Pacsin 2-dependent N-cadherin internalization regulates the migration behaviour of malignant cancer cells.

Collective cell migration is the coordinated movement of multiple cells connected by cadherin-based adherens junctions and is essential for physiological and pathological processes. Cadherins undergo dynamic intracellular trafficking, and their surface level is determined by a balance between endocytosis, recycling and degradation. However, the regulatory mechanism of cadherin turnover in collective cell migration remains elusive. In this study, we show that the Bin/amphiphysin/Rvs (BAR) domain protein pacsin 2 (protein kinase C and casein kinase substrate in neurons protein 2) plays an essential role in collective cell migration by regulating N-cadherin (also known as CDH2) endocytosis in human cancer cells. Pacsin 2-depleted cells formed cell-cell contacts enriched with N-cadherin and migrated in a directed manner. Furthermore, pacsin 2-depleted cells showed attenuated internalization of N-cadherin from the cell surface. Interestingly, GST pull-down assays demonstrated that the pacsin 2 SH3 domain binds to the cytoplasmic region of N-cadherin, and expression of an N-cadherin mutant defective in binding to pacsin 2 phenocopied pacsin 2 RNAi cells both in cell contact formation and N-cadherin endocytosis. These data support new insights into a novel endocytic route of N-cadherin in collective cell migration, highlighting pacsin 2 as a possible therapeutic target for cancer metastasis.

Structural basis of Irgb6 inactivation by Toxoplasma gondii through the phosphorylation of switch I.

Irgb6 is a priming immune-related GTPase (IRG) that counteracts Toxoplasma gondii. It is known to be recruited to the low virulent type II T. gondii parasitophorous vacuole (PV), initiating cell-autonomous immunity. However, the molecular mechanism by which immunity-related GTPases become inactivated after the parasite infection remains obscure. Here, we found that Thr95 of Irgb6 is prominently phosphorylated in response to low virulent type II T. gondii infection. We observed that a phosphomimetic T95D mutation in Irgb6 impaired its localization to the PV and exhibited reduced GTPase activity in vitro. Structural analysis unveiled an atypical conformation of nucleotide-free Irgb6-T95D, resulting from a conformational change in the G-domain that allosterically modified the PV membrane-binding interface. In silico docking corroborated the disruption of the physiological membrane binding site. These findings provide novel insights into a T. gondii-induced allosteric inactivation mechanism of Irgb6.

Methylglyoxal activates transient receptor potential A1/V1 via reactive oxygen species in the spinal dorsal horn.

Methylglyoxal (MGO), a highly reactive dicarbonyl metabolite of glucose primarily formed during the glycolytic pathway, is a precursor of advanced glycation end-products (AGEs). Recently, numerous studies have shown that MGO accumulation can cause pain and hyperalgesia. However, the mechanism through which MGO induces pain in the spinal dorsal horn remains unclear. The present study investigated the effect of MGO on spontaneous excitatory postsynaptic currents (sEPSC) in rat spinal dorsal horn neurons using blind whole-cell patch-clamp recording. Perfusion of MGO increased the frequency and amplitude of sEPSC in spinal horn neurons in a concentration-dependent manner. Additionally, MGO administration increased the number of miniature EPSC (mEPSC) in the presence of tetrodotoxin, a sodium channel blocker. However, 6-cyano-7-nitroqiunocaline-2,3-dione (CNQX), an AMPA/kainate receptor antagonist, blocked the enhancement of sEPSC by MGO. HC-030031, a TRP ankyrin-1 (TRPA1) antagonist, and capsazepine, a TRP vanilloid-1 (TRPV1) antagonist, inhibited the action of MGO. Notably, the effects of MGO were completely inhibited by HC-030031 and capsazepine. MGO generates reactive oxygen species (ROS) via AGEs. ROS also potentially induce pain via TRPA1 and TRPV1 in the spinal dorsal horn. Furthermore, we examined the effect of MGO in the presence of N-tert-butyl-α-phenylnitrone (PBN), a non-selective ROS scavenger, and found that the effect of MGO was completely inhibited. These results suggest that MGO increases spontaneous glutamate release from the presynaptic terminal to spinal dorsal horn neurons through TRPA1, TRPV1, and ROS and could enhance excitatory synaptic transmission.

The fatal case of "Pigmentibacter" bacteremia following aspiration pneumonia in elderly patient.

