Primary tumor-induced immunity suppresses bone metastases of breast cancer in syngeneic immunocompetent mouse models.

The immune system plays a crucial role in cancer development and progression. More than a century ago, mouse models showed that primary tumors suppressed the growth of newly implanted secondary tumors. This phenomenon, in which tumor-primed T cells mediate the rejection of tumor growth at a distant site, is known as concomitant tumor immunity. Here, we investigated the role of concomitant immunity in the development of breast cancer bone metastases using newly developed syngeneic immunocompetent mouse models. The presence of primary breast tumors developed by tumor cell injection into the mammary fat pads (MFPs) significantly reduced bone metastases of mouse breast cancer 4T1 and EMT6 cells induced by cell injection through the caudal artery (CA). Similar results were obtained when primary tumors were surgically resected prior to CA injection of tumor cells. In contrast, no inhibition was found when MFP and CA injections were performed using different cell combinations. Immunohistochemical studies revealed that the number of CD8+ T cells in bone metastases of 4T1 and EMT6 cells was significantly increased in the presence of primary tumors. The primary tumor-induced inhibition of bone metastases was not reproduced in T cell-deficient athymic nude mice. Furthermore, depletion of CD8+ T cells using an anti-CD8α antibody also abolished the primary tumor-induced inhibition of bone metastases. Taken together, these results suggest that immune cell priming by orthotopic breast tumors inhibits the development of breast cancer bone metastases, which is predominantly mediated by CD8+ cytotoxic T lymphocytes.

Long-term Observation in Patients with Duchenne Muscular Dystrophy with Early Introduction of a Standing Program Using Knee-ankle-foot Orthoses.

Objectives: This study investigated the outcomes of the early introduction of a standing program for patients with Duchenne muscular dystrophy (DMD). Methods: This was a retrospective observational study of 41 outpatients with DMD aged 15-20 years. We introduced the standing program using knee-ankle-foot orthoses (KAFO) to slow the progression of scoliosis when ankle dorsiflexion became less than 0° in the ambulatory period. Results: Thirty-two patients with DMD were offered the standing program with KAFO; 12 continued the program until the age of 15 years (complete group) and 20 discontinued the program before the age of 15 years (incomplete group). The non-standing program group included 9 patients. The standing program with KAFO was significantly associated with the Cobb angle at the age of 15 years after adjustment for the duration of corticosteroid use and DMD mutation type (P=0.0004). At the age of 15 years, significant correlations were found between the ankle dorsiflexion range of motion (ROM) and non-ambulatory period (P=0.0010), non-ambulatory period and Cobb angle (P<0.0001), Cobb angle and percent predicted forced vital capacity (P=0.0004), and ankle dorsiflexion ROM and Cobb angle (P=0.0066). In the complete group, the age at ambulation loss (log-rank P=0.0015), scoliosis progression (log-rank P=0.0032), and pulmonary dysfunction (log-rank P=0.0006) were significantly higher than in the non-standing program group. Conclusions: The early introduction of a standing program for DMD patients may prolong the ambulation period and slow the progression of scoliosis and pulmonary dysfunction.

Risk factors for intolerance of oral 5-aminosalicylic acid preparations in pediatric ulcerative colitis.

BACKGROUND: No previous study of Japanese children with ulcerative colitis (UC) has reported the risk factors for intolerance of 5-aminosalicylic acid (5-ASA). We aimed to identify risk factors for intolerance of oral 5-ASA preparations in pediatric UC. METHODS: Patients with childhood-onset UC who were seen at our hospital between November 2003 and March 2020 were investigated. Intolerance of 5-ASA was defined as having clinical symptoms (pyrexia, abdominal pain, diarrhea, bloody stool) that worsened after starting oral administration of 5-ASA and improved after discontinuation of 5-ASA. Patient sex, age, body size, laboratory data, pediatric UC activity index scores, and colonoscopy-based determinations of the extent and severity of the affected lesion at initiation of 5-ASA of intolerant and tolerant groups were compared. RESULTS: Fifteen patients were in the intolerant group, and 37 were in the tolerant group. The leukocyte count, C-reactive protein level, and erythrocyte sedimentation rate were significantly higher in the intolerant group than the tolerant group; the albumin level in the intolerant group was significantly lower. All intolerant patients and 68% of tolerant patients had pancolitis (Paris classification E4). Patients with a large, affected area (Paris classifications E3 and E4) more frequently had intolerance to 5-ASA than patients with a small lesion. The cumulative Mayo endoscopic subscore (cMES), which is the sum of MES scores for six regions of the large intestine, was significantly higher in the intolerant group. CONCLUSIONS: Pediatric UC patients with more intense inflammation and a large lesion could have an increased risk of intolerance for 5-ASA.

