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OBJECTIVE Diffuse idiopathic skeletal hyperostosis (DISH)–related vertebral fractures essentially require operative treatment due to severe fracture site instability and high potential risk of posttraumatic neurological deficit. However, the optimal surgical procedure remains unclear. The purpose of this study was to assess the efficacy of posterior spinal fixation with penetrating endplate screws (PESs) for DISH-related thoracolumbar fractures. METHODS The authors conducted a retrospective, single-center, observational study. They included data from 26 consecutive patients with DISH-related thoracolumbar fractures who were treated with posterior spinal fixation using either conventional pedicle screws (PS group, n = 8) or a combined PES technique (PES group, n = 18) between 2013 and 2019. Age, sex, BMI, bone mineral density, fracture level, use of antithrombotic drug, blood loss, operation time, fixation range, perioperative American Spinal Injury Association Impairment Scale score, implant failure, revision surgery, complications, and mortality were compared. The authors also evaluated screw loosening and bone healing on radiographs and CT scans. RESULTS More patients had vertebral fractures in the lumbar spine in the PS group than in the PES group (3 vs 0; p = 0.019). Patients in the PES group had less blood loss (63 vs 173 ml; p = 0.048) and shorter range of fixation (5 vs 5.5 levels; p = 0.041). The screw loosening rate was significantly lower in the PES group than in the PS group (3% vs 49%; p < 0.001). CONCLUSIONS Posterior spinal fixation using a PES technique may be an ideal surgical procedure for thoracolumbar fractures with DISH, providing more rigid and less invasive fixation than PS.

Sjögren’s syndrome (SS) is an autoimmune disease characterized by inflammation with lymphoid infiltration and destruction of the salivary glands. Although many genome-wide association studies have revealed disease-associated risk alleles, the functions of the majority of these alleles are unclear. Here, we show previously unrecognized roles of GTF2I molecules by using two SS-associated single nucleotide polymorphisms (SNPs), rs73366469 and rs117026326 (GTF2I SNPs). We found that the risk alleles of GTF2I SNPs increased GTF2I expression and enhanced nuclear factor-kappa B (NF-κB) activation in human salivary gland cells via the NF-κB p65 subunit. Indeed, the knockdown of GTF2I suppressed inflammatory responses in mouse endothelial cells and in vivo. Conversely, the over-expression of GTF2I enhanced NF-κB reporter activity depending on its p65-binding N-terminal leucine zipper domain. GTF2I is highly expressed in the human salivary gland cells of SS patients expressing the risk alleles. Consistently, the risk alleles of GTF2I SNPs were strongly associated with activation of the IL-6 amplifier, which is hyperactivation machinery of the NF-κB pathway, and lymphoid infiltration in the salivary glands of SS patients. These results demonstrated that GTF2I expression in salivary glands is increased in the presence of the risk alleles of GTF2I SNPs, resulting in activation of the NF-κB pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS.

Recent studies suggest that blood flow changes in the median nerve may help confirm a diagnosis of carpal tunnel syndrome (CTS). Herein, we examined the utility of superb microvascular imaging (SMI), a new ultrasonographic (US) technique for visualizing microvascular flow, for detecting blood flow differences between CTS patients and healthy controls. We performed a retrospective analysis of 28 hands with suspected CTS. Patients received both nerve conduction and US examinations. Ten healthy volunteers were enrolled as the control group. The nerve compression ratio and the blood flow signal area were quantified using color Doppler US (CDUS), power Doppler US (PDUS), and SMI. Correlation analyses between the blood flow signal area, the compound muscle action potential of the thenar muscle, and the nerve compression ratio were performed. As a result, the mean nerve compression ratio was found to be significantly higher in the CTS group. There were no differences in the blood flow signal area between the groups using CDUS, while PDUS and SMI showed higher blood flow signals in the CTS group. The blood flow signal area measured by SMI had stronger correlations with the compound muscle action potential amplitude and the nerve compression ratio than those for PDUS. The diagnostic utility of SMI was equivalent to PDUS, but superior to conventional CDUS. Nevertheless, the blood flow signal by SMI was more strongly correlated with the electrophysiological severity and compression ratio than for PDUS. Use of SMI in future studies may help clarify the underlying mechanisms of blood flow changes in CTS.

