Search

Background The detrimental repercussions of the COVID-19 pandemic on the quality of care and clinical outcomes for patients with acute coronary syndrome (ACS) necessitate a rigorous re-evaluation of prognostic prediction models in the context of the pandemic environment. This study aimed to elucidate the adaptability of prediction models for 30-day mortality in patients with ACS during the pandemic periods.Methods A total of 2041 consecutive patients with ACS were included from 32 institutions between December 2020 and April 2023. The dataset comprised patients who were admitted for ACS and underwent coronary angiography for the diagnosis during hospitalisation. The prediction accuracy of the Global Registry of Acute Coronary Events (GRACE) and a machine learning model, KOTOMI, was evaluated for 30-day mortality in patients with ST-elevation acute myocardial infarction (STEMI) and non-ST-elevation acute coronary syndrome (NSTE-ACS).Results The area under the receiver operating characteristics curve (AUROC) was 0.85 (95% CI 0.81 to 0.89) in the GRACE and 0.87 (95% CI 0.82 to 0.91) in the KOTOMI for STEMI. The difference of 0.020 (95% CI −0.098–0.13) was not significant. For NSTE-ACS, the respective AUROCs were 0.82 (95% CI 0.73 to 0.91) in the GRACE and 0.83 (95% CI 0.74 to 0.91) in the KOTOMI, also demonstrating insignificant difference of 0.010 (95% CI −0.023 to 0.25). The prediction accuracy of both models had consistency in patients with STEMI and insignificant variation in patients with NSTE-ACS between the pandemic periods.Conclusions The prediction models maintained high accuracy for 30-day mortality of patients with ACS even in the pandemic periods, despite marginal variation observed.

Introduction: Three-dimensional (3D) magnetic resonance imaging (MRI) is reportedly superior to two-dimensional (2D) MRI for diagnosing lumbar foraminal stenosis at L5-S1. In this study, we strictly distinguished the intra- and extraforaminal regions and compared the diagnostic reliability and accuracy of 2D and 3D MRI in each region. Methods: A total of 92 surgical cases of unilateral L5 radiculopathy were selected for imaging analysis, including 46 of foraminal stenosis at L5-S1 (Group F) and 46 of intraspinal canal stenosis at L4-5 (Group C) (48 men, 44 women; mean age, 66 years). The 2D and 3D MRI sets were assessed twice by two examiners. They were informed only of the laterality of the lesion in each case and asked to select among the following for each modality: “absence of foraminal stenosis,”“intraforaminal stenosis,”“extraforaminal stenosis,” and “coincident intraforaminal and extraforaminal stenosis.” The intra- and interobserver reliabilities were evaluated using kappa (κ) statistics for the intra- and extraforaminal regions and compared between 2D and 3D MRI. For each case, disagreements between examiners were resolved through discussion to obtain a diagnostic judgment for each modality. Subsequently, the final diagnosis of intra- and/or extraforaminal stenosis in Group F was made using multiple modalities and intraoperative findings. A comparison between 2D and 3D MRI in terms of diagnostic accuracy was performed for the intra- and extraforaminal regions. Results: No significant difference was observed in the κ statistics between 2D and 3D MRI for the intraforaminal region, whereas 3D MRI had significantly larger κ statistic than 2D MRI for the extraforaminal region. Ultimately, 3D MRI perfectly judged the extraforaminal region, whereas 2D MRI detected only 44.8% of the cases of extraforaminal stenosis. Conclusions: More than half of extraforaminal stenosis was overlooked by 2D MRI, suggesting that it is unreliable for diagnosing extraforaminal stenosis at L5-S1.

Abstract The source imaging for offshore earthquakes using terrestrial geodetic data has a limited estimation performance due to the low data resolution. One approach to overcome this limitation is the use of seafloor geodetic data. In this study, we focus on tsunami-source data, which is the spatial distribution of vertical crustal displacements above the source area and can be derived from tsunami waveform records. We evaluate how the use of this spatial seafloor geodetic data improves the estimation of a rectangular fault model. Here, the fault model of the 2016 off-Fukushima earthquake in Japan, which was a shallow intraplate earthquake (M w 7.0), was estimated by three inversions: terrestrial Global Navigation Satellite System (GNSS) data only, tsunami-source data only, and a combination of the GNSS data and tsunami-source data. A Bayesian inversion approach was used to understand the distribution of the estimated fault parameters and their relationship. The results indicated that the terrestrial GNSS data have a low resolution for the analysis of the offshore earthquake, which resulted in a biased solution with large uncertainty. Conversely, the use of tsunami-source data significantly improved the resolution and reliability of source imaging and reduced the dependency among fault parameters. These results suggested that the high-spatial-resolution information of tsunami source is a powerful tool in source imaging of offshore shallow earthquakes. Moreover, the combined use of the two different geodetic data leads to a more robust estimation of fault parameters. We believe that the use of tsunami-source data is useful, not only for the post hoc source analysis, but also for estimating an earthquake rupture area just after a large earthquake, where GNSS data are currently used. Graphical Abstract

PurposeBone-conduction devices can be considered a viable treatment option for patients experiencing asymmetric hearing loss (AHL), especially those with severe to profound hearing loss (HL) present in one ear. However, there are only a few reports on the effects of bone-anchored hearing aids (BAHAs) on patients with AHL. This retrospective study analyzed in detail the effects of BAHA on softer sounds than other hearing aids and identified situations in which BAHA had a negative effect.MethodsPatients with AHL, characterized by severe to profound hearing loss in one ear with a difference of ≥45 dB from that of the contralateral ear, underwent BAHA implantation in the ear with worse hearing. The BAHA effects were evaluated by assessing the word recognition score (WRS) and speech reception threshold (SRT) using the Japanese Oldenburg Sentence Test for various signal settings and noise directions. For a subjective analysis, the Speech, Spatial and Qualities of Hearing Scale (SSQ12) score was determined.ResultsThirteen patients who underwent BAHA implantation at the Miyazaki University Hospital between 2007 and 2021 were included. The BAHA demonstrated a significant improvement in the WRS from 40 to 70 dB sound pressure levels. Although the SRT showed significant improvement in noisy environments when speech was presented to the BAHA-wearing side, it worsened significantly when noise was presented to this side. In the survey of subjective hearing ability, both the total and subscale SSQ12 scores improved significantly after wearing the BAHA.ConclusionThis study identified scenarios in which BAHAs were beneficial and detrimental to individuals with AHL. Generally used audiological tests, such as the WRS with fixed sound pressure, may underestimate the effectiveness of BAHAs for softer sounds. In addition, depending on the direction of the noise, BAHAs may have adverse effects. These results could help patients comprehend the potential benefits and limitations of bone-conduction devices for their hearing.

