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Pancreatic cancer is one of the most refractory malignancies. In situ vaccines (ISV), in which intratumorally injected immunostimulatory adjuvants activate innate immunity at the tumor site, utilize tumor-derived patient-specific antigens, thereby allowing for the development of vaccines in patients themselves. Near-infrared photoimmunotherapy (NIR-PIT) is a novel therapy that selectively kills cancer cells exclusively in the NIR-irradiated region. Extending our previous research showing that ISV using the unique nanoparticulate Toll-like receptor 9 (TLR9) ligand K3-SPG induced effective antitumor immunity, here we incorporated NIR-PIT into K3-SPG-ISV so that local tumor destruction by NIR-PIT augments the antitumor effect of ISV. In the mouse model of pancreatic cancer, the combination of K3-SPG-ISV and CD44-targeting NIR-PIT showed synergistic systemic antitumor effects and enhanced anti-programmed cell death-1 (PD-1) blockade. Mechanistically, strong intratumoral upregulation of interferon-related genes and dependency on CD8 + T cells were observed, suggesting the possible role of interferon and cytotoxic T cell responses in the induction of antitumor immunity. Importantly, this combination induced immunological memory in therapeutic and neoadjuvant settings. This study represents the first attempt to integrate NIR-PIT with ISV, offering a promising new direction for cancer immunotherapy, particularly for pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The call for second generation malaria vaccines needs not only the identification of novel candidate antigens or adjuvants but also a better understanding of immune responses and the underlying protective processes. Plasmodium parasites have evolved a range of strategies to manipulate the host immune system to guarantee survival and establish parasitism. These immune evasion strategies hamper efforts to develop effective malaria vaccines. In the case of a malaria vaccine targeting the N-terminal domain of P. falciparum serine repeat antigen 5 (SE36), now in clinical trials, we observed reduced responsiveness (lowered immunogenicity) which may be attributed to immune tolerance/immune suppression. Here, immunogenicity data and insights into the immune responses to SE36 antigen from epidemiological studies and clinical trials are summarized. Documenting these observations is important to help identify gaps for SE36 continued development and engender hope that highly effective blood-stage/multi-stage vaccines can be achieved., Competing Interests: Declaration of Competing Interest TH is the inventor of BK-SE36; TH, KJI, and TT are inventors of BK-SE36/CpG. NP and TH are both supported by a research fund from Nobelpharma Co., Ltd. (NPC), the clinical trial sponsor of Burkina Faso trials. These involvements did not influence the writing of this review and the decision to submit the article for publication., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Reoperation is usually associated with poor results and increased morbidity and hospital costs. However, the rates, causes, and risk factors for reoperation in patients undergoing lumbar spinal fusion surgery remain controversial. This study aimed to identify the risk factors for early reoperation after posterior lumbar interbody fusion surgery and to compare the clinical outcomes between patients who underwent reoperation and those who did not., Methods: We investigated a multicenter medical record database of 1263 patients who underwent posterior lumbar interbody fusion surgery between 2012 and 2015. A total of 72 (5.7%) reoperations within two years after surgery were identified and were propensity-matched for age, sex, number of fusion segments, and surgeon's experience., Results: We analyzed a total of 114 patients (57 who underwent reoperation (R group) and 57 who did not (C group)). The mean age was 62.6 ± 13.4 years, with 78 men and 36 women. The mean number of fused segments was 1.2 ± 0.5. Surgical site infection was the most common cause of reoperation. There were significant differences in the incidence of diabetes mellitus (p = 0.024), preoperative ambulation status (p = 0.046), and ASA grade (p < 0.001) between the C and R groups. The recovery rate of the Japanese Orthopaedic Association score was significantly lower in the R group compared to the C group (R: 50.5 ± 28.8%, C: 63.9 ± 33.7%, p = 0.024). There were significant differences in the bone fusion rate (R: 63.2%, C: 96.5%, p < 0.001) and incidence of screw loosening (R: 31.6%; C: 10.5%; p = 0.006)., Conclusion: Diabetes mellitus, preoperative ambulation status, and ASA grade were significant risk factors for early reoperation following posterior lumbar interbody fusion surgery. The patients who underwent early reoperation had worse clinical outcomes than those who did not., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Competing Interests: All authors, except CB, are members of the Science and Technology Expert Group for the 100 Days Mission. CB is the Deputy Head of the International Pandemic Preparedness Secretariat, which is hosted by Wellcome, and is a former employee of WHO. VD is the President of the US National Academy of Medicine. SS is the former Chief Scientist at WHO. RAB is the former Director of the US Biomedical Advanced Research and Development Authority (BARDA), is on the Scientific Advisory Board for Qiagen, is on the Board of Directors for Foundation for Innovative New Diagnostics, and holds stock in Cue Health. JC is the Chief Technology Officer of Univercells and the Chief Executive Officer of Quantoom Biosciences. TCC is the Chief Health Scientist at the Singapore Ministry of Health and is the Executive Director of the Office for Healthcare Transformation of the Singapore Ministry of Health. RD-A is the Global Head at Johnson & Johnson Global Public Health Research and Development, which receives grants and contracts from BARDA, the US National Institutes of Health (NIH), the EU (including the Innovative Health Initiative), the Bill & Melinda Gates Foundation, Flanders Agency Innovation and Entrepreneurship, the European and Developing Countries Clinical Trials Partnership, and the Singapore Agency for Science, Technology and Research; is Co-Chair of the Therapeutics Clinical Working Group of Accelerating COVID-19 Therapeutic Interventions and Vaccines at NIH; is a board member of the INTREPID Alliance; is a member of the American Society of Gene Therapy; and holds stock and stock options with Merck Sharp & Dohme and Johnson & Johnson. RE-P is the acting Chief of Staff for the Coalition of Epidemic Preparedness Innovations (CEPI) Manufacturing and Supply Chain division. GFG is the Dean of the Savaid Medical School (University of Chinese Academy of Sciences, Beijing, China). KI is the Director of the International Vaccine Design Center (Institute of Medical Science, University of Tokyo, Tokyo, Japan) and is a member of Scientific Advisory Committees for CEPI and the Global Health Innovative Technology Fund. YKT is the Head of the Division of Laboratory Systems and Networks at Africa Centres for Disease Control and Prevention (Africa CDC). TL received support through a grant from the University of Oxford (Oxford, UK) to support the running of the Vaccine Taskforce via the UK National Institute for Health and Care Research trial and the AstraZeneca partnership for development of COVID-19 vaccines, was a consultant to Vaccitech, and is an inventor on a patent application for a vaccine against SARS CoV-2. SM is Chief Science Officer for Africa CDC. J-AR is the Ambassador for Global Health at the Norwegian Ministry of Foreign Affairs; is a Gavi, the Vaccine Alliance board member representing the Nordic+ constituency; and is the former technical-level Co-Chair of the Access to COVID-19 Tools Accelerator Facilitation Council. US is the Executive Director of the Serum Institute of India. MS is the former WHO Assistant Director-General for Drug Access, Vaccines and Pharmaceuticals. RS is the former Secretary of the Department of Biotechnology at the Indian Ministry of Science and Technology. J-FT is the Head of Research and Development at Sanofi Vaccines; owns shares from Sanofi; and received shares from GlaxoSmithKline until January, 2021, as a former employee. NSW is the Founder and Chief Executive Officer of Vaccines for All and is a consultant to Africa CDC for the Partnership for Africa Vaccine Manufacturing initiative at CEPI India.