We have reported the gateway reflex, which describes specific neural activations that regulate immune cell gateways at specific blood vessels in the central nervous system (CNS). Four types of gateway reflexes exist, all of which induce alterations in endothelial cells at specific vessels of the blood-brain barrier followed by inflammation in the CNS in the presence of CNS-autoreactive T cells. Here we report a new gateway reflex that suppresses the development of retinal inflammation by using an autoreactive T cell-mediated ocular inflammation model. Exposure to photopic light down-regulated the adrenoceptor pathway to attenuate ocular inflammation by suppressing breaching of the blood-retina barrier. Mechanistic analysis showed that exposure to photopic light down-regulates the expression of α1A-adrenoceptor (α1AAR) due to high levels of norepinephrine and epinephrine, subsequently suppressing inflammation. Surgical ablation of the superior cervical ganglion (SCG) did not negate the protective effect of photopic light, suggesting the involvement of retinal noradrenergic neurons rather than sympathetic neurons from the SCG. Blockade of α1AAR signaling under mesopic light recapitulated the protective effect of photopic light. Thus, targeting regional adrenoceptor signaling might represent a novel therapeutic strategy for autoimmune diseases including those that affect organs separated by barriers such as the CNS and eyes.

Background: Surgical indications for fragility fracture of the pelvis (FFP) have been reconsidered recently, and the indications to perform surgery have increased. However, the optimal surgical method to obtain sufficiently strong fixation in elderly patients with minimal invasiveness is not yet clear. In this report, we present the case of a patient with FFP who was treated with a novel posterior within ring fixation technique using a combination of iliac screws and an implant that locks the original iliosacral (IS) screw in the sacrum. Case Description: A 90-year-old man was diagnosed with FFP (Rommens classification: Type IIc) and hospitalized for conservative treatment. However, 6 weeks after the injury, pain reappeared in his right buttock and computed tomography showed additional fractures of the right subpubic branch and right sacrum (Rommens classification: Type IVb). The fracture was considered to have progressed from being stable to unstable, and surgical treatment was planned. To obtain strong fixation with minimal invasion, we performed posterior fixation using E.Spine Tanit (Euros, France) compact posterior thoracolumbar instrumentation, an implant that combines an IS screw with a sacral anchoring system. The patient started walking unaided 2 weeks after the surgery, suggesting a good outcome of this surgical approach to FFP. Conclusion: We performed posterior fixation surgery for a patient with an unstable FFP that recurred and progressed after conservative treatment. We have achieved good results using a minimally invasive, strong, and within ring fixation technique.

Case A 53-year-old woman presented with Charcot arthropathy of the shoulder joint secondary to residual sensory neuropathy of Guillain-Barre syndrome, which was accompanied by swollen shoulder and restricted range of motion of the right shoulder. We performed a reverse shoulder arthroplasty (RSA). The range of motion had improved 15 months postoperatively, and there was no postoperative complication after RSA. Conclusion Clinicians should be aware that Guillain-Barre syndrome can cause Charcot arthropathy of the shoulder joint. RSA is regarded as a useful treatment, although careful follow-up is needed.

Bmi1 is a polycomb group protein and regulator that stabilizes the ubiquitination complex PRC1 in the nucleus with no evidently direct link to the NF-κB pathway. In this study, we report a novel function of Bmi1: its regulation of IκBα ubiquitination in the cytoplasm. A deficiency of Bmi1 inhibited NF-κB–mediated gene expression in vitro and a NF-κB–mediated mouse model of arthritis in vivo. Mechanistic analysis showed that Bmi1 associated with the SCF ubiquitination complex via its N terminus and with phosphorylation by an IKKα/β-dependent pathway, leading to the ubiquitination of IκBα. These effects on NF-κB–related inflammation suggest Bmi1 in the SCF complex is a potential therapeutic target for various diseases and disorders, including autoimmune diseases.

We recently reported that NF-κB–mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the α subunit of casein kinase II (CK2α) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the γ-secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR–CK2α–p65 complex to induce NF-κB activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-κB p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-κB responsive elements and IL-6 promoter. Furthermore, the transcription of NF-κB target genes was not inhibited by a γ-secretase inhibitor, suggesting that Psen1 regulates NF-κB activation in a manner independent of γ-secretase activity. Mechanistically, Psen1 associated with the BCR–CK2α complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-α–induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR–CK2α–p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR–CK2α–p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease.