Abstract Aims This study aimed to clarify the relationship between cardiovascular prognosis and left ventricular hypertrophy (LVH) in patients with severe aortic stenosis who underwent transcatheter aortic valve replacement (TAVR) and to investigate the relationship between cardiac sympathetic nerve (CSN) function and these factors using 123I‐metaiodobenzylguanidine scintigraphy. Methods and results In this single‐centre, retrospective observational study, 349 patients who underwent TAVR at our institution between July 2017 and May 2020 were divided into two groups: those with severe LVH pre‐operatively [severe LVH (+) group] and those without LVH pre‐operatively [severe LVH (−) group]. The rates of freedom from cardiovascular events (cardiovascular death and heart failure hospitalization) were compared. The relationship between changes in left ventricular mass index (LVMi) and changes in delay heart–mediastinum ratio (H/M) from before TAVR to 6 months after TAVR was also investigated. The event‐free rate was significantly lower in the severe LVH (+) group (87.1% vs. 96.0%, log‐rank P = 0.021). The severe LVH (+) group exhibited a significantly lower delay H/M value, scored by 123I‐metaiodobenzylguanidine scintigraphy, than the severe LVH (−) group (2.33 [1.92–2.67] vs. 2.67 [2.17–3.68], respectively, P

BackgroundThrough contrastive analysis, we aimed to identify the white matter brain regions that show microstructural changes in patients with neuropathic pain (NP) after spinal cord injury (SCI).MethodsWe categorized patients with SCI into NP (n = 30) and non-NP (n = 15) groups. We extracted diffusion tensor maps of fractional anisotropy (FA) and mean (MD), axial (AD), and radial (RD) diffusivity. A randomization-based method in tract-based spatial statistics was used to perform voxel-wise group comparisons among the FA, MD, AD, and RD for nonparametric permutation tests.ResultsAtlas-based analysis located significantly different regions (p

Abstract Aims No study has evaluated the prognostic value of the chronic kidney disease (CKD) classification by cystatin C‐based estimated glomerular filtration rate (eGFR) (CKDCys classification) in patients undergoing transcatheter aortic valve replacement (TAVR). This study aimed to compare the prognostic value of CKDCys classification and CKD classification by creatinine‐based eGFR (CKDCr classification) in risk prediction after TAVR. Methods and results We retrospectively analysed consecutive 219 patients with symptomatic severe aortic stenosis who underwent TAVR at our institute between December 2016 and June 2019. Pre‐operative CKDCr and CKDCys classifications were evaluated for their prognostic value of 2‐year major adverse cardiovascular and cerebrovascular events (MACCE) after TAVR. MACCE was defined as the composite of all‐cause mortality, non‐fatal myocardial infarction, stroke, and rehospitalization for worsening congestive heart failure. Participants had a median age of 86.0 years and were predominantly female (76.9%). In 96.6% of the cases, TAVR was performed using transfemoral access. The median creatinine‐based eGFR (52.85 mL/min/1.73 m2) was higher than the cystatin C‐based eGFR (41.50 mL/min/1.73 m2). Downward reclassification in CKD stages based on eGFRCys was observed in 49.0% of patients. During a median follow‐up period of 575.5 (interquartile range: 367.0–730.0) days, 58 patients presented with MACCE. CKDCys classification, but not CKDCr classification, significantly stratified the risk of 2‐year MACCE in patients after TAVR by log‐rank test (P = 0.003). In multivariate Cox regression analysis, only CKDCys stage 3b [hazard ratio (HR) = 4.37; 95% confidence interval (CI): 1.28–14.91; P = 0.019] and CKDCys stage 4 + 5 (HR = 3.72; 95% CI: 1.06–12.99; P = 0.040) were significant predictors of MACCE after adjustment for potential confounders. Conclusions The CKDCys classification could better assess the risk than the CKDCr classification in patients undergoing TAVR. CKDCys stage 3b and stage 4 + 5 correlated with adverse outcomes.

In the acute phase of spinal cord injury, the initial injury triggers secondary damage due to neuroinflammation, leading to the formation of cavities and glial scars that impair nerve regeneration. Following injuries to the central nervous system, early mobilization promotes the recovery of physical function. Therefore, in the present study, we investigated the effects of early mobilization on motor function recovery and neuroinflammation in rats. Early mobilization of rats with complete spinal cord transection resulted in good recovery of hindlimb motor function after 3 weeks. At 1 week after spinal cord injury, the early-mobilized rats expressed fewer inflammatory M1 microglia/macrophages and more anti-inflammatory M2 microglia. In addition, significantly more matrix metalloproteinase 2 (MMP2)-positive cells were observed at the lesion site 1 week after injury in the early-mobilized rats. Multiple labeling studies suggested that many MMP2-positive cells were M2 microglia. MMP9-positive cells that highly co-expressed GFAP were also observed more frequently in the early-mobilized rats. The density of growth-associated protein-positive structures in the lesion center was significantly higher in the early-mobilized rats at 3 weeks after spinal cord injury. The present results suggest that early mobilization after spinal cord injury reduced the production of M1 microglia/macrophages while increasing the production of M2 microglia at the lesion site. Early mobilization might also activate the expression of MMP2 in M2 microglia and MMP9 in astrocytes. These cellular dynamics might suppress neuroinflammation at the lesion site, thereby inhibiting the progression of tissue destruction and promoting nerve regeneration to recover motor function.

