Overview of LiteraturePRP enriches tissue repair and regeneration, and is a novel treatment option for musculoskeletal pathologies. However, whether biological activity is preserved during PRP storage remains uncertain.MethodsPRP was prepared from blood of 12 healthy human volunteers (200 mL/person) and stored using three methods: PRP was stored at RT with shaking, PRP was frozen and stored at −80℃, or PRP was freeze-dried and stored at RT. Platelet counts and growth factor content were examined immediately after preparation, as well as 2, 4, and 8 weeks after storage. Platelet activation rate was quantified by flow cytometry.ResultsPlatelet counts were impossible to determine in many RT samples after 2 weeks, but they remained at constant levels in frozen and freeze-dried samples, even after 8 weeks of storage. Flow cytometry showed approximately 80% activation of the platelets regardless of storage conditions. Almost no growth factors were detected in the RT samples after 8 weeks, while low but significant expression was detected in the frozen and freeze-dried PRP. Over time, the mean relative concentrations of various growth factors decreased significantly or disappeared in the RT group. In the frozen group, levels were maintained for 4 weeks, but decreased significantly by 8 weeks (p

Study DesignRetrospective case series.PurposeThe purpose of this study was to determine whether discontinuing teriparatide treatment and replacing it with bisphosphonate treatment maintains the volume of the fusion mass after posterolateral fusion (PLF) in women with postmenopausal osteoporosis.Overview of LiteratureClinical data support the efficacy of parathyroid hormone (PTH) for lumbar PLF. However, the use of PTH is limited to 2 years.MethodsWe treated 19 women diagnosed with osteoporosis and degenerative spondylolisthesis with teriparatide (20 µg daily subcutaneously). All patients underwent one-level instrumented PLF. Teriparatide was used during 2 months prior to surgery and more than 8 months after surgery. After discontinuing teriparatide treatment, all patients used bisphosphonate (17.5 mg risedronate weekly, oral administration). Area of the fusion mass across the transverse processes at one segment was determined on an anteroposterior radiograph at 1, 2, and 3 years after surgery.ResultsWe followed 19 patients for 3 years. The average duration of teriparatide treatment was 11.5 months. The bone union rate was 95%. The average area of the bone fusion mass was not significantly different between the right and left sides at 1, 2, or 3 years after surgery (p>0.05).ConclusionsThis study showed that replacing teriparatide treatment with bisphosphonate maintained the bone fusion mass volume after PLF in women with postmenopausal osteoporosis.

Study DesignRetrospective, observational, single-center study.PurposeTo investigate the long-term outcomes of in situ fusion procedures for treating dysplastic spondylolisthesis.Overview of LiteratureIn situ fusion performed in patients with dysplastic spondylolisthesis avoids the development of nerve complications.MethodsIn total, 12 of 28 patients who underwent in situ fusion for treating dysplastic spondylolisthesis at Chiba University Hospital from 1974 to 2004 were followed up in August 2013. Surgical complications were evaluated. Low back pain and leg pain were assessed using a visual analog scale (VAS). Vertebral alignment, including the lumbosacral angle and lumbar lordosis angle measurement on radiographic images (profile view in the neutral standing position), was evaluated during preoperative, postoperative, and final examinations.ResultsThe mean follow-up duration, patient age at the final examination, and patient age at operation were 20.0±7.2, 42.3±13.3, and 22.3±11.4 years, respectively. No complications were reported. Mean VAS scores for low back pain and leg pain were significantly lower at the final examination than at the preoperative examination (p

Purpose: We examined duloxetine's effectiveness in the treatment of neuropathic pain in patients who were intolerant to continuous pregabalin administration. Materials and Methods: The present study is a retrospective study of patients diagnosed with neuropathic pain with neuropathic leg pain as the chief complaint. We analyzed 20 cases in which pregabalin was changed to duloxetine because of adverse effects (16 cases) or treatment failure (4 cases). The incidence of adverse events after duloxetine administration was used as the primary endpoint, with the secondary endpoint being the leg pain level based on a numerical rating scale (NRS). Results: The incidence of adverse events after starting duloxetine was 40%. Average leg pain scores measured on the NRS were 8.4±1.4, 6.4±1.4, and 4.1±2.0 at the time of the patients' first visit, pregabalin discontinuation, and after switching to duloxetine, respectively. A significant difference in NRS scores was found between the first visit and pregabalin discontinuation and also between pregabalin discontinuation and after the switch to duloxetine (p0.05). Conclusion: When patients with neuropathic pain are unable to tolerate pregabalin because of adverse effects, changing the medication to duloxetine may be an option.

