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BackgroundDelirium frequently affects the consciousness of the elderly, particularly those in hospitals. Evidence increasingly associates linking delirium history to an increased risk of dementia. However, most studies are limited in scope, focusing mainly on postoperative or intensive care units with small patient samples, which affects the broader applicability of their findings.AimsTo elucidate the precise incidence of delirium and the subsequent onset of dementia within whole inpatients. Additionally, we aimed to explore the correlation between the emergence of delirium during hospitalization and the subsequent manifestation of dementia.Design, setting, and participantsWe conducted a retrospective cohort analysis employing a decade-long electronic medical record dataset consisted of 261,123 patients in Osaka Medical and Pharmaceutical University Hospital. Key analyses were performed October 2022 to January 2023.Main outcomes and measuresThe primary outcome, dementia onset, was determined by prescriptions for the anti-dementia drugs donepezil, galantamine, memantine, or rivastigmine, which are approved for use in Japan.Results10,781 patients met the inclusion criteria. The median interval between the onset of dementia was 972.5 days for individuals without a history of delirium, whereas for those with a history of delirium, it was notably shorter at 592.5 days. This disparity culminated in a hazard ratio of 5.29 (95% confidence interval: 1.35-20.75) for subsequent dementia onset.Conclusions and relevanceThis investigation underscores the imperative significance of directing attention toward preventive measures against delirium during hospitalization, alongside the necessity of diligent monitoring and intervention for cognitive decline in patients who encounter delirium.

Abstract Background The purpose of this study was to examine two techniques for Carpal Tunnel Syndrome, mini-Open Carpal Tunnel Release (mini-OCTR) and Endoscopic Carpal Tunnel Release (ECTR), to compare their therapeutic efficacy. Methods Sixteen patients who underwent mini-OCTR in palmar incision and 17 patients who underwent ECTR in the wrist crease incision were included in the study. All patients presented preoperatively and at 1, 3, and 6 months postoperatively and were assessed with the Visual Analogue Scale (VAS) and the Disabilities of Arm, Shoulder and Hand Score (DASH). We also assessed the pain and cosmetic VAS of the entire affected hand or surgical wound, and the patient’s satisfaction with the surgery. Results In the objective evaluation, both surgical techniques showed improvement at 6 months postoperatively. The DASH score was significantly lower in the ECTR group (average = 3 months: 13.6, 6 months: 11.9) than in the mini-OCTR group (average = 3 months: 27.3, 6 months: 20.6) at 3 and 6 months postoperatively. Also, the pain VAS score was significantly lower in the ECTR group (average = 17.1) than in the mini-OCTR group (average = 36.6) at 3 months postoperatively. The cosmetic VAS was significantly lower in the ECTR group (average = 1 month: 15.3, 3 months: 12.2, 6 months: 5.41) than in the mini-OCTR group (average = 1 month: 33.3, 3 months: 31.2, 6 months: 24.8) at all time points postoperatively. Patient satisfaction scores tended to be higher in the ECTR group (average = 3.3) compared to the mini-OCTR group (average = 2.7). Conclusions ECTR in wrist increase incision resulted in better pain and cosmetic recovery in an early postoperative phase compared with mini-OCTR in palmar incision. Our findings suggest that ECTR is an effective technique for patient satisfaction.

Abstract This review focuses on the development of therapeutic interventions for Alzheimer's dementia. While established treatments targeted acetylcholine and NMDA receptors, there is a growing demand for innovative therapies as the aging population increases. The paper highlights the US Food and Drug Administration's approval of aducanumab (Aduhelm) and lecanemab (Leqembi), emphasizing the developmental status of new treatments. Specifically, it covers seven principal drugs in Phase III trials, detailing their mechanisms of action, clinical trial specifics in the United States and Japan, and the current status of regulatory applications. The review focuses on amyloid removal (donanemab), tau protein mitigation (E2814), drug repositioning (Semaglutide, GV1001), and disease‐modifying small molecules (fosgonimeton, hydralazine, masitinib). However, Gantenerumab and Solanezumab, unsuccessful in Phase III, are not covered. While the future approval status remains uncertain, we hope these drugs will offer beneficial therapeutic effects for potential dementia patients.