The skin is a protective interface between the internal organs and environment and functions not only as a physical barrier but also as an immune organ. However, the immune system in the skin is not fully understood. A member of the thermo-sensitive transient receptor potential (TRP) channel family, TRPM4, which acts as a regulatory receptor in immune cells, was recently reported to be expressed in human skin and keratinocytes. However, the function of TRPM4 in immune responses in keratinocytes has not been investigated. In this study, we found that treatment with BTP2, a known TRPM4 agonist, reduced cytokine production induced by tumor necrosis factor (TNF) α in normal human epidermal keratinocytes and in immortalized human epidermal keratinocytes (HaCaT cells). This cytokine-reducing effect was not observed in TRPM4-deficient HaCaT cells, indicating that TRPM4 contributed to the control of cytokine production in keratinocytes. Furthermore, we identified aluminum potassium sulfate, as a new TRPM4 activating agent. Aluminum potassium sulfate reduced Ca 2+ influx by store-operated Ca 2+ entry in human TRPM4-expressing HEK293T cells. We further confirmed that aluminum potassium sulfate evoked TRPM4-mediated currents, showing direct evidence for TRPM4 activation. Moreover, treatment with aluminum potassium sulfate reduced cytokine expression induced by TNFα in HaCaT cells. Taken together, our data suggested that TRPM4 may serve as a new target for the treatment of skin inflammatory reactions by suppressing the cytokine production in keratinocytes, and aluminum potassium sulfate is a useful ingredient to prevent undesirable skin inflammation through TRPM4 activation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Oxidative metabolism in mitochondria regulates cellular differentiation and gene expression through intermediary metabolites and reactive oxygen species. Its role in kidney development and pathogenesis is not completely understood. Here we inactivated ubiquinone-binding protein QPC, a subunit of mitochondrial complex III, in two types of kidney progenitor cells to investigate the role of mitochondrial electron transport in kidney homeostasis. Inactivation of QPC in sine oculis-related homeobox 2 (SIX2)-expressing cap mesenchyme progenitors, which give rise to podocytes and all nephron segments except collecting ducts, resulted in perinatal death from severe kidney dysplasia. This was characterized by decreased proliferation of SIX2 progenitors and their failure to differentiate into kidney epithelium. QPC inactivation in cap mesenchyme progenitors induced activating transcription factor 4-mediated nutritional stress responses and was associated with a reduction in kidney tricarboxylic acid cycle metabolites and amino acid levels, which negatively impacted purine and pyrimidine synthesis. In contrast, QPC inactivation in ureteric tree epithelial cells, which give rise to the kidney collecting system, did not inhibit ureteric differentiation, and resulted in the development of functional kidneys that were smaller in size. Thus, our data demonstrate that mitochondrial oxidative metabolism is critical for the formation of cap mesenchyme-derived nephron segments but dispensable for formation of the kidney collecting system. Hence, our studies reveal compartment-specific needs for metabolic reprogramming during kidney development., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: The preoperative skin antiseptic, olanexidine gluconate (OLG), which has been available in Japan since 2015, is also known to be effective against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and Pseudomonas aeruginosa. This study attempted to clarify OLG efficacy against surgical site infections and antiseptic-related adverse events as compared to conventionally used povidone iodine (PVP-I)., Methods: Propensity score matching was performed on 307 patients who underwent surgery for colorectal tumors at our hospital. All 116 cases (58 PVP-I cases, 58 OLG cases) who were diagnosed with colorectal cancer were included. We examined surgical site infection rate after disinfection using PVP-I and OLG, length of hospitalization stay (days) after surgery, adverse events associated with antiseptics, and additional medical costs associated with adverse events caused by antiseptics., Results: The surgical site infection rate was 8.6% in both the PVP-I and OLG groups, with no significant difference observed. The number of postoperative hospitalization days in the PVP-I group was 12.9 (±6.9) days and 16.4 (±14.6) days in the OLG group, which exhibited no significant difference (p = 0.10). Although no complications due to antiseptics were observed in the PVP-I group, skin-related side effects were observed in 8 patients (13.8%) in the OLG group. The median additional medical cost was 730 [120-1823] yen., Conclusions: OLG was as effective as the conventional PVP-I for surgical site infections during colorectal cancer elective surgery. However, significantly higher skin disorders occurred in OLG, thereby making it necessary to evaluate antiseptic use in conjunction with patient burden., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The complication rate for palliative surgery in spinal metastasis is relatively high, and major complications can impair the patient's activities of daily living. However, surgical indications are determined based primarily on the prognosis of the cancer, with the risk of complications not truly considered. We aimed to identify the risk predictors for perioperative complications in palliative surgery for spinal metastasis., Methods: A multicentered, retrospective review of 195 consecutive patients with spinal metastasis who underwent palliative surgeries with posterior procedures from 2001 to 2016 was performed. We evaluated the type and incidence of perioperative complications within 14 days after surgery. Patients were categorized into either the complication group (C) or no-complication group (NC). Univariate and multivariate analyses were used to identify potential predictors for perioperative complications., Results: Thirty patients (15%) experienced one or more complications within 14 days of surgery. The most frequent complications were surgical site infection (4%) and motor weakness (3%). A history of diabetes mellitus (C; 37%, NC; 9%: p < 0.01) and surgical time over 300 min (C; 27%, NC; 12%: p < 0.05) were significantly associated with complications according to univariate analysis. Increased blood loss and non-ambulatory status were determined to be potential risk factors. Of these factors, multivariate logistic regression revealed that a history of diabetes mellitus (OR: 6.6, p < 0.001) and blood loss over 1 L (OR: 2.7, p < 0.05) were the independent risk factors for perioperative complications. There was no difference in glycated hemoglobin A1c between the diabetes patients with and without perioperative complications., Conclusions: Diabetes mellitus should be used for the risk stratification of surgical candidates regardless of the treatment status, and strict prevention of bleeding is needed in palliative surgeries with posterior procedures to mitigate the risk of perioperative complications., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Objective: We assessed the sequential magnetic resonance imaging changes of indirect neural decompression after minimally invasive lumbar lateral interbody fusion (LIF) combined with posterior percutaneous pedicle screw (PPS) fixation for degenerative spondylolisthesis (DS) according to the severity of preoperative lumbar spinal stenosis., Methods: A total of 43 patients (mean age, 68.7 years; 16 men and 27 women) with DS who had undergone LIF and closed reduction with PPS fixation were enrolled. The intervertebral levels were divided into the moderate stenosis (MS) group (preoperative cross-sectional area [CSA] of the thecal sac >50 mm 2 ) and severe stenosis (SS) group (CSA ≤50 mm 2 ). The CSA, ligamentum flavum thickness, and diameter of the thecal sac at the affected level were measured on cross-sectional magnetic resonance images at baseline, immediately postoperatively, and 2 years postoperatively., Results: For the 31 and 29 intervertebral levels in the MS and SS groups, the mean CSA at baseline, immediately