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Objective: We investigated whether air in the cisterns or ventricles on postoperative computed tomography (CT) (reflecting the opening of the cerebrospinal fluid spaces during surgery) is a predictor of classical or nodular leptomeningeal disease (LMD) after resection of brain metastases., Methods: We retrospectively analyzed 73 patients who underwent gross total resection of brain metastases between 2012 and 2020. Patients with air in the cisterns or ventricles on postoperative day 1 CT were categorized into the air-positive group, whereas those without air in the cisterns or ventricles on postoperative day 1 CT were categorized into the air-negative group. The primary outcome was the occurrence of classical or nodular LMD (nLMD), which was assessed using survival analysis., Results: There were 15 (21%) patients in the air-positive group and 58 (79%) in the air-negative group. The air-positive group exhibited significantly more cerebellar and ventricular contact lesions than the air-negative group. The 4-year rate of classical or nLMD was significantly higher in the air-positive group than in the air-negative group (67% vs. 33%, P < 0.001). Multivariate analysis identified air in the cisterns or ventricles on postoperative CT as the only significant predictor of classical or nLMD (P < 0.001)., Conclusions: Postoperative air in the cisterns or ventricles can predict early classical or nodular leptomeningeal disease., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objectives: Photodynamic therapy (PDT) with talaporfin sodium is an intraoperative local therapy administered after the surgical removal of malignant gliomas. However, its clinical efficacy in a large patient population has not been determined. To analyze the clinical outcomes and prognosis in isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients treated with PDT., Methods: This retrospective study included patients with newly diagnosed IDH-wildtype glioblastoma treated at Kobe University Hospital between January 2013 and December 2022. PDT involves irradiation of the resection cavity with a 664-nm semiconductor laser after an intravenous infusion of talaporfin sodium. The main outcome measures were the recurrence patterns and survival times, which were compared between the PDT and non-PDT groups. Univariate and multivariate analyses were used to determine the prognostic factors. In addition, adverse events and prognostic factors in the PDT group were analyzed., Results: A total of 44 and 56 patients were included in the PDT and non-PDT groups, respectively. The local recurrence rate was significantly lower in the PDT group than in the non-PDT group (51.3% vs 83.9%), whereas the distant recurrence and dissemination rates were significantly higher in the PDT group than in the non-PDT group (48.7% vs 16.1%). Two grade 3 adverse events were observed in the PDT group. The median progression-free survival and overall survival times were significantly longer in the PDT group than in the non-PDT group (progression-free survival: 10.8 vs 9.3 months, respectively, and overall survival: 24.6 vs 17.6 months, respectively). Multivariate analysis of the PDT groups revealed that younger age was an independent prognostic factor., Conclusion: PDT with talaporfin sodium provided effective local control with minimal adverse effects. The survival time of the patients treated with PDT was significantly longer than that of the patients who did not receive PDT. Therefore, a randomized controlled clinical trial on PDT is warranted., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Objective: Epileptic seizures are common in patients with gliomas, and their control represents an important aspect of treatment. The oncometabolite 2-hydroxyglutarate (2HG), produced by mutant isocitrate dehydrogenase (IDH), is thought to be associated with seizures due to its structural similarity to the excitatory neurotransmitter glutamate. Using 3T MR spectroscopy (MRS), the authors investigated whether 2HG accumulation might indicate preoperative glioma-associated seizures., Methods: The authors included 196 consecutive patients with diffuse glioma who underwent preoperative MRS and neurological surgery from August 2013 to August 2022. IDH mutation status was confirmed by immunohistochemical analysis and direct DNA sequencing. Concentrations of metabolites, including 2HG, were measured by 3T MRS. The authors set a single voxel (15 mm × 15 mm × 15 mm) and used LCModel software to obtain the quantitative information of the metabolites. They assessed the correlations of preoperative seizures with patient characteristics, tumor size and location, metabolite concentration on MRS, histopathological diagnosis, WHO grade, and IDH-mutant status., Results: Preoperative seizures were observed in 57.8% of patients with IDH-mutant glioma and in 15.2% of patients with IDH-wildtype glioma (p < 0.0001). MRS indicated a higher glutamate concentration in IDH-wildtype gliomas (n = 132) than in IDH-mutant gliomas (n = 64, p < 0.0001). The 2HG concentrations were higher in IDH-mutant tumors than in IDH-wildtype tumors (median 0.71 mM vs 0 mM, respectively; p < 0.001). Glutamate was not associated with a high frequency of preoperative seizures in patients with either IDH-mutant or IDH-wildtype gliomas. In IDH-mutant glioma, 2HG levels were higher in the group with preoperative seizures than in the group without preoperative seizures (median 1.429 mM and 0.187 mM, respectively; p = 0.0231). Multivariate analysis revealed that 2HG concentration was associated with preoperative seizures in IDH-mutant glioma (OR 4.164, 95% CI 1.320-14.50)., Conclusions: An elevated 2HG concentration on MRS could be associated with preoperative seizure, suggesting that 2HG accumulation increases the risk of preoperative seizures in IDH-mutant gliomas.