"Pigmentibacter ruber" was first reported in 2021, a novel bacterium of the family Silvanigrellaceae, isolated from human blood of the patient with aspiration pneumonia after the drowning accident in Republic of China. However, until now, there is only one report describing "P. ruber" infection, and no case of isolation from natural environment has been reported so far. Thus, the infectivity and pathogenicity of "Pigmentibacter" spp. has not been clearly understood. In this report, we described the fatal case of "Pigmentibacter" bacteremia subsequently occurred after aspiration pneumonia probably due to accidental ingestion of irrigation water in the elderly patient. Despite administration of broad-spectrum antibiotic, the patient dramatically deteriorated and eventually deceased. Whole-genome sequencing showed the strain isolated from the patient was identified as "Pigmentibacter" sp. (designated as strain Takaoka) and antimicrobial sensitivity testing showed it displayed high minimum inhibitory concentrations against various antibiotics including ß-lactam. Further studies are needed to clarify the clinical characteristics of "Pigmentibacter" and its relative's infections and their antimicrobial sensitivity; however, the present case supported the clinical characteristics of "Pigmentibacter" infection, which can lead to bacteremia following aspiration pneumonia caused by mis-swallowing contaminated water, and poor outcome potentially due to multidrug resistances.

Prevalence and distribution of Schmorl node and endplate signal change, and correlation with disc degeneration in a population-based cohort: the Wakayama Spine Study.

PURPOSE: Degenerative spinal conditions, including disc degeneration (DD), Schmorl nodes (SN), and endplate signal changes (ESC), are pervasive age-associated phenomena that critically affect spinal health. Despite their prevalence, a comprehensive exploration of their distribution and correlations is lacking. This study examined the prevalence, distribution, and correlation of DD, SN, and ESC across the entire spine in a population-based cohort. METHODS: The Wakayama Spine Study included 975 participants (324 men, mean age 67.2 years; 651 women, mean age 66.0 years). Magnetic resonance imaging (MRI) was used to evaluate the intervertebral space from C2/3 to L5/S1. DD was classified using Pfirrmann's system, ESC was identified by diffuse high-intensity signal changes on the endplates, and SN was defined as a herniation pit with a hypointense signal. We assessed the prevalence and distribution of SN, ESC, and DD across the entire spine. The correlations among these factors were examined. RESULTS: Prevalence of ≥ 1 SN over the entire spine was 71% in men and 77% in women, while prevalence of ≥ 1 ESC was 57.9% in men and 56.3% in women. The prevalence of ESC and SN in the thoracic region was the highest among the three regions in both sexes. Positive linear correlations were observed between the number of SN and DD (r = 0.41, p < 0.001) and the number of ESC and DD (r = 0.40, p < 0.001), but weak correlations were found between the number of SN and ESC (r = 0.29, p < 0.001). CONCLUSION: The prevalence and distribution of SN and ESC over the entire spine were observed, and correlations between SN, ESC, and DD were established. This population-based cohort study provides a comprehensive analysis of these factors.

A longitudinal population-based study identifies THBS2 as a susceptibility gene for intervertebral disc degeneration.

PURPOSE: Intervertebral disc degeneration (IDD) is a common degenerative disease associated with ageing. Additionally, IDD is recognized as one of the leading causes of low back pain and disability in the working-age population and is the first step in the process leading to degenerative spinal changes. However, the genetic factors and regulatory mechanisms of IDD remain unknown. Therefore, we selected eight single nucleotide polymorphisms of genes to reveal the progression of IDD in a 7-year longitudinal study of the general population in Japan. METHODS: IDD was evaluated in the Wakayama Spine Study (WSS), which is a population-based cohort study. Overall, 574 participants from the general population cohort who underwent whole spine magnetic resonance imaging and provided clinical information were included in this longitudinal survey. RESULTS: The progression of IDD was affected only by THBS2 at the lumbar region, T12-L1 (p = 0.0044) and L3-4 (p = 0.0045). The significant interaction between THBS2 and age with IDD negatively affected the thoracic spines and passively influenced both the thoracolumbar junction and thoracic spines. The higher progression per year of Pfirrmann's score was rapid in young people with age; however, this decelerated the IDD progression per year in different ages. CONCLUSION: Our longitudinal study found the genes associated with IDD progression and that genetic factors' impact on IDD differs depending on disc level and age.

Development and validation of a survival nomogram and calculator for male patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate and/or enzalutamide.