Nodular fasciitis (NF) is a benign reactive proliferation of myofibroblasts that predominantly occurs subcutaneously. Commonly, it presents as a rapidly growing swelling in 4-8 weeks. NF mostly occurs in adults aged 20-50 years and usually has a diameter4 cm is rare. Owing to its rapidly growing nature, a precise clinical diagnosis is difficult; it is frequently misdiagnosed as an aggressive or malignant tumor. Herein, we present the case of a 15-year-old male who presented with a large protruding mass on the anterior chest wall. The tumor appeared clinically malignant as it was protruding and had doubled in size within a few weeks, reaching approximately 8×6 cm. Furthermore, the tumor separated and fell off spontaneously due to its large size. As the remaining tumor continued to grow rapidly, surgery was performed. Following wide tumor resection, no recurrence, metastases, or other complications were noted 1 year postsurgery. NF was diagnosed after pathological evaluation, including immunohistochemical analysis, molecular genetic testing, and cytogenetic testing via fluorescence in situ hybridization analysis. Knowledge of the atypical clinical course and a combination of histopathological examinations are necessary to accurately diagnose NF.

Dermatofibromas are common benign fibrohistiocytic lesions, usually appearing as slow growing firm dermal nodules with a predilection for the extremities (mostly the lower legs). They are found mostly in middle-aged women and are usually smaller than 2 cm in diameter. Giant dermatofibromas exceeding 5 cm in diameter are rare. In recent years, reports have suggested a relationship between the primary size of dermatofibromas and rates of local recurrence and metastases after surgery. This relationship is however debated. The present report describes the case of a giant muscle invasive tumor in a 51-year-old female patient who presented with a large ulcerated mass in the right upper arm. The tumor appeared clinically malignant, measuring approximately 12 cm × 6 cm in size, with ulceration and invasion of surrounding muscle. Wide resection of the tumor was performed with myocutaneous flap-plasty. Histopathological examination showed evidence of a dermatofibroma. No recurrence, metastases, or other complications were noted at 5 years after surgery. The present case demonstrates that although dermatofibromas are essentially benign, they may present with atypical features including large size, ulceration, and muscle invasion, clinically mimicking malignant tumors.

Study DesignRetrospective study.PurposeTo determine whether low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy could prevent the transition of acute low back pain to chronic low back pain.Overview of LiteratureInadequately treated early low back pain transitions to chronic low back pain occur in approximately 30% of affected individuals. The administration of non-steroidal anti-inflammatory drugs is effective for treatment of low back pain in the early stages. However, the treatment of low back pain that is resistant to non-steroidal anti-inflammatory drugs is challenging.MethodsPatients who presented with acute low back pain at our hospital were considered for inclusion in this study. After the diagnosis of acute low back pain, non-steroidal anti-inflammatory drug administration was started. Forty patients with a visual analog scale score of >5 for low back pain 1 month after treatment were finally enrolled. The first 20 patients were included in a non-steroidal anti-inflammatory drug group, and they continued non-steroidal anti-inflammatory drug therapy for 1 month. The next 20 patients were included in a combination group, and they received low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy for 1 month. The incidence of adverse events and the improvement in the visual analog scale score at 2 months after the start of treatment were analyzed.ResultsNo adverse events were observed in the non-steroidal anti-inflammatory drug group. In the combination group, administration was discontinued in 2 patients (10%) due to adverse events immediately following the start of tramadol administration. At 2 months, the improvement in the visual analog scale score was greater in the combination group than in the non-steroidal anti-inflammatory drug group (p

Study DesignExperimental animal study.PurposeWe aimed to determine the optimal dose of a single direct injection of the tumor necrosis factor (TNF)-α inhibitor, etanercept, by using the rat model of degenerative intervertebral disc from injury.Overview of LiteratureThe pain-related peptide expression was suppressed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner.MethodsThe neurotracer FluoroGold (FG) was applied to the surfaces of L4/5 discs to label their innervating dorsal root ganglion (DRG) neurons (n=50). Ten rats were included in the nonpunctured disc sham surgery control group, whereas the other 40 were included in the experimental group in which intervertebral discs were punctured with a 23-gauge needle. Saline or etanercept (10 µg, 100 µg, or 1,000 µg) was injected into the punctured discs (n=10 for each treatment). After 14 days of surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP). The proportion of FG-labeled CGRP-immunoreactive DRG neurons was evaluated in all the groups.ResultsThere were no significant differences between the puncture+saline group and the puncture+10-µg etanercept group (p >0.05). However, a significant decrease in the percentage of FG and CGRP double-positive cells in FG-positive cells was observed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner (p