Background: The K-line, which is a virtual line between the midpoints of the antero-posterior canal diameter at C2 and C7, can be useful for determination of surgical procedures for cervical ossification of the posterior longitudinal ligament (OPLL). Although K-line is originally measured with plain radiogram, computed tomography multiplanar reconstruction (CT-MPR) is applied for K-line measurement by several surgeons. The purpose of the present study was to analyze whether there is a difference in K-lines obtained from radiographs of standing patients and those obtained from CT-MPR images of supine patients. Methods: The present study included 65 patients with cervical OPLL underwent surgical treatment. We investigated the K-line (+ or −) before surgery, measured from lateral cervical spine radiographs taken in standing patients in a neutral position (X-P-based K-line) and CT-MPR mid-sagittal images obtained in supine patients (CT-based K-line). The X-P-based and CT-based K-lines were compared and differences between them were assessed. Results: The-X-P-based K-line was found to be (+) in 35 patients and (−) in 30 patients. Four of 35 patients with an X-P-based K-line (11%) showed a change from K-line (+) to (−) in CT-based K-line measurements. One of 30 patients with an X-P-based K-line (3%) showed a change from (−) to (+) in CT-based measurements. Conclusions: The K-line should be measured with plain radiogram of standing patients because X-P-based K-line and CT-based K-line can be different.

OBJECTIVEFusion surgery with instrumentation is a widely accepted treatment for cervical spine pathologies. The authors propose a novel technique for subaxial cervical fusion surgery using paravertebral foramen screws (PVFS). The authors consider that PVFS have equal or greater biomechanical strength than lateral mass screws (LMS). The authors’ goals of this study were to conduct a biomechanical study of PVFS, to investigate the suitability of PVFS as salvage fixation for failed LMS, and to describe this novel technique.METHODSThe authors harvested 24 human cervical spine vertebrae (C3–6) from 6 fresh-frozen cadaver specimens from donors whose mean age was 84.3 ± 10.4 years at death. For each vertebra, one side was chosen randomly for PVFS and the other for LMS. For PVFS, a 3.2-mm drill with a stopper was advanced under lateral fluoroscopic imaging. The drill stopper was set to 12 mm, which was considered sufficiently short not to breach the transverse foramen. The drill was directed from 20° to 25° medially so that the screw could purchase the relatively hard cancellous bone around the entry zone of the pedicle. The hole was tapped and a 4.5-mm-diameter × 12-mm screw was inserted. For LMS, 3.5-mm-diameter × 14-mm screws were inserted into the lateral mass of C3–6. The pullout strength of each screw was measured. After pullout testing of LMS, a drill was inserted into the screw hole and the superior cortex of the lateral mass was pried to cause a fracture through the screw hole, simulating intraoperative fracture of the lateral mass. After the procedure, PVFS for salvage (sPVFS) were inserted on the same side and pullout strength was measured.RESULTSThe CT scans obtained after screw insertion revealed no sign of pedicle breaching, violation of the transverse foramen, or fracture of the lateral mass. A total of 69 screws were tested (23 PVFS, 23 LMS, and 23 sPVFS). One vertebra was not used because of a fracture that occurred while the specimen was prepared. The mean bone mineral density of the specimens was 0.29 ± 0.10 g/cm3. The mean pullout strength was 234 ± 114 N for PVFS, 158 ± 91 N for LMS, and 195 ± 125 N for sPVFS. The pullout strength for PVFS tended to be greater than that for LMS. However, the difference was not quite significant (p = 0.06).CONCLUSIONSThe authors introduce a novel fixation technique for the subaxial cervical spine. This study suggests that PVFS tend to provide stronger fixation than LMS for initial applications and fixation equal to LMS for salvage applications. If placement of LMS fails, PVFS can serve as a salvage fixation technique.

Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR.

OBJECTIVE We have previously reported that the coactivation of NF-κB and STAT3 in nonimmune cells, including synovial fibroblasts, enhances the expression of NF-κB target genes and plays a role in chronic inflammation and rheumatoid arthritis (RA). This study was undertaken to examine the role of NF-κB activation in chondrocytes and better understand the pathogenesis of RA. Furthermore, transmembrane protein 147 (TMEM147) was investigated as a representative NF-κB activator in chondrocytes. METHODS Clinical samples from RA patients were analyzed by immunohistochemistry. Specimens obtained from patients with polydactyly were used as control samples. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several murine models of RA. In vitro experiments (quantitative polymerase chain reaction, RNA interference, immunoprecipitation, and confocal microscopy) were performed to investigate the mechanism of action of TMEM147 in chondrocytes. RESULTS Samples obtained from RA patients and mouse models of RA showed coactivation of NF-κB and STAT3 in chondrocytes (P < 0.001). This coactivation induced a synergistic expression of NF-κB targets in vitro (P < 0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (P < 0.01). TMEM147 was highly expressed in chondrocytes from RA patient samples and the mouse models of RA. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-κB in vitro (P < 0.01) and suppressed cytokine-induced RA in vivo (P < 0.01). Mechanistically, TMEM147 molecules acted as scaffold proteins for the NF-κB complex, which included breakpoint cluster region and casein kinase 2, and enhanced NF-κB activity. CONCLUSION These results suggest that chondrocytes play a role in the development of RA via TMEM147-mediated NF-κB activation and indicate a novel therapeutic strategy for RA.