Abstract Background In chronic musculoskeletal pain patients, detection of sarcopenia is of significant clinical interest. Phase angle, which can be measured through bioelectrical impedance analysis (BIA), can detect sarcopenia; however, the evidence in chronic musculoskeletal pain patients is limited. This study aimed to assess the relationship between phase angle and sarcopenia in patients with chronic musculoskeletal pain. Our hypothesis was that phase angle would be a useful indicator to identify sarcopenia in patients with chronic musculoskeletal pain. Methods A total of 190 patients (51 men and 139 women) with chronic musculoskeletal pain were included in this retrospective cross-sectional study. Patient data of backgrounds, numeric rating scale score for pain, skeletal muscle index, and phase angle assessed using BIA were retrospectively reviewed. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia criteria 2019. Results A total of 51 patients (26.7%), including 10 men (19.6%) and 41 women (29.5%), were diagnosed with sarcopenia. Phase angle, sarcopenia-related factors, age, and body mass index (BMI) differed significantly in patients with and without sarcopenia. On multiple logistic regression analysis, the prevalence of sarcopenia was significantly correlated with phase angle and BMI. The areas under the curve exhibited high accuracy in discriminating sarcopenia in men and moderate accuracy in both sexes and in women. Conclusions Phase angle may be a valid discriminator of sarcopenia in patients with chronic musculoskeletal pain.

AimsThere are concerns regarding complications and longevity of total elbow arthroplasty (TEA) in young patients, and the few previous publications are mainly limited to reports on linked elbow devices. We investigated the clinical outcome of unlinked TEA for patients aged less than 50 years with rheumatoid arthritis (RA).MethodsWe retrospectively reviewed the records of 26 elbows of 21 patients with RA who were aged less than 50 years who underwent primary TEA with an unlinked elbow prosthesis. The mean patient age was 46 years (35 to 49), and the mean follow-up period was 13.6 years (6 to 27). Outcome measures included pain, range of motion, Mayo Elbow Performance Score (MEPS), radiological evaluation for radiolucent line and loosening, complications, and revision surgery with or without implant removal.ResultsThe mean MEPS significantly improved from 47 (15 to 70) points preoperatively to 95 (70 to 100) points at final follow-up (p < 0.001). Complications were noted in six elbows (23%) in six patients, and of these, four with an ulnar neuropathy and one elbow with postoperative traumatic fracture required additional surgeries. There was no revision with implant removal, and there was no radiological evidence of loosening around the components. With any revision surgery as the endpoint, the survival rates up to 25 years were 78.1% (95% confidence interval 52.8 to 90.6) as determined by Kaplan-Meier analysis.ConclusionThe clinical outcome of primary unlinked TEA for young patients with RA was satisfactory and comparable with that for elderly patients. A favourable survival rate without implant removal might support the use of unlinked devices for young patients with this disease entity, with a caution of a relatively high complication rate regarding ulnar neuropathy.Level of Evidence: Therapeutic Level IVCite this article: Bone Jt Open 2023;4(1):19–26.

Abstract Background Although drug treatment strategies for rheumatoid arthritis (RA) are relatively well established, there is a paucity of evidence on the treatment in older patients. The purpose of this study is to build a registry for late-onset RA (LORA), which is expected to increase rapidly worldwide. In addition, we aim to propose optimal treatment strategies according to the patient background including frailty, thereby contributing to improving the quality of treatment and daily living in patients with RA. Methods/design The LORIS (Late-onset Rheumatoid Arthritis Registry) Study is a prospective nation-wide multicenter observational study of patients with LORA. The inclusion criteria were patients aged ≥ 65 years at onset, meeting 2010 ACR/EULAR classification criteria for RA, and starting either any disease-modifying antirheumatic drugs (DMARDs) in a DMARD-naïve patient or the first biologic/targeted synthetic DMARDs during the study period. Enrollment was started on 11 January, 2022 and will be closed on 31 December, 2023. Patients will undergo a comprehensive baseline assessment including clinical data, medication, cognitive and physical function, psychosocial factors, and frailty. Data will be collected at baseline, Month 3, 6, 12, 18, 24, 36, and summarized descriptively. The factors associated with adverse events and achieving remission will be determined. Discussion A multi-disciplinary panel including patients, rheumatologists, and geriatric specialists will discuss the results and build a consensus regarding the treatment goals of LORA. We expect to provide a broad range of information for evidence-based shared decision making in the treatment of LORA. Study registration: Registered at the UMIN registry (UMIN000046086) on 1 January 2022.