Purpose: To investigate the relationship between the tumor microenvironment (TME), tumor-related seizures (TRS), and cerebrospinal fluid (CSF) markers that predict preoperative seizures in patients with glioblastoma., Methods: In total, 47 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma who underwent preoperative CSF examination, 3-T magnetic resonance spectroscopy (MRS), and neurological surgery between January 2017 and December 2023 were included. We measured the concentrations of soluble CD163 (sCD163), a soluble form of the M2 macrophage marker, in the CSF, the metabolite concentration on MRS, and the number of CD163-positive M2 macrophages in the tumor tissue. Factors associated with preoperative seizures were examined., Results: Twelve patients (25.5%) had preoperative seizures. sCD163 levels in the CSF were positively correlated with the number of CD163-positive M2 macrophages in the tumor tissue, and both were significantly lower in the preoperative seizure group than in the non-preoperative seizure group (p = 0.0124 and p < 0.0001, respectively). MRS indicated that only glutathione (GSH) concentrations were higher in the preoperative seizure group than in the non-preoperative seizure group (2.55 mM and 1.87 mM, respectively; p = 0.0171). CD163-positive M2 macrophages were inversely correlated with GSH levels. sCD163 in the CSF had a high predictive accuracy (sensitivity, 91.7%; specificity, 54.3%; and area under the receiver operator curve, 0.745) for preoperative seizures., Conclusions: The CSF level of sCD163 is useful for predicting the TME and preoperative seizures in IDH wild-type glioblastoma., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Spinal dural arteriovenous fistulas (SDAVFs) lead to progressive neurological decline with symptoms such as paraparesis, bowel and bladder dysfunction, and sensory disturbances because of impaired spinal cord venous drainage. This study aimed to systematically review the literature on multiple synchronous SDAVFs and present 2 cases from our institution., Methods: A comprehensive search was performed to identify all published cases of multiple synchronous SDAVFs. Overall, 23 patients with multiple synchronous SDAVFs were identified, including 21 from 19 articles and 2 from this study. The clinical presentation, lesion location, radiographic features, surgical treatment, and outcomes were analyzed in each patient., Results: All patients in this study were male, and the duration from symptom onset to diagnosis in many of these patients was longer than that previously reported. Previous studies suggested that multiple SDAVFs typically occurred within 3 or fewer vertebral levels. However, >50% of the examined patients had remote lesions separated by more than 3 vertebral levels. Patients with remote lesions had a significantly worse outcome (1/7 vs 8/11, 95% CI 0.001-0.998; P = .049)., Conclusion: Accurately locating fistulas before spinal angiography is critical for managing multiple remote SDAVFs. Considering the possibility of multiple remote SDAVFs, careful interpretation of imaging findings is essential for an accurate diagnosis and appropriate treatment planning., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Pencil-beam presaturation (BeamSAT) magnetic resonance imaging (MRI) produces selective magnetic resonance angiography (MRA) images of specific arteries, including the unilateral internal carotid artery (ICA-selective MRA) or vertebral artery (VA-selective MRA). We evaluate the influence of flow pattern, visualized using BeamSAT MRI, on preoperative cerebral hemodynamic status and postoperative hyperperfusion syndrome (HPS). Patients undergoing carotid artery stenting or carotid endarterectomy were categorized into two groups to evaluate flow pattern. Patients with neither crossflow on BeamSAT MRI nor mismatch in middle cerebral artery (MCA) signal intensity between ICA-selective and conventional MRA were classified into Group I, comprising 29 patients. Group II included all other patients comprising 19 patients, who were suspected of experiencing changes in intracranial flow patterns. Cerebral blood flow and cerebrovascular reactivity (CVR) were assessed using single-photon emission computed tomography, and potential HPS symptoms were retrospectively assessed by chart review. Preoperative ipsilateral CVR was significantly lower in Group II than in Group I (18.0% ± 20.0% vs. 48.3% ± 19.5%; P < 0.0001). Group II showed significantly impaired CVR (odds ratio 17.7, 95% confidence interval 1.82-171; P = 0.013) in multivariate analysis. The partial areas under the curve of the BeamSAT logistic model (0.843) were significantly larger than those of the conventional logistic model (0.626) over the range of high sensitivity (0.6-1) (P = 0.04). The incidence of postoperative HPS symptoms was significantly higher in Group II than in Group I (8/19 vs. 1/29; P = 0.001). BeamSAT MRI may be a valuable and non-invasive tool for assessing cerebral hemodynamics and predicting postoperative HPS., Competing Interests: Declaration of competing interest The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glioblastoma is the most common malignant brain tumor in adults, the survival rate of which has not significantly improved over the past three decades. Therefore, there is an urgent need to develop novel treatment modalities. We previously reported that G1 to S phase transition 1 (GSPT1) depletion induces delayed cell cycle in primary astrocytes. Herein, we examined the potential of GSPT1 as a novel target for glioblastoma therapy. CC-885, a cereblon modulator that degrades GSPT1 by bridging GSPT1 to the CRL4 E3 ubiquitin ligase complex, was administered to nude mice with transplanted brain tumors of U87 glioblastoma cells. The survival period was significantly longer in CC-885 treated mice than in control mice. Furthermore, we generated GSPT1-knockout (KO) U87 cells and GSPT1-KO U87 cells with stable overexpression of FLAG-tagged GSPT1 (Rescued GSPT1-KO). Mice with transplanted GSPT1-KO U87 cells and Rescued GSPT1-KO U87 cells showed significantly longer and similar survival periods, respectively, as those with wild-type (WT) U87 cells. GSPT1-KO U87 cells showed enhanced apoptosis, detected by cleaved PARP1, compared to WT U87 cells. Brain tumors with transplantation of GSPT1-KO U87 cells also showed enhanced apoptosis compared to those with transplantation of WT and Rescued GSPT1-KO U87 cells. GSPT1 expression was confirmed in patients with glioblastoma. However, the clinical study using 87 glioblastoma samples showed that GSPT1 mRNA levels were not associated with overall survival. Taken together, we propose that GSPT1 is an essential protein for glioblastoma growth, but not its malignant characteristics, and that GSPT1 is a potential target for developing glioblastoma therapeutics., (© 2024. The Author(s).)