BACKGROUND: Despite the widespread availability of medication choices for metastatic castration-resistant prostate cancer (mCRPC), biomarkers to predict the efficacy of each mCRPC treatment have not yet been established. This study developed a prognostic nomogram and a calculator to predict the prognosis of patients with mCRPC who received abiraterone acetate (ABI) and/or enzalutamide (ENZ). METHODS: In total, 568 patients with mCRPC who underwent ABI and/or ENZ between 2012 and 2017 were enrolled. A prognostic nomogram based on the risk factors was developed using the Cox proportional hazards regression model and clinically important factors. The discriminatory ability of the nomogram was assessed according to the concordance index (C-index). A 5-fold cross-validation was repeated 2000 times to estimate the C-index, and the means of the estimated C-index for the training and validation sets were determined. A calculator based on this nomogram was then developed. RESULTS: The median overall survival (OS) was 24.7 months. Multivariate analysis showed that the time to CRPC, pre-chemotherapy, baseline prostate-specific antigen, baseline alkaline phosphatase, and baseline lactate dehydrogenase levels were independent risk factors for OS (hazard ratio [HR]: 0.521, 1.681, 1.439, 1.827, and 12.123, p = 0.001, 0.001, < 0.001, 0.019, and < 0.001, respectively). The C-index was 0.72 in the training cohort and 0.71 in the validation cohort. CONCLUSIONS: We developed a nomogram and calculator to predict OS in Japanese patients with mCRPC who received ABI and/or ENZ. Reproducible prognostic prediction calculators for mCRPC will facilitate greater accessibility for clinical use.

The DNA integrity number and concentration are useful parameters for successful comprehensive genomic profiling test for cancer using formalin-fixed paraffin embedded tissue.

The acquisition of high-quality biospecimens and the appropriate handling of these materials are indispensable for successful clinical sequencing. We developed a cancer clinical sequencing system targeting 160 cancer genes: PleSSision-Rapid. Through the PleSSision-Rapid system, we have analyzed DNA quality evaluated by DIN (DNA integrity number) with 1329 formalin-fixed paraffin embedded (FFPE) samples including 477 prospectively collected tissues for genomic test (P) and 852 archival samples after routine pathological diagnosis (A1/A2). As a result, the samples with more than DIN 2.1 was 92.0% (439/477) in prospectively collected sample (P), while it was 85.6% (332/388) and 76.7% (356/464) in two types of archival samples (A1/A2). We performed the PleSSision-Rapid sequence using the samples with over DIN 2.1 and DNA concentration >10 ng/µL with which we were able to construct a DNA library, and the probability of sequence success was almost equivalent during all types of specimen processing, at 90.7% (398/439) in (P), 92.5% (307/332) in (A1) and 90.2% (321/356) in (A2), respectively. Our result indicated the clinical benefit to prepare the prospective collection of FFPE materials for indisputable clinical sequence, and that DIN ≥ 2.1 would be a solid parameter for sample preparation of comprehensive genomic profiling tests.

Analytical sensitivity of six lateral flow antigen test kits for variant strains of SARS-CoV-2.

INTRODUCTION: The lateral flow antigen test is a useful tool for rapid diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The analytical sensitivity of six lateral flow antigen test kits was compared. METHODS: The limit of detection (LoD) and time to positive results were evaluated for six lateral flow tests including ImmunoArrow®, ESPLINE® SARS-CoV-2, QuickNavi™ COVID19 Ag, ImmunoAce® SARS-CoV-2, Panbio™ COVID-19 Ag Rapid Test Device, and SARS-CoV-2 Rapid Antigen Test using the heat-inactivated virus. The LoD of ImmunoArrow® against the Omicron variants was compared with that against the wild-type using recombinant proteins. RESULTS: ImmunoArrow® and ESPLINE® showed the lowest LoD. The time to positive results of all tests except for ESPLINE® was within 200 s in the evaluation at high dose of antigens (2.5 × 105 TCID50/mL) and 500 s in the evaluation at low dose of antigens (2.5 × 104 TCID50/mL). The LoD of ImmunoArrow® against the Omicron variants was the same concentration against the wild-type antigen. CONCLUSIONS: ImmunoArrow® detected SARS-CoV-2 antigens including the Omicron variants with good sensitivity among the six lateral flow antigen tests. These finding support that it can support the rapid diagnosis of COVID-19 with the good sensitivity.