Abstract Background Multiple primary malignancies of breast cancer and diffuse large B-cell lymphoma (DLBCL) are rare. Here, we report a case of advanced breast cancer and DLBCL managed with multidisciplinary therapy preceded by surgery with a successful outcome. Case presentation During a medical examination, a 71-year-old woman was diagnosed with a right breast mass, enlarged lymph nodes throughout the body, and a splenic tumor. The results of the clinical examination and imaging were suggestive of widely spread breast cancer with lymph node metastasis and malignant lymphoma with systemic metastasis. The histological evaluation of the biopsied breast tissue revealed human epidermal growth factor receptor 2 (HER2)-positive breast cancer, whereas the histological evaluation of the excised inguinal lymph node revealed DLBCL. 18F-FDG PET/computed tomography was performed, and it was determined that both breast cancer and DLBCL were in an advanced stage. Thus, mastectomy was performed, and the axillary lymph nodes showed mixed metastasis of breast cancer and DLBCL. Soon after, the R-CHOP therapy was initiated (375-mg/m2 rituximab, 2-mg/m2 vincristine, 50-mg/m2 doxorubicin, 750-mg/m2 cyclophosphamide, and 125-mg methylprednisolone). After irradiation of the spleen, trastuzumab was administered for 1 year. Conclusions We experienced a case of combined breast cancer and DLBCL, which was difficult to treat because both were in advanced stages. Thorough staging of the malignancy and discussion by a multidisciplinary team are necessary to determine the optimal treatment strategy.

Abstract Six-minute walk distance (6MWD) of 300 and 400 m are important targets of functional capacity. The present study was performed to determine cutoff values of physical function associated with 6MWD 65 years (median age, 75: interquartile range, 71–80, 607 men) with HF. 6MWD

This study investigated the acute effect of an 18-hole round of golf on serum interleukin-6 (IL-6) and brain-derived neurotropic factor (BDNF) concentration. Nine young, healthy males, unaccustomed to playing golf, completed an 18-hole round of golf (course length: 5,807 m.). Blood samples were collected prior to, immediately after and 1 h following completion of the exercise session. Interleukin-6 and BDNF, as well as creatine kinase (CK) and myoglobin concentrations were analysed in serum, while adrenaline concentrations were assessed in plasma. The participants completed the course in 303 ± 4 min. Serum IL-6 and BDNF concentrations were respectively elevated 8.6 ± 5.4-fold and 1.2 ± 0.3-fold immediately post-exercise (IL-6 p = 0.008; BDNF p = 0.038). Creatine kinase (p = 0.008), myoglobin (p = 0.011) and adrenaline concentrations (p = 0.038) were also acutely elevated following completion of the golf course. Creatine kinase and myoglobin concentrations were significantly correlated with the acute increase in IL-6 concentration post-exercise (r = 0.70 p = 0.034, r = 0.79 p = 0.012, respectively), while no such relationship was found for BDNF concentration. (r = 0.37 p = 0.333, r = 0.08 p = 0.833, respectively). An 18-hole round of golf was found to acutely elevate IL-6 and BDNF concentration in young, healthy males unaccustomed to playing golf. The correlation of CK and myoglobin with the acute IL-6 response suggests that muscle damage may have influenced the acute increase in this marker. Together, this pilot-study indicates that golf may be promoted as an accessible, low-intensity activity to acutely elevate markers suggested to stimulate improvements in metabolic health and cognitive function.

BackgroundBalloon pulmonary angioplasty (BPA) is used for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and residual pulmonary hypertension after pulmonary endarterectomy (PEA) to improve hemodynamics, right ventricular function, and exercise capacity. However, the effectiveness and safety of guide extension catheters for BPA treatment in patients with CTEPH have not been demonstrated.MethodsWe retrospectively analyzed 91 lesions in 55 sessions of 28 patients with CTEPH who underwent BPA using a guide extension catheter. The purpose (backup, coaxial, and extension), efficacy, and safety of the guide extension catheters were explored. The efficacy of the guide extension catheter was assessed based on the success of the procedures and safety was evaluated based on procedure-related complications.ResultsRegarding the intended use, a guide extension catheter was used to strengthen the backup force of the guiding catheter in 52% of cases, extend the tip of the catheter in 38% of cases, and maintain the coaxiality of the guiding catheter in 10% of cases. Procedural success was achieved in 92.7% of 55 sessions and in 95.6% of 91 lesions. Complex lesions had a lower success rate than simple lesions (p = 0.04). Regarding safety concerns, complications were observed in 5 of 55 sessions (9.1%) and 6 of 91 lesions (6.6%). Only one case of pulmonary artery dissection using a guide extension catheter was reported. Except for this one case, extension catheter-related complications were not observed.ConclusionsA guide extension catheter can be used safely in BPA procedures with anatomically complex pulmonary artery branches and complex lesions by increasing backup support.

Abstract Aims In patients with aortic valve stenosis (AS), cardiac sympathetic nervous (CSN) dysfunction and its improvement after transcatheter aortic valve replacement (TAVR) have been reported. The prognostic impact of CSN function remains unclear. This study investigated the prognostic value of cardiac 123I‐metaiodobenzylguanidine (MIBG) imaging for predicting cardiac events after TAVR. Methods and results This single‐centre prospective observational study enrolled patients with AS between July 2017 and May 2019. MIBG scintigraphy was performed before and soon after TAVR to evaluate the late heart–mediastinum ratio (L‐H/M). Patients were classified into three pairs of groups based on the baseline and post‐TAVR L‐H/M (≥2.0 or

Abstract Although heart failure (HF) and liver dysfunction often coexist because of complex cardiohepatic interactions, the association between liver dysfunction and physical dysfunction, and between coexistence of both and prognosis in HF patients remains unclear. We reviewed 895 patients with HF (mean age, 69.4 ± 14.2 years) who underwent liver function test using model for end-stage liver disease excluding international normalized ratio (MELD-XI) score and physical function test (grip strength, leg strength, gait speed, and 6-min walking distance [6MWD]). In the multiple regression analysis, MELD-XI score was independently associated with lower grip strength, leg strength, gait speed, and 6MWD (all P

Noriaki Miyanaga and Hideaki Takagi et al. identify an essential role for migratory dendritic cells in mediating immunotherapy treatment against allergies in mice. They show that submandibular lymph node dendritic cells induce regulatory T cells, and their absence abrogates the effectiveness of immunotherapy treatment.