Objectives: This systematic review assessed the efficacy and safety of tumor necrosis factor (TNF) inhibitors in patients with systemic juvenile idiopathic arthritis (JIA)., Methods: Studies were searched using PubMed, Embase, Cochrane, Ichushi-Web, and clinical trial registries (from 2000 to 2021). The risk of bias was assessed using the Cochrane Risk of Bias version 2 for randomized controlled trials (RCTs) and the manual for development clinical practice guidelines by Minds, a project promoting evidence-based medicine in Japan, for observational studies., Results: One RCT and 22 observational studies were included. In the RCT on infliximab, the American College of Rheumatology pediatric (ACR Pedi) 30/50/70 responses at 14 weeks were 63.8%/50.0%/22.4%, with relative risks of 1.30 (95% confidence interval [CI]: 0.94-1.79)/1.48 (95% CI: 0.95-2.29)/1.89 (95% CI: 0.81-4.40), respectively. In the observational studies, ACR Pedi 30/50/70 responses for etanercept at 12 months were 76.7%/64.7%/46.4%, respectively. Infliximab treatment caused anaphylaxis in 17% and an infusion reaction in 23% of patients. The incidence of macrophage activation syndrome, serious infection and malignancy caused by TNF inhibitors was 0%-4%., Conclusions: Thus, although TNF inhibitors were relatively safe, they were unlikely to be preferentially administered in patients with systemic JIA because of their inadequate efficacy. Further studies, particularly well-designed RCTs, are necessary to confirm the efficacy and safety of TNF inhibitors for systemic JIA., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objectives: This systematic review assessed the efficacy and safety of abatacept in patients with systemic juvenile idiopathic arthritis (JIA)., Methods: Studies published between 2000 and 2021 were searched using PubMed, Embase, Cochrane, Ichushi-Web and clinical trial registries. The risk of bias was assessed according to the manual for development clinical practice guidelines by Minds, a project to promote evidence-based medicine in Japan., Results: Seven observational studies were included. American College of Rheumatology pediatric 30/50/70 responses at 3, 6 and 12 months were 64.8%/50.3%/27.9%, 85.7%/71.4%/42.9% and 80.0%/50.0%/40.0%, respectively. Outcomes on systemic symptoms, joint symptoms and activities of daily living were not obtained. No macrophage activation syndrome or infusion reaction occurred. Serious infection occurred in 2.6% of cases., Conclusions: Abatacept improved the disease activity index. In addition, abatacept was as safe as interleukin-6 (IL -6) and IL-1 inhibitors. However, both the efficacy and safety data in this systematic review should be reviewed with caution because their quality of evidence is low or very low. Further studies are needed to confirm the efficacy and safety of abatacept for systemic JIA, especially its efficacy on joint symptoms., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Trisomy 21 (Down syndrome) is sometimes complicated by congenital heart disease; however, comorbid type I diabetes mellitus and diseases involving autoantibodies, such as Hashimoto disease and Graves disease, are not uncommon. Autoinflammatory diseases such as Kawasaki disease and systemic juvenile idiopathic arthritis are rare. We report a rare case of trisomy 21 with systemic juvenile idiopathic arthritis that responded well to the initial course of methylprednisolone pulse therapy but flared up and was complicated by macrophage activation syndrome (MAS). Subsequent methylprednisolone pulse therapy and cyclosporine resolved this condition. Cytokines were analyzed at several time points during the clinical course and revealed that interleukin-18, interleukin-6, and chemokine ligand 9 levels were elevated at MAS onset in the present patient, even though clinical symptoms had abated. Thus, early analysis of cytokine profiles should be performed to assess MAS risk and determine treatment intensity, even in T21 patients.