SEGA-like circumscribed astrocytoma in a non-NF1 patient, harboring molecular profile of GBM. A case report.

Subependymal giant cell astrocytoma (SEGA) is a low-grade periventricular tumor that is closely associated with tuberous sclerosis complex (TSC). SEGA typically arises during the first two decades of life and rarely arises after the age of 20-25 years. Nevertheless, it has also been reported that glioma histologically resembling SEGA, so-called SEGA-like astrocytoma, can arise in neurofibromatosis type 1 (NF1) patients, even in the elderly. Herein, we report a case of SEGA-like circumscribed astrocytoma arising in the lateral ventricle of a 75-year-old woman. Whole-exome sequencing revealed a somatic variant of NF1. Methylation array analysis led to a diagnosis of "methylation class glioblastoma, IDH-wildtype, mesenchymal-type (GBM, MES)" with a high calibrated score (0.99). EGFR amplification, CDKN2A/B homozygous deletion, chromosomal +7/-10 alterations, and TERT promoter mutation, typical molecular abnormalities usually found in GBM, were also observed. While most reported cases of SEGA-like astrocytoma have arisen in NF1 patients, the patient was neither TSC nor NF1. Near total removal was accomplished with endoscopic cylinder surgery. At the 36-month follow-up, there was no tumor recurrence without adjuvant therapies. This clinical behavior did not match GBM. SEGA-like astrocytoma of the elderly is rare, and this is the oldest case reported so far. In addition, high-grade molecular features found in circumscribed tumor remain unclear. Further investigations among larger series are needed for clarifying the underlying molecular mechanisms.

Association between modic changes, disc degeneration, and pelvic incidence-lumbar lordosis mismatch in a large population based cohort: the Wakayama spine study.

PURPOSE: Sagittal plane alignment is crucial for treating spinal malalignment and low back pain. Pelvic incidence-lumbar lordosis (PI-LL) mismatch is commonly used to evaluate clinical outcomes in patients with sagittal malalignment. The association between PI-LL mismatch and changes surrounding the intervertebral disc is very important to understand the compensatory mechanisms involved. This study aimed to examine the association between PI-LL mismatch and magnetic resonance imaging (MRI) changes surrounding the intervertebral disc in a large population-based cohort. METHODS: We evaluated participants from the second Wakayama Spine Study, recruiting the general population aged 20 years or older, irrespective of sex, who were registered residents in one region in 2014. In total, 857 individuals underwent an MRI of the whole spine; however, 43 MRI results were not included due to incomplete or inadequate quality images. PI-LL mismatch was defined as > 11°. We compared the MRI changes, such as Modic change (MC), disc degeneration (DD), and high-intensity zones (HIZ), between PI-LL mismatch and non-PI-LL mismatch groups. Multivariate logistic regression analysis was conducted to determine the association between the MRI changes and PI-LL mismatch with adjustment for age, sex, and body mass index in the lumbar region and at each level. RESULTS: A total of 795 participants (243 men, 552 women, mean age 63.5 ± 13.1 years old) were evaluated; 181 were included in the PI-LL mismatch group. MC and DD in the lumbar region were significantly higher in the PI-LL mismatch group. MC in the lumbar region was significantly associated with PI-LL mismatch (odds ratio (OR); 1.81, 95% confidence interval (CI) 1.2-2.7). MC at each level was significantly associated with PI-LL mismatch (OR; 1.7-1.9, 95%CI 1.1-3.2), and DD at L1/2, L3/4, and L4/5 was associated with PI-LL mismatch (OR; 2.0- 2.4. 95%CI 1.2-3.9). CONCLUSION: MC and DD were significantly associated with PI-LL mismatch. Therefore, profiling MC may be helpful in improving the targeted treatment of LBP associated with the adult spinal deformity.

Spinopelvic fusion surgery from lower thoracic spine to pelvis increased hip joint moment-motion analysis.