Abstract Background Hyperhomocysteinemia is caused by genetic and environmental factors, which can result in systemic arteriosclerosis and arteriovenous thrombosis including acute coronary syndrome. Thrombus burden in patients with acute coronary syndrome and hyperhomocysteinemia might involve the culprit lesion as compared with those without any coagulopathy. The primary percutaneous coronary intervention with stent implantation had been established as the treatment strategy for patients with acute coronary syndrome. However, in patients with acute coronary syndrome with high thrombus burden or uncontrolled coagulopathy, stent implantation might lead to slow-flow phenomenon or stent thrombosis. Therefore, the treatment strategy in these patients was not established. Case presentation A 49-year-old Japanese man with history of splenic infarction of unknown cause had continued anticoagulant therapy since its diagnosis, but stopped taking the medication several months ago. He presented with sudden-onset chest dorsalgia. Contrast computed tomography showed a small pulmonary embolism and his troponin I level was elevated on initial laboratory test. Coronary angiography revealed a contrast defect caused by a large thrombus from the proximal to mid portion of the left anterior descending artery. Near-infrared spectroscopy–intravascular ultrasonography showed a large amount of thrombus without lipid plaque. Therefore, revascularization was performed using a thrombus-aspiration catheter and intracoronary thrombolysis. In addition, , hyperhomocysteinemia and a deep vein thrombosis occurred. He was diagnosed with acute coronary syndrome complicated with pulmonary embolism and deep vein thrombosis simultaneously induced by hyperhomocysteinemia. After 1 week of antithrombotic therapy, near-infrared spectroscopy–intravascular ultrasonography and optical coherence tomography revealed a decreased thrombus and no significant residual organic stenosis in the left anterior descending artery. He continued conservative therapy with antithrombotic medications including aspirin and warfarin and had no cardiovascular events after discharge. Follow-up coronary angiography and optical coherence tomography at 9 months revealed complete disappearance of the thrombus and no severe stenosis. Conclusions Hyperhomocysteinemia should be considered as a cause of arterial vein thrombosis of unknown cause. The antithrombotic therapy and percutaneous revascularization without stenting based on intravascular imaging might be a safe and effective treatment option in patients with acute coronary syndrome complicated with hyperhomocysteinemia.

Abstract Aims The area of the pupil can be used as an indicator of autonomic function. However, the relation between pupil area and prognosis in heart failure (HF) patients remains unclear. This study was performed to examine whether pupil area can be used as a prognostic indicator in patients with HF. Methods and results This retrospective review was performed in 870 consecutive patients (mean age: 67.0 ± 14.1 years, 37.0% women) hospitalized for acute HF. Pupil area was measured with a pupilometer at least 7 days after hospitalization for HF. The primary endpoint was all‐cause mortality, and the secondary endpoint was readmission due to HF. A total of 131 patients died, and 328 patients were readmitted because of HF over a median follow‐up of 1.9 (interquartile range: 1.0–3.7 years) years. After adjustment for several pre‐existing prognostic factors, including Seattle Heart Failure Score (SHFS), pupil area was shown to be independently associated with all‐cause mortality (hazard ratio: 0.72; 95% confidence interval: 0.59–0.88; P = 0.001) and readmission due to HF (hazard ratio: 0.82; 95% confidence interval: 0.73–0.93; P = 0.003). Addition of pupil area to SHFS significantly increased the area under the receiver‐operating characteristic curve for all‐cause mortality (0.69 vs. 0.72, respectively; P = 0.034). Conclusions Pupil area is an independent predictor of all‐cause mortality and readmission due to HF and adds prognostic information to SHFS in patients with HF. The results presented here suggest that pupil area may be useful as a prognostic marker in patients with HF.

Abstract We have identified “N”-shaped Y/X amplitude spectral ratios in S-coda records from a significant number of OBSs (ocean bottom seismometers) belonging to in-line-type ocean bottom networks of S-net and ETMC deployed around the Japan Trench and Sagami Trough, respectively. The “N”-shape reflects a sharp peak and notch at approximately 5–13 Hz and 10–23 Hz, respectively. This shape does not characterize OBSs belonging to node-type ocean bottom network of DONET deployed near the Nankai Trough. For S-net stations, the “N”-shape is not clearly formed for stations installed within grooves dug in the seafloor. We interpret the “N”-shaped Y/X amplitude spectral ratio is caused by the natural vibrations of a cylindrical pressure vessel that is placed sideways (long-axis lies in the horizontal plane) on the seafloor. The notch and peak frequencies in the Y/X amplitude spectral ratio likely correspond to natural frequencies of longitudinal (X-direction) and torsional and/or bending (Y-direction) vibrations, respectively. These natural vibrations are not observed for buried OBSs or those installed within grooves in the seafloor probably because they are better coupled to the seafloor. We propose a simple model to evaluate the extent to which the peak and notch have formed, which depends on the natural frequencies and coupling of the pressure vessel. We suggest users of in-line-type OBSs carefully examine if there are different responses between the X and Y components when frequencies about > 3 Hz are used. When installing OBS networks in the future, installing OBSs and cables within grooves dug in the seafloor or by burial will be effective in suppressing such natural vibrations.

Abstract Background Acute limb ischemia (ALI) and critical limb ischemia (CLI) following ALI are life-threatening diseases. The rare potential causes of ALI include hypercoagulable state diseases, such as antiphospholipid syndrome (APS) and essential thrombocythemia (ET). Hypercoagulability often make revascularization for arterial occlusion, especially associated with infrapopliteal lesions, difficult. This is because the vessels have poor run-off, and elevated peripheral vascular resistance associated with microcirculation failure, due to a high thrombus burden. There is no established treatment for this issue. Case presentation A 45 years-old and a 56 years-old male suffered from thrombotic arterial occlusion as a first manifestation of APS and ET, respectively. Combination therapy with aggressive anti-thrombotic therapy and revascularization, such as endovascular therapy and surgical thrombectomy based on the angiosome concept, was performed. However, the high thrombus burden caused a poor pedal outflow, and significant limb ischemia remained. Additional pedal artery angioplasty was performed to improve residual limb ischemia in each case and provided sufficient blood flow to the foot. Conclusion The pedal artery angioplasty for thrombotic pedal artery occlusion cases, associated with hypercoagulable state diseases, seems to be a treatment option for relieving residual limb ischemia.

