ABSTRACT
We aimed to evaluate the materials based on 4-methacryloxyethyl trimellitate anhydride/methyl methacrylate tri-n-butylborane (Super-bond [SB]) and nano hydroxyapatite (naHAp) for the repair of perforation at pulp chamber floor (PPF) in vitro and in vivo models. SB and naHAp were mixed in the mass ratio of 10% or 30% to produce naHAp/SB. Human periodontal ligament stem cells (HPDLSCs) were cultured on resin discs of SB or naHAp/SB to analyze the effects of naHAp/SB on cell adhesion, proliferation, and cementoblastic differentiation. A rat PPF model was treated with SB or naHAp/SB to examine the effects of naHAp/SB on the healing of defected cementum and periodontal ligament (PDL) at the site of PPF. HPDLSCs were spindle-shaped and adhered to all resin discs. Changing the resin from SB to naHAp/SB did not significantly alter cell proliferation. Both 10% and 30% naHAp/SB were more effective than SB in promoting cementoblastic differentiation of HPDLSCs. In the rat PPF model, 30% naHAp/SB was more effective than SB in promoting the formation Sharpey's fiber-like structures with expression of the PDL-related marker and cementum-like structures with expression of cementum-related markers. In conclusion, 30% naHAp/SB can be the new restorative material for PPF because it exhibited the abilities of adhering to dentin and healing of defected periodontal tissue.
Subject(s)
Boron Compounds , Durapatite , Methacrylates , Periodontal Ligament , Animals , Rats , Humans , Durapatite/chemistry , Durapatite/pharmacology , Periodontal Ligament/drug effects , Periodontal Ligament/cytology , Periodontal Ligament/metabolism , Boron Compounds/pharmacology , Boron Compounds/chemistry , Methacrylates/chemistry , Methacrylates/pharmacology , Cell Differentiation/drug effects , Wound Healing/drug effects , Male , Cell Proliferation/drug effects , Dental Pulp Cavity/metabolism , Dental Pulp Cavity/drug effects , Stem Cells/drug effects , Stem Cells/cytology , Stem Cells/metabolism , Cells, Cultured , Rats, Sprague-Dawley , Methylmethacrylates/chemistry , Methylmethacrylates/pharmacology , Cell Adhesion/drug effectsSubject(s)
Lupus Erythematosus, Systemic , Lupus Nephritis , Serositis , Humans , Lupus Nephritis/complications , Lupus Nephritis/drug therapy , Lupus Nephritis/diagnosis , Serositis/etiology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/drug therapy , Female , Adult , Male , Middle Aged , Treatment OutcomeABSTRACT
INTRODUCTION: Serpiginous choroiditis presents with large yellow-white exudative lesions that occur near the optic nerve papillae, that progresses slowly with repeated relapses and cures. Although infection and autoimmunity have been implicated, the cause is unknown. METHODS: A man was diagnosed with serpiginous choroiditis on clinical and other examinations. He started treatment with oral corticosteroids, cyclophosphamide, adalimumab, azathioprine, rituximab, and mycophenolate mofetil. Only the steroids and cyclophosphamide had a therapeutic effect. Plasma exchange was initiated, and the lesions quickly resolved. RESULTS: Disease control has been maintained by plasma exchange and cyclophosphamide during flare-ups in the fall and winter, suggesting that plasma exchange is effective in the treatment of serpiginous choroiditis. CONCLUSION: The reproducible response with each recurrence suggests a strong association between the disease and autoimmunity. Furthermore, that some, as yet unknown, autoantibodies are involved in the pathogenesis of serpiginous choroiditis.
Subject(s)
Choroiditis , Plasma Exchange , Humans , Male , Plasma Exchange/methods , Choroiditis/diagnosis , Retrospective Studies , Treatment Outcome , Middle Aged , Adult , Recurrence , Immunosuppressive Agents/therapeutic useABSTRACT
To survive, animals need to balance their exploratory drive with their need for safety. Subcortical circuits play an important role in initiating and modulating movement based on external demands and the internal state of the animal; however, how motivation and onset of locomotion are regulated remain largely unresolved. Here, we show that a glutamatergic pathway from the medial septum and diagonal band of Broca (MSDB) to the ventral tegmental area (VTA) controls exploratory locomotor behavior in mice. Using a self-supervised machine learning approach, we found an overrepresentation of exploratory actions, such as sniffing, whisking, and rearing, when this projection is optogenetically activated. Mechanistically, this role relies on glutamatergic MSDB projections that monosynaptically target a subset of both glutamatergic and dopaminergic VTA neurons. Taken together, we identified a glutamatergic basal forebrain to midbrain circuit that initiates locomotor activity and contributes to the expression of exploration-associated behavior.