PURPOSE: Spinal fusion surgery is often performed with pelvic fixation to prevent distal junctional kyphosis. The inclusion of spinopelvic fixation has been reported to induce progression of hip joint arthropathy in a radiographic follow-up study. However, its biomechanical mechanism has not yet been elucidated. This study aimed to compare the changes in hip joint moment before and after spinal fusion surgery. METHODS: This study was an observational study and included nine patients (eight women and one man) who were scheduled to undergo spinopelvic fusion surgery. We calculated the three-dimensional external joint moments of the hip during gait, standing, and climbing stairs before and 1 year after surgery. RESULTS: During gait, the maximum extension moment was 0.51 ± 0.29 and 0.63 ± 0.40 before and after spinopelvic fusion surgery (p = 0.011), and maximum abduction moment was 0.60 ± 0.33 and 0.83 ± 0.34 before and after surgery (p = 0.004), respectively. During standing, maximum extension moment was 0.76 ± 0.32 and 1.04 ± 0.21 before and after spinopelvic fusion surgery (p = 0.0026), and maximum abduction moment was 0.12 ± 0.20 and 0.36 ± 0.22 before and after surgery (p = 0.0005), respectively. During climbing stairs, maximum extension moment was - 0.31 ± 0.30 and - 0.48 ± 0.15 before and after spinopelvic fusion surgery (p = 0.040), and maximum abduction moment was 0.023 ± 0.18 and - 0.02 ± 0.13 before and after surgery (p = 0.038), respectively. CONCLUSION: This study revealed that hip joint flexion-extension and abduction-adduction moments increased after spinopelvic fixation surgery in the postures of standing, walking, and climbing stairs. The mechanism was considered to be adjacent joint disease after spinopelvic fusion surgery including sacroiliac joint fixation.

Dynamic cord compression induced by proximal junctional failure and loose pedicle screws after thoracolumbar fusion surgery: a case report.

BACKGROUND: One of the common mechanical complications following spinal fusion surgery is proximal junctional failure (PJF). The incidence of neurological deficit associated with PJF has been poorly described in the literature. Here, we report a case in which numbness in the lower extremities was recognized as the first symptom, but the discrepancy in the imaging findings made PJF difficult to diagnose. METHODS: A 71-year-old female underwent corrective fusion surgery. Three weeks later, she complained of persistent right leg numbness. Standing X-ray showed the back-out of the pedicle screws (PSs) in the upper instrumented vertebra (UIV), but there was no obvious evidence of cord compression on computed tomography (CT), which caused the delay of diagnosis. Five weeks later, magnetic resonance image (MRI) did not show cord compression on an axial view, but there were signal changes in the spinal cord. RESULTS: The first reason for the delayed diagnosis was the lack of awareness that leg numbness could occur as the first symptom of PJF. The second problem was the lack of evidence for spinal cord compression in various imaging tests. Loosened PSs were dislocated on standing, but were back to their original position on supine position. In our case, these contradictory images led to a delay in diagnosis. CONCLUSION: Loosened PSs caused dynamic cord compression due to repeated deviation and reduction. Supine and standing radiographs may be an important tool in the diagnosis of PJF induced by dynamic cord compression.

Ultrasonography is an effective tool for the evaluation of traumatic vertebral artery injuries distal to fourth cervical vertebra in the emergency room.

BACKGROUND: This study aimed to determine the feasibility of ultrasonography in the assessment of cervical vertebral artery (VA) injury as an alternative to computed tomography angiography (CTA) in the emergency room. METHODS: We analyzed 50 VAs from 25 consecutive patients with cervical spine injury that had been admitted to our emergency room. Ultrasonography and CTA were performed to assess the VA in patients with cervical spine injury. We examined the sensitivity and specificity of ultrasonography compared with CTA. RESULTS: Among these VAs, six were occluded on CTA. The agreement between ultrasonography and CTA was 98% (49/50) with 0.92 Cohen's Kappa index. The sensitivity, specificity, and positive and negative predictive values of ultrasonography were 100%, 97.7%, 85.7%, and 100%, respectively. In one case with hypoplastic VA, the detection of flow in the VA by ultrasonography differed from detection by CTA. Meanwhile, there were two cases in which VAs entered at C5 transverse foramen rather than at C6 level. However, ultrasonography could detect the blood flow in these VAs. CONCLUSIONS: Ultrasonography had a sensitivity of 100% compared with CTA in assessment of the VA. Ultrasonography can be used as an initial screening test for VA injury in the emergency room.

Clinical and radiographic characteristics of increased signal intensity of the spinal cord at the vertebral body level in patients with cervical myelopathy.