Ring finger 213 ( RNF213 ) is a susceptibility gene for moyamoya disease (MMD), a progressive cerebrovascular disease. Recent studies suggest that RNF213 plays an important role not only in MMD, but also in extracranial vascular diseases, such as pulmonary hypertension (PH). In this study, we undertook genetic screening of RNF213 in patients with PH and performed functional analysis of an RNF213 variant using mouse models. Direct sequencing of the exons in the C-terminal region of RNF213 , where MMD-associated mutations are highly clustered, and of the entire coding exons of BMPR2 and CAV1 , the causative genes for PH, was performed in 27 Japanese patients with PH. Two MMD-associated rare variants (p.R4810K and p.A4399T) in RNF213 were identified in two patients, three BMPR2 mutations (p.Q92H, p.L198Rfs*4, and p.S930X) were found in three patients, whereas no CAV1 mutations were identified. To test the effect of the RNF213 variants on PH, vascular endothelial cell (EC)-specific Rnf213 mutant transgenic mice were exposed to hypoxia. Overexpression of the EC-specific Rnf213 mutant, but neither Rnf213 ablation nor EC-specific wild-type Rnf213 overexpression, aggravated the hypoxia-induced PH phenotype (high right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels). Under hypoxia, electron microscopy showed unique EC detachment in pulmonary vessels, and western blots demonstrated a significant reduction in caveolin-1 (encoded by CAV1 ), a key molecule involved in EC functions, in lungs of EC-specific Rnf213 mutant transgenic mice, suggestive of EC dysfunction. RNF213 appears to be a genetic risk factor for PH and could play a role in systemic vasculopathy.

Pseudoaneurysm is one of the most serious complications of femoral trochanteric fracture surgery. Since the rupture of pseudoaneurysm may lead to death, early detection is important. We report the case of an 80-year-old male who developed pain in the proximal thigh and severe swelling after internal fixation of a femoral trochanteric fracture with a hip nail. Angiography revealed a pseudoaneurysm of a branch of the deep femoral artery near the interlocking screw. The vascular lesion was immediately treated by transcatheter embolization, and the vascular leakage was completely resolved with catheter embolization. After embolization, the patient’s clinical state improved rapidly, and the laboratory values improved to normal after several weeks. The current case study reminds us that pseudoaneurysm can occur after intramedullary nail placement to treat a femoral trochanteric fracture.

BackgroundRecent studies have shown that plasma levels of the biologically inactive prohormone for brain natriuretic peptide (proBNP) are increased in patients with heart failure. This can contribute to a reduction in the effectiveness of circulating BNP and exacerbate heart failure progression. The precise mechanisms governing the increase in proBNP remain unclear, however. Methods and ResultsWe used our recently developed, highly sensitive human proBNP assay system to investigate the mechanisms underlying the increase in plasma proBNP levels. We divided 53 consecutive patients hospitalized with heart failure into 2 groups based on their aortic plasma levels of immunoreactive BNP. Patients with higher levels exhibited more severe heart failure, a higher proportion of proBNP among the immunoreactive BNP forms secreted from failing hearts, and a weaker effect of BNP as estimated from the ratio of plasma cyclic guanosine monophosphate levels to log‐transformed plasma BNP levels. Glycosylation at threonines 48 and 71 of human proBNP contributed to the increased secretion of proBNP by attenuating its processing, and GalNAc‐transferase (GALNT) 1 and 2 mediated the glycosylation‐regulated increase in cardiac human proBNP secretion. Cardiac GALNT1 and 2 expression was suppressed by microRNA (miR)‐30, which is abundantly expressed in the myocardium of healthy hearts, but is suppressed in failing hearts. ConclusionsWe have elucidated a novel miR‐30‐GALNT1/2 axis whose dysregulation increases the proportion of inactive proBNP secreted by the heart and impairs the compensatory actions of BNP during the progression of heart failure.

Spinal metastasis of differentiated thyroid cancer can have a favorable prognosis if radical surgery is performed. We encountered a case of spinal metastasis involving three anterior vertebral bodies at the posterior element fusion level and successfully achieved adequate stability by radical surgery involving only the anterior elements. A 67-year-old woman who had numbness and muscle weakness in the lower limbs caused by metastatic spinal tumor at the posterior element fusion level of L1–L3 vertebrae was treated with radical surgery of only the anterior element to gain stability. Similar situations may occur in cases involving other malignant tumor metastases or spinal primary tumors. If such a case occurs, this method could be useful in preventing metastasis to the posterior element.