Subject(s)
Exploratory Behavior , Ventral Tegmental Area , Mice , Animals , Ventral Tegmental Area/physiology , Dopaminergic Neurons/metabolism , MotivationABSTRACT
OBJECTIVE: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.
Subject(s)
Antibodies, Monoclonal, Humanized , Cryopyrin-Associated Periodic Syndromes , Humans , Cryopyrin-Associated Periodic Syndromes/drug therapy , Cryopyrin-Associated Periodic Syndromes/genetics , Antibodies, Monoclonal, Humanized/therapeutic use , Japan , Female , Male , Retrospective Studies , Child , Child, Preschool , Adult , Adolescent , Young Adult , Treatment Outcome , Middle Aged , Infant , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Mutation , Remission InductionABSTRACT
BACKGROUND: Liposarcoma originating from peripancreatic fat tissue is extremely rare. This case report presents a surgical case of a giant liposarcoma originating from peripancreatic fat tissue with origin identification using 3-Dimensional Computed Tomography Angiography (3D-CTA). CASE PRESENTATION: A 59-year-old female was referred to our hospital with a giant abdominal tumor. Computed tomography revealed a 34 cm tumor composed of fatty tissue, exerting pressure on the posterior aspect of the pancreas. Suspecting liposarcoma, we planned for surgery. At first, the tumor appeared to be intra-abdominal tumor, based on the identification of the tumor's feeding artery as a branch of the dorsal pancreatic artery using 3D-CTA, we concluded that the liposarcoma originated from the peripancreatic fat tissue and situated in the retroperitoneum. During surgery, we observed a well-capsulated, elastic, yellowish mass without infiltration into surrounding tissues. We carefully dissected the tumor from the greater omentum and transverse mesocolon while preserving the tumor capsule. We ligated the feeding artery at the border with the pancreatic parenchyma and successfully completed the excision of the tumor. The resected specimen weighted 2620 g and was pathologically diagnosed as a well-differentiated liposarcoma. There was no injury to the tumor's capsule, and the surgical margins were negative. CONCLUSIONS: In this report, we present an extremely rare case of a liposarcoma originating in the peripancreatic fat tissue. The use of 3D-CTA was instrumental in identifying the primary site of this giant tumor, enabling us to guide the surgery and achieve complete resection successfully.
ABSTRACT
IMPORTANCE: USA300 is an MRSA clone producing PVL, a toxin associated with SSTIs. ΨUSA300 is a USA300 variant recently identified in Japan by Takadama et al. (15). Here, we found that the prevalence rate of PVL-positive MRSA in S. aureus was elevated in the Japanese community, and ΨUSA300 accounted for most of them. ΨUSA300 strains have been isolated from several areas in Japan and were associated with deep-seated SSTIs. This study highlighted the emerging threat posed by ΨUSA300 in Japan.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Methicillin-Resistant Staphylococcus aureus/genetics , Japan/epidemiology , Staphylococcus aureus/genetics , Prevalence , Staphylococcal Infections/epidemiology , Exotoxins/geneticsABSTRACT
OBJECTIVE: To clarify the clinical characteristics of organizing pneumonia (OP) in rheumatoid arthritis (RA; RA-OP) and the association of OP development with RA exacerbation, and to identify OP recurrence predictors. METHODS: Data from 33 patients with RA-OP admitted to our hospital were retrospectively analyzed (2006-2016). RESULTS: RA onset preceded OP onset in 82% of patients, whereas OP onset preceded (OP-preceding) or co-occurred with RA in 9% of patients each. Median age at first OP onset was 64.0 years, and the period from RA onset to first OP onset was 5.5 years. At OP onset, 42% of events exhibited unilateral involvement and 76% had normal Krebs von den Lungen-6. RA disease control remained optimal in 52% of events and was exacerbated in 18% of events. Ten patients (30%) experienced OP recurrence with an interval of 13.0 months between events, and the first OP recurrence rate was 127/1000 person-years. Compared with nonrecurrent cases (n = 14), recurrent cases (n = 10) showed lower age at first OP onset (59.5 vs 67.1 yrs; P = 0.04) and a shorter period from RA onset to first OP onset (6.4 vs 14.2 yrs; P = 0.047); moreover, these cases included a higher number of OP-preceding patients (30% vs 0%; P = 0.03) and ever smokers (80% vs 36%; P = 0.03). OP-preceding patients showed shorter median recurrence-free survival time (15 vs 136 months; P = 0.01) and higher recurrence risk (hazard ratio 5.45; P = 0.02). CONCLUSION: RA-OP showed a high recurrence rate and was not associated with RA exacerbation. Four RA-OP recurrence predictors were identified.