BACKGROUND: Increased signal intensity (ISI) is usually recognized at the disc level of the responsible lesion in the patients with cervical myelopathy. However, it is occasionally seen at the vertebral body level, below the level of compression. We aimed to investigate the clinical significance and the radiographic characteristics of ISI at the vertebral body level. METHODS: This retrospective study included 135 patients with cervical spondylotic myelopathy who underwent surgery and with local ISI. We measured the local and C2-7 angle at flexion, neutral, and extension. We also evaluated the local range of motion (ROM) and C2-7 ROM. The patients were classified into group D (ISI at disc level) and group B (ISI at vertebral body level). RESULTS: The prevalence was 80.7% (109/135) and 19.3% (26/135) for groups D and B, respectively. Local angle at flexion and neutral were more kyphotic in group B than in group D. The local ROM was larger in group B than in group D. Moreover, C2-7 angle at flexion, neutral and extension were more kyphotic in group B than in group D. Two years later, local angle at flexion, neutral, and extension were also kyphotic in group B than group D; however, local and C2-7 ROM was not significantly different between the two groups. There was no significant difference of clinical outcomes 2 years postoperatively between both groups. CONCLUSIONS: Group B was associated with the kyphotic alignment and local greater ROM, compared to group D. As the spinal cord is withdrawn in flexion, the ISI lesion at vertebral body might be displaced towards the disc level, which impacted by the anterior components of the vertebrae. ISI at the vertebral body level might be related to cord compression or stretching at flexion position. This should be different from the conventionally held pincer-mechanism concept.

Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of lumbar spinal stenosis, 2021 - Secondary publication.

BACKGROUND: The Japanese Orthopaedic Association (JOA) guideline for the management of lumbar spinal stenosis (LSS) was first published in 2011. Since then, the medical care system for LSS has changed and many new articles regarding the epidemiology and diagnostics of LSS, conservative treatments such as new pharmacotherapy and physical therapy, and surgical treatments including minimally invasive surgery have been published. In addition, various issues need to be examined, such as verification of patient-reported outcome measures, and the economic effect of revised medical management of patients with lumbar spinal disorders. Accordingly, in 2019 the JOA clinical guidelines committee decided to update the guideline and consequently established a formulation committee. The purpose of this study was to describe the formulation we implemented for the revision of the guideline, incorporating the recent advances of evidence-based medicine. METHODS: The JOA LSS guideline formulation committee revised the previous guideline based on the method for preparing clinical guidelines in Japan proposed by the Medical Information Network Distribution Service in 2017. Background and clinical questions were determined followed by a literature search related to each question. Appropriate articles based on keywords were selected from all the searched literature. Using prepared structured abstracts, systematic reviews and meta-analyses were performed. The strength of evidence and recommendations for each clinical question was decided by the committee members. RESULTS: Eight background and 15 clinical questions were determined. Answers and explanations were described for the background questions. For each clinical question, the strength of evidence and the recommendation were both decided, and an explanation was provided. CONCLUSIONS: The 2021 clinical practice guideline for the management of LSS was completed according to the latest evidence-based medicine. We expect that this guideline will be useful for all medical providers as an index in daily medical care, as well as for patients with LSS.

[Characteristics of Adverse events of Dietary Supplements Provided byMedical Professionals and their Application in Causality Evaluation Algorithm].

This study aimed to characterize the adverse events of dietary supplements provided by medical professionals and to examine whether there are challenges when applying each case to the causality evaluation algorithm. Data from 290 individual cases collected by the Tokyo Metropolitan Government in cooperation with the Tokyo Medical Association and Tokyo Pharmaceutical Association were analyzed. The causality evaluation algorithm that was used in this study was reported previously. Female patients accounted for 73% of those who experienced adverse events. Both male and female patients who had adverse events were in their 60s and 70s. Many of the participants had underlying diseases and aimed to improve their medical conditions. Furthermore, skin symptoms were the most common. Many of the supplements were made from natural substances, with an average of 7.7 ingredients in each product. More than half of the products were used for less than one month. In most cases, symptoms improved after discontinuation of the products or after the administration of medications. When each event was applied to the causality assessment algorithm, it was necessary to understand the information as follows: in cases of product discontinuation with simultaneous medications recovery was not concluding the product discontinuation, and the physician's judgement should be place as objective evidence. The algorithm was successfully applicable to cases provided by medical professionals and the evaluated results for all cases were 30% possible and 62% highly possible. The evaluated results indicate the relationship between products/ingredients and the symptom, and by adding information on the symptom and its severity, it is possible to clarify the phenomenon to be noted.

Relationship between medial partite hallux sesamoid and hallux valgus in the general population.