postoperatively, and 2 years postoperatively was 76.9 mm 2 and 35.8 mm 2 , 104.3 mm 2 and 81.4 mm 2 , and 130.9 mm 2 and 105.7 mm 2 , respectively. The mean ligamentum flavum thicknesses at 2 years postoperatively became thinner than that immediately after surgery in both groups (P < 0.01). The mean diameter of the thecal sac at 2 years was longer than that immediately after surgery in both groups (MS group, P < 0.05; SS group, P < 0.01) The expansion ratio of the CSA at 2 years postoperatively was significantly greater in the SS group than that in the MS group (P < 0.01)., Conclusions: Sequential enlargement of the spinal canal was obtained by the thinning of the ligamentum flavum after LIF and PPS fixation in patients with DS with both mild and severe stenosis. The effect of indirect neural decompression was equivalent even in those with severe lumbar spinal stenosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A (TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM in sine oculis-related homeobox 2-expressing kidney progenitor cells. TFAM deficiency resulted in significantly decreased mitochondrial gene expression, mitochondrial depletion, inhibition of nephron maturation and the development of severe postnatal cystic disease, which resulted in premature death. This was associated with abnormal mitochondrial morphology, a reduction in oxygen consumption and increased glycolytic flux. Furthermore, we found that TFAM expression was reduced in murine and human polycystic kidneys, which was accompanied by mitochondrial depletion. Thus, our data suggest that dysregulation of TFAM expression and mitochondrial depletion are molecular features of kidney cystic disease that may contribute to its pathogenesis., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family and plays critical roles in facilitating type-2 immune responses. IL-33 is localized in the nucleus and released to the extracellular milieu during cell death, although the precise mechanisms underlying IL-33 mobilization remain unclear. Here, we found that nigericin, a toxin derived from Streptomyces hygroscopicus, promoted IL-33 translocation from the nucleus to the cytosol before extracellular release. This translocation was inhibited by chelating Ca 2+ with EGTA or membrane protection by glycine treatment. Ca 2+ ionophore A23187 stimulation caused IL-33 translocation to the cytoplasm but was not sufficient for extracellular release. However, IL-33 release was induced by detergent treatment, which indicates that membrane rupture is required for IL-33 release. The pore-forming pyroptosis executor gasdermin D was cleaved following nigericin stimulation, and overexpression of the cleaved gasdermin D-N-terminal fragment that forms the membrane pore sufficiently induced IL-33 release, which was blocked by EGTA and glycine. Together, these findings suggest that Ca 2+ -dependent signals and gasdermin D pore formation are required for robust IL-33 production., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Anti-desmoglein (Dsg) 1 and Dsg3 IgG autoantibodies in pemphigus foliaceus and pemphigus vulgaris cause blisters through loss of desmosomal adhesion. It is controversial whether blister formation is due to direct inhibition of Dsg, intracellular signaling events causing desmosome destabilization, or both. Recent studies show that heterophilic binding between Dsg and desmocollin (Dsc) is the fundamental adhesive unit of desmosomes. To eliminate cellular contributions to potential pathogenicity of pemphigus antibodies, bead assays coated with recombinant Dsg1, Dsc1, Dsg3, or Dsc3 ectodomains were developed. A mixture of Dsg beads and Dsc beads formed large aggregates, confirming that the heterophilic binding is dominant. The pathogenic anti-Dsg1 and anti-Dsg3 mAbs, which bind the transadhesive interface, blocked the aggregation of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively, whereas nonpathogenic mAbs did not. All sera tested from eight patients with pemphigus foliaceus and eight patients with mucosal pemphigus vulgaris with active disease inhibited the adhesion of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively. When paired sera obtained from seven patients with pemphigus foliaceus and six patients with pemphigus vulgaris in active disease and remission were compared, the former inhibited aggregation better than the latter. These findings strongly suggest that steric hindrance of heterophilic transinteraction between Dsg and Dsc is important for disease pathology in both pemphigus foliaceus and pemphigus vulgaris., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Strategic Outlook toward 2030: Japan's Research for Allergy and Immunology (Strategy 2030) is the national research strategy based on Japan's Basic Law on Measures Against Allergic Diseases, a first of its kind worldwide. This strategy was established by a multi-disciplinary committee consisting of administrators of the Ministry of Health, Labour and Welfare of Japan, young and senior experts from various research societies and associations, and representatives of patient and public groups. Whereas the issues of transition, integration, and international collaboration have yet to be solved in this research realm in Japan, identification of unmet needs, digitization of information and transparent procedures, and strategic planning for complex problems (a process dubbed MIERUKA by the Toyota Way) are crucial to share and tackle the same vision and goals. The committee developed three specific actions focusing on preemptive treatment, interdisciplinarity and internationality, and life stage. The real success of Strategy 2030 is made by the spontaneous contributions of doctors, dentists, veterinarians, and other medical professionals; basic and clinical research scientists, research supporters, and pharmaceutical/medical device companies; manufacturers of food, healthcare, and home appliances; and patients, their families, and the public. The hope is to establish a stable society in which people can live long, healthy lives, as free as possible from allergic and immunological diseases, at each individual life stage. This article is based on a Japanese review first reported in Arerugi, introduces the developmental process and details of Strategy 2030., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Owing to musculoskeletal dysfunction, locomotive syndrome elevates the risk of requiring nursing care. Among degenerative musculoskeletal disorders, lumbar spinal canal stenosis (LSS) associates with locomotive syndrome; however, whether lumbar spinal surgery for LSS improves locomotive syndrome remains unclear. Hence, this study aimed to identify the efficacy of lumbar spinal surgery on locomotive syndrome among elderly patients with LSS., Methods: We prospectively collected the clinical data from multiple institutions of patients (age >65 years) who underwent lumbar spinal surgery. Patients were examined for the locomotive syndrome risk test, including the stand-up Test, the two-step Test, and the 25-question risk assessment, 1-day preoperatively and 6-month and 1-year postoperatively. Using a logistic regression model, we identified factors associated with improvement of locomotive syndrome in the total assessment., Results: Overall, we examined the data of 166 patients in this study. Upon converting each score of three tests to the stage of locomotive syndrome, the two-step test and the 25-question risk assessment revealed marked improvement in the postoperative distribution of stages. However, the stand-up test revealed a comparable distribution of stages pre- and postoperatively. In the total assessment, the postoperative distribution of stages was significantly improved than that preoperatively. The multivariable analysis revealed that failed back surgery syndrome [odds ratio (OR), 0.2; 95% confidence interval (CI): 0.04-1.05; P = 0.057)] and preoperative stage of 2 in stand-up test (OR, 0.2; 95% CI: 0.05-1.02; P = 0.054) tended to have inverse association with postoperative improvement of locomotive syndrome in the total assessment., Conclusions: Lumbar spinal surgery improved the stage of locomotive syndrome among elderly patients with LSS. This study suggests that lumbar spinal surgery for LSS could be beneficial in