White adipose tissue (WAT) is important for maintenance of homeostasis, because it stores energy and secretes adipokines. The WAT of obese people demonstrates mitochondrial dysfunction, accompanied by oxidative stress, which leads to insulin resistance. WW domain‐containing E3 ubiquitin protein ligase 1 (WWP1) is a member of the HECT‐type E3 family of ubiquitin ligases and is associated with several diseases. Recently, we demonstrated that WWP1 is induced specifically in the WAT of obese mice, where it protects against oxidative stress. Here, we investigated the function of WWP1 in WAT of obese mice by analyzing the phenotype of Wwp1 knockout (KO) mice fed a high‐fat diet. The levels of oxidative stress markers were higher in obese WAT from Wwp1 KO mice. Moreover, Wwp1 KO mice had lower activity of citrate synthase, a mitochondrial enzyme. We also measured AKT phosphorylation in obese WAT and found lower levels in Wwp1 KO mice. However, plasma insulin level was low and glucose level was unchanged in obese Wwp1 KO mice. Moreover, both glucose tolerance test and insulin tolerance test were improved in obese Wwp1 KO mice. These findings indicate that WWP1 participates in the antioxidative response and mitochondrial function in WAT, but knockdown of WWP1 improves whole‐body glucose metabolism.

BackgroundBalloon pulmonary angioplasty (BPA) is an effective treatment for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The purpose of this study is to evaluate the therapeutic effect and safety of the non-slip element percutaneous transluminal angioplasty (NSE PTA) scoring balloons in BPA.Methods108 pulmonary artery branches in 14 CTEPH patients who underwent BPA using NSE PTA scoring balloon (the NSE PTA group) or plain balloon (the POBA group) and pressure gradient evaluation were analyzed. We compared the improvement of the pressure ratios after BPA (Δ Pressure ratio) of both groups.ResultsThere was no significant difference in the Δ Pressure ratios of the two groups (0.241 ± 0.196 POBA, 0.259 ± 0.177 NSE PTA, p = 0.63). No complications occurred in the NSE PTA group, while 3 episodes of hemoptysis were seen in the POBA group. This, however, was not found to be significant (p = 0.27). In the cases where balloon-to-vessel ratio exceeded 1.0 (n = 35), multivariate analysis showed that the use of NSE PTA scoring balloon and pressure ratio before BPA were significantly correlated with Δ Pressure ratio (β coefficient: 0.047, 95% CI: 0.0016 to 0.093, p = 0.043 and β coefficient: -0.60, 95% CI: -0.78 to -0.42, p < 0.01, respectively).ConclusionsAlthough NSE PTA scoring balloon was safe, there was no significant pressure gradient improvement with NSE PTA scoring balloon compared to conventional BPA. Nevertheless, the NSE PTA scoring balloon showed effective blood-flow improvement in the case of large balloon-to-vessel ratio.

Removal of borate in mine drainages by co-precipitation with hydroxyapatite (HAp) was developed from a laboratory scale to a pilot scale. Weakly acidic initial pH facilitated to enhance dissolution of Ca(OH)2 and decrease the dissolved carbonate concentration, leading to efficient immobilization of borate and arsenate. The NH4H2PO4 lowered best the equilibrium B concentration among different phosphate sources, avoiding the lattice strain of HAp. The added molar ratio of P/Ca significantly influenced the decreasing behavior of the B concentration, showing the optimal value of 0.3. In case of P/Ca larger than 0.30, the excess concentration of PO43- was probably adsorbed on Ca(OH)2 particles to prevent the dissolution, resulting in inhibiting the formation of HAp. In case of P/Ca smaller than 0.30, the production of HAp was limited, leading to less immobilized borate. All the optimized conditions as above were applied to the pilot scale with a 250 L reactor, where borate concentration was effectively reduced in also both batch and continuous tests.

IntroductionThe post-intensive care syndrome (PICS) encompasses multiple, diverse conditions, such as physical disability, cognitive impairment, and depression. We sought to evaluate whether conditions within PICS have similar associations with mortality among survivors of critical illness.Materials and methodsIn this retrospective cohort study, we identified 248 critically ill patients with intensive care unit stay ≥72 hours, who underwent PICS evaluation. Patients with disability in activities of daily living, cognitive impairment, or depression before hospitalization were excluded. We defined PICS using established measures of physical disability (usual gait speed), cognitive impairment (Mini-Cog test), and depression (Patient Health Questionnaire-2) at hospital discharge. The endpoint was all-cause mortality.ResultsPatients had a median age of 69 years and Acute Physiology and Chronic Health Evaluation (APACHE) II score of 16. One hundred thirty-two patients were classified as having PICS, and 19 patients died. 81/248 (34%) patients had physical disability, 42/248 (19%) had cognitive impairment, and 44/248 (23%) had depression. After adjusting for covariates on multivariable Cox regression analyses, PICS was significantly associated with all-cause mortality (hazard ratio [HR] 3.78, 95% confidence interval [CI] 1.02 - 13.95; P = 0.046). However, the association between PICS and all-cause mortality was related to physical disability and cognitive impairment (P = 0.001 and P = 0.027, respectively), while depression was not (P = 0.623).ConclusionWhile PICS as a syndrome has been useful in gaining attention to the sequelae of critical illness, its relationship with long-term mortality is driven largely by physical disability and cognitive impairment and not depression.

BackgroundEach of the currently available (1→3)-β-D-glucan (BDG) measurement kits follows a different measurement method and cut-off value. Comparisons of diagnostic performance for invasive fungal infections (IFIs) are desirable. Additionally, ecological considerations are becoming increasingly important in the development of new measurement kits.MethodsThe plasma BDG levels in clinical samples were measured using the following currently available kits: the Fungitec G test MKII, the Fungitec G test ES, Fungitell, the β-Glucan test Wako, and the newly developed Wako kit (Wako-Eu). Wako-Eu uses a pre-treatment solution that conforms to European regulations for the registration, evaluation, authorisation, and restriction of chemicals. The values obtained for the samples using each kit were studied and compared.ResultsOf the 165 patients evaluated, 12 had IFIs, including pneumocystis pneumonia, aspergillosis, and candidiasis. BDG values obtained using the kits were moderately correlated with each other. Clinical diagnoses of the evaluated cases indicated that 21 false positives were diagnosed by at least one kit. The sensitivity of the Fungitell kit was relatively low, but those of the other four were over 90%. The specificity was above 90% for all kits. For positive predictive value, the Wako and the Wako-Eu methods were superior to the others owing to fewer false positive results.ConclusionsThe newly developed Wako-Eu method, which considers ecological concerns, shows diagnostic performance equivalent to that of its predecessor. To improve the diagnostic accuracy of IFIs, it is necessary to interpret the results carefully, giving due consideration to the characteristics of each measurement kit.