BACKGROUND: An association between the medial partite hallux sesamoid (MPHS) and hallux valgus (HV) has been suggested; however, a causal relationship has not been confirmed. This study aimed to determine their causal relationship using a cross-sectional radiographic survey of a large-scale population cohort covering a wide age group. PATIENTS AND METHODS: The fifth survey of the Research on Osteoarthritis/Osteoporosis against Disability study involved 1997 participants aged 21-95 years who had undergone anteroposterior radiography of bilateral feet. The presence of MPHS, its morphology, and radiographic parameters related to the HV were assessed using radiographs. Changes in the prevalence of MPHS with age were assessed using trend tests. The relationship between the MPHS and HV was assessed based on sex and age. RESULTS: MPHS was found in 508 out of 3994 feet (12.7 %), with a significant difference in prevalence between men and women (10.0 % vs. 13.7 %, p < 0.001). Trend analysis demonstrated a significant decrease in MPHS occurrence with age in both sexes. HV angle was significantly higher in feet with MPHS than in those without (Men: 17.8 ± 7.0° vs. 14.0 ± 5.9°, p < 0.0001; Women: 19.6 ± 7.7° vs. 17.7 ± 7.9°, p < 0.0001). The prevalence of HV angle ≥ 20° was also significantly higher in feet with MPHS than in those without (Men: 33.3 % vs. 14.6 %, p < 0.0001; Women: 46.5 % vs. 34.6 %, p < 0.0001). This association between MPHS and HV was noticeable in younger adults and became less prominent with age. CONCLUSIONS: MPHS is associated with HV. The weakening of this relationship and the decreased prevalence of MPHS with age suggest that MPHS is not caused by HV, but is one of the causes of HV, especially in younger adults.

Neural Population Dynamics Underlying Expected Value Computation.

Computation of expected values (i.e., probability × magnitude) seems to be a dynamic integrative process performed by the brain for efficient economic behavior. However, neural dynamics underlying this computation is largely unknown. Using lottery tasks in monkeys (Macaca mulatta, male; Macaca fuscata, female), we examined (1) whether four core reward-related brain regions detect and integrate probability and magnitude cued by numerical symbols and (2) whether these brain regions have distinct dynamics in the integrative process. Extraction of the mechanistic structure of neural population signals demonstrated that expected value signals simultaneously arose in the central orbitofrontal cortex (cOFC; medial part of area 13) and ventral striatum (VS). Moreover, these signals were incredibly stable compared with weak and/or fluctuating signals in the dorsal striatum and medial OFC. Temporal dynamics of these stable expected value signals were unambiguously distinct: sharp and gradual signal evolutions in the cOFC and VS, respectively. These intimate dynamics suggest that the cOFC and VS compute the expected values with unique time constants, as distinct, partially overlapping processes.SIGNIFICANCE STATEMENT Our results differ from those of earlier studies suggesting that many reward-related regions in the brain signal probability and/or magnitude and provide a mechanistic structure for expected value computation employed in multiple neural populations. A central part of the orbitofrontal cortex (cOFC) and ventral striatum (VS) can simultaneously detect and integrate probability and magnitude into an expected value. Our empirical study on these neural population dynamics raises a possibility that the cOFC and VS cooperate on this computation with unique time constants as distinct, partially overlapping processes.

Imaging-based evaluation of pathogenicity by novel DNM2 variants associated with centronuclear myopathy.

A centronuclear myopathy (CNM) is a group of inherited congenital diseases showing clinically progressive muscle weakness associated with the presence of centralized myonuclei, diagnosed by genetic testing and muscle biopsy. The gene encoding dynamin 2, DNM2, has been identified as a causative gene for an autosomal dominant form of CNM. However, the information of a DNM2 variant alone is not always sufficient to gain a definitive diagnosis as the pathogenicity of many gene variants is currently unknown. In this study, we identified five novel DNM2 variants in our cohort. To establish the pathogenicity of these variants without using clinicopathological information, we used a simple in cellulo imaging-based assay for T-tubule-like structures to provide quantitative data that enable objective determination of pathogenicity by novel DNM2 variants. With this assay, we demonstrated that the phenotypes induced by mutant dynamin 2 in cellulo are well correlated with biochemical gain-of-function features of mutant dynamin 2 as well as the clinicopathological phenotypes of each patient. Our approach of combining an in cellulo assay with clinical information of the patients also explains the course of a disease progression by the pathogenesis of each variant in DNM2-associated CNM.