alleviating locomotive syndrome., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: We conducted a finite element study to assess the effectiveness of a novel pedicle screw design with two alterations in the distal and proximal portions., Methods: Finite element (FE) models of 24 vertebrae were constructed using computed tomographic data. Pull-out strength of 4 different pedicle screws were compared. The basic screw design was a dual threaded one (PS0), in which the proximal portion is double-threaded (cortical thread), and the distal portion is single-threaded (cancellous thread). In PS1, the inter-thread double-core shape was added to PS0 in the distal portion. Compared to PS0, in PS2, the proximal portion was elongated by 5 mm. PS3 had both PS1 and PS2 features. In addition, the 24 vertebrae were classified into 3 groups based on volumetric bone mineral density (vBMD) of the vertebral body: low <120 mg/cm 3 , moderate 120-170 mg/cm 3 , and high >170 mg/cm 3 ., Results: The mean pull-out strengths (±SD) were 1137 ± 500 N, 1188 ± 520 N, 1191 ± 512 N, and 1242 ± 538 N for PS0, PS1, PS2, and PS3, respectively. In PS1, there was significant difference in the incremental ratio of pull-out strength to PS0 between the low and high vBMD groups (3.7 ± 1.6% vs. 5.0 ± 1.0%, p = 0.006). In PS2, there was a significant difference in the incremental ratio to PS0 between the moderate and high vBMD groups (7.6 ± 4.0% vs. 3.3 ± 1.8%, p < 0.001). In PS3, there was a significant difference in the incremental ratio to PS0 between the moderate and high vBMD groups (12.1 ± 4.8% vs. 8.5 ± 2.1%, p = 0.003)., Conclusions: The two design alterations showed the combined additive effect in the PS3 design. The moderate vBMD group has a balanced bone property to reflect the combined effects of the PS1 and PS2 design alterations., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: There have been few reports on the incidence and risk factors of the complications after spinal fixation surgery for osteoporotic vertebral collapse (OVC) with neurological deficits. This study aimed to identify the incidence and risk factors of the complications after OVC surgery., Methods: In this retrospective multicenter study, a total of 403 patients (314 women and 89 men; mean age 73.8 years) who underwent spinal fixation surgery for OVC with neurological deficits between 2005 and 2014 were enrolled. Data on patient demographics were collected, including age, sex, body mass index, smoking, steroid use, medical comorbidities, and surgical procedures. All postoperative complications that occurred within 6 weeks were recorded. Patients were classified into two groups, namely, complication group and no complication group, and risk factors for postoperative complications were investigated by univariate and multivariate analyses., Results: Postoperative complications occurred in 57 patients (14.1%), and the most common complication was delirium (5.7%). In the univariate analysis, the complication group was found to be older (p = 0.039) and predominantly male (p = 0.049), with higher occurrence rate of liver disease (p = 0.001) and Parkinson's disease (p = 0.039) compared with the no-complication group. In the multivariate analysis, the significant independent risk factors were age (p = 0.021; odds ratio [OR] 1.051, 95% confidence interval [CI] 1.007-1.097), liver disease (p < 0.001; OR 8.993, 95% CI 2.882-28.065), and Parkinson's disease (p = 0.009; OR 3.636, 95% CI 1.378-9.599)., Conclusions: Complications after spinal fixation surgery for OVC with neurological deficits occurred in 14.1%. Age, liver disease, and Parkinson's disease were demonstrated to be independent risk factors for postoperative complications., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: A consensus on the optimal surgical procedure for thoracolumbar OVF has yet to be reached due to the previous relatively small number of case series. The study was conducted to investigate surgical outcomes for osteoporotic vertebral fracture (OVF) in the thoracolumbar spine., Methods: In total, 315 OVF patients (mean age, 74 years; 68 men and 247 women) with neurological symptoms who underwent spinal fusion with a minimum 2-year follow-up were included. The patients were divided into 5 groups by procedure: anterior spinal fusion alone (ASF group, n = 19), anterior/posterior combined fusion (APSF group, n = 27), posterior spinal fusion alone (PSF group, n = 40), PSF with 3-column osteotomy (3CO group, n = 92), and PSF with vertebroplasty (VP + PSF group, n = 137)., Results: Mean operation time was longer in the APSF group (p < 0.05), and intraoperative blood loss was lower in the VP + PSF group (p < 0.05). The amount of local kyphosis correction was greater in the APSF and 3CO groups (p < 0.05). Clinical outcomes were approximately equivalent among all groups., Conclusion: All 5 procedures resulted in acceptable neurological outcomes and functional improvement in walking ability. Moreover, they were similar with regard to complication rates, prevalence of mechanical failure related to the instrumentation, and subsequent vertebral fracture. Individual surgical techniques can be adapted to suit patient condition or severity of OVF., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Short stride length is one of clinical symptoms associated with lumbar spinal stenosis (LSS). Short stride is a risk factor for falls; therefore, identification of factors associated with short stride is critical for fall prevention in LSS patients. Although the Two-Step test can conveniently assess maximal stride length, it has not become widely used; therefore, its data are limited. We identified the potential factors associated with short stride of elderly LSS patients using Two-Step test., Methods: Clinical data of patients aged >65 years who planned to undergo surgery for LSS were prospectively collected at multiple institutions. Patients were assessed with the Two-Step test and Timed Up-and-Go Test prior to surgery; 357 consecutive patients were enrolled. We determined the cut-off value of the Two-Step test score for short stride, referring to the Timed Up-and-Go Test score of 13.5 s, used to indicate high risk of falls in elderly individuals. Logistic regression model was constructed to identify factors associated with short stride., Results: The Two-Step test score showed moderate-to-strong inverse correlation with that of Timed Up-and-Go Test (r = -0.65, p < 0.001). Using the tentative Two-Step test cut-off value (0.93) for short stride, multivariable analysis showed that age ≥80 years (OR = 2.3, 95% CI:1.1-4.8), a score of <60 for lumbar function in Japanese Orthopedic Association Back Pain Evaluation Questionnaire (OR = 2.7, 95% CI:1.5-4.7), motor deficit (OR = 2.7, 95% CI:1.2-6.1), and sagittal vertical axis ≥50 mm (OR = 2.1, 95% CI:1.2-3.5) were factors significantly associated with short stride in elderly patients with LSS., Conclusions: Using the Two-Step test, we found that 80 years old and over, lumbar dysfunction, motor deficit of the lower extremities, and forward-bent posture were associated with short stride in LSS patients. Therefore, elderly LSS patients with these conditions may have a higher risk for falls., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Leukotriene B 4 receptor 1 (BLT1) triggers the migration of granulocytes and activated T cells; however, its role in B-cell function remains unclear. Here we report that BLT1 is required to induce the production of antigen-specific IgA against oral vaccine through mediating innate immune signals from commensal bacteria. B cells acquire BLT1 expression during their differentiation to IgA + B cells and plasma cells in Peyer's patches and the small intestinal lamina propria, respectively. BLT1 KO mice exhibited impaired production of antigen-specific fecal IgA to oral vaccine despite normal IgG responses to systemically immunized antigen. Expression of MyD88 was decreased in BLT1 KO gut B cells and consequently led to diminished proliferation of commensal bacteria-dependent plasma cells. These results indicate that BLT1 enhances the proliferation of commensal bacteria-dependent IgA + plasma cells through the induction of MyD88 and thereby plays a key role in the production of antigen-specific intestinal IgA.

