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GJA1 is the causative gene for oculodentodigital dysplasia (ODDD). A novel de novo GJA1 variant, NM 000165:c263C > T [p.P88L], was identified in a mosaic state in a patient with short stature, seizures, delayed myelination, mild hearing loss, and tooth enamel hypoplasia. Although the patient exhibited severe neurodevelopmental delay, other clinical features of ODDD, including limb anomalies, were mild. This may be due to differences in the mosaic ratios in different organs., (© 2024. The Author(s).)

Objective: Developing new therapies to improve motor function in patients with severe chronic stroke remains a major focus of neurorehabilitation. In this prospective, non-controlled, pilot study, we aimed to investigate the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) combined with occupational therapy (OT) on the motor function recovery of the affected upper limb in chronic stroke patients with severe upper limb hemiparesis., Methods: Consecutive patients (n = 40) diagnosed with chronic stroke (time since stroke, ≥1 year) and upper limb hemiparesis were enrolled in this study. Patients were classified according to the Brunnstrom recovery stage (BRS) for fingers. The severity of upper limb hemiparesis was categorized as mild (BRS IV-VI) or severe (BRS I-III). Patients received low-frequency rTMS to the contralesional primary motor area (M1) followed by OT for 12 consecutive days. The primary outcome was upper limb motor recovery, as measured with the Fugl-Meyer assessment (FMA). Secondary outcomes included manual dexterity, upper limb use, spasticity of the fingers and wrist, and motor evoked potential (MEP)., Results: Patients with severe hemiparesis showed a significant increase in upper limb use, significantly improved quality of movement, and significantly reduced spasticity. Those with mild hemiparesis showed significant improvements in the FMA scores and manual dexterity, a significant increase in upper limb use and MEP, and significantly reduced spasticity., Conclusions: Low-frequency rTMS applied to the contralesional M1 combined with OT was effective in the rehabilitation of chronic stroke patients with severe upper limb hemiparesis by reducing the spasticity of the fingers., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Department of Regenerative Systems Neuroscience, Graduate school of Medicine 10.13039/501100005683Kyoto University is an endowed department funded by Kodama Foundation. - S.K., (© 2023 The Authors.)

Background: A small lateral medullary lesion could produce isolated impairment of temperature sensation without concomitant impaired pain sensation. However, only one such case has ever been reported, and there are no reports on subjective symptoms and detailed somatosensory testing., Case Presentation: Herein, we report the case of a 53-year-old female patient presenting with impaired temperature sensation on the left half of her body, from the neck down, following a small infarction of the right midlateral medulla. The chronological changes in the patient's introspection regarding impairment of thermoception and the results of detailed somatosensory tests, including thermal sense, are shown in this report., Conclusions: Thorough somatosensory tests, personal descriptions of symptoms, and electrophysiological quantification of similar cases are needed to improve our understanding of the neurological separation of the sensations of pain and temperature at the medullary level., (© 2022. The Author(s).)

Transcranial static magnetic stimulation (tSMS) is a novel non-invasive brain stimulation technique that reduces cortical excitability at the stimulation site. We investigated the effects of tSMS over the left primary motor cortex (M1) for 20 min on the local electroencephalogram (EEG) power spectrum and interregional EEG coupling. Twelve right-handed healthy subjects participated in this crossover, double-blind, sham-controlled study. Resting-state EEG data were recorded for 3 min before the intervention and 17 min after the beginning of the intervention. The power spectrum at the left central electrode (C3) and the weighted phase lag index (wPLI) between C3 and the other electrodes was calculated for theta (4-8 Hz), alpha (8-12 Hz), and beta (12-30 Hz) frequencies. The tSMS significantly increased theta power at C3 and the functional coupling in the theta band between C3 and the parietal midline electrodes. The tSMS over the left M1 for 20 min exhibited modulatory effects on local cortical activity and interregional functional coupling in the theta band. The neural oscillations in the theta band may have an important role in the neurophysiological effects induced by tSMS over the frontal cortex.