Subject(s)
Arthritis, Rheumatoid , Cryptogenic Organizing Pneumonia , Organizing Pneumonia , Pneumonia , Humans , Aged , Retrospective Studies , Cryptogenic Organizing Pneumonia/etiology , Cryptogenic Organizing Pneumonia/complications , Arthritis, Rheumatoid/complicationsABSTRACT
OBJECTIVES: Recent studies demonstrate that extracellular-released aminoacyl-tRNA synthetases (aaRSs) play unique roles in immune responses and diseases. This study aimed to understand the role of extracellular aaRSs in the pathogenesis of rheumatoid arthritis (RA). METHODS: Primary macrophages and fibroblast-like synoviocytes were cultured with aaRSs. aaRS-induced cytokine production including IL-6 and TNF-α was detected by ELISA. Transcriptomic features of aaRS-stimulated macrophages were examined using RNA-sequencing. Serum and synovial fluid (SF) aaRS levels in patients with RA were assessed using ELISA. Peptidyl arginine deiminase (PAD) 4 release from macrophages stimulated with aaRSs was detected by ELISA. Citrullination of aaRSs by themselves was examined by immunoprecipitation and western blotting. Furthermore, aaRS inhibitory peptides were used for inhibition of arthritis in two mouse RA models, collagen-induced arthritis and collagen antibody-induced arthritis. RESULTS: All 20 aaRSs functioned as alarmin; they induced pro-inflammatory cytokines through the CD14-MD2-TLR4 axis. Stimulation of macrophages with aaRSs displayed persistent innate inflammatory responses. Serum and SF levels of many aaRSs increased in patients with RA compared with control subjects. Furthermore, aaRSs released PAD4 from living macrophages, leading to their citrullination. We demonstrate that aaRS inhibitory peptides suppress cytokine production and PAD4 release by aaRSs and alleviate arthritic symptoms in a mouse RA model. CONCLUSIONS: Our findings uncovered the significant role of aaRSs as a novel alarmin in RA pathogenesis, indicating that their blocking agents are potent antirheumatic drugs.
Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Animals , Mice , Alarmins , Cells, Cultured , Cytokines , Disease Models, Animal , Fibroblasts/pathology , Inflammation , Synovial Fluid , HumansABSTRACT
OBJECTIVES: Some MRSA strains produce Panton-Valentine leucocidin (PVL) and/or toxic shock syndrome toxin 1 (TSST-1), which are associated with severe infectious diseases. Although PVL- or TSST-1-positive strains have been isolated worldwide, strains carrying both PVL and TSST-1 genes are rare and sporadic. The objective of this study was to characterize these strains from Japan. METHODS: A total of 6433 MRSA strains isolated in Japan between 2015 and 2021 were analysed. Molecular epidemiological and comparative genomic analyses were conducted on PVL- and TSST-1-positive MRSA strains. RESULTS: A total of 26 strains from 12 healthcare facilities were PVL positive and TSST-1 positive, and all were classified as clonal complex (CC) 22. These strains exhibited similar genetic features to each other and were named as ST22-PT according to a previous report. Twelve and one of the ST22-PT strains were identified in patients with deep-seated skin infections and toxic shock syndrome-like symptoms, which are typical clinical features of PVL-positive and TSST-1-positive Staphylococcus aureus, respectively. Whole-genome comparative analysis revealed that the ST22-PT strains were highly similar to PVL- and TSST-1-positive CC22 strains isolated in several countries. Evaluation of the genome structure showed that ST22-PT possessed ΦSa2 harbouring PVL genes and a unique S. aureus pathogenicity island harbouring the TSST-1 gene. CONCLUSIONS: ST22-PT strains have recently emerged from several healthcare facilities in Japan, and ST22-PT-like strains have been identified in several countries. Our report highlights that the risk of international spread of PVL- and TSST-1-positive MRSA clone ST22-PT needs to be further investigated.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Shock, Septic , Staphylococcal Infections , Humans , Staphylococcus aureus , Leukocidins/genetics , Exotoxins/genetics , Staphylococcal Infections/epidemiologyABSTRACT
Synaptic dysfunction caused by soluble ß-amyloid peptide (Aß) is a hallmark of early-stage Alzheimer's disease (AD), and is tightly linked to cognitive decline. By yet unknown mechanisms, Aß suppresses the transcriptional activity of cAMP-responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that Aß elicits nucleocytoplasmic trafficking of Jacob, a protein that connects a NMDA-receptor-derived signalosome to CREB, in AD patient brains and mouse hippocampal neurons. Aß-regulated trafficking of Jacob induces transcriptional inactivation of CREB leading to impairment and loss of synapses in mouse models of AD. The small chemical compound Nitarsone selectively hinders the assembly of a Jacob/LIM-only 4 (LMO4)/ Protein phosphatase 1 (PP1) signalosome and thereby restores CREB transcriptional activity. Nitarsone prevents impairment of synaptic plasticity as well as cognitive decline in mouse models of AD. Collectively, the data suggest targeting Jacob protein-induced CREB shutoff as a therapeutic avenue against early synaptic dysfunction in AD.