In paediatric primary Sjögren's syndrome (SS), the initial symptoms manifest systemically, such as fever, general fatigue, and lymphadenopathy, rather than sicca symptoms. Most children with primary SS have autoantibodies, such as antinuclear, anti-Ro/SS-A, and/or anti-La/SS-B antibodies; however, some patients are seronegative. Similar to paediatric patients with primary SS, those with Takayasu arteritis (TAK) initially only present constitutional symptoms, making it difficult to suspect, unless characteristic features are present. To our knowledge, there have been no reports of the coexistence of both diseases in children. We present a rare case of seronegative SS complicated by TAK in a 9-year-old girl who presented with a persistent low-grade fever, general fatigue, cervical lymphadenopathy, and multiple caries. Although blood examination revealed all autoantibodies to be negative, a lip biopsy revealed lymphocytic sialadenitis, and a sialoscintigraphy indicated hypofunctional salivary glands, leading to the diagnosis of seronegative SS. The patient was treated with low-dose glucocorticoid and immunosuppressant administration to inhibit persistent inflammation and the progression of salivary gland dysfunction; although the symptoms resolved, inflammatory markers remained elevated. When the patient was 14 years old, cervical bruits were incidentally found, and TAK was suspected based on cervical ultrasonography and magnetic resonance angiography findings. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography results demonstrated increased fluorodeoxyglucose accumulation from the ascending to descending aorta. Therefore, she was diagnosed with SS complicated by TAK, which is rare. Aortitis should be suspected when the cause of persistent inflammation cannot be ascertained in patients with SS., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

IgA vasculitis (IgAV) is the most frequent form of vasculitis in childhood which classically presents with purpura of the lower extremities, joint pain or swelling and abdominal pain. Though it is a self-limiting disease, and its prognosis is generally good, glomerulonephritis is one of the most important complications. IgAV is classified as a small vessel vasculitis, and though glomerulonephritis develops in IgAV, necrotizing arteritis is rarely seen. Here, we present a case of a 13-year-old girl with IgAV, glomerulonephritis, and necrotizing arteritis in the small renal arteries. There have been only a few reports of adult cases of IgAV with necrotizing arteritis in the kidneys, but there have been no pediatric cases. Some previous reports showed a high mortality rate and implied the possibility of overlap with other vasculitides. In the current report, a rare case of IgAV is described which exhibited necrotizing arteritis rather than overlap with another vasculitis, with a relatively typical clinical course for IgAV and laboratory tests., (© 2021. Japanese Society of Nephrology.)

Objectives: Knowledge gaps exist in the use of biologics for pregnant patients with Crohn's disease (CD), especially the usage of ustekinumab (UST) and infliximab (IFX) infusion during the late gestation period. In this case series, we investigated perinatal and neonatal outcomes and pharmacokinetics of these biologics in pregnant CD patients., Methods: Pregnant CD patients under treatment with IFX or UST during January 2017 to December 2019 were monitored. Growth and development of their babies were followed up to six months. Drug concentrations were measured in maternal peripheral and cord blood at delivery and infants' blood at six months of age., Results: Four cases were kept IFX treatment until late gestation (median last dose: 31.2 weeks). One case received UST until 23 weeks of gestation. All cases were in clinical remission but moderately undernourished. Babies were delivered by cesarean section at full term without any complications or congenital abnormalities. No growth or developmental defects and no susceptibility to infections were observed by six months. However, two babies whose mothers received IFX after 30 weeks of gestation were detected IFX in their blood at six months of age (0.94 and 0.24 pg/ml). Concentrations of UST in maternal and cord blood were 267.7 and 756.5 ng/ml, respectively. UST was not detected in the infant at six months of age., Conclusions: Administration of UST or IFX to pregnant patients with CD is safe, particularly IFX to be given in the late gestation period. Understanding of the pharmacokinetics of biologics in maternal-infant interactions may improve the management of pregnant CD patients., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2021 by The Japan Society of Coloproctology.)