We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain (COL2A1), aggrecan (ACAN), SRY-box9 (SOX9), TNKS-1/2, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and matrix metalloproteinase-13 (MMP-13) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and β-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1β in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1β, as well as the nuclear translocation of NF-κB and β-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of β-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis.

Abstract Transcranial direct current stimulation (tDCS) have revealed the capability to augment various types of behavioural interventions. We aimed to augment the effects of mindfulness, suggested for reducing anxiety, with concurrent use of tDCS. We conducted a double-blind randomized study with 58 healthy individuals. We introduced treadmill walking for focused meditation and active or sham tDCS on the left dorsolateral prefrontal cortex for 20 min. We evaluated outcomes using State-Trait Anxiety Inventory-State Anxiety (STAI) before the intervention as well as immediately, 60 min, and 1 week after the intervention, and current density from electroencephalograms (EEG) before and after the intervention. The linear mixed-effect models demonstrated that STAI-state anxiety showed a significant interaction effect between 1 week after the intervention and tDCS groups. As for alpha-band EEG activity, the current density in the rostral anterior cingulate cortex (rACC) was significantly reduced in the active compared with the sham stimulation group, and a significant correlation was seen between changes in STAI-trait anxiety and the current density of the rACC in the active stimulation group. Our study provided that despite this being a one-shot and short intervention, the reduction in anxiety lasts for one week, and EEG could potentially help predict its anxiolytic effect.

Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.

Purpose We investigated objective and patient-reported outcomes after resection arthroplasty or shortening oblique osteotomy (SOO) of the lesser metatarsals combined with arthrodesis of the first metatarsophalangeal (MTP) joint for severe rheumatoid forefoot deformities. Methods 17 feet from 14 women (mean age, 67.8 years) underwent resection arthroplasty of the lesser metatarsal heads (MTH resection group), while 13 feet from nine women and two men (mean age, 68.7 years) underwent SOO of the lesser metatarsals (MTH preservation group). Arthrodesis of the first MTP joint was performed in all cases. Mean follow-up in the MTH resection and preservation groups was 25.0 and 21.3 months, respectively. Preoperative and postoperative clinical evaluation included Japanese Society for Surgery of the Foot (JSSF) scale and self-administered foot evaluation questionnaire (SAFE-Q) scores. Results Mean total JSSF scale significantly improved from 53.4 to 76.4 in the MTH resection group ( p < .001) and from 50.1 to 74.2 in the MTH preservation group ( p = .002). Pain and pain-related and shoe-related SAFE-Q subscale scores significantly improved after surgery in both groups. In the MTH resection group, recurrence of painful callosities and claw toe deformity was observed in four and three feet, respectively. In the MTH preservation group, one patient experienced recurrence of painful callosities and one underwent revision surgery for IP joint dislocation. Conclusion Resection arthroplasty or SOO of the lesser metatarsals combined with arthrodesis of the first MTP joint achieved significant improvement with respect to pain relief, deformity correction, and footwear comfort.