Transcranial static magnetic stimulation (tSMS) has been focused as a new non-invasive brain stimulation, which can suppress the human cortical excitability just below the magnet. However, the non-regional effects of tSMS via brain network have been rarely studied so far. We investigated whether tSMS over the left primary motor cortex (M1) can facilitate the right M1 in healthy subjects, based on the hypothesis that the functional suppression of M1 can cause the paradoxical functional facilitation of the contralateral M1 via the reduction of interhemispheric inhibition (IHI) between the bilateral M1. This study was double-blind crossover trial. We measured the corticospinal excitability in both M1 and IHI from the left to right M1 by recording motor evoked potentials from first dorsal interosseous muscles using single-pulse and paired-pulse transcranial magnetic stimulation before and after the tSMS intervention for 30 min. We found that the corticospinal excitability of the left M1 decreased, while that of the right M1 increased after tSMS. Moreover, the evaluation of IHI revealed the reduced inhibition from the left to the right M1. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of tSMS in human.

The performance of indoor localization methods is highly dependent on the situations in which they are used. Various competitions on indoor localization have been held for fairly comparing the existing indoor localization methods in shared and controlled testing environments. However, it is difficult to evaluate the practical performance in industrial scenarios through the existing competitions. This paper introduces two indoor localization competitions, which are named the "PDR Challenge in Warehouse Picking 2017" and "xDR Challenge for Warehouse Operations 2018" for tracking workers and vehicles in a warehouse scenario. For the PDR Challenge in Warehouse Picking 2017, we conducted a unique competition based on the data measured during the actual picking operation in an actual warehouse. We term the dead-reckoning of a vehicle as vehicle dead-reckoning (VDR), and the term "xDR" is derived from pedestrian dead-reckoning (PDR) plus VDR. As a sequel competition of the PDR Challenge in Warehouse Picking 2017, the xDR Challenge for Warehouse Operations 2018 was conducted as the world's first competition that deals with tracking forklifts by VDR with smartphones. In the paper, first, we briefly summarize the existing competitions, and clarify the characteristics of our competitions by comparing them with other competitions. Our competitions have the unique capability of evaluating the practical performance in a warehouse by using the actual measured data as the test data and applying multi-faceted evaluation metrics. As a result, we successfully organize the competitions due to the many participants from many countries. As a conclusion of the paper, we summarize the findings of the competitions.

Background: Carney complex (CNC) is a very rare disease. Although thyroid lesions are included in the diagnostic criteria for CNC, they are an infrequent occurrence., Case Presentation: The patient was a 69-year-old woman who had undergone the removal of a left atrial myxoma 10 years earlier, at the age of 59. At the time of the operation, thyroid ultrasonography (US) revealed multiple hypoechoic nodules. Thyroid scintigraphy revealed an increased uptake of 99m Tc in these lesions, which was consistent with toxic multinodular goiter, and she was diagnosed with CNC. Genetic studies showed no mutation in the PRKAR1A (protein kinase A regulatory subunit 1-α) gene. From then on, she received annual brain magnetic resonance imaging (MRI), abdominal computed tomography (CT), and thyroid US examinations. Her follicular thyroid nodules gradually increased in number and size. Although aspiration cytology samples from the thyroid nodules diagnosed them as class III, thyroid cancer could not be ruled out. The patient underwent a partial thyroidectomy, and the pathological diagnosis was multiple follicular adenomas., Conclusion: Careful and frequent evaluation of the thyroid gland should be required for CNC patients due to the potential for carcinoma to develop in the context of a variety of follicular thyroid lesions.

Aims: Alpha-2-macroglobulin ( α2 MG) is thought to be associated with inflammatory reactions and procoagulant properties that might cause ischemic stroke. Endothelial dysfunction plays an important role in atherosclerosis development and in the occurrence of cardiovascular events. In this study, we investigated whether serum α2 MG levels, endothelial function, and endothelial progenitor cell (EPC) number were associated in patients with chronic stroke or cardiovascular risk factors., Methods: Patients with a history of stroke or any established cardiovascular risk factors were enrolled in this study (n=102; 69 men, 70.1±9.2 years). Endothelial function was assessed by flow-mediated dilation (FMD). EPC numbers (CD34＋/CD133＋) were measured using flow cytometry (n=91). Serum α2 MG levels were measured by nephelometry., Results: Patients in the highest tertile of serum α2 MG levels were older (P=0.019) and more frequently exhibited dyslipidemia (P=0.021). Univariate-regression analysis revealed that increased α2 MG levels were negatively associated with FMD values (r=-0.25; P=0.010), whereas increased EPC numbers were positively associated (r=0.21; P=0.044). Multivariate-regression analysis adjusted for male gender, hypertension, and severe white-matter lesions showed that serum α2 MG levels were independently associated with FMD values (standardized partial regression coefficient [β] -0.185; P=0.033), although not significantly associated with EPC numbers., Conclusion: Serum α2 MG levels might reflect endothelial dysfunction evaluated by FMD in patients with chronic stroke or cardiovascular risk factors.