Patients with cervical compression myelopathy (CCM) generally present bilateral neurological symptoms in their extremities. However, a substantial portion of patients with CCM exhibit laterality of neurological symptoms. The aim of this study was to assess the correlation between intrinsic structural damage and laterality of symptoms using spinal cord diffusion tensor imaging (DTI) of the corticospinal tract.We enrolled 10 healthy volunteers and 40 patients with CCM in this study. We evaluated motor function using the American Spinal Injury Association (ASIA) motor score for left and right extremities. For DTI acquisitions, a 3.0-T magnetic resonance imaging system with diffusion-weighted spin-echo sequence was used. Regions-of-interest in the lateral column tracts were determined. We determined the correlations between fractional anisotropy (FA) and ASIA motor scores. An FA asymmetry index was calculated using left and right regions-of-interest.Four patients exhibited laterality of symptoms in their extremities, for which left and right ASIA scores correlated moderately with FA in the left and right lateral columns, respectively (left: ρ = 0.64, P0.001; right: ρ = 0.67, P0.001). The area under the receiver-operator characteristic curve showed that the FA asymmetry index indicated laterality of symptoms.Using tract-specific DTI, we demonstrated that microstructural damages in the left and right corticospinal tracts correlated with corresponding neurological symptoms in the ipsilateral side and the FA asymmetry index could indicate laterality in neurological symptoms of patients with CCM.

Laminoplasty (LMP) is a widely accepted surgical procedure for ossification of the posterior longitudinal ligament (OPLL) of the cervical spine. Progression of OPLL can occur in the long term after LMP. The aim of the present study was to determine whether addition of the instrumented fusion, (posterior decompression with instrumented fusion [PDF]), can suppress progression of OPLL or not. The present study included 50 patients who underwent LMP (n=23) or PDF (n=27) for OPLL of the cervical spine. We performed open door laminoplasty. PDF surgery was performed by double-door laminoplasty followed by instrumented fusion. We observed the non-ossified segment of the OPLL and measured the thickness of the OPLL at the thickest segment with pre- and postoperative sagittal CT multi-planar reconstruction images. Postoperative CT scan revealed fusion of the non-ossified segment of the OPLL was obtained in 4/23 patients (17%) in the LPM group and in 23/27 patients (85%) in the PDF group, showing a significant difference between both groups (p=0.003). Progression of the thickness of the OPLL in the PDF group (-0.1±0.4mm) was significantly smaller than in the LMP group (0.6±0.7mm, p=0.0002). The proportion of patients showing the decrease in thickness of OPLL was significantly larger in the PDF group (6/27 patients; 22%) than in the LMP group (0/23 patients; 0%, p=0.05). In conclusion, PDF surgery can suppress the thickening of OPLL.

The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography–tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR–CK2α complex could be a novel therapeutic target for various inflammatory diseases.

Study design Retrospective case series. Purpose To elucidate the impact of postoperative occiput-C2 (O-C2) angle change on subaxial cervical alignment. Overview of literature In the case of occipito-upper cervical fixation surgery, it is recommended that the O-C2 angle should be set larger than the preoperative value postoperatively. Methods The present study included 17 patients who underwent occipito-upper cervical spine (above C4) posterior fixation surgery for atlantoaxial subluxation of various etiologies. Plain lateral cervical radiographs in a neutral position at standing were obtained and the O-C2 angle and subaxial lordosis angle (the angle between the endplates of the lowest instrumented vertebra (LIV) and C7 vertebrae) were measured preoperatively and postoperatively soon after surgery and ambulation and at the final follow-up visit. Results There was a significant negative correlation between the average postoperative alteration of O-C2 angle (DO-C2) and the average postoperative alteration of subaxial lordosis angle (Dsubaxial lordosis angle) (r=-0.47, p=0.03). Conclusions There was a negative correlation between DO-C2 and Dsubaxial lordosis angles. This suggests that decrease of mid-to lower-cervical lordosis acts as a compensatory mechanism for lordotic correction between the occiput and C2. In occipito-cervical fusion surgery, care must be taken to avoid excessive O-C2 angle correction because it might induce mid-to-lower cervical compensatory decrease of lordosis.