Abstract Background Mirogabalin, which is approved for the treatment of peripheral neuropathic pain in Japan, is a ligand for the α2δ subunit of voltage-gated calcium channels. Both pregabalin and mirogabalin act as nonselective ligands at the α2δ-1 and α2δ-2 subunits. Mirogabalin has a unique binding profile and long duration of action. Pregabalin has been reported to produce intolerable adverse effects in some patients. This study investigated outcomes associated with mirogabalin administration in patients with peripheral neuropathic pain who ceased treatment with pregabalin. Methods We retrospectively assessed peripheral neuropathic pain using the neuropathic pain screening questionnaire (NeP score) in 187 patients (58 men, 129 women) who were treated with mirogabalin. All patients had switched from pregabalin to mirogabalin due to lack of efficacy or adverse events. Differences in the treatment course (i.e., numeric rating scale (NRS) scores) were compared using one-way analysis of variance with Bonferroni post hoc tests. Results The mean age of the patients was 72.3 years (range, 30–94 years), and the mean duration of disease was 37 months (range, 3–252 months). After treatment with mirogabalin for 1 week, NRS scores significantly decreased compared with baseline and continued to decrease over time. After 8 weeks, NRS scores improved by ≥ 30% from baseline in 113 patients (69.3%). Twenty-four patients (12.8%) stopped mirogabalin treatment due to adverse events. Somnolence (26.7%), dizziness (12.3%), edema (5.9%), and weight gain (0.5%) were noted as adverse events of mirogabalin. Conclusions The results of this investigation indicate that mirogabalin is safe and effective for reducing peripheral neuropathic pain.

Abstract Background To reveal trends in bone microarchitectural parameters with increasing spatial resolution on ultra-high-resolution computed tomography (UHRCT) in vivo and to compare its performance with that of conventional-resolution CT (CRCT) and micro-CT ex vivo. Methods We retrospectively assessed 5 tiger vertebrae ex vivo and 16 human tibiae in vivo. Seven-pattern and four-pattern resolution imaging were performed on tiger vertebra using CRCT, UHRCT, and micro-CT, and on human tibiae using UHRCT. We measured six microarchitectural parameters: volumetric bone mineral density (vBMD), trabecular bone volume fraction (bone volume/total volume, BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), and connectivity density (ConnD). Comparisons between different imaging resolutions were performed using Tukey or Dunnett T3 test. Results The vBMD, BV/TV, Tb.N, and ConnD parameters showed an increasing trend, while Tb.Sp showed a decreasing trend both ex vivo and in vivo. Ex vivo, UHRCT at the two highest resolutions (1024- and 2048-matrix imaging with 0.25-mm slice thickness) and CRCT showed significant differences (p ≤ 0.047) in vBMD (51.4 mg/cm3 and 63.5 mg/cm3 versus 20.8 mg/cm3), BV/TV (26.5% and 29.5% versus 13.8 %), Tb.N (1.3 l/mm and 1.48 l/mm versus 0.47 l/mm), and ConnD (0.52 l/mm3 and 0.74 l/mm3 versus 0.02 l/mm3, respectively). In vivo, the 512- and 1024-matrix imaging with 0.25-mm slice thickness showed significant differences in Tb.N (0.38 l/mm versus 0.67 l/mm, respectively) and ConnD (0.06 l/mm3 versus 0.22 l/mm3, respectively). Conclusions We observed characteristic trends in microarchitectural parameters and demonstrated the potential utility of applying UHRCT for microarchitectural analysis.

Abstract Background The fear-avoidance model is a theoretical paradigm for explaining acute and chronic pain. In this model, pain catastrophizing plays an important role. On the other hand, self-efficacy influences whether patients view their pain optimistically, ultimately preventing the conversion of pain into intractable pain. The aim of the present study was to evaluate the factors that influence self-efficacy in patients with chronic pain. Methods Study participants included 147 outpatients (35 men, 112 women) with intractable chronic pain who visited our hospital between September 2014 and July 2015. Their mean age was 71.0 (range 32–92) years. Pain sites were as follows: low back, 97 patients; knee, 71 patients; shoulder, 34 patients; and hip, 15 patients. All patients were assessed using the following measures: Numeric Rating Scale (NRS), Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS), Pain Disability Assessment Scale (PDAS), and Pain Self-Efficacy Questionnaire (PSEQ). All participants were further divided into two groups based on median PSEQ scores (group L: PSEQ of 35 points or less, n = 74; group H: PSEQ greater than 35 points, n = 73). The factors that influenced self-efficacy in these patients were analyzed using univariate and multiple linear regression analyses. Results Significant differences were observed in gender; pain duration; and NRS, PDAS, HADS, and PCS scores between group L and group H. Multiple linear regression analysis revealed that self-efficacy was correlated with PDAS score, HADS depression score, and pain duration. Conclusions Patients with longer pain duration indicated greater self-efficacy and patients with higher pain disability and depression exhibited lower self-efficacy.