Background: Locomotive syndrome is a condition in which the ability to lead a normal life is restricted owing to a dysfunction in one or more of the parts of the musculoskeletal system. Although lumbar spinal canal stenosis (LSS) is considered to cause locomotive syndrome, a detailed assessment of the association between two pathologies has not yet been reported., Methods: The clinical data of patients aged > 65 years old who planned to undergo surgery for LSS at multiple institutions were prospectively collected from April 2016 to August 2017. A total of 200 participants comprising 120 men and 80 women were enrolled in this study. Association of severity of LSS evaluated by Zurich Claudication Questionnaire scores with three locomotive syndrome risk tests (Stand-up Test, the Two-step Test, and a 25-question risk assessment) and Timed Up-and-Go Test were evaluated., Results: In the total assessment of locomotive syndrome, 96.5% of the participants were diagnosed as grade 2, and the remaining 3.5% were diagnosed as grade 1. When the participants were divided into 3 groups according to the LSS severity, the scores of all locomotive syndrome risk tests were significantly worse with increasing LSS severity. Logistic regression analysis revealed that LSS severity was positively correlated with the risk level of locomotive syndrome evaluated by the Two-step Test (OR = 3.45, CI = 1.33-8.96)., Conclusions: All LSS patients with surgical indications were diagnosed as having locomotive syndrome. In addition, our results indicated that LSS severity is potentially associated with the progression of locomotive syndrome. The treatment of LSS may be beneficial in alleviating the risk for locomotive syndrome., (Copyright © 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Spinal extradural arachnoid cyst (SEDAC) is a cystic lesion that protrudes into the epidural space from a small dural defect. Early diagnosis of SEDAC is important because its expansion causes neurological damage. Two types of SEDAC, syndromic and sporadic, are present. Syndromic SEDAC is inherited as a part of lymphedema-distichiasis syndrome caused by mutations in the FOXC2 gene; however, it is often mistaken as sporadic because of low penetrance. It is not reasonable to conduct a genetic testing for all SEDAC patients and their family members. The aim of this study is to establish an effective screening method to distinguish syndromic SEDAC from sporadic SEDAC., Methods: We performed a retrospective review of medical records and imaging studies of 29 subjects who were diagnosed with SEDAC. Clinical features, family history and magnetic resonance imaging (MRI) were analyzed. Mutations in FOXC2 were examined by Sanger-sequencing of the entire coding region of the genes. SEDAC having a mutation in FOXC2 gene was defined with syndromic SEDAC., Results: Eleven subjects had a heterozygous mutation in FOXC2. They were all familial and hence syndromic SEDAC. Only one proband had known family history of SEDAC at diagnosis. MRI findings and physical examinations, especially eye and leg examinations, were quite useful to screen syndromic SEDAC. Physical examination often showed accompanying lymphedema and distichiasis in syndromic SEDAC. Syndromic SEDAC tended to have multiple cysts out of the thoracolumbar area., Conclusions: We established an effective screening method based on physical examinations and MRI findings., (Copyright © 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Minimally invasive techniques for hallux valgus have been widely used to treat mild to moderate hallux valgus deformities. The purpose of this study was to evaluate the clinical and radiographic outcomes of distal linear metatarsal osteotomy (DLMO), which is one of the minimally invasive techniques, for severe hallux valgus., Methods: 95 patients (141 feet) with severe hallux valgus underwent DLMOs. Lateral soft tissue release (LSTR) was performed at the same time for the cases selected by an original manual test. The satisfaction level, the Japanese Society of Surgery of the Foot (JSSF) hallux scale score, and weight-bearing radiographs of the foot were assessed preoperatively and after more than 24 months. In addition, the clinical and radiographic outcomes were compared among three groups divided by the kind of LSTR: no LSTR; manual correction; and open release through skin incision., Results: Although the first metatarsal bone was significantly shortened, dorsiflexed, and elevated on postoperative radiographs, the rate of satisfaction was 87.2% (123/141), and the mean JSSF hallux scale score improved significantly from 60.4 (44-73) to 90.4 (65-100). The mean hallux valgus and intermetatarsal angles also improved significantly from 45.5° (40.0-60.0°) to 10.3° (-28.0-40.9°) and from 19.9° (14.0-28.7°) to 8.3° (-1.6-18.5°), respectively. Delayed union (18 feet), metatarsalgia (16 feet), recurrence (22 feet), and hallux varus (22 feet) were observed, and they were more obvious in DLMO combined with open release through a skin incision., Conclusions: DLMO combined selectively with LSTR is an effective procedure for correcting severe hallux valgus. However, the indication for open release with DLMO should be considered carefully., (Copyright © 2018. Published by Elsevier B.V.)

Alcaligenes are opportunistic commensal bacteria that reside in gut-associated lymphoid tissues such as Peyer's patches (PPs); however, how they create and maintain their homeostatic environment, without inducing an excessive inflammatory response remained unclear. We show here that Alcaligenes-derived lipopolysaccharide (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 and promotes IL-6 production from dendritic cells, which consequently enhances IgA production. The inflammatory activity of Alcaligenes LPS was weaker than that of Escherichia coli-derived LPS and therefore no excessive inflammation was induced by Alcaligenes LPS in vitro or in vivo. Alcaligenes LPS also showed adjuvanticity, inducing antigen-specific immune responses without excessive inflammation. These findings reveal the presence of commensal bacteria-mediated homeostatic inflammatory conditions within PPs that produce optimal IgA induction without causing pathogenic inflammation and suggest that Alcaligenes LPS could be a safe and potent adjuvant.

Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Study Design: Multicenter retrospective study., Background: Postoperative surgical site infection is one of the most serious complications following spine surgery. Previous studies do not appear to have investigated pyogenic discitis following lumbar laminectomy without discectomy. This study aimed to identify risk factors for postoperative pyogenic discitis following lumbar decompression surgery., Methods: We examined data from 2721 patients undergoing lumbar laminectomy without discectomy in five hospitals from April 2007 to March 2012. Patients who developed postoperative discitis following laminectomy (Group D) and a 4:1 matched cohort (Group C) were included. Fisher's exact test was used to determine risk factors, with values of p < 0.05 considered statistically significant., Results: The cumulative incidence of postoperative discitis was 0.29% (8/2721 patients). All patients in Group D were male, with a mean age of 71.6 ± 7.2 years. Postoperative discitis was at L1/2 in 1 patient, at L3/4 in 3 patients, and at L4/5 in 4 patients. Except for 1 patient with discitis at L1/2, every patient developed discitis at the level of decompression. The associated pathogens were methicillin-resistant Staphylococcus aureus (n = 3, 37.5%), methicillin-susceptible Staphylococcus epidermidis (n = 1, 12.5%), methicillin-sensitive S. aureus (n = 1, 12.5%), and unknown (n = 3, 37.5%). In the analysis of risk factors for postoperative discitis, Group D showed a significantly lower ratio of patients who underwent surgery in the winter and a significantly higher ratio of patients who had Modic type 1 in the lumbar vertebrae compared to Group C., Conclusions: Although further prospective studies, in which other preoperative modalities are used for the evaluation, is needed, our data suggest the presence of Modic type 1 as a risk factor for discitis following laminectomy. Latent pyogenic discitis should be carefully ruled out in patients with Modic type 1. If lumbar laminectomy is performed for such patients, more careful observation is necessary to prevent the development of postoperative discitis., (Copyright © 2017 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Pemphigus foliaceus (PF) is an autoimmune blistering disease caused by autoantibodies (Abs) against desmoglein 1 (Dsg1). PF sera contain polyclonal Abs which are heterogeneous mixture of both pathogenic and non-pathogenic Abs, as shown by isolation of monoclonal Abs (mAbs)., Objective: To investigate how pathogenic and non-pathogenic anti-Dsg1 Abs contribute to blister formation in PF., Methods: Using organ-cultured human skin, we compared the effect of a single pathogenic anti-Dsg1 IgG mAb, a single non-pathogenic anti-Dsg1 IgG mAb, and their mixture on blister formation as analyzed by histology, subcellular localization of IgG deposits and desmosomal proteins by confocal microscopy, and desmosomal structure by electron microscopy. In addition, we measured keratinocyte adhesion by an in vitro dissociation assay., Results: 24h after injection, a single pathogenic anti-Dsg1 IgG caused a subcorneal blister with IgG and Dsg1 localized linearly on the cell surface of keratinocytes. A single non-pathogenic anti-Dsg1 IgG bound linearly on the keratinocytes but did not induce blisters. A