Electrically Induced Sensory Trick in a Patient with Musician's Dystonia: A Case Report.

A sensory trick is a specific maneuver that temporarily improves focal dystonia. We describe a case of musician's dystonia in the right-hand fingers of a patient, who showed good and immediate improvement after using an electrical stimulation-mimicking sensory trick. A 49-year-old professional guitarist presented with chronic involuntary flexion of the right-hand third and fourth fingers that occurred during guitar performances. Electrical stimulation with a frequency of 40 Hz and an intensity of 1.5 times the sensory threshold was administered on the third and fourth fingernails of the right hand, which facilitated fluent guitar playing. While he played guitar with and without electrical stimulation, we measured the surface electromyograms (sEMG) of the right extensor digitorum and flexor digitorum superficialis muscles to evaluate the sensory-trick-like effects of electrical stimulation. This phenomenon can offer clues for developing electrical stimulation-based treatment devices for focal dystonia. Electrical stimulation has the advantage that it can be turned off to avoid habituation. Moreover, the device is easy to use and portable. These findings warrant further investigation into the use of sensory stimulation for treating focal dystonia.

Expert consensus on vaccination in patients with inflammatory bowel disease in Japan.

Immunosuppressive therapies can affect the immune response to or safety of vaccination in patients with inflammatory bowel disease (IBD). The appropriateness of vaccination should be assessed prior to the initiation of IBD treatment because patients with IBD frequently undergo continuous treatment with immunosuppressive drugs. This consensus was developed to support the decision-making process regarding appropriate vaccination for pediatric and adult patients with IBD and physicians by providing critical information according to the published literature and expert consensus about vaccine-preventable diseases (VPDs) [excluding cervical cancer and coronavirus disease 2019 (COVID-19)] in Japan. This consensus includes 19 important clinical questions (CQs) on the following 4 topics: VPDs (6 CQs), live attenuated vaccines (2 CQs), inactivated vaccines (6 CQs), and vaccination for pregnancy, childbirth, and breastfeeding (5 CQs). These topics and CQs were selected under unified consensus by the members of a committee on intractable diseases with support by a Health and Labour Sciences Research Grant. Physicians should provide necessary information on VPDs to their patients with IBD and carefully manage these patients' IBD if various risk factors for the development or worsening of VPDs are present. This consensus will facilitate informed and shared decision-making in daily IBD clinical practice.

Neural correlates of spatial attention bias: Changes in functional connectivity in attention networks associated with tDCS.

The prevailing theory concerning the pathophysiology of unilateral spatial neglect is that it is caused by an interhemispheric imbalance in attention networks. Previous studies have demonstrated that repetitive transcranial magnetic stimulation or transcranial direct current stimulation (tDCS) delivered over the right posterior parietal cortex can induce transitory neglect-like deficits in healthy individuals. We examined whether right cathodal and left anodal tDCS delivered over the posterior parietal cortex could produce neglect-like deficits and change the resting-state functional connectivity (rsFC) of attention networks. We found that the reaction time for targets in the left hemifield was significantly prolonged during two different types of visual search tasks, and rsFC of the attention networks was altered by tDCS. Furthermore, the change in the reaction times for the left visual target in the two different tasks significantly correlated with the change in the rsFC of either the right dorsal attention network (DAN) or right ventral attention network (VAN) based on the tasks. These results suggest that tDCS delivered to the posterior parietal cortex bilaterally induced neglect-like deficits by altering the connectivity of the attentional networks through excitability changes in the cortical area under the electrode. The results of this study are consistent with the hypothesis that the cause of neglect is the interhemispheric imbalance of attention networks. This is the first study to demonstrate that local cortical stimulation can induce changes not only in the local brain function but also in the cortical networks in healthy individuals.

Assessment of type I interferon signatures in undifferentiated inflammatory diseases: A Japanese multicenter experience.

Purpose: Upregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature. Methods: The type I IFN signature was measured in patients' whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature. Results: A total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling. Conclusions: Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.

A simplified prediction model for end-stage kidney disease in patients with diabetes.