We have been interested in the reactivities of small-ring compounds and have reported reactions that proceed through cyclopropane intermediates starting from coumarin derivatives bearing an electron-withdrawing group at the 3-position or 2-oxo-2H-pyran-3-carboxylate derivatives and dimethylsulfoxonium methylide. This time, the reaction between 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate and dimethylsulfoxonium methylide has been investigated. 3a,4,5,7a-Tetrahydro-7-hydroxybenzofuran-6-carboxylate and/or 2-hydroxybicyclo[4.1.0]hept-2-ene-3-carboxylate were obtained. The compounds were characterized using various spectral and X-ray crystallographic techniques. A plausible reaction mechanism has been discussed. This reaction was applied to some 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate derivatives to clarify the generality.

Objective: We aimed to investigate the characteristics and operative results of elderly patients with cervical spondylotic myelopathy(aged ≧80 years)treated using the posterior approach., Methods: Between April 2010 and December 2018, 21 patients aged ≧80 years(older group:8 men and 13 women;age range, 80-90 years)who underwent laminoplasty were reviewed and compared with 23 patients aged <80 years(younger group;13 men and 10 women;age range, 42-79 years)who underwent laminoplasty. The following data were obtained from chart reviews:age;sex;cervical canal stenosis level;time to operation;symptoms(e.g., gait disturbance);comorbidities(hypertension, diabetes mellitus, cancer, heart disease, ischemic cerebrovascular disease, and lumbar canal stenosis);antithrombotic drug use;cardiac, pulmonary, and renal functions;operative time;volume of blood loss during the operation;postoperative delirium;and follow-up period. Neurological deficits before and after the surgery were assessed using the neurosurgical cervical spine scale(NCSS). Data were statistically analyzed, and p-values <0.05 were considered statistically significant., Results: The operative time, symptoms(hypertension), renal function, and preoperative NCSS score were significantly different between the older and younger groups. Meanwhile, most variables showed no significant differences between the groups. Although the preoperative NCSS score was lower in the older group, there was no significant difference in the degree of improvement in the NCSS score after surgery., Conclusions: The findings of this study suggest that we should not hesitate to perform surgery for cervical spondylotic myelopathy in elderly patients with favorable cardiorespiratory function.

Hemophagocytic lymphohistiocytosis (HLH) associated with Epstein-Barr virus (EBV) infection can be self-limiting, severe/aggressive, or fatal. We report a case of EBV-HLH with persistent fever, severe pancytopenia, hypertriglyceridemia, and hypofibrinogenemia in a 4-year-old boy. Levels of plasma cytokines and chemokines were measured with a Bio-Plex system at 1, 2, 3, 4, 5, and 8 days after hospital admission. Administration of steroid and high-dose intravenous immunoglobulin (1 g/kg) did not alleviate fever or reduce cytokine production; however, after administration of etoposide (an antineoplastic agent), fever decreased immediately, the patient's general condition improved, and levels of IL-6, IL-10, IL-8, MCP-1, IFN-γ, and TNF-α declined after etoposide administration. In particular, IFN-γ production sharply declined, from 1,104.1 pg/mL to 101.5 pg/mL, and IL-6 level decreased from 229.8 pg/mL to 11.0 pg/mL, on the day after initial etoposide administration. There was no later recurrence of symptoms during treatment with dexamethasone, etoposide, and cyclosporine A. This case suggests that early etoposide administration is critical for treatment success and indicates that etoposide promptly inhibits cytokine production.

Food-dependent exercise-induced anaphylaxis (FDEIA) is a life-threatening but relatively rare disorder which occurs mainly in older children and young adults and manifests with symptoms of anaphylaxis upon exercise following ingestion of certain kinds of food. We herewith report 3 cases of soybean-induced FDEIA. We also highlight 2 types of soybean-induced FDEIA, one caused by storage protein components Gly m 5 and Gly m 6 and the other caused by pollen-related allergen components., Competing Interests: The authors declare that all the authors have no relevant conflicts of interest in relation to this work., (© 2020 The Authors.)