pathogenic and a non-pathogenic IgG mAb injected together caused an aberrant granular pattern of IgG and Dsg1 in the lower epidermis with blister formation in the superficial epidermis. Electron microscopy demonstrated that the mixture of mAbs shortened desmosomal lengths more than a single mAb in the basal and spinous layers. Furthermore, although Dsg1 clustering required both cross-linking of Dsg1 molecules by the non-pathogenic IgG plus a pathogenic antibody, the latter could be in the form of a monovalent single chain variable fragment, suggesting that loss of trans-interaction of Dsg1 is required for clustering. Finally, a p38MAPK inhibitor blocked Dsg1 clustering. When pathogenic strength was measured by the dissociation assay, a mixture of pathogenic and non-pathogenic IgG mAbs disrupted keratinocyte adhesion more than a single pathogenic mAb. This pathogenic effect was only partially suppressed by the p38MAPK inhibitor., Conclusion: These findings indicate that a polyclonal mixture of anti-Dsg1 IgG antibodies enhances pathogenic activity for blister formation associated with p38MAPK-dependent Dsg1 clustering and that not only pathogenic antibodies but also non-pathogenic antibodies coordinately contribute to blister formation in PF., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Ossification of the posterior longitudinal ligament (OPLL) can cause myelopathy that is often managed surgically. Knowledge of predictors of surgical outcomes can provide decision support to surgeons. The aims of this study were to investigate the relationships between preoperative physical signs and postoperative functional outcomes in patients with OPLL and to clarify whether physical signs could predict functional outcomes., Methods: Fifty-five patients with OPLL who had undergone cervical laminoplasty were included in this study. Six physical signs including hyperreflexia, Babinski sign, sensory disturbance, grip strength, 10-s grip and release test, and bladder dysfunction, and four other factors including age, duration of symptoms, history of minor trauma and preoperative Japanese Orthopaedic Association (JOA) score were investigated as potential predictive prognostic factors using both univariate and multivariate analyses., Results: The mean recovery rate of JOA score was 62.5 ± 32.5%. The neurological recovery rate was negatively associated with age (P = 0.002), the duration of symptoms (P = 0.002) and Babinski sign (P = 0.007), whereas it was positively correlated with grip strength (P = 0.011). Multiple logistic regression analyses revealed that age (Odds ratio: 0.89, 95% CI: 0.81-0.99) and Babinski sign (Odds ratio: 0.18, 95% CI: 0.04-0.89) were factors associated with functional outcomes., Conclusions: Satisfactory functional outcomes could be expected for patients who are young and do not exhibit the Babinski sign, showing that the Babinski sign could be useful as an indicator of the window of opportunity for achieving satisfactory functional outcomes., (Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

The algicidal and growth-inhibiting bacteria associated with seagrasses and macroalgae were characterized during the summer of 2012 and 2013 throughout Puget Sound, WA, USA. In 2012, Heterosigma akashiwo-killing bacteria were observed in concentrations of 2.8×10 6 CFUg -1 wet in the outer organic layer (biofilm) on the common eelgrass (Zostera marina) in north Padilla Bay. Bacteria that inhibited the growth of Alexandrium tamarense were detected within the biofilm formed on the eelgrass canopy at Dumas Bay and North Bay at densities of ∼10 8 CFUg -1 wet weight. Additionally, up to 4100CFUmL -1 of algicidal and growth-inhibiting bacteria affecting both A. tamarense and H. akashiwo were detected in seawater adjacent to seven different eelgrass beds. In 2013, H. akashiwo-killing bacteria were found on Z. marina and Ulva lactuca with the highest densities of ∼10 8 CFUg -1 wet weight at Shallow Bay, Sucia Island. Bacteria that inhibited the growth of H. akashiwo and A. tamarense were also detected on Z. marina and Z. japonica at central Padilla Bay. Heterosigma akashiwo cysts were detected at a concentration of 3400cystsg -1 wet weight in the sediment from Westcott Bay (northern San Juan Island), a location where eelgrass disappeared in 2002. These findings provide new insights on the ecology of algicidal and growth-inhibiting bacteria, and suggest that seagrass and macroalgae provide an environment that may influence the abundance of harmful algae in this region. This work highlights the importance of protection and restoration of native seagrasses and macroalgae in nearshore environments, in particular those regions where shellfish restoration initiatives are in place to satisfy a growing demand for seafood., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: To clarify correlations between spinal fracture and delayed paralysis in patients with diffuse idiopathic skeletal hyperostosis (DISH) using computed tomography (CT) with multiplanar reformatting (CT-MPR). DISH increases susceptibility to unstable spinal fractures, leading to neurological deterioration. The pathomechanism of the neurological injury is unclear., Methods: This multicenter retrospective study included 42 DISH patients (32 male; 10 female) treated for 45 spinal fractures during a 5-year period. The mean age at the time of injury was 77.1 ± 10.1 years. The cause of injury, delay in diagnosis, fracture location, and neurological status were recorded, and anterior- and posterior-column fractures, a fracture displacement over 3 mm, and posterior-column ankylosis were assessed using CT-MPR., Results: Most fractures (73.8%) resulted from trivial trauma, such as falling from a standing or sitting position. Diagnosis was delayed in 47.6% of the patients, primarily due to delays in seeking medical attention (65.0%). Although 78.6% of the patients were neurologically intact at the time of injury, 54.8% developed paralysis, defined by a change in one or more Frankel-score levels during short-term follow-up. Of the fractures, 39.1% were in the vertebral body, and 60.9% were at the disc level. Fractures with posterior-column ankylosis were significantly associated with delayed paralysis., Conclusions: CT-MPR was useful for evaluating spinal fractures and determining treatment in patients with DISH. Fractures associated with posterior-column ankylosis resulted in unstable three-column injuries that led to delayed neurological deterioration. Early surgical stabilization of such fractures is recommended to avoid delayed paralysis., (Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Spondylodiscitis still remains a serious problem, especially in immunocompromised patients. Surgery is necessary when nonsurgical treatment is unsuccessful. Although minimally invasive spine stabilization (MISt) with percutaneous pedicle screws is less invasive, percutaneous sacropelvic fixation techniques are not common practice. Here, we describe 2 cases in which spondylodiscitis in the lumbosacral spine was treated with percutaneous stabilization using an S2 alar-iliac (S2AI) screw technique., Case Description: Case 1 is a 77-year-old man who presented with low back pain and high fever. He was diagnosed with spondylodiscitis at L4-5. He had a history of lung cancer, which was complicated by the recurrence. Because nonsurgical treatment failed, MISt with percutaneous S2AI screws was performed. The patient's low back pain subsided markedly 1 week after surgery, and there was no screw/rod breakage or recurrence of infection during the follow-up period. Case 2 is a 71-year-old man who presented with hemiparesis because of a stroke. He also developed high fever and was diagnosed with spondylodiscitis at L5-S1. Because nonsurgical treatment failed, the patient was treated by MISt with percutaneous S2AI screws while being maintained on anticoagulants for stroke. Although his clinical symptoms had markedly improved, a postoperative lumbar computed tomography scan demonstrated a bone defect at L5-S1. An anterior spinal fusion with an iliac bone graft at L5-S1 was performed when a temporary cessation of anticoagulants was permitted. Both patients tolerated the procedures well and had no major perioperative complications., Conclusions: MISt with percutaneous S2AI screws was less invasive and efficacious for lumbosacral spondylodiscitis in providing rigid percutaneous sacropelvic fixation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: In Japan, ossification of the posterior longitudinal ligament (OPLL) has been designated as an intractable disease by the Ministry of Health, Labour, and Welfare. Here we aimed to clarify the epidemiological characteristics of severe OPLL patients by analyzing a national registry of this disease that uses clinical investigation registration forms., Methods: We retrospectively investigated clinical investigation registration forms for 24,502 patients with OPLL. We examined the sex distribution, age of disease onset, period from disease onset to registration, family history, site of ossification as determined by plain radiographs, Japanese Orthopaedic Association score, and number of OPLL surgeries., Results: The male-to-female ratios were 2.7:1 and 1.9:1 for new and renewed registrations, respectively. The mean ages at disease onset were 61.1 and 59.7 years for new and renewed registrations, respectively. The mean periods from disease onset to registration were 2.6 and 8.4 years for new and renewed registrations, respectively. The percentages of new registrations with and without family history were 5.3% and 51.5%, respectively (unknown for 43.3%). Of the new registrations, 3511, 359, and 200 cases exhibited ossification in the cervical spine, thoracic spine, and lumbar spine, respectively; the corresponding numbers for renewed registrations were 13,710, 2484, and 1508. The Japanese Orthopaedic Association score was 9.9 ± 3.6 for new registrations, and the mean score recovery rate for renewed registrations was 6.0%. The number of OPLL surgeries was one or zero, two, three, four, or five for 21,785, 2167, 412, 99, and 39 patients, respectively, with 11.1% of all patients having undergone multiple surgeries., Conclusions: This study offers new insight into the epidemiological characteristics of severe OPLL. In particular, we found that the age of disease onset was higher than previously reported, the period from disease onset to registration (surgery) was relatively short, and about 90% of the patients required only a single surgery., (Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: It has been clinically demonstrated that intradermal (ID) vaccines have a potential to confer a superior immunogenic profile compared to intramuscular (IM) or subcutaneous (SC) vaccines. In terms of distribution of a vaccine antigen depending on the administration routes, at least two independent immunogenic pathways of the vaccines have been proposed: (1) the antigen recognition by the immune cells present at the vaccine-administered site and (2) the antigen recognition by the lymph node (LN)-resident immune cells through the lymphatic flow from the vaccine-administered site after the antigen is directly delivered into the draining LNs., Objective: In order to clarify the key components for the immunogenic pathway of the ID vaccine, the correlation between the kinetics of the antigen distribution to the draining LNs and antibody responses to the antigen were evaluated., Methods: We compared the antibody responses in the groups with by surgical removal of the administration site immediately after the ID administration, and by surgical removal of the draining LNs before the ID administration., Results: The results suggested that the efficient and direct antigen delivery to the draining LNs plays an important role in the antibody responses to the ID vaccine. Indeed, it was confirmed that the direct administration into the draining LNs with the antigen elicited comparable levels of the antibody responses with the ID vaccine. At the cellular level, it was shown that the LN-resident immune cells such as B cells, dendritic cells, and macrophages including medullary macrophages and subcapsular sinus macrophages interacting with the antigens following the ID administration. Finally, we demonstrated by immunofluorescence analysis that the lymphatic vessels are more diffusely distributed in the dermis as compared with the subcutaneous area and muscle., Conclusion: The results of the present study suggested that the skin is an optimal tissue to facilitate the vaccine antigen access to the draining LNs, which is an important immunogenic pathway of the ID vaccine. Further elucidation of regulatory mechanisms underlying such an immunogenic pathway of the ID vaccine would provide us with elements for the development of novel adjuvants and devices to enhance the immunogenicity of the ID vaccines., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Although various risk factors have been reported for adjacent segment degeneration after lumbar fusion, the exact mechanisms and risk factors related to adjacent segment degeneration have not been clear. The present study was conducted to evaluate the risk factors for radiological adjacent segment degeneration in patients surgically treated for single-level L4 spondylolisthesis focusing on a single pathology, a specific fusion level, at a set interval., Methods: We assessed preoperative and five-year postoperative radiographs for 72 patients who underwent L4-5 anterior or posterior lumbar interbody fusion for single-level L4 degenerative spondylolisthesis. Adjacent segment degeneration was defined as imaging evidence of one or more of the following conditions at L1-2, L2-3, or L3-4: 1) a loss of more than 20% of the preoperative disc height, 2) anterolisthesis or retrolisthesis greater than 3 mm, 3) or osteophyte formation greater than 3 mm., Results: We found adjacent segment degeneration in 21 patients, with 31 discs affected. Multiple logistic regression analysis identified the following significant independent risk factors for adjacent segment degeneration: female gender (odds ratio 10.80; 95% confidence interval 1.20-96.89), posterior lumbar interbody fusion (odds ratio 7.70; 95% confidence interval 1.82-32.66), and pre-existing disc degeneration (odds ratio 12.29; 95% confidence interval 1.69-89.27)., Conclusions: Female gender, posterior lumbar interbody fusion, and pre-existing disc degeneration were significant independent risk factors for radiologically diagnosed adjacent segment degeneration in patients treated for L4 degenerative spondylolisthesis by interbody lumbar fusion., (Copyright © 2015 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Posttranscriptional regulatory elements in the 3'-untranslated region (UTR) of mRNAs play an important role in mRNA stabilization. Induction of IκB-ζ, a critical transcriptional regulator in the innate immune response, is mediated via specific mRNA stabilization by lipopolysaccharide (LPS) and interleukin (IL)-1β. It is known that the 3'-UTR of IκB-ζ, especially 165 nucleotides after the stop codon, plays a crucial role in mRNA stability. Herein, we show that AU-rich elements and miRNA targets in these 165 3'-UTR nucleotides are dispensable for stability of IκB-ζ mRNA. Additionally, NF-κB activation is important for IκB-ζ transcription, but dispensable for IκB-ζ mRNA stability. Interestingly, high-throughput screening results show that MyD88, a signal molecule responsive to LPS/IL-1β stimulation, is key for stabilizing IκB-ζ mRNA expression. Moreover, MyD88-deficient macrophages exhibited a decreased half-life of IκB-ζ mRNA expression. These results indicate that the LPS/IL-1β-MyD88 axis plays a crucial role for stabilization of IκB-ζ mRNA., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The tight junction (TJ) barrier is located in the granular layer of the epidermis. Filaggrin deficiency predisposes patients to atopic dermatitis (AD) by impairing stratum corneum (SC) barrier function. Altered TJ barrier function has been observed in the skin of patients with AD; however, it remains unclear whether TJ function is influenced by filaggrin deficiency directly or secondarily via skin inflammation., Objective: To investigate the in vivo effects of filaggrin deficiency and skin inflammation on epidermal TJ function., Methods: Morphological changes in the TJ were investigated in filaggrin knockout mice and mice with hapten-induced dermatitis using en face visualization of epidermal sheets, and functional changes in the TJ were assessed with an in vivo permeation assay using tracers of various sizes., Results: In filaggrin knockout mice, there was no apparent change in the honeycomb morphology of the TJ, TJ component mRNA expression, or TJ barrier function in neonates and adults, indicating that filaggrin-deficiency had no direct effects on the TJ. By contrast, in mice with hapten-induced dermatitis, the mRNA expression of TJ components was decreased markedly and the TJ barrier function was size-dependently impaired: the TJ leaked small tracers (<5 kDa), but not large tracers (>30 kDa)., Conclusion: Filaggrin deficiency did not affect the epidermal TJ barrier directly, but once dermatitis occurred, the skin inflammation induced TJ dysfunction. Since TJ dysfunction induces the SC barrier impairment, skin inflammation will enhance skin permeability to external antigens and result in a vicious cycle of barrier dysfunction and skin inflammation., (Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Diabetes mellitus (DM) is reported to be a risk factor for surgical site infection (SSI), which is a serious complication after spinal surgery. The effect of DM on SSI after instrumented spinal surgery remains to be clarified. The aim was to elucidate perioperative risk factors for infection at the surgical site after posterior thoracic and lumbar spinal arthrodesis with instrumentation in patients with DM., Methods: Consecutive patients who underwent posterior instrumented thoracic and lumbar spinal arthrodesis during the years 2005-2011, who could be followed for at least 1 year after surgery, were included. These included 36 patients with DM (19 males and 17 females; mean age 64.3 years). The patients' medical records were retrospectively reviewed to determine the SSI rate. The characteristics of the DM patients were examined in detail, including the levels of serum glucose and HbA1c, which indicate the level of diabetes control., Results: Patients with DM had a higher rate of SSI (6 of 36 patients, 16.7 %) than patients without DM (10 of 309 patients, 3.2 %). Although the perioperative serum glucose level did not differ between DM patients that did or did not develop SSI, the preoperative HbA1c value was significantly higher in the patients who developed SSI (7.6 %) than in those who did not (6.9 %). SSI developed in 0.0 % of the patients with controlled diabetes (HbA1c <7.0 %) and in 35.3 % of the patients with uncontrolled diabetes (HbA1c ≥7.0 %)., Conclusions: DM patients whose blood glucose levels were poorly controlled before surgery were at high risk for SSI. To prevent SSI in DM patients, we recommend lowering the HbA1c to <7.0 % before performing surgery.