We enrolled 100 patients who underwent preoperative CT angiography before cervical spine instrumentation and investigated the morphology of the C2 pedicle from the perspective of pedicle screw (PS) trajectory using volume rendering and multiplanar reconstruction. The narrowest portion of the pedicle was identified as the pedicle isthmus. Safe C2 PS insertion was regarded to be not feasible when the height of the medullary cavity of the pedicle isthmus and/or width of the medullary cavity of the pedicle isthmus was ⩽4mm. Forty-five (22.5%) pedicles were ⩽4mm in width, and safe insertion of a PS was determined to be not feasible. Among these, seven pedicles were ⩽4mm in both height and width. The remaining 38 pedicles were ⩽4mm in width with heights >4mm. There was no pedicle with a width >4mm and height

The K-line, which is a virtual line that connects the midpoints of the anteroposterior diameter of the spinal canal at C2 and C7 in a plain lateral radiogram, is a useful preoperative predictive indicator for sufficient decompression by laminoplasty (LMP) for ossification of the posterior longitudinal ligament (OPLL). K-line is defined as (+) when the peak of OPLL does not exceed the K-line, and is defined as (–) when the peak of OPLL exceeds the K-line. For patients with K-line (–) OPLL, LMP often results in poor outcome. The aim of the present study was to compare the clinical outcome of LMP, posterior decompression with instrumented fusion (PDF) and anterior decompression and fusion (ADF) for patients with K-line (–) OPLL. The present study included patients who underwent surgical treatment including LMP, PDF and ADF for K-line (–) cervical OPLL. We retrospectively compared the clinical outcome of those patients in terms of Japanese Orthopedic Association score (JOA score) recovery rate. JOA score recovery rate was significantly higher in the ADF group compared with that in the LMP group and the PDF group. The JOA score recovery rate in the PDF group was significantly higher than that in the LMP group. LMP should not be used for K-line (–) cervical OPLL. ADF is one of the suitable surgical treatments for K-line (–) OPLL. Both ADF and PDF are applicable for K-line (–) OPLL according to indications set by each institute and surgical decisions.

Neuroimmunology is a research field that intersects neuroscience and immunology, with the larger aim of gaining significant insights into the pathophysiology of chronic inflammatory diseases such as multiple sclerosis. Conventional studies in this field have so far mainly dealt with immune responses in the nervous system (i.e. neuroinflammation) or systemic immune regulation by the release of glucocorticoids. On the other hand, recently accumulating evidence has indicated bidirectional interactions between specific neural activations and local immune responses. Here we discuss one such local neuroimmune interaction, the gateway reflex. The gateway reflex represents a mechanism that translates specific neural stimulations into local inflammatory outcomes by changing the state of specific blood vessels to allow immune cells to extravasate, thus forming the gateway. Several types of gateway reflex have been identified, and each regulates distinct blood vessels to create gateways for immune cells that induce local inflammation. The gateway reflex represents a novel therapeutic strategy for neuroinflammation and is potentially applicable to other inflammatory diseases in peripheral organs.

Spinal cord injury (SCI) can cause neuropathic pain (NeP), often reducing a patient's quality of life. We recently reported that granulocyte colony-stimulating factor (G-CSF) could attenuate NeP in several SCI patients. However, the mechanism of action underlying G-CSF-mediated attenuation of SCI-NeP remains to be elucidated. The purpose of the present study was to elucidate the therapeutic effect and mechanism of action of granulocyte colony-stimulating factor for SCI-induced NeP. T9 level contusive SCI was introduced to adult male Sprague Dawley rats. Three weeks after injury, rats received intraperitoneal recombinant human G-CSF (15.0 μg/kg) for 5 days. Mechanical allodynia was assessed using von Frey filaments. Immunohistochemistry and western blot analysis were performed in spinal cord lumbar enlargement samples. Testing with von Frey filaments showed significant increase in the paw withdrawal threshold in the G-CSF group compared with the vehicle group 4 weeks, 5 weeks, 6 weeks and 7 weeks after injury. Immunohistochemistry for CD11b (clone OX-42) revealed that the number of OX-42-positive activated microglia was significantly smaller in the G-CSF group than that in the vehicle rats. Western blot analysis indicated that phosphorylated-p38 mitogen-activated protein kinase (p38MAPK) and interleukin-1β expression in spinal cord lumbar enlargement were attenuated in the G-CSF-treated rats compared with that in the vehicle-treated rats. The present results demonstrate a therapeutic effect of G-CSF treatment for SCI-induced NeP, possibly through the inhibition of microglial activation and the suppression of p38MAPK phosphorylation and the upregulation of interleukin-1β.