We investigated the expression and localization of the receptor activator nuclear factor κB ligand (RANKL) in cartilage from patients with rheumatoid arthritis (RA) of relevance to cartilage degeneration. We also examined the role of exogenous lymphotoxin (LT)-α on RANKL expression in human chondrocytes and its effect on in vitro osteoclast differentiation. Cartilage and synovial fluid samples were obtained from 45 patients undergoing total joint replacement surgery or joint puncture, including 24 patients with osteoarthritis (OA) and 21 patients with RA. RANKL expression in articular cartilage was examined by immunohistochemistry. LT-α concentrations in synovial fluid were measured using an enzyme-linked immunosorbent assay (ELISA). Normal human chondrocytes were stimulated with LT-α, and the relative mRNA levels of RANKL, osteoprotegerin (OPG), matrix metalloproteinase-9, and vascular endothelial growth factor were examined by real-time polymerase chain reaction. Soluble RANKL protein in culture media was measured using ELISA, and membrane-bound RANKL protein in cells was examined by western blotting. Co-cultures of human chondrocytes with peripheral blood mononuclear cells (PBMCs) were stimulated with macrophage-colony stimulating factor and LT-α, and osteoclast differentiation was evaluated by staining for tartrate-resistant acid phosphatase. LT-α concentrations were higher in RA synovial fluid than in OA samples. The population of RANKL-positive chondrocytes of RA cartilage was higher than that of OA cartilage, and correlated with cartilage degeneration. Stimulation of cultured human chondrocytes by LT-α increased RANKL expression, the RANKL/OPG ratio, and angiogenic factors. Membrane-bound RANKL in chondrocytes was up-regulated after stimulation of LT-α, whereas soluble RANKL in culture medium did not increase. Co-cultures of human chondrocytes and PBMCs demonstrated that LT-α stimulated human chondrocytes to produce RANKL and induced osteoclastic differentiation of PBMCs. RANKL produced by chondrocytes may contribute to cartilage destruction during RA and LT-α could promote the expression of RANKL in human chondrocytes.

Major depressive disorder (MDD) is a life-impairing disorder, and early successful treatment is important for a favorable prognosis. However, early response to antidepressants differs widely among individuals, and is difficult to predict pre-treatment. As miRNAs have been reported to play important roles in depression, identification of miRNAs associated with antidepressant treatment responses and their interacting genes and pathways will be beneficial in understanding the predictors and molecular mechanisms of depression treatment. This randomized control trial examined miRNAs correlated with the early therapeutic effect of selective serotonin reuptake inhibitors (SSRIs; paroxetine or sertraline) and mirtazapine monotherapy. Before medication, we comprehensively analyzed the miRNA expression of 92 depressed participants and identified genes and pathways interacting with miRNAs. A total of 228 miRNAs were significantly correlated with depressive symptoms improvements after 2 weeks of SSRIs treatment, with miR-483.5p showing the most robust correlation. These miRNAs are involved in 21 pathways, including TGF-β, glutamatergic synapse, long-term depression, and the mitogen-activated protein kinase (MAPK) signaling pathways. Using these miRNAs enabled us to predict SSRI response at week 2 with a 57% difference. This study shows that pre-treatment levels of miRNAs could be used to predict early responses to antidepressant administration, a knowledge of genes, and an identification of genes and pathways associated with the antidepressant response.

We investigated the effects of adipose-derived extract (AE) on cultured chondrocytes and in vivo cartilage destruction. AE was prepared from human adipose tissues using a nonenzymatic approach. Cultured human chondrocytes were stimulated with interleukin-1 beta (IL-1β) with or without different concentrations of AE. The effects of co-treatment with AE on intracellular signaling pathways and their downstream gene and protein expressions were examined using real-time PCR, Western blotting, and immunofluorescence staining. Rat AE prepared from inguinal adipose tissues was intra-articularly delivered to the knee joints of rats with experimental osteoarthritis (OA), and the effect of AE on cartilage destruction was evaluated histologically. In vitro, co-treatment with IL-1β combined with AE reduced activation of the p38 and ERK mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-κB), and subsequently downregulated the expressions of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, IL-6, and IL-8, whereas it markedly upregulated the expression of IL-1 receptor type 2 (IL-1R2) in chondrocytes. Intra-articular injection of homologous AE significantly ameliorated cartilage destruction six weeks postoperatively in the rat OA model. These results suggested that AE may exert a chondroprotective effect, at least in part, through modulation of the IL-1β-induced inflammatory signaling pathway by upregulation of IL-1R2 expression.