Background: Thromboembolic events are rare but critical complications in childhood nephrotic syndrome. The veins are more commonly affected, while arterial thrombosis is extremely rare but often life-threatening. Herein, we describe the clinical course of a 10-years-old girl with catastrophic multiple arterial thrombosis at the primary onset of nephrotic syndrome who underwent bilateral above-knee amputation.Case diagnosis/treatment: A previous healthy 10-years-old girl contracted the influenza B virus. Five days later, she suddenly developed severe ischemia in both legs. Physical examination showed eyelid and leg edema, and laboratory tests revealed hypoalbuminemia and acute kidney injury. After undergoing contrast-enhanced computed tomography, the patient was diagnosed with multiple arterial thrombosis (including the bilateral iliac arteries) due to nephrotic syndrome. Despite the performance of surgical thrombectomies, fasciotomy, and systematic heparinization, she required bilateral above-knee amputation. The patient achieved spontaneous remission of nephrotic syndrome, and her renal function fully recovered. There were no findings suggestive of secondary nephrotic syndrome and antiphospholipid syndrome. Her protein C and protein S concentrations were slightly decreased at admission. However, whole-exome sequencing revealed a thrombotic risk variant (T630I) in the PROS1 gene encoding protein S. This missense variant is often reported in patients with thrombosis or protein S deficiency, and may result in a thrombotic predisposition in some situations, such as nephrotic syndrome.Conclusions: Arterial thrombosis is a rare complication; however, it must be considered, especially in patients with new-onset nephrotic syndrome. Early recognition is important for early intervention and prevention of serious sequelae.

Abstract Seismic wave propagation from shallow subduction-zone earthquakes can be strongly affected by 3D heterogeneous structures, such as oceanic water and sedimentary layers with irregular thicknesses. Synthetic waveforms must incorporate these effects so that they reproduce the characteristics of the observed waveforms properly. In this paper, we evaluate the accuracy of synthetic waveforms for small earthquakes in the source area of the 2011 Tohoku–Oki earthquake (M JMA 9.0) at the Japan Trench. We compute the synthetic waveforms on the basis of a land–ocean unified 3D structure model using our heterogeneity, oceanic layer, and topography finite-difference method. In estimating the source parameters, we apply the first-motion augmented moment tensor (FAMT) method that we have recently proposed to minimize biases due to inappropriate source parameters. We find that, among several estimates, only the FAMT solutions are located very near the plate interface, which demonstrates the importance of using a 3D model for ensuring the self-consistency of the structure model, source position, and source mechanisms. Using several different filter passbands, we find that the full waveforms with periods longer than about 10 s can be reproduced well, while the degree of waveform fitting becomes worse for periods shorter than about 10 s. At periods around 4 s, the initial body waveforms can be modeled, but the later large-amplitude surface waves are difficult to reproduce correctly. The degree of waveform fitting depends on the source location, with better fittings for deep sources near land. We further examine the 3D sensitivity kernels: for the period of 12.8 s, the kernel shows a symmetric pattern with respect to the straight path between the source and the station, while for the period of 6.1 s, a curved pattern is obtained. Also, the range of the sensitive area becomes shallower for the latter case. Such a 3D spatial pattern cannot be predicted by 1D Earth models and indicates the strong effects of 3D heterogeneity on short-period ($${ \lesssim }\;10 {\text{s}}$$ ≲10s ) waveforms. Thus, it would be necessary to consider such 3D effects when improving the structure and source models.

In the Nankai subduction zone a low-velocity zone (LVZ) has been detected. Here, the authors present shear wave velocity profiles to show that low frequency earthquakes correlate with the distribution of the LVZ in the Nankai subduction zone.

Abstract Background Carnitine is reported to improve insulin resistance and reduce oxidative stress. Hyperglycemia and increased oxidative stress are well known to promote the production of advanced glycation end products (AGEs) that can lead to arteriosclerosis in patients with maintenance hemodialysis (HD). In the present study, we aimed to determine whether decreased level of serum carnitine accelerated arteriosclerosis and to clarify the relationships between carnitine, AGEs, and arteriosclerosis in HD patients. Methods We recruited 116 patients (65 men and 51 women, 62 ± 13 years) undergoing HD three times a week. We measured pre-HD serum free carnitine prior to the first weekly session. AGE level was quantitatively evaluated by measuring skin autofluorescence (SAF) with AGE reader. Arteriosclerosis was evaluated by measuring carotid intima-media thickness (cIMT). Relationships between free carnitine, SAF, and cIMT were analyzed, and significant limiting factors for arteriosclerosis were identified using univariate and multivariate regression analyses. Results Free carnitine ranged from 14.9 to 53.3 μmol/L (mean, 28.6 ± 8.1 μmol/L). Free carnitine was negatively correlated with SAF (r = − 0.223, P = 0.017) and cIMT (r = − 0.252, P = 0.006). SAF was positively correlated with cIMT (r = 0.263, P = 0.005). Free carnitine was identified as a significant independent limiting factor for cIMT (β = -0.194, P = 0.037). Conclusions Decreased level of serum carnitine might lead to the progression of arteriosclerosis via the AGE accumulation in HD patients.