Dropped head syndrome (DHS) is characterized by apparent neck extensor muscle weakness and difficulty extending the neck to raise the head against gravity. The aim of the present study was to elucidate possible risk factors for DHS after cervical laminoplasty. Five patients who developed DHS after cervical laminoplasty (DHS group) and twenty age-matched patients who underwent laminoplasty without DHS after surgery (control group) were compared. The surgical procedure was single-door laminoplasty with strut grafting using resected spinous processes or hydroxyapatite spacers from C3 to C6 or C7. Analyses of preoperative images including the C2-C7 angle, C7-T1 kyphosis, T1 tilt, center of gravity line from the head-C7 sagittal vertical axis (CGH-C7 SVA) were performed on lateral plain cervical spine radiographs. Preoperative T2-weighted MRI at the C5 vertebral level was used to measure the cross-sectional area of the deep extensor muscles. Widths of the lateral gutters were assessed postoperatively using CT scans of the C5 vertebral body. The average preoperative C2-C7 angle was significantly smaller in the DHS group compared with the control group. The average preoperative C7-T1 angle was significantly larger in the DHS group compared with the control group. The average preoperative CGH-C7 SVA was significantly larger in the DHS group compared with the control group. In conclusion, patients with more pronounced preoperative C2-C7 kyphosis, C7-T1 kyphosis, and CGH-C7 SVA are more likely to develop DHS following laminoplasty.

Background Elimination of preexisting donor-reactive antibodies is essential for antibody-incompatible kidney transplantation. Double filtration plasmapheresis (DFPP) using albumin (Alb) replacement fluid (Rf) removes immunoglobulin more selectively than plasma exchange; however, fixed-dose treatment can result in insufficient removal of antibody or excess loss of osmotic pressure and subsequent hypotension. The aim of this study was to determine the optimal setting (volume and concentration of Rf) of DFPP to remove donor-reactive antibodies. Materials and Methods One hundred seventeen DFPPs were performed in 41 patients for kidney transplant in an ABO-incompatible or crossmatch-positive setting. A formula for Rf volume was determined based on volume-removal rate (RR) curve of IgG. Another formula for Alb concentration of Rf was also established to keep plasma volume within pre-DFPP plasma volume ± 10% calculated by post- to pre-DFPP hematocrit ratio to avoid hypotensive events. Results RR-IgG was obtained based on patient data: Rf (mL) = BW (kg) × eX, [X = (RR-IgG + 10.757)/25.603] (R2 = 0.401, P Conclusions Optimal volume and concentration of Alb Rf can be calculated using our formulae with targeted RR-IgG.

RNA-binding motif 10 (Rbm10) is an RNA-binding protein that regulates alternative splicing, but its role in inflammation is not well defined. Here, we show that Rbm10 controls appropriate splicing of DNA (cytosine-5)-methyltransferase 3b (Dnmt3b), a DNA methyltransferase, to regulate the activity of NF-κB-responsive promoters and consequently inflammation development. Rbm10 deficiency suppressed NF-κB-mediated responses in vivo and in vitro. Mechanistic analysis showed that Rbm10 deficiency decreased promoter recruitment of NF-κB, with increased DNA methylation of the promoter regions in NF-κB-responsive genes. Consistently, Rbm10 deficiency increased the expression level of Dnmt3b2, which has enzyme activity, while it decreased the splicing isoform Dnmt3b3, which does not. These two isoforms associated with NF-κB efficiently, and overexpression of enzymatically active Dnmt3b2 suppressed the expression of NF-κB targets, indicating that Rbm10-mediated Dnmt3b2 regulation is important for the induction of NF-κB-mediated transcription. Therefore, Rbm10-dependent Dnmt3b regulation is a possible therapeutic target for various inflammatory diseases.

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis. DOI: http://dx.doi.org/10.7554/eLife.25517.001

How aging affects the spinal cord at a molecular level is unclear. The aim of this study was to explore spinal cord aging–related proteins that may be involved in pathological mechanisms of age-related changes in the spinal cord. Spinal cords of 2-year-old and 8-week-old female Sprague-Dawley rats were dissected from the animals. Protein samples were subjected to 2-dimentional polyacrylamide gel electrophoresis followed by mass spectrometry. Screened proteins were further investigated with immunohistochemistry and Western blotting. Among the screened proteins, we selected α-crystallin B-subunit (αB-crystallin) and peripherin for further investigation because these proteins were previously reported to be related to central nervous system pathologies. Immunohistochemistry and Western blotting revealed significant upregulation of αB-crystallin and peripherin expression in aged rat spinal cord. Further exploration is needed to elucidate the precise mechanism and potential role of these upregulated proteins in spinal cord aging processes.