Study DesignRetrospective analysis using magnetic resonance imaging (MRI).PurposeTo identify MRI features that could discriminate benign from malignant vertebral fractures.Overview of LiteratureDiscrimination between benign and malignant vertebral fractures remains challenging, particularly in patients with osteoporosis and cancer. Presently, the most sensitive means of detecting and assessing fracture etiology is MRI. However, published reports have focused on only one or a few discriminators.MethodsTotally, 106 patients were assessed by MRI within six weeks of sustaining 114 thoracic and/or lumbar vertebral fractures (benign, n=65; malignant, n=49). The fractures were pathologically confirmed if malignant or clinically diagnosed if benign and were followed up for a minimum of six months. Seventeen features were analyzed in all fractures' magnetic resonance images. Single parameters were analyzed using the chi-square test; a logit model was established using multivariate logistic regression analysis.ResultsThe chi-square test revealed 11 malignant and 4 benign parameters. Multivariate logistic regression analysis selected (i) posterior wall diffuse protrusion (odds ratio [OR], 48; 95% confidence interval [CI], 4.2–548; p=0.002), (ii) pedicle involvement (OR, 21; 95% CI, 2.0–229; p=0.01), (iii) posterior involvement (OR, 21; 95% CI, 1.5–21; p=0.02), and (iv) band pattern (OR, 0.047; 95% CI, 0.0005–4.7; p=0.19). The logit model was expressed as P=1/[1+exp (x)], x=−3.88×(i)−3.05×(ii)−3.02×(iii)+3.05×(iv)+5.00, where P is the probability of malignancy. The total predictive value was 97.3%. The only exception was multiple myeloma with features of a benign fracture.ConclusionsAlthough each MRI feature had a different meaning with a variable differentiation power, combining them led to an accurate diagnosis. This study identified the most relevant MRI features that would be helpful in discriminating benign from malignant vertebral fractures.

Objectives: The aim of this paper is to investigate cortical electric neuronal activity as an indicator of brain function, in a mental arithmetic task that requires sustained attention, as compared to the resting state condition. The two questions of interest are the cortical localization of different oscillatory activities, and the directional effective flow of oscillatory activity between regions of interest, in the task condition compared to resting state. In particular, theta and alpha activity are of interest here, due to their important role in attention processing. Methods: We adapted mental arithmetic as an attention ask in this study. Eyes closed 61-channel EEG was recorded in 14 participants during resting and in a mental arithmetic task (“serial sevens subtraction”). Functional localization and connectivity analyses were based on cortical signals of electric neuronal activity estimated with sLORETA (standardized low resolution electromagnetic tomography). Functional localization was based on the comparison of the cortical distributions of the generators of oscillatory activity between task and resting conditions. Assessment of effective connectivity was based on the iCoh (isolated effective coherence) method, which provides an appropriate frequency decomposition of the directional flow of oscillatory activity between brain regions. Nine regions of interest comprising nodes from the dorsal and ventral attention networks were selected for the connectivity analysis. Results: Cortical spectral density distribution comparing task minus rest showed significant activity increase in medial prefrontal areas and decreased activity in left parietal lobe for the theta band, and decreased activity in parietal-occipital regions for the alpha1 band. At a global level, connections among right hemispheric nodes were predominantly decreased during the task condition, while connections among left hemispheric nodes were predominantly increased. At more detailed level, decreased flow from right inferior frontal gyrus to anterior cingulate cortex for theta, and low and high alpha oscillations, and increased feedback (bidirectional flow) between left superior temporal gyrus and left inferior frontal gyrus, were observed during the arithmetic task. Conclusions: Task related medial prefrontal increase in theta oscillations possibly corresponds to frontal midline theta, while parietal decreased alpha1 activity indicates the active role of this region in the numerical task. Task related decrease of intracortical right hemispheric connectivity support the notion that these nodes need to disengage from one another in order to not interfere with the ongoing numerical processing. The bidirectional feedback between left frontal-temporal-parietal regions in the arithmetic task is very likely to be related to attention network working memory function. Significance: The methods of analysis and the results presented here will hopefully contribute to clarify the roles of the different EEG oscillations during sustained attention, both in terms of their functional localization and in terms of how they integrate brain function by supporting information flow between different cortical regions. The methodology presented here might be clinically relevant in evaluating abnormal attention function. Keywords: Quantitative EEG, sLORETA, iCoh, Directional connectivity, Frontal midline theta, Attention network, Mental arithmetic, Fronto-parietal network, Directional flow, Attention task, Granger causality