Hydroxyapatite (HAp), with its high biocompatibility and osteoconductivity, readily absorbs proteins, amino acids and other substances, which in turn favor the adsorption and colonization of bacteria. To prevent bacterial growth and biofilm formation on HAp discs, silver-containing (1-20 mol%) HAp (Ag-HAp) powders were synthesized using an ultrasonic spray pyrolysis (USSP) technique. The X-ray diffraction (XRD) peaks were very broad, indicating low crystallinity, and this induced the release of Ag(+) ions from Ag-HAp powders. In addition, a gradual increase in Ca(2+) ion release was observed. These results suggest that dissolution of Ca(2+) ion in Ag-HAp triggered the release of Ag(+) ions. The antimicrobial efficacy of Ag-HAp disc was tested against Staphylococcus aureus. Samples with Ag contents of more than 5 mol% were found to be highly effective against bacterial colonization and biofilm formation in vitro. In vivo antibacterial tests using bioluminescent strains also showed reductions in the viability of bacteria with Ag-HAp (5 mol%) discs. Biocompatibility tests using a modified Transwell® insert method showed that Ag-HAp (5 mol%) discs have negative effects on osteoblast proliferation. These results indicate that Ag-HAp (5 mol%) has effective antibacterial activity and good biocompatibility both in vitro and in vivo together with good biocompatibility, thus confirming its utility as a bactericidal material., (© 2013.)

Background: Mammalian epidermis has two diffusion barriers, the stratum corneum (SC) and tight junctions (TJs). We reported previously that a single living cell layer exists between the SC and TJ-forming keratinocytes in mice; however, the exact location of the TJ barrier in human epidermis has not been defined., Objective: To investigate the precise distribution of epidermal TJs in relation to various cell-cell junction proteins and the SC and to clarify the barrier function of TJs against macromolecules in human skin., Methods: The localization of various junctional proteins was investigated in human skin sections and in the roofs of bullae formed by ex vivo exfoliative toxin (ET) treatment in three dimensions. ET and single-chain variable fragments (scFv) against desmoglein 1 were used as large diffusion probes., Results: Human stratum granulosum (SG) cells have a distinct distribution of TJ, adherens junction, and desmosome proteins in the uppermost three layers (SG1-SG3 from the surface inward). Ex vivo injection of ET or scFv demonstrated that only SG2-SG2 junctions function as a TJ barrier, limiting the inside-out diffusion of these proteins. The roofs of bullae formed by ex vivo ET treatment consisted of SC, SG1 cells, and TJ-forming SG2 cells, probably mimicking bulla formation in bullous impetigo., Conclusion: Human epidermis has three SG cell layers with distinct properties just beneath the SC, of which only SG2 cells have functional TJs. Our results suggest that human epidermal TJs between SG2 cells form a paracellular diffusion barrier against soluble proteins, including immunoglobulins and bacterial toxins., (Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Study Design: Retrospective case series., Objective: To evaluate our treatment strategy for cervical dumbbell neurinoma. In treating cervical dumbbell neurinoma, possible difficulties include reoperation due to recurrent tumor, denervation due to nerve root resection, and postoperative spinal deformity due to extensive bony removal., Methods: We reviewed 75 cases of cervical dumbbell neurinoma that were treated surgically between 1985 and 2006. Postoperative neurological deficits, effects of surgical margins on tumor recurrence, and surgical complications were investigated retrospectively., Results: Sensory and motor deficits due to resection of specific nerve roots appeared temporarily in 33 and 23 % of all cases, and persisted in 8 and 8 % at final evaluation, respectively. Total, subtotal, and partial resection was performed in 57, 13, and 5 cases, respectively. The total resection rate was low in the tumors that had large extraforaminal components. Of the subtotally resected 13 cases, only two cases of high tumor-growth rate required re-operation or showed tumor growth. Among the five partially resected cases, re-operation was necessary in two cases 13 and 15 years later because of aggravated neurological symptoms due to tumor growth. Two patients who underwent C2 laminectomy developed kyphosis, and three patients who underwent facet joint resection and curettage of vertebral body lesions developed scoliosis., Conclusion: Total resection should be attempted for cervical dumbbell tumors. In cases where total resection was potentially of high risk, however, subtotal resection (within the capsule) was found to be a practical choice yielding favorable long-term outcome when the tumor growth rate (MIB-1 index) was low.

Adenovirus vector (Adv) vaccination at a systemic site, such as intramuscular (i.m.) immunization, can induce antigen-specific CD8(+) T cell responses in both systemic and mucosal compartments. It remains unclear, however, how antigen-specific CD8(+) T cell response is induced in the mucosa. In this study, we found that type-I IFN signaling is required for the induction of mRNA expression of retinal dehydrogenase in the draining lymph nodes following the i.m. Adv vaccination. We show that type-I IFN signaling is required for the induction of antigen-specific CD8(+) T cell response in the gut-mucosal compartment following the i.m. Adv vaccination., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Study Design: Retrospective case series., Objective: To examine central neuropathic pain after surgical resection of intramedullary spinal cord tumor (IMSCT). Because of the rarity of IMSCT, there is little information about postoperative neuropathic pain after surgical resection., Methods: Eighty-five of 105 patients treated surgically for IMSCT at our hospital between 2000 and 2008 completed the Neuropathic Pain Symptom Inventory (NPSI) and the short form (SF)-36 health inventory. The NPSI score was analyzed against the tumor type and the postoperative Japanese Orthopaedic Association (JOA) score for neurological symptoms., Results: The mean NPSI score of the patients was 13.5. The subscore for paresthesia/dysesthesia was significantly higher than the other subscores. Analysis of the NPSI scores by tumor type revealed no significant differences among patients with ependymoma, astrocytoma, and vascular tumors. The postoperative JOA score showed a weak negative correlation with the NPSI score in patients with thoracic spinal cord tumor, and no correlation in those with cervical tumor. In the 11 patients with hemangioblastoma, intense pain was reported at the level of the tumor, although postoperative paralysis was mild. All the postoperative SF-36 subscores of our study patients were significantly lower than the national average, and a significant negative correlation was observed between the SF-36 and the NPSI subscores., Conclusion: Neuropathic pain after surgical resection reduces the QOL of patients with IMSCTs, and pain severity varies with the tumor's location and histological features, the severity of paralysis, and the location of pain relative to the tumor.