A chronic traumatic hyperextension of the proximal interphalangeal (PIP) joint can result from traumatic volar plate (VP) disruption. For the treatment of this disorder, reconstruction procedures have been traditionally recommended, because the condition of the VP was not considered susceptible to repair due to retraction or attenuation. The purpose of this paper is to present the operative technique and report the clinical results of late VP repair. Late VP repair was performed for chronic, post-traumatic hyperextension deformity of the PIP joint of the little finger resulting from VP disruption in seven consecutive patients. The range of motion and the lateral stability of the PIP joint were evaluated. The radiographic images were also used to evaluate the alignment and degenerative changes of the PIP joint. Clinical results were classified according to Catalano's criteria. Intraoperative findings showed that the VP could be mobilised and repaired in all cases. The hyperextension was well corrected, and none showed recurrence of the initial deformity. Average flexion of the PIP joint was 92° (range = 75-98°), and flexion contracture was 9° (range = 0-20°). On clinical evaluation, there were two excellent, three good, and two fair results. The postoperative radiographs revealed no degenerative change in the PIP joint in six patients. Late VP repair is a successful and reliable alternative and more physiologic than other reconstruction methods. One should first consider late VP repair, despite a long interval between injury and repair.

We performed a phase I/IIa clinical trial and confirmed the safety and feasibility of granulocyte colony-stimulating factor (G-CSF) as neuroprotective therapy in patients with acute spinal cord injury (SCI). In this study, we retrospectively analyzed the clinical outcome in SCI patients treated with G-CSF and compared these results to a historical cohort of SCI patients treated with high-dose methylprednisolone sodium succinate (MPSS). In the G-CSF group (n = 28), patients were treated from August 2009 to July 2012 within 48 h of the injury, and G-CSF (10 μg/kg/day) was administered intravenously for five consecutive days. In the MPSS group (n = 34), patients underwent high-dose MPSS therapy from August 2003 to July 2005 following the NASCIS II protocol. We evaluated the ASIA motor score and the AIS grade elevation between the time of treatment and 3-month follow-up and adverse events. The ΔASIA motor score was significantly higher in the G-CSF group than in the MPSS group (p

PURPOSE: The aim of this study was to assess the potential role of diffusion tensor imaging (DTI) as a predictor of surgical outcomes in patients with cervical compressive myelopathy (CCM). Surgical decompression is often recommended for symptomatic CCM. It is important to know the prognosis of surgical outcomes and to recommend appropriate timing for surgery. \nMETHODS: We enrolled 26 patients with CCM who underwent surgery. The Japanese Orthopaedic Association (JOA) score for cervical myelopathy was evaluated before and 6 months after surgery. Surgical outcomes were regarded as good if there was a change in JOA score of three points or more, or the recovery rate of JOA score was 50% or more. The patients were examined using a 3.0 T magnetic resonance system before surgery. Measured diffusion parameters were fractional anisotropy (FA) and mean diffusivity (MD). The correlations between DTI parameters and surgical outcomes were analyzed. \nRESULTS: Both change and recovery rate of JOA score moderately correlated with FA. Furthermore, the area under the receiver-operator characteristic curve based on FA for prognostic precision of surgical outcomes indicates that FA is a good predictive factor. The cut-off values of FA for predicting good surgical outcomes evaluated by change and recovery rate of JOA score were 0.65 and 0.57, respectively. Neither change nor recovery rate of JOA score correlated with MD. \nCONCLUSIONS: FA in spinal cord DTI can moderately predict surgical outcomes. DTI can serve as a supplementary tool for decision-making to guide surgical intervention in patients with CCM.

We investigated the outcome of posterior decompression and instrumented fusion (PDF) surgery for patients with K-line (-) ossification of the posterior longitudinal ligament (OPLL) of the cervical spine, who may have a poor surgical prognosis. We retrospectively analyzed the outcome of a series of 27 patients who underwent PDF without correction of cervical alignment for K-line (-) OPLL and were followed-up for at least 1 year after surgery. We had performed double-door laminoplasty followed by posterior instrumented fusion without excessive correction of cervical spine alignment. The preoperative Japanese Orthopedic Association (JOA) score for cervical myelopathy was 8.0 points and postoperative JOA score was 11.9 points on average. The mean JOA score recovery rate was 43.6%. The average C2-C7 angle was 2.2° preoperatively and 3.1° postoperatively. The average maximum occupation ratio of OPLL was 56.7%. In conclusion, PDF without correcting cervical alignment for patients with K-line (-) OPLL showed moderate neurological recovery, which was acceptable considering K-line (-) predicts poor surgical outcomes. Thus, PDF is a surgical option for such patients with OPLL.