Transcranial direct current stimulation is a promising neuromodulation method for treating depression. However, compared with pharmacological treatment, previous studies have reported that a relatively limited proportion of patients respond to tDCS treatment. In addition, the neurophysiological mechanisms underlying tDCS treatment remain unclear, making it difficult to identify response predictors for tDCS treatment based on neurophysiological function. Because treatment effects are achieved by repetitive application of tDCS, studying the immediate effects of tDCS in depressive patients could extend understanding of its treatment mechanisms. However, immediate changes in a single session of tDCS are not well documented. Thus, in the current study, we focused on the immediate impact of tDCS and its association with pre-stimulus brain activity. To address this question, we applied anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC) or dorsomedial prefrontal cortex (DMPFC) in 14 patients with major depressive disorder (MDD) and 19 healthy controls (HCs), at an intensity of 1.0 mA for 20 min in a single session. To evaluate anxiety, the state trait anxiety inventory was completed before and after tDCS. We recorded resting electroencephalography before tDCS, and calculated electrical neuronal activity in the theta and alpha frequency bands using standardized low-resolution electromagnetic tomography. We found that, during application of left DLPFC tDCS to patients with MDD, the anxiety reduction effect of tDCS was related to higher baseline theta-band activity in the rostral anterior cingulate cortex (rACC) and no medication with benzodiazepine used as hypnotic. For DMPFC stimulation in MDD, the anxiety reduction effect was associated with lower baseline alpha-band activity in the left inferior parietal lobule. In contrast, in HCs, the anxiety reduction effect was associated with higher baseline alpha activity in the precuneus during DMPFC stimulation. The current results suggest that the association between pre-tDCS brain activity and the anxiety reduction effect of tDCS depends on psychopathology (depressed or non-depressed) as well as the site of stimulation (DMPFC or left DLPFC) and insomnia. Furthermore, the results suggest that tDCS response might be associated with baseline resting state electrophysiological neural activity.

In patients with osteoarthritis (OA), there is a decrease in both the concentration and molecular size of hyaluronan (HA) in the synovial fluid and cartilage. Cell migration-inducing hyaluronidase 1 (CEMIP), also known as hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), was recently reported as an HA depolymerization-related molecule expressed in the cartilage of patients with OA. However, the underlying mechanism of CEMIP regulation is not well understood. We found that CEMIP expression was transiently increased by interleukine-1β (IL-1β) stimulation in chondrocytic cells. We also observed that ERK activation and NF-κB nuclear translocation were involved in the induction of CEMIP by IL-1β. In addition, both administration of HA and mechanical strain attenuated the CEMIP induction in IL-1β-stimulated chondrocytes. In conclusion, we clarified the regulatory mechanism of CEMIP in chondrocytes by inflammatory cytokines and suggested the potential involvement in osteoarthritis development.