Abstract Seismic activity occurred off western Kyushu, Japan, at the northern end of the Okinawa Trough on May 6, 2016 (14:11 JST), 22 days after the onset of the 2016 Kumamoto earthquake sequence. The area is adjacent to the Beppu–Shimabara graben where the 2016 Kumamoto earthquake sequence occurred. In the area off western Kyushu, a M7.1 earthquake also occurred on November 14, 2015 (5:51 JST), and a tsunami with a height of 0.3 m was observed. In order to better understand these seismic activity and tsunamis, it is necessary to study the sources of, and strong motions due to, earthquakes in the area off western Kyushu. For such studies, validation of synthetic waveforms is important because of the presence of the oceanic water layer and thick sediments in the source area. We show the validation results for synthetic waveforms through nonlinear inversion analyses of small earthquakes (~M5). We use a land–ocean unified 3D structure model, 3D HOT finite-difference method (“HOT” stands for Heterogeneity, Ocean layer and Topography) and a multi-graphic processing unit (GPU) acceleration to simulate the wave propagations. We estimate the first-motion augmented moment tensor (FAMT) solution based on both the long-period surface waves and short-period body waves. The FAMT solutions systematically shift landward by about 13 km, on average, from the epicenters determined by the Japan Meteorological Agency. The synthetics provide good reproductions of the observed full waveforms with periods of 10 s or longer. On the other hand, for waveforms with shorter periods (down to 4 s), the later surface waves are not reproduced well, while the first parts of the waveforms (comprising P- and S-waves) are reproduced to some extent. These results indicate that the current 3D structure model around Kyushu is effective for generating full waveforms, including surface waves with periods of about 10 s or longer. Based on these findings, we analyze the 2015 M7.1 event using the cross-correlations between the observed and synthetic waveforms. The result suggests a rupture propagation toward the NNE, with a major radiation about 25 km north of the onset point. Graphical Abstract .

Abstract A simple and efficient finite-difference scheme is developed to calculate seismic wave propagation in a partial spherical shell model of a three-dimensionally (3-D) heterogeneous global Earth structure for modeling on regional or sub-global scales where the effects of the Earth’s spherical geometry cannot be ignored. This scheme solves the elastodynamic equation in the quasi-Cartesian coordinate form similar to the local Cartesian one, instead of the spherical polar coordinate form, with a staggered-grid finite-difference method in time domain (FDTD) that is one of the most popular numerical methods in seismic-motion simulations for local-scale models. The proposed scheme may be a local-friendly approach for modeling on a sub-global scale to link regional-scale and local-scale simulations. It can be easily implemented using an available 3-D Cartesian FDTD local-scale modeling code by changing a very small part of the code. We implement the scheme in an existing Cartesian FDTD code and demonstrate the accuracy and validity of the present scheme and the feasibility to apply it to real large simulations through numerical examples. Graphical abstract .

Basophils, which are the rarest granulocytes, play crucial roles in protective immunity against parasites and development of allergic disorders. Although immunoglobulin (Ig)E-dependent responses via receptor for IgE (FcεRI) in basophils have been extensively studied, little is known about cell surface molecules that are selectively expressed on this cell subset to utilize the elimination in vivo through treatment with monoclonal antibody (mAb). Since CD200 receptor 3 (CD200R3) was exclusively expressed on basophils and mast cells (MCs) using a microarray screening, we have generated anti-CD200R3 mAb recognizing CD200R3A. In this study we examined the expression pattern of CD200R3A on leukocytes, and the influence of the elimination of basophils by anti-CD200R3A mAb on allergic responses. Flow cytometric analysis showed that CD200R3A was primarily expressed on basophils and MCs, but not on other leukocytes. Administration with anti-CD200R3A mAb led to the prominent specific depletion of tissue-resident and circulating basophils, but not MCs. Furthermore, in vivo depletion of basophils ameliorated IgE-mediated systemic and local anaphylaxis. Taken together, these findings suggest that CD200R3A is reliable cell surface marker for basophils in vivo, and targeting this unique molecule with mAb for the elimination of basophils may serve as a novel therapeutic strategy in ameliorating the allergic diseases.

Clec4A4 is a C-type lectin receptor highly expressed by CD8α− dendritic cells. Here the authors show that its loss of function results in enhanced T cell responses and exacerbated autoimmunity, implicating Clec4A4 in limiting activation of the CD8α−dendritic cells.

Disruption of skin homeostasis can lead to inflammatory cutaneous diseases resulting from the dysregulated interplay between epithelial keratinocytes and immune cells. Interleukin (IL)-22 signaling through membrane-bound IL-22 receptor 1 (IL-22R1) is crucial to maintain cutaneous epithelial integrity, and its malfunction mediates deleterious skin inflammation. While IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling, how IL-22BP controls epithelial functionality to prevent skin inflammation remains unclear. Here, we describe the pivotal role of IL-22BP in mediating epithelial autoregulation of IL-22 signaling for the control of cutaneous pathogenesis. Unlike prominent expression of IL-22BP in dendritic cells in lymphoid tissues, epidermal keratinocytes predominantly expressed IL-22BP in the skin in the steady state, whereas its expression decreased during the development of psoriatic inflammation. Deficiency in IL-22BP aggravates psoriasiform dermatitis, accompanied by abnormal hyperproliferation of keratinocytes and excessive cutaneous inflammation as well as enhanced dermal infiltration of granulocytes and γδT cells. Furthermore, IL-22BP abrogates the functional alternations of keratinocytes upon stimulation with IL-22. On the other hand, treatment with IL-22BP alleviates the severity of cutaneous pathology and inflammation in psoriatic mice. Thus, the fine-tuning of IL-22 signaling through autocrine IL-22BP production in keratinocytes is instrumental in the maintenance of skin homeostasis.

Clinical evidence suggests that early mobilization of patients with acute stroke improves activity of daily living (ADL). The purpose of this study was to compare the utility of the physiatrist and registered therapist operating acute rehabilitation (PROr) applied early or late after acute stroke.This study was prospective cohort study, assessment design. Patients with acute stroke (n = 227) admitted between June 2014 and April 2015 were divided into three groups based on the time of start of PROr: within 24 hours (VEM, n = 47), 24-48 hours (EM, n = 77), and more than 48 hours (OM, n = 103) from stroke onset. All groups were assessed for the number of deaths during hospitalization, and changes in the Glasgow Coma Scale (GCS), National Institute of Health Stroke Scale (NIHSS), and Functional Independence Measure (FIM) at hospital discharge.All patients were assessed by physiatrists, who evaluated the specific needs for rehabilitation, and then referred them to registered physical therapists and occupational therapists to provide early mobilization (longer than one hour per day per patient).The number of deaths encountered during the PROr period was 13 (out of 227, 5.7%), including 2 (4.3%) in the VEM group. GCS improved significantly during the hospital stay in all three groups, but the improvement on discharge was significantly better in the VEM group compared with the EM and OM groups. FIM improved significantly in the three groups, and the gains in total FIM and motor subscale were significantly greater in the VEM than the other groups.PROr seems safe and beneficial rehabilitation to improve ADL in patients with acute stroke.