This study aimed to develop a simplified model for predicting end-stage kidney disease (ESKD) in patients with diabetes. The cohort included 2549 individuals who were followed up at Kyushu University Hospital (Japan) between January 1, 2008 and December 31, 2018. The outcome was a composite of ESKD, defined as an eGFR < 15 mL min-1 [1.73 m]-2, dialysis, or renal transplantation. The mean follow-up was 5.6 [Formula: see text] 3.7 years, and ESKD occurred in 176 (6.2%) individuals. Both a machine learning random forest model and a Cox proportional hazard model selected eGFR, proteinuria, hemoglobin A1c, serum albumin levels, and serum bilirubin levels in a descending order as the most important predictors among 20 baseline variables. A model using eGFR, proteinuria and hemoglobin A1c showed a relatively good performance in discrimination (C-statistic: 0.842) and calibration (Nam and D'Agostino [Formula: see text]2 statistic: 22.4). Adding serum albumin and bilirubin levels to the model further improved it, and a model using 5 variables showed the best performance in the predictive ability (C-statistic: 0.895, [Formula: see text]2 statistic: 7.7). The accuracy of this model was validated in an external cohort (n = 5153). This novel simplified prediction model may be clinically useful for predicting ESKD in patients with diabetes.

Piezo1-pannexin-1-P2X3 axis in odontoblasts and neurons mediates sensory transduction in dentinal sensitivity.

According to the "hydrodynamic theory," dentinal pain or sensitivity is caused by dentinal fluid movement following the application of various stimuli to the dentin surface. Recent convergent evidence in Vitro has shown that plasma membrane deformation, mimicking dentinal fluid movement, activates mechanosensitive transient receptor potential (TRP)/Piezo channels in odontoblasts, with the Ca2+ signal eliciting the release of ATP from pannexin-1 (PANX-1). The released ATP activates the P2X3 receptor, which generates and propagates action potentials in the intradental Aδ afferent neurons. Thus, odontoblasts act as sensory receptor cells, and odontoblast-neuron signal communication established by the TRP/Piezo channel-PANX-1-P2X3 receptor complex may describe the mechanism of the sensory transduction sequence for dentinal sensitivity. To determine whether odontoblast-neuron communication and odontoblasts acting as sensory receptors are essential for generating dentinal pain, we evaluated nociceptive scores by analyzing behaviors evoked by dentinal sensitivity in conscious Wistar rats and Cre-mediated transgenic mouse models. In the dentin-exposed group, treatment with a bonding agent on the dentin surface, as well as systemic administration of A-317491 (P2X3 receptor antagonist), mefloquine and 10PANX (non-selective and selective PANX-1 antagonists), GsMTx-4 (selective Piezo1 channel antagonist), and HC-030031 (selective TRPA1 channel antagonist), but not HC-070 (selective TRPC5 channel antagonist), significantly reduced nociceptive scores following cold water (0.1 ml) stimulation of the exposed dentin surface of the incisors compared to the scores of rats without local or systemic treatment. When we applied cold water stimulation to the exposed dentin surface of the lower first molar, nociceptive scores in the rats with systemic administration of A-317491, 10PANX, and GsMTx-4 were significantly reduced compared to those in the rats without systemic treatment. Dentin-exposed mice, with somatic odontoblast-specific depletion, also showed significant reduction in the nociceptive scores compared to those of Cre-mediated transgenic mice, which did not show any type of cell deletion, including odontoblasts. In the odontoblast-eliminated mice, P2X3 receptor-positive A-neurons were morphologically intact. These results indicate that neurotransmission between odontoblasts and neurons mediated by the Piezo1/TRPA1-pannexin-1-P2X3 receptor axis is necessary for the development of dentinal pain. In addition, odontoblasts are necessary for sensory transduction to generate dentinal sensitivity as mechanosensory receptor cells.

Odontoblast death drives cell-rich zone-derived dental tissue regeneration.

Severe dental tissue damage induces odontoblast death, after which dental pulp stem and progenitor cells (DPSCs) differentiate into odontoblast-like cells, contributing to reparative dentin. However, the damage-induced mechanism that triggers this regeneration process is still not clear. We aimed to understand the effect of odontoblast death without hard tissue damage on dental regeneration. Herein, using a Cre/LoxP-based strategy, we demonstrated that cell-rich zone (CZ)-localizing Nestin-GFP-positive and Nestin-GFP-negative cells proliferate and differentiate into odontoblast-like cells in response to odontoblast depletion. The regenerated odontoblast-like cells played a role in reparative dentin formation. RNA-sequencing analysis revealed that the expression of odontoblast differentiation- and activation-related genes was upregulated in the pulp in response to odontoblast depletion even without damage to dental tissue. In this regenerative process, the expression of type I parathyroid hormone receptor (PTH1R) increased in the odontoblast-depleted pulp, thereby boosting dentin formation. The levels of PTH1R and its downstream mediator, i.e., phosphorylated cyclic AMP response element-binding protein (Ser133) increased in the physically damaged pulp. Collectively, odontoblast death triggered the PTH1R cascade, which may represent a therapeutic target for inducing CZ-mediated dental regeneration.