Background: Alzheimer's disease (AD) is affected by apolipoprotein E (ApoE); however, its effects assessed by means of cognitive tests and by neuroimaging have not been sufficiently studied. Methods: We administered the Alzheimer's Disease Assessment Scale (ADAS) and single-photon emission computed tomography imaging in patients with AD medicated with donepezil at baseline and after 1 year. Patients were classified as with or without ApoE4 and we evaluated the progress of AD. Results: Analysis of covariance showed that cerebral blood flow after 1 year in subjects with ApoE4 is significantly reduced in some areas including the left lenticular nucleus, left thalamus, and right hippocampus compared with subjects without ApoE4. Paired t tests showed significantly reduced blood flow in several regions including the right hippocampus in subjects with ApoE4 and significant deterioration of ideational praxis in subjects without ApoE4. Conclusion: This study provides evidence that supports the notion of ApoE4 playing an important role in the progress of AD.

Background. The contribution of apathy, frequently recognized in individuals with neurodegenerative diseases, to chronic low back pain (LBP) remains unclear. Objectives. To investigate levels of apathy and clinical outcomes in patients with chronic LBP treated with tramadol-acetaminophen. Methods. A retrospective case-control study involving 73 patients with chronic LBP (23 male, 50 female; mean age 71 years) treated with tramadol-acetaminophen (n=36) and celecoxib (n=37) was performed. All patients were assessed using the self-reported questionnaires. A mediation model was constructed using a bootstrapping method to evaluate the mediating effects of pain relief after treatment. Results. A total of 35 (55.6%) patients met the criteria for apathy. A four-week treatment regimen in the tramadol group conferred significant improvements in the Apathy scale and numerical rating scale but not in the Rolland-Morris Disability Questionnaire, Pain Disability Assessment Scale, or Pain Catastrophizing Scale. The depression component of the Hospital Anxiety and Depression Scale was lower in the tramadol group than in the celecoxib group. The mediation analysis found that the impact of tramadol-acetaminophen on the change in apathy was not mediated by the pain relief. Conclusions. Tramadol-acetaminophen was effective at reducing chronic LBP and conferred a prophylactic motivational effect in patients with chronic LBP.

C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with β2-glycoprotein I (β2GPI), implicating oxLDL/β2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/β2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/β2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and β2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of atherosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/β2GPI complexes correlated with total cholesterol and hemoglobin A1c. Thus, the generation of CRP/oxLDL/β2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/β2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis.

SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model.CIA was induced in wild-type (Sh3bp2(+/+)) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2(KI/+)) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-α production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures.Sh3bp2(KI/+) mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-α and osteoclast marker genes were higher in the joints of Sh3bp2(KI/+) mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-γ and IL-17 production were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) mice. In vitro experiments showed that TNF-α production in Sh3bp2(KI/+) BMMs is elevated compared with Sh3bp2(+/+) BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2(KI/+) BMMs associated with increased NFATc1 nuclear localization.Gain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis.

Objectives: To report 24-week safety and effectiveness of certolizumab pegol (CZP) in Japanese patients with rheumatoid arthritis from a post-marketing surveillance study. Methods: Enrolled patients were newly receiving CZP. All adverse events (AEs) and adverse drug reactions (ADRs) were recorded for patients who received ≥1 CZP dose. Effectiveness outcomes included: 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) and European Alliance of Associations for Rheumatology (EULAR) response. Missing data were imputed using the last observation carried forward. Results: 3727 patients were enrolled; safety and effectiveness were evaluated in 3586 and 1794 patients, respectively. 24.9% of patients reported AEs (893/3586), 14.7% reported ADRs (528/3586), 8.3% (298/3586) reported serious AEs and 5.3% (190/3586) reported serious ADRs. Selected serious ADRs of interest: infections (110; 3.1%), tuberculosis (6; 0.2%), interstitial pneumonia (15; 0.4%), malignancy (8; 0.2%), and hepatic function disorder (7; 0.2%). No allergic reactions, autoimmune disease, cardiac failure, demyelinating diseases, or pancytopenia were reported. Mean DAS28-ESR reduced from 4.8 (baseline) to 3.4 (final evaluation). At final evaluation, 34.7% of patients achieved EULAR good response. Conclusions: These real-world safety and effectiveness results were consistent with previously reported data, with no new safety signals identified. Long-term, real-world CZP safety and effectiveness data are needed. [ABSTRACT FROM AUTHOR]