The purpose of this study was to determine the effect of aerobic training under noninvasive positive pressure ventilation (NPPV) on maximal oxygen uptake ([Formula: see text]).Ten healthy young male volunteers participated in the study. Before the training, stroke volume (SV) and cardiac output (CO) were measured in all subjects under 0, 4, 8, and 12 cmH2O NPPV at rest. Then, the subjects exercised on a cycle ergometer at 60% of pre-training [Formula: see text] for 30 min daily for 5 consecutive days with/without NPPV. The 5-day exercise protocol was repeated after a three-week washout period without/with NPPV. The primary endpoint was changes in [Formula: see text]. The secondary endpoints were changes in SV, CO, maximum heart rate (HRmax), maximum respiratory rate (RRmax), maximum expiratory minute volume (VEmax) and the percent change in plasma volume (PV).NPPV at 12 cmH2O significantly reduced SV and CO at rest. [Formula: see text] significantly increased after 5 days training with and without NPPV, but the magnitude of increase in [Formula: see text] after training under 12 cmH2O NPPV was significantly higher than after training without NPPV. VEmax significantly increased after training under NPPV, but not after training without NPPV. HRmax and RRmax did not change during training irrespective of NPPV. The percent change in PV was similar between training with and without NPPV. The 5-day training program with NPPV resulted in greater improvement in [Formula: see text] than without NPPV.Aerobic training under NPPV has add-on effects on [Formula: see text] and exercise-related health benefits in healthy young men.

Today, a large proportion of persons with spinal cord injury (SCI) can return to society thanks to advances in biomedical care. Various sports activities are recommended, especially for wheelchair-bound disabled persons with SCI, in order to maintain proper physical fitness. It is important to know sports activities-induced physiological specificity in persons with SCI before recommending sports activities. Natural killer cell activity (NKCA) is commonly used to study immune response during exercise. Interleukin (IL)-6 is produced by contracting skeletal muscles and then released into the circulation; and is considered to mediate the health benefits of exercise against chronic diseases. We investigated the responses of NKCA and IL-6 in SCI persons during arm exercise and a wheelchair marathon race. Similar NKCA and IL-6 responses were found in thoracolumbar SCI persons and able-bodied (AB) persons. On the other hand, changes in NKCA and IL-6 in cervical SCI persons elicited different characteristic patterns compared to thoracolumbar SCI and AB persons.

Many mortality risk scoring tools exist among patients with ST-elevation Myocardial Infarction (STEMI). A risk stratification model that evaluates STEMI prognosis more simply and rapidly is preferred in clinical practice.We developed a simple stratification model for blood examination by using the STEMI data of AMI-Kyoto registry in the derivation set (n = 1,060) and assessed its utility for mortality prediction in the validation set (n = 521). We selected five variables that significantly worsen in-hospital mortality: white blood cell count, hemoglobin, C-reactive protein, creatinine, and blood sugar levels at >10,000/μL, 1.0 mg/dL, >1.0 mg/dL, and >200 mg/dL, respectively. In the derivation set, each of the five variables significantly worsened in-hospital mortality (p < 0.01). We developed the risk stratification model by combining laboratory variables that were scored based on each beta coefficient obtained using multivariate analysis and divided three laboratory groups. We also found a significant trend in the in-hospital mortality rate for three laboratory groups. Therefore, we assessed the utility of this model in the validation set. The prognostic discriminatory capacity of our laboratory stratification model was comparable to that of the full multivariable model (c-statistic: derivation set vs validation set, 0.81 vs 0.74). In addition, we divided all cases (n = 1,581) into three thrombolysis in myocardial infarction (TIMI) risk index groups based on an In TIME II substudy; the cases were further subdivided based on this laboratory model. The high laboratory group had significantly high in-hospital mortality rate in each TIMI risk index group (trend of in-hospital mortality; p < 0.01).This laboratory stratification model can predict in-hospital mortality of STEMI simply and rapidly and might be useful for predicting in-hospital mortality of STEMI by further subdividing the TIMI risk index.

Background and study aims: The number of patients with chronic kidney disease (CKD) is increasing worldwide and gastric cancer sometimes occurs with CKD. However, the safety and feasibility of endoscopic submucosal dissection (ESD) for patients with CKD are not clear. The aim of this study is to clarify the feasibility and safety of gastric ESD for patients with CKD. Patients and methods: This was a multicenter retrospective cohort study. In total, 144 patients with CKD who underwent gastric ESD between May 2003 and October 2012 were enrolled. The patients were divided into three groups: stage 3 (estimated glomerular filtration rate [eGFR]: 30 – 59 mL/min), stage 4 (eGFR: 15 – 29 mL/min), and stage 5 (eGFR:

Although mannitol has been used as an osmotherapeutic drug on brain injury, the clinical efficiency of the drug are still controversial. In the present study, we examined the effects of mannitol on the edema in a hippocampal slice due to brief ischemia. To evaluate the effects, we employed an image analysis system that consists of an infrared-differential interference contrast (IR-DIC) microscope, an infrared CCD camera, and a computer with custom-made software. By this system, severity of the edema can be quantified as the coefficient of variation (CV) of digitalized slice images. The dose-dependent improvement on the deteriorated hippocampal slices could be obtained by administration of mannitol (10, 50, and 100 mM) after 10-min ischemia. However, field excitatory postsynaptic potentials (fEPSP) in CA1 stratum radiatum, which disappeared during 10-min ischemia, were never recovered by mannitol after more than 20-min treatment. fEPSP were blocked by the effective dose of mannitol for morphological recovery, but the effects found to be reversible. Although we failed to find positive rescuing effects of mannitol on the synaptic activities after ischemia, the protective effects of the drug