Correlation between the brain activity with gait imagery and gait performance in adults with Parkinson's disease: A data set.

This article describes data related to the research study entitled "The neural correlate of gait improvement by rhythmic sound stimulation in adults with Parkinson's disease - A functional magnetic resonance imaging study" [1]. We evaluated gait performance using the 10-meter walk test (10MWT) in adults with Parkinson's disease (PD) and age-matched healthy controls (HC). Gait speed (GS) and step length (SL) were calculated from the results of the 10MWT. We also evaluated neural activities in regions that were significantly activated by gait imagery in adults with PD using functional magnetic resonance imaging (fMRI). The correlation among GS, SL, and activation of blood oxygenation level-dependent (BOLD) signals by gait imagery in adults with PD. Both GS and SL were smaller in adults with PD than in HCs. The left parietal operculum (PO), left supplementary motor area (SMA), and right cerebellum were activated by gait imagery in adults with PD. No significant correlation was found in any pair of gait performance and neural activation of such regions. This data set could be reused for studies to investigate the relationship between gait performance and neural activities in adults with PD.

Behavioral Assessment of Unilateral Spatial Neglect with the Catherine Bergego Scale (CBS) Using the Kessler Foundation Neglect Assessment Process (KF-NAP) in Patients with Subacute Stroke during Rehabilitation in Japan.

The Kessler Foundation Neglect Assessment Process (KF-NAP) is an assessment tool for unilateral spatial neglect (USN), which is the scoring method for the Catherine Bergego Scale (CBS) based on detailed instructions. This study is aimed at determining the reliability and validity of the Japanese version of the KF-NAP (KF-NAP-J), evaluating the improvement of neglect assessment with KF-NAP-J, and comparing it with the original CBS for subacute stroke patients. We assessed subacute stroke patients admitted to our intensive rehabilitation hospital. Two KF-NAP-trained occupational therapists (OTs) assessed 22 patients. Before implementing the KF-NAP at the hospital, two other OTs assessed the other 23 patients using the CBS. We evaluated the interrater reliability of the KF-NAP and CBS using intraclass correlation coefficients (ICC) for the total scores, weighted kappa statistics for each subscale, and internal consistency using Cronbach's alpha. We assessed the validity of the KF-NAP against the Behavioral Inattention Test (BIT) and Functional Independence Measure (FIM) using Spearman's correlation coefficient. The reliability of both the KF-NAP and CBS was excellent. The weighted kappa results demonstrated that each subscale was in better agreement with the KF-NAP than with the CBS. In the KF-NAP, all eight subscales in which weighted kappa could be calculated were in significant agreement, and two were almost in perfect agreement. The KF-NAP moderately correlated with the subscales of BIT and FIM representing USN and activities of daily living. The USN detection rates of KF-NAP and BIT in the KF-NAP group were 63.6% and 22.7%, respectively. These results suggest that the KF-NAP, as well as the CBS, is useful to assess USN, which strongly impacts the rehabilitation outcomes in subacute stroke patients.

RANKL/OPG ratio regulates odontoclastogenesis in damaged dental pulp.

Bone-resorbing osteoclasts are regulated by the relative ratio of the differentiation factor, receptor activator NF-kappa B ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG). Dental tissue-localized-resorbing cells called odontoclasts have regulatory factors considered as identical to those of osteoclasts; however, it is still unclear whether the RANKL/OPG ratio is a key factor for odontoclast regulation in dental pulp. Here, we showed that odontoclast regulators, macrophage colony-stimulating factor-1, RANKL, and OPG were detectable in mouse pulp of molars, but OPG was dominantly expressed. High OPG expression was expected to have a negative regulatory effect on odontoclastogenesis; however, odontoclasts were not detected in the dental pulp of OPG-deficient (KO) mice. In contrast, damage induced odontoclast-like cells were seen in wild-type pulp tissues, with their number significantly increased in OPG-KO mice. Relative ratio of RANKL/OPG in the damaged pulp was significantly higher than in undamaged control pulp. Pulp damages enhanced hypoxia inducible factor-1α and -2α, reported to increase RANKL or decrease OPG. These results reveal that the relative ratio of RANKL/OPG is significant to pulpal odontoclastogenesis, and that OPG expression is not required for maintenance of pulp homeostasis, but protects pulp from odontoclastogenesis caused by damages.

The neural correlates of gait improvement by rhythmic sound stimulation in adults with Parkinson's disease - A functional magnetic resonance imaging study.