We investigated the depth profiles of radioactive Cs, ignition loss, and cation exchange capacity (CEC) in five types of forest soils sampled using scraper plates. We then simulated the monitored depth profiles in a compartment model, taking ignition loss as a parameter based on experimental results showing a positive correlation between ignition loss and the CEC. The calculated values were comparable with the monitored values, though some discrepancy was observed in the middle of the soil layer. Based on decontamination data on the surface dose rate and surface contamination concentration, we newly defined a surface residual index (SRI) to evaluate the residual radioactive Cs on surfaces. The SRI value tended to gradually decrease in forests and unpaved roads and was much smaller in forests and on unpaved roads than on paved roads. The radioactive Cs was assumed to have already infiltrated underground 18 months after the nuclear power plant accident, and the sinking was assumed to be ongoing. The SRI values measured on paved roads suggested that radioactive Cs remained on the surfaces, though a gradual infiltration was observed towards the end of the monitoring term. The SRI value is thought to be effective in grasping the rough condition of residual radioactive Cs quickly at sites of decontamination activity in the field. The SRI value may be serviceable for actual contamination works after further research is done to elucidate points such as the relation between the SRI and the infiltration of radioactive Cs in various types of objects.

Objective: 11 C-Pittsburgh compound-B ( 11 C-PIB) positron emission tomography (PET) is used to visualize and quantify amyloid deposition in the brain cortex in pathological conditions such as Alzheimer's disease (AD). Intense 11 C-PIB retention is also observed in the white matter (WM) of both healthy individuals and AD patients. However, the clinical implications of this retention in brain WM have not been clarified. We investigated the relationship between the extent of white matter lesions (WMLs) and the binding potential of 11 C-PIB (BP ND ) in the WM in patients with hypertensive small vessel disease. We further examined the relationship between the extent of WMLs and BP ND in WML and in normal-appearing white matter (NAWM)., Methods: Twenty-one hypertensive vasculopathy patients, without AD and major cerebral arterial stenosis and/or occlusion, were enrolled (9 women, 68 ± 7 years). Regions of WML and NAWM were extracted using magnetization-prepared rapid gradient-echo and fluid-attenuated inversion recovery of magnetic resonance images. Volumes of interest (VOIs) were set in the cortex-subcortex, basal ganglia, and centrum semiovale (CS). BP ND in the cortex-subcortex, basal ganglia, CS, WML, and NAWM were estimated on 11 C-PIB PET using Logan graphical analysis with cerebellar regions as references. The relationships between WML volume and BP ND in each region were examined by linear regression analysis., Results: BP ND was higher in the CS and basal ganglia than in the cortex-subcortex regions. WML volume had a significant inverse correlation with BP ND in the CS (Slope = -0.0042, R 2  = 0.44, P < 0.01). For intra WM comparison, BP ND in NAWM was significantly higher than that in WML. In addition, although there were no correlations between WML volume and BP ND in WML, WML volume was significantly correlated inversely with BP ND in NAWM (Slope = -0.0017, R 2  = 0.26, P = 0.02)., Conclusions: 11 C-PIB could be a marker of not only cortical amyloid-β deposition but also WM injury accompanying the development of WMLs in hypertensive small vessel disease.

The effect of changes in the mucosal fluid volume on the nasal drug absorption of powder formulations was evaluated using warfarin (WF), piroxicam (PXC), and norfloxacin (NFX) as model drugs. Lactose and sodium chloride (NaCl), which are water soluble and small-sized chemicals that increase osmotic pressure after dissolution, were used as excipients to change the mucosal fluid volume. The in vitro study using a Madin-Darby canine kidney (MDCK) cell monolayer indicated that lactose and NaCl, sprayed over the surface of air interface monolayers, increased the fluid volume on the monolayer surface and enhanced the transepithelial transport of the model drugs. The in vivo animal study indicated that the nasal absorption of PXC is enhanced by lactose and NaCl after nasal administration of the powder formulations. This is likely due to the enhanced dissolution of PXC on fluid-rich nasal mucosa and an increase in the effective surface area for drug permeation, which lead to better nasal absorption. However, both excipients failed to increase the nasal absorption of WF and NFX. To clarify the mechanism of the drug-dependent effect of lactose and NaCl, the nasal residence of the formulation was examined using FD70 as a non-absorbable marker. The nasal clearance of FD70 was enhanced by lactose and NaCl, leading to a decrease in the nasal drug absorption. Lactose and NaCl caused no damage to the nasal tissue. These results indicate that the addition of water-soluble excipients such as lactose to powder formulations can enhance the nasal absorption of highly permeable but poorly soluble drugs.