BACKGROUND: Plasma BNP levels are predictive of prognosis in hemodialysis patients. However, recent studies showed that the current BNP immunoassay cross-reacts with glycosylated proBNP, and the NT-proBNP assay underestimates glycosylated NT-proBNP. In addition, the recently developed high performance dialyzer removes medium-sized molecular solutes such as β2-microgloburin. We therefore investigated the effects of high performance dialysis on measured levels of glycosylated proBNP, glycosylated NT-proBNP and other BNP-related peptides in end-stage renal disease (ESRD) patients on hemodialysis. METHOD: The relationships between clinical parameters and BNP-related molecule were also investigated. We used our newly developed immunoassay to measure plasma total BNP and proBNP in 105 normal subjects and 36 ESRD patients before and after hemodialysis. Plasma NT-proBNP was measured using Elecsys II after treatment with or without deglycosylating enzymes. We also measured plasma ANP and cGMP using radioimmunoassays. RESULTS: All the measured BNP-related peptides were significantly higher in ESRD patients than healthy subjects. Total BNP (-38.9%), proBNP (-29.7%), glycoNT-proBNP (-45.5%), nonglycoNT-proBNP (-53.4%), ANP (-50.4%) and cGMP (-72.1%) were all significantly reduced after hemodialysis, and the magnitude of the reduction appeared molecular weight- dependent. Both the proBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios were increased after hemodialysis. The former correlated positively with hemodialysis vintage and negatively with systolic blood pressure, while the latter correlated positively with parathyroid hormone levels. CONCLUSION: These results suggest that hemodialysis using super-flux dialyzer removes BNP-related peptides in a nearly molecular weight-dependent manner. The ProBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios appear to be influenced by hemodialysis-related parameters in ESRD patients on hemodialysis.

BACKGROUND: Recent studies have shown that in addition to brain (or B-type) natriuretic peptide (BNP) and the N-terminal proBNP fragment, levels of intact proBNP are also increased in heart failure. Moreover, present BNP immunoassays also measure proBNP, as the anti-BNP antibody cross-reacts with proBNP. It is important to know the exact levels of proBNP in heart failure, because elevation of the low-activity proBNP may be associated with the development of heart failure. METHODOLOGY/PRINCIPAL FINDINGS: We therefore established a two-step immunochemiluminescent assay for total BNP (BNP+proBNP) and proBNP using monoclonal antibodies and glycosylated proBNP as a standard. The assay enables measurement of plasma total BNP and proBNP within only 7 h, without prior extraction of the plasma. The detection limit was 0.4 pmol/L for a 50-µl plasma sample. Within-run CVs ranged from 5.2%-8.0% in proBNP assay and from 7.0%-8.4% in total BNP assay, and between-run CVs ranged from 5.3-7.4% in proBNP assay and from 2.9%-9.5% in total BNP assay, respectively. The dilution curves for plasma samples showed good linearity (correlation coefficients = 0.998-1.00), and analytical recovery was 90-101%. The mean total BNP and proBNP in plasma from 116 healthy subjects were 1.4 ± 1.2 pM and 1.0 ± 0.7 pM, respectively, and were 80 ± 129 pM and 42 ± 70 pM in 32 heart failure patients. Plasma proBNP levels significantly correlate with age in normal subjects. CONCLUSIONS/SIGNIFICANCE: Our immunochemiluminescent assay is sufficiently rapid and precise for routine determination of total BNP and proBNP in human plasma.

We have developed an in vivo transfection method for naked plasmid DNA (pDNA) and siRNA in mice by using a tissue suction device. The target tissue was suctioned by a device made of polydimethylsiloxane (PDMS) following the intravenous injection of naked pDNA or siRNA. Transfection of pDNA encoding luciferase was achieved by the suction of the kidney, liver, spleen, and heart, but not the duodenum, skeletal muscle, or stomach. Luciferase expression was specifically observed at the suctioned region of the tissue, and the highest luciferase expression was detected at the surface of the tissue (0.12±0.03 ng/mg protein in mice liver). Luciferase expression levels in the whole liver increased linearly with an increase in the number of times the liver was suctioned. Transfection of siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene significantly suppressed the expression of GAPDH mRNA in the liver. Histological analysis shows that severe damage was not observed in the suctioned livers. Since the suction device can be mounted onto the head of the endoscope, this method is a minimally invasive. These results indicate that the in vivo transfection method developed in this study will be a viable approach for biological research and therapies using nucleic acids.