Tenascin-X (TNX) is a member of the extracellular matrix glycoprotein tenascin family, and TNX deficiency leads to Ehlers-Danlos syndrome, a heritable human disorder characterized mostly by skin hyperextensibility, joint hypermobility, and easy bruising. TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. However, the molecular mechanisms by which TNX deficiency complicates pain are unknown. Here, we examined the nociceptive behavioral responses of TNX-deficient mice. Compared with wild-type mice, TNX-deficient mice exhibited mechanical allodynia but not thermal hyperalgesia. TNX deficiency also increased pain sensitivity to chemical stimuli and aggravated early inflammatory pain elicited by formalin. TNX-deficient mice were significantly hypersensitive to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not to stimuli at frequency of 5 Hz (C fiber responses). In addition, the phosphorylation levels of extracellular signal-related kinase, an active neuronal marker, and the activity of NADPH-diaphorase, a neuronal nitric oxide activation marker, were enhanced in the spinal dorsal horns of TNX-deficient mice. These results suggest that TNX deficiency contributes to the development of mechanical allodynia and hypersensitivity to chemical stimuli, and it induces hypersensitization of myelinated A fibers and activation of the spinal dorsal horn.

Purpose of Review: The prevalence of chronic upper airway inflammatory diseases such as allergic rhinitis and chronic rhinosinusitis (CRS) is increasing markedly posing a potential health threat globally. The involvement of the upper respiratory microbiota in chronic inflammatory diseases of the upper airways has been of considerable interest. The purpose of this review is to understand the characteristics of upper respiratory microbiota in both healthy and chronic inflammatory diseases of the upper airways like allergic rhinitis and CRS and to know the potential role of interventions with probiotics., Recent Findings: We present here the studies on the nasal microbiota in healthy infants, allergic rhinitis, and CRS. The results demonstrate that there are stable and unstable profiles of microbiota during infancy. Decreased diversity or an imbalance of the microbial composition could be an important factor in the development of both allergic rhinitis and CRS. We also discuss here several recent animal and human studies that demonstrate the effect of probiotics in allergic rhinitis and chronic rhinosinusitis. Results from human studies (clinical trials) have demonstrated that probiotics may be effective for allergic rhinitis, but there are no consistent results in human CRS trials., Summary: Several strains of probiotics revealed potential efficacy for allergic rhinitis but not for CRS. Large clinical trials are essential to establish robust data on probiotics for chronic inflammatory upper airways diseases like allergic rhinitis and CRS.

Background: Pseudoaneurysm after mechanical thrombectomy (MT) is rare but is one of the potential complications associated with endovascular procedures. There is limited information regarding its mechanism of formation and the potential risk of delayed bleeding., Case Description: An 84-year-old woman was admitted to our institution with right hemiplegia and global aphasia. Magnetic resonance imaging and angiography revealed occlusion of the M2 segment of the left middle cerebral artery with subtle acute ischemic change in this territory. After initiating intravenous thrombolysis, MT was performed for persistent occlusion of the M2. Successful revascularization was finally achieved with a single pass of a Trevo XP 3 mm × 20 mm stent retriever; significant deviation of the vessel occurred during withdrawal of the stent retriever. Anticoagulation was initiated after confirming resolution of a small amount of postprocedural subarachnoid hemorrhage 1 day after the procedure. However, 4 days after the procedure, computed tomography and angiography revealed a massive sylvian hematoma with de novo formation of a small pseudoaneurysm at the site where the stent retriever was deployed. Open surgery revealed a small artery avulsion at this site. The lesion was closed by microsurgical suturing., Conclusions: Angiographic and intraoperative findings showed that the mechanism of formation of the pseudoaneurysm was small artery avulsion resulting from deviation of the vessel during withdrawal of the stent retriever. When performing MT in a tortuous distal vessel, the possibility of small artery avulsion should be kept in mind to both prevent and manage critical hemorrhagic complications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Most cases of the primary brainstem injuries(PBSI)are fatal, and disturbance of consciousness is often prolonged even if lifesaving is obtained. The mechanisms of PBSI are as follows: diffuse axonal injury from acceleration/deceleration, shear strain at the midbrain, direct injury of neurovascular structures by tentorial margin, and lower brainstem injury by hyperextension of the cervical vertebrae. Though we can use both CT and MRI to diagnose, MRI is more helpful than CT in detecting, localizing, and characterizing PBSI. When the location of PBSI is limited in the ventral side of pons, it may occasionally result in locked in syndrome(LIS). Generally it is difficult to diagnose LIS with severe trauma due to the rarity of this syndrome caused by head injury. Here, we report a case of an elderly man with traumatic brainstem hemorrhage, who transiently presented LIS and finally improved.