Subject(s)
Alzheimer Disease , Animals , Mice , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Mice, Transgenic , Neurons/metabolism , Synapses/metabolismSubject(s)
Bacterial Toxins , Community-Acquired Infections , Fasciitis, Necrotizing , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Fasciitis, Necrotizing/diagnosis , Fasciitis, Necrotizing/drug therapy , Japan , Exotoxins/genetics , Leukocidins/genetics , Staphylococcal Infections/diagnosis , Staphylococcal Infections/drug therapy , Anti-Bacterial Agents/therapeutic useABSTRACT
Coronal angular deformities of the lower limbs are common in young children with skeletal dysplasia . The guided growth technique has been applied to correct deformities in children, but there are few comprehensive reports on the effectiveness of the procedure in skeletal dysplasia. We reviewed 44 limbs of 22 patients with various types of skeletal dysplasias who underwent guided growth surgery. Fifteen varus and 29 valgus limbs were treated with 102 epiphysiodesis. The average age at surgery, at implant removal, and at the latest examination was 10.4 ± 3.6 years, 11.8 ± 3.7 years and 14.1 ± 4.4 years, respectively. The mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (mMPTA), lateral distal tibial angle (mLDTA) and mechanical axis deviation (MAD) were measured from standing anteroposterior radiographs of both lower limbs. The mLDTA, mMPTA and MAD were successfully improved after surgery. Moderate or severe deformities were observed in 100% of the varus and 83% of the valgus limbs preoperatively, whereas only 14% of the varus and 20% of the valgus limbs had residual deformities at the latest examination. Correction of deformities was limited in some older children. Fifteen limbs (34%) required repeated implantations due to recurrence or inverted deformity. The guided growth surgery is effective in correcting coronal angular deformities in children with skeletal dysplasia with a limited risk of complications. The timing of surgery and implant removal is critical in obtaining satisfactory correction and preventing recurrence or inverted deformities.
Subject(s)
Osteochondrodysplasias , Tibia , Adolescent , Child , Humans , Femur/diagnostic imaging , Femur/surgery , Femur/abnormalities , Lower Extremity/diagnostic imaging , Lower Extremity/surgery , Radiography , Retrospective Studies , Tibia/diagnostic imaging , Tibia/surgery , Tibia/abnormalitiesABSTRACT
BACKGROUND: Although factors associated with the antibody response to the BNT162b2 mRNA COVID-19 vaccine have been reported, psychological factors have not been examined. Depression or anxiety may affect vaccine reactions because these factors influence immune responses. This study aimed to determine whether psychological status at the time of vaccination predicts antibody responses. METHODS: A prospective observational study of the BNT162b2 mRNA COVID-19 vaccine response was carried out among individuals attending for an annual health check-up. Participants included 78 volunteers out of 80 hospital workers in Nagoya, Japan. No participants had been infected with COVID-19 and all gave written informed consent to participate in the study. Blood samples were obtained approximately 28 days after the second dose of the vaccine, and antibody titers of the SARS-CoV-2 spike protein were determined using the SARS-CoV-2 IgG II Quant assay. Participants completed the Japanese version of the hospital anxiety and depression scale (HADS) questionnaire, one day before both vaccinations. Participants also recorded any adverse reactions, such as body temperature and other side effects, every day for two weeks after each dose. The relationships between antibody titers and the predictive factors were analyzed using multiple linear regression analysis, with the antibody titers as the dependent variables, followed by univariate analysis. RESULTS: Multiple linear regression analysis revealed that no or excessive alcohol intake (p = 0.039), poor results from a health check-up (p = 0.011), a longer duration between the second dose and blood collection (p = 0.039), and increased degree of depressive symptoms (p = 0.041) were significant negative predictors of antibody titers, while body temperature one day after the second dose as a significant positive predictor of antibody titers (p < 0.0005). CONCLUSION: We identified that depressive symptoms just before the second dose of the BNT162b2 mRNA COVID-19 were an independent negative predictor of antibody responses, in addition to other factors. Our results highlight the importance of mental health at the time of vaccination to achieve the higher antibody responses necessary to acquire humoral immunity.