Study design A cross-sectional study. Objective The aim of this study was to quantify spinal cord dysfunction at the tract level in patients with cervical compressive myelopathy (CCM) using reduced field-of-view (rFOV) diffusion tensor imaging (DTI). Summary of background data Although magnetic resonance imaging (MRI) is the standard used for radiological evaluation of CCM, information acquired by MRI does not necessarily reflect the severity of spinal cord disorder. There is a growing interest in developing imaging methods to quantify spinal cord dysfunction. To acquire high-resolution DTI, a new scheme using rFOV has been proposed. Methods We enrolled 10 healthy volunteers and 20 patients with CCM in this study. The participants were studied using a 3.0-T MRI system. For DTI acquisitions, diffusion-weighted spin-echo rFOV single-shot echo-planar imaging was used. Regions-of-interest (ROI) for the lateral column (LC) and posterior column (PC) tracts were determined on the basis of a map of fractional anisotropy (FA) of the spinal cord and FA values were measured. The FA of patients with CCM was compared with that of healthy controls and correlated with Japanese Orthopaedic Association (JOA) score. Results In LC and PC tracts, FA values in patients with CCM were significantly lower than in healthy volunteers. Total JOA scores correlated moderately with FA in LC and PC tracts. JOA subscores for motor dysfunction of the lower extremities correlated strongly with FA in LC and PC tracts. Conclusion It is feasible to evaluate the cervical spinal cord at the tract level using rFOV DTI. Although FA values at the maximum compression level were not well correlated with total JOA scores, they were strongly correlated with JOA subscores for motor dysfunction of the lower extremities. Our findings suggest that FA reflects white matter dysfunction below the maximum compression level and FA can be used as an imaging biomarker of spinal cord dysfunction. Level of evidence 4.

Granulocyte colony-stimulating factor (G-CSF) mobilizes peripheral blood stem cells (PBSCs) derived from bone marrow. We hypothesized that intraspinal transplantation of PBSCs mobilized by G-CSF could promote functional recovery after spinal cord injury. Spinal cords of adult nonobese diabetes/severe immunodeficiency mice were injured using an Infinite Horizon impactor (60 kdyn). One week after the injury, 3.0 μl of G-CSF-mobilized human mononuclear cells (MNCs; 0.5 × 105/μl), G-CSF-mobilized human CD34-positive PBSCs (CD34; 0.5 × 105/μl), or normal saline was injected to the lesion epicenter. We performed immunohistochemistry. Locomotor recovery was assessed by Basso Mouse Scale. The number of transplanted human cells decreased according to the time course. The CD31-positive area was significantly larger in the MNC and CD34 groups compared with the vehicle group. The number of serotonin-positive fibers was significantly larger in the MNC and CD34 groups than in the vehicle group. Immunohistochemistry revealed that the number of apoptotic oligodendrocytes was significantly smaller in cell-transplanted groups, and the areas of demyelination in the MNC- and CD34-transplanted mice were smaller than that in the vehicle group, indicating that cell transplantation suppressed oligodendrocyte apoptosis and demyelination. Both the MNC and CD34 groups showed significantly better hindlimb functional recovery compared with the vehicle group. There was no significant difference between the two types of transplanted cells. Intraspinal transplantation of G-CSF-mobilized MNCs or CD34-positive cells promoted angiogenesis, serotonergic fiber regeneration/sparing, and preservation of myelin, resulting in improved hindlimb function after spinal cord injury in comparison with vehicle-treated control mice. Transplantation of G-CSF-mobilized PBSCs has advantages for treatment of spinal cord injury in the ethical and immunological viewpoints, although further exploration is needed to move forward to clinical application.

Background We report on Japanese patients who showed neurological deterioration induced by sitting after cervicothoracic posterior decompression with instrumented fusion, but showed immediate neurological recovery after bed rest. Case Presentation Patients showed incomplete paraparesis caused by the ossification of the posterior longitudinal ligament at uppermost thoracic spine. Cervicothoracic posterior decompression with instrumented fusion was performed. Postoperatively, the patients showed partial paraparesis when they were sitting. They showed rapid recovery from lower extremity paralysis upon lying down. After strict bed rest for one month, those patients showed no apparent development of paralysis during sitting. Conclusion In patients with postoperative residual anterior spinal cord compression, micromotion might exacerbate neurological symptoms.