Background: Therapeutic outcomes for childhood malignancy have dramatically improved. However, secondary malignancies are a major concern, as they greatly affect the quality of life of survivors. This retrospective study evaluated the cumulative incidence, clinical features, and outcomes of secondary malignancies at Nippon Medical School Hospital., Methods: We examined data from 275 cases of primary childhood malignancy diagnosed between 1980 and 2014. Information regarding treatment of the primary malignancy, including irradiation dose, site, and cumulative dose of anticancer drugs, was assessed. We also collected data on secondary malignancy, including patient sex, age at diagnosis, malignancy site, time from primary to secondary malignancy, and outcomes., Results: Secondary malignancies developed in 11 patients and included acute myeloid leukemia (AML) (4), meningioma (4), Ewing sarcoma (1), germ cell tumor (1), and malignant parotid gland tumor (1). The primary malignancies included acute lymphoblastic leukemia (ALL) (9), non-Hodgkin lymphoma (1) and brain tumor (1). In 7 of the 9 ALL patients, chemoradiotherapy was the primary treatment. The meningiomas and 1 solid tumor developed within the radiation field. All AMLs and meningiomas developed within 5 years and after 20 years, respectively, of the primary diagnosis. The 10- and 20-year cumulative incidence rates for secondary malignancy in our hospital were 1.9% and 5.8%, respectively., Conclusions: Our results revealed that the type of secondary malignancy depends on the interval after the end of treatment for primary malignancy. Meningioma, notably, develops many years after completion of primary malignancy treatment. Early detection during long-term follow-up is therefore essential.

X-Linked severe combined immunodeficiency (X-SCID) is a severe form of primary immunodeficiency characterized by absence of T cells and NK cells. X-SCID is caused by a loss-of-function mutation in the IL2RG gene that encodes common gamma chain (γc), which plays an essential role in lymphocyte development. We report the first case of hypomorphic X-SCID caused by a synonymous mutation in the IL2RG gene leading to a splice anomaly, in a family including two patients with diffuse cutaneous warts, recurrent molluscum contagiosum, and mild respiratory infections. The mutation caused aberrant splicing of IL2RG mRNA, subsequently resulted in reduced γc expression. The leaky production of normally spliced IL2RG mRNA produced undamaged protein; thus, T cells and NK cells were generated in the patients. Functional assays of the patients' T cells and NK cells revealed diminished cytokine response in the T cells and absent cytokine response in the NK cells. In addition, the TCR repertoire in these patients was limited. These data suggest that a fine balance between aberrant splicing and leaky production of normally spliced IL2RG mRNA resulted in late-onset combined immunodeficiency in these patients.

Background: Intracerebral aneurysms co-existing with meningiomas are rare. Treatment strategies for intracerebral aneurysms co-existing with meningiomas have not yet been established., Methods: We studied 62 patients with intracerebral aneurysms co-existing with meningiomas in the literature including our seven cases, evaluated the various managements and outcomes, and discussed the strategy for intracerebral aneurysms, especially unruptured cases, co-existing with meningiomas. The aim of this study was to develop a guide for the management of non-subarachnoid hemorrhage (SAH) intracerebral aneurysms co-existing with meningiomas., Results: Most intracerebral aneurysms co-existing with meningiomas are unruptured. Of course, aneurysms presenting with SAH should be treated first followed by the resection of meningiomas. In addition, intracerebral aneurysms inside or adjacent to meningiomas have a high risk of intraoperative rupture during the surgery for meningiomas, and it may be necessary to treat them first followed by the resection of meningiomas with one or two-step surgery. In nine out of 62 patients, ten intracerebral unruptured aneurysms were not treated; however, no intracerebral aneurysms ruptured during the follow-up period, and outcomes of these patients were good in eight and poor in only one., Conclusions: Intracerebral unruptured aneurysms remote from meningiomas may be treated according to the guidelines for unruptured aneurysms. In advance of microsurgery and endovascular techniques, both lesions should be treated, if possible., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

Purpose of Review: Cytokines are immunomodulatory proteins important in cell signaling. Complex interactions of innate and adaptive immune cells, as well as structural cells and their cytokines, play crucial roles in regulating allergic airway inflammation. Here, we summarize current knowledge about the potential roles of known and newly identified helper T cells and epithelial cell-derived cytokines [interleukin (IL)-9, IL-17, IL-22, IL-25, and IL-33] in allergic rhinitis and asthma., Recent Findings: Although T-helper (Th)2 cells were considered to be the main orchestrators of allergic airway inflammation, recent studies have revealed the potential interaction of other helper T cells and their cytokines in this process. Th17 cells may have a role in allergic rhinitis and asthma, and chronic rhinosinusitis with nasal polyps. An IL-9-producing subset called Th9 cells, Th22 cells which primarily secrete IL-22, IL-13, tumor necrosis factor-α, Th25 cells via producing IL-25 and epithelial cell-derived thymic stromal lymphopoietin, IL-33, IL-31, and IL-25 are believed to be important for the initiation of allergic reactions and inducing airway inflammation., Summary: A new paradigm of an interplay of cytokines is important in allergic rhinitis and asthma in orchestrating the allergic inflammatory response. Potential therapeutic applications emerging from the roles of these cytokines are promising, but need further research.

Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP:, (Copyright © 2014 Elsevier Inc. All rights reserved.)

Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation.

Helicobacter pylori infection is associated with several autoimmune diseases, in which autoantibody-producing B cells must be activated. Among these B cells, CD5-positive B-1a cells from BALB/c mice were confirmed to secrete autoantibodies when cocultured with purified H. pylori urease in the absence of T cells. To determine the mechanisms for autoantibody production, CD5-positive B-1a cells were sorted from murine spleen cells and stimulated with either purified H. pylori urease or H. pylori coated onto plates (referred to hereafter as plate-coated H. pylori), and autoantibody production was measured by enzyme-linked immunosorbent assay (ELISA). Complete urease was not secreted from H. pylori but was visually expressed over the bacterium-like endotoxin. Urease-positive plated-coated H. pylori stimulated B-1a cells to produce autoantibodies, although urease-deficient isotype-matched H. pylori did not. Autoantibody secretion by B-1a cells was inhibited when bacteria were pretreated with anti-H. pylori urease-specific antibody having neutralizing ability against urease enzymatic activity but not with anti-H. pylori urease-specific antibody without neutralizing capacity. The B-1a cells externally express various Toll-like receptors (TLRs): TLR1, TLR2, TLR4, and TLR6. Among the TLRs, blocking of TLR2 on B-1a cells with a specific monoclonal antibody (MAb), T2.5, inhibited autoantibody secretion when B-1a cells were stimulated with plate-coated H. pylori or H. pylori urease. Moreover, B-1a cells from TLR2-knockout mice did not produce those autoantibodies. The present study provides evidence that functional urease expressed on the surface of H. pylori will directly stimulate B-1a cells via innate TLR2 to produce various autoantibodies and may induce autoimmune disorders.

Purpose: Lid-wiper epitheliopathy (LWE) is characterized by one part of the marginal conjunctiva of the upper eyelid being affected and is correlated with dry eye symptoms. This is a study of the clinical features of LWE., Methods: Three hundred and sixty-four eyes of 182 patients with dry eye symptoms were studied. In all subjects the presence of LWE was determined by lissamine green staining followed by tests for dry eye., Results: LWE was detected in 48 of 364 eyes (13.2%). One hundred thirty-four eyes were diagnosed with dry eye and LWE was detected in 25 of 134 eyes (18.7%). This rate was higher than that of non-dry eyes with LWE (23 of 230 eyes, 10.0%). Since LWE was detected at a high rate in contact lens (CL) wearers (22 of 37 eyes, 59.4%), LWE background factors in CL wearers and non-CL wearers were compared. Significantly higher fluorescein staining scores were detected in the LWE positive CL wearers compared to LWE negative CL wearers, whereas no significant differences were detected between the LWE positive and negative groups in any other dry eye examination. LWE-like lissamine green staining was detected on the lower eyelids in 122 eyes (33.0%)., Conclusion: LWE was detected in more than 10% of patients with dry eye symptoms. Although LWE was detected in dry eye patients, no clear relationship was recognized between LWE and the presence of dry eye.

A 6-year-old female was admitted with abdominal pain and a mass in the right abdomen. Her lactose dehydrogenase level was 1,200 IU/L, and neuron specific enolase was 120 ng/ml. Computed tomography scan confirmed a large right renal mass with necrosis. A right radical nephrectomy was performed. The tumor was completely encapsulated. Based on small round cell histology, strong MIC-2 (CD99) positive tumor cells, and EWS-FLI-1 fusion transcript, Ewing sarcoma/primitive neuroectodermal tumor of the kidney was diagnosed. Induction and follow-up with seven cycles of chemotherapy were given after surgery. She has had no evidence of recurrence 90 months from diagnosis., ((c) 2007 Wiley-Liss, Inc.)