INTRODUCTION: Adults with Parkinson's disease (PD) experience gait disturbances that can sometimes be improved with rhythmic auditory stimulation (RAS); however, the underlying physiological mechanism for this improvement is not well understood. We investigated brain activation patterns in adults with PD and healthy controls (HC) using functional magnetic resonance imaging (fMRI) while participants imagined gait with or without RAS. METHODS: Twenty-seven adults with PD who could walk independently and walked more smoothly with rhythmic auditory cueing than without it, and 25 age-matched HC participated in this study. Participants imagined gait in the presence of RAS or white noise (WN) during fMRI. RESULTS: In the PD group, gait imagery with RAS activated cortical motor areas, including supplementary motor areas and the cerebellum, while gait imagery with WN additionally recruited the left parietal operculum. In HC, the induced activation was limited to cortical motor areas and the cerebellum for both the RAS and WN conditions. Within- and between-group analyses demonstrated that RAS reduced the activity of the left parietal operculum in the PD group but not in the HC group (condition-by-group interaction by repeated measures analysis of variance, p < 0.05). CONCLUSION: During gait imagery in adults with PD, the left parietal operculum was less activated by RAS than by WN, while no change was observed in HC, suggesting that rhythmic auditory stimulation may support the sensory-motor networks involved in gait, thus alleviating the overload of the parietal operculum and compensating for its dysfunction in these patients.

Development of a method for the identification of receptor activator of nuclear factor-κB+ populations in vivo.

OBJECTIVES: Osteoclasts are induced by macrophage colony-stimulating factor-1 (CSF-1) and receptor activator of nuclear factor-κB (RANK) ligand (RANKL). Monocyte/macrophage lineages are thought to be osteoclast precursors; however, such cells have not been fully characterized owing to a lack of tools for their identification. Osteoclast precursors express colony-stimulating factor-1 receptor (CSF-1R) and RANK. However, the capacity of conventional methods using anti-RANK antibodies to detect RANK+ cells by flow cytometry is insufficient. Here, we developed a high-sensitivity method for detecting RANK+ cells using biotinylated recombinant glutathione S-transferase-RANKL (GST-RANKL-biotin). METHODS: We sorted sub-populations of mouse bone marrow (BM) or peripheral blood (PB) cells using GST-RANKL-biotin, anti-CSF1R, and anti-B220 antibodies and induced osteoclastogenesis in vitro. RESULTS: The frequency of the RANK+ population in BM detected by GST-RANKL-biotin was significantly higher than that detected by anti-RANK antibodies. Although RANK+ cells were detected in both the B220+ and B220- populations, the macrophage lineage was present only in B220-. Unexpectedly, a significantly higher number of osteoclasts was induced in RANK-CSF-1R+ cells than in RANK+CSF-1R+ cells contained in the B220- population. In contrast, the PB-derived B220-RANK+CSF-1R+ population contained a significantly higher frequency of osteoclast precursors than the B220-RANK-CSF-1R+ population. CONCLUSIONS: These results suggest that GST-RANKL-biotin is useful for the detection of RANK+ cells and that RANK and CSF-1R may be helpful indicators of osteoclast precursors in PB.

Test-retest reliability and minimal detectable change of the Balance Evaluation Systems Test and its two abbreviated versions in persons with mild to moderate spinocerebellar ataxia: A pilot study.

BACKGROUND: The reliability of the evaluation of the Balance Evaluation Systems Test (BESTest) and its two abbreviated versions are confirmed for balance characteristics and reliability. However, they are not utilized in cases of spinocerebellar ataxia (SCA). OBJECTIVE: We aimed to examine the test-retest reliability and minimal detectable change (MDC) of the BESTest and its abbreviated versions in persons with mild to moderate spinocerebellar ataxia. METHODS: The BESTest was performed in 20 persons with SCA at baseline and one month later. The scores of the abbreviated version of the BESTest were determined from the BESTest scores. The interclass correlation coefficient (1,1) was used as a measure of relative reliability. Furthermore, we calculated the MDC in the BESTest and its abbreviated versions. RESULTS: The intraclass correlation coefficients (1,1) and MDC at 95% confidence intervals were 0.92, 8.7(8.1%), 0.91, 4.1(14.5%), and 0.81, 5.2(21.6%) for the Balance, Mini-Balance, and Brief-Balance Evaluation Systems Tests, respectively. CONCLUSIONS: The BESTest and its abbreviated versions had high test-retest reliability. The MDC values of the BESTest could enable clinicians and researchers to interpret changes in the balance of patients with SCA more precisely.