Background: Few existing stroke registries allow for evaluation of stroke severity, stroke subtype and antithrombotic usage prior to stroke onset over a given time period. The present study aimed to elucidate temporal trends in initial presenting stroke severity, stroke subtype and prior antithrombotic use over a 12-year period in a Japanese multicenter stroke registry., Methods and results: We included 71,017 acute ischemic stroke patients (72±12 years old; 27,445 women) from the Japan Standard Stroke Registry Study (JSSRS) who were admitted to 94 hospitals between 2001 and 2012. The mean age of stroke onset increased gradually over time (P<0.001). Cardioembolic stroke patients (n=19,247) exhibited more severe NIHSS scores when compared with those with non-cardioembolic stroke (n=50,427). The proportion of cardioembolic stroke patients tended to increase over time, rising from 25.9% in 2001-2002 to 30.2% in 2011-2012 (P<0.001). Among the cardioembolic stroke patients, the frequency of prior anticoagulant use significantly increased from 15.6% in 2001-2002 to 24.8% in 2011-2012 (P<0.001). The frequency of prior antiplatelet use increased from 2001-2002 to 2007-2008 but decreased after 2007-2008. Among both cardioembolic and non-cardioembolic stroke patients, initial stroke severity at admission decreased over time, particularly after 2008., Conclusions: In this Japanese study, the mean age of ischemic stroke onset increased, while the initial neurological severity at presentation decreased, over a 12-year period. (Circ J 2016; 80: 2033-2036).

Objective: Cerebral microbleeds (CMBs), probably reflecting microangiopathy, have not yet sufficiently been examined in association with cerebral blood flow (CBF) and metabolism. We investigated the relationships between CMBs, and CBF and metabolism in symptomatic small vessel disease., Methods: We enrolled 22 patients with symptomatic small vessel disease without severe stenosis (>50 %) in major cerebral arteries. Volumes of white matter lesions (WMLs) and number of CMBs were assessed on images of fluid-attenuated inversion recovery and gradient-echo T2*-weighted magnetic resonance imaging, respectively. Patients were divided into two groups according to the median number of CMBs (group I <5, n = 10; group II ≥5, n = 12). Parametric images of CBF, cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction and cerebral blood volume were estimated using positron emission tomography and (15)O-labeled gases. The functional values in the cortex-subcortex, basal ganglia, and centrum semiovale were compared between the two groups., Results: Volumes of WMLs of group II were larger than those of group I (median: 38.4; range: 25.1-91.5 mL vs. median: 11.3; range: 4.2-73.4 mL, p = 0.01). In the centrum semiovale, the mean CBF of group II was significantly lower than that of group I (12.6 ± 2.6 vs. 15.6 ± 3.3 mL/100 g/min, p = 0.04). In the other regions, there were no significant differences in either CBF or CMRO2 between the two groups., Conclusions: Our study indicated that increases in the number of CMBs with larger volumes of WMLs were associated with cerebral ischemia in the deep white matter in patients with symptomatic small vessel disease.

Purpose: To better understand microRNA miR-21 function in carcinogenesis, we analyzed miR-21 expression patterns in different stages of colorectal cancer development using in situ hybridization (ISH)., Experimental Design: Locked nucleic acid (LNA)/DNA probes and a biotin-free tyramide signal amplification system were used in ISH analyses of miRNA expression. Conditions for specific detection of miR-21 were determined using human cell lines and miR-21-expressing lentiviral vectors. Expression was determined in 39 surgically excised colorectal tumors and 34 endoscopically resected colorectal polyps., Results: In the surgical samples, miR-21 expression was much higher in colorectal cancers than in normal mucosa. Strong miR-21 expression was also observed in cancer-associated stromal fibroblasts, suggesting miR-21 induction by cancer-secreted cytokines. Protein expression of PDCD4, a miR-21 target, was inversely correlated with miR-21 expression, confirming that miR-21 is indeed a negative regulator of PDCD4 in vivo. In the endoscopic samples, miR-21 expression was very high in malignant adenocarcinomas but was not elevated in nontumorigenic polyps. Precancerous adenomas also frequently showed miR-21 up-regulation., Conclusion: Using the LNA-ISH system for miRNA detection, miR-21 was detectable in precancerous adenomas. The frequency and extent of miR-21 expression increased during the transition from precancerous colorectal adenoma to advanced carcinoma. Expression patterns of miR-21 RNA and its target, tumor suppressor protein PDCD4, were mutually exclusive. This pattern may have clinical application as a biomarker for colorectal cancer development and might be emphasized by self-reinforcing regulatory systems integrated with the miR-21 gene, which has been previously shown in cell culture.

The enzyme-labeled antigen method is a histochemical technique that visualizes antigen-specific antibody-producing cells in tissue sections, originally documented in 1968. In this study, we attempted to reemerge this hidden but potentially useful method in rat models immunized with horseradish peroxidase (HRP), ovalbumin (OA), or keyhole limpet hemocyanin (KLH). After repeated immunization in footpads, popliteal, groin, and axillary lymph nodes and spleen were sampled. Paraformaldehyde-prefixed frozen sections were incubated with HRP, biotinylated OA, or biotinylated KLH. Proteinase K pretreatment and the secondary use of HPR-labeled streptavidin were applied in the latter two situations. Plasma cells producing antigen-specific antibodies were visualized. Proportions of antigen-specific antibody-producing cells in total plasma cells shown with the immunoperoxidase method for rat immunoglobulins were evaluated. The percentage of antigen-specific plasma cells reached approximately 50% of total plasma cells in the regional lymph nodes. The specificity was confirmed by (a) negativity in non-immune rat tissue, (b) negativity with indifferent antigen probes, and (c) abolishment of the reactivity with the corresponding rat serum. In buffered formalin-fixed, paraffin-embedded tissues, fewer plasma cells were labeled for HRP and KLH antibody reactivity after strong proteolysis and prolonged incubation. Expectedly, this method allows us to observe antigen-specific antibody-producing cells under varied pathological conditions.

Background: Our previous analyses on the expression of thymidylate synthase (TS) and p16(INK4a) in colorectal cancer patients administered 5-fluorouracil (5-FU) pre-operatively demonstrated that a high level of TS expression was a predictor of 5-FU resistance, and that the combination of a low level of TS expression and induction of p16(INK4a) after chemotherapy implicated chemosensitivity. The present study aimed to assess the relationship between the biological behavior of advanced colorectal cancer treated post-operatively by 5-FU-based chemotherapy and the expression of TS and p16(INK4a) in primary tumors., Methods: Formalin-fixed, paraffin-embedded specimens from 132 colorectal cancers (Dukes' B, 36 cases; Dukes' C, 60 cases; and Dukes' D, 36 cases) treated by 5-FU post-operatively were immunostained for TS and p16(INK4a). Antigenicities were suitably retrieved., Results: Primary tumors expressing high levels of TS in the Dukes' C group showed a significantly shorter recurrence-free interval (RFI) (P = 0.0002). The overall survival (OS) was shorter in high TS expressors than in low TS expressors (P = 0.001). A high level of TS expression also correlated with advanced Dukes' staging and the severity of nodal metastasis (Dukes' B versus Dukes' D, P = 0.001; Dukes' C versus Dukes' D, P = 0.008; N0 versus N2, P = 0.002; N1 versus N2, P = 0.03). p16(INK4a) expression was not correlated with the prognosis or clinicopathological features., Conclusions: Appropriate immunohistochemical evaluation is essentially important. We suggest that, in the Dukes' C group, a 5-FU-based regimen can be chosen as a first-line chemotherapy for low TS expressors. TS-high cancer should be treated with anti-cancer agents acting through different mechanisms. Further research should be conducted on applying TS immunostaining to the treatment strategy.

Phosphorylated sites of calf thymus H2B histone were investigated with a catalytic fragment of 72 kDa protein-tyrosine kinase (p72syk). Three of five tyrosine residues in H2B histone can be phosphorylated by this kinase. In this analysis, H2B histone was thoroughly phosphorylated in vitro with [gamma-32P]ATP and the kinase, and then digested with a lysylendopeptidase. The resulting radioactive phosphopeptides were separated by a reverse-phase column on high performance liquid chromatography. Subsequent sequential Edman degradation of the purified phosphopeptides revealed that 40Y, 83Y and 121Y were phosphorylated. 121Y is the major phosphorylated residue in H2B histone. No phosphorylation was detected in 37Y and 42Y. Although the consensus sequence was not defined from these analyses, our data suggest that higher-order structure(s) in addition to primary one may participate in recognition of H2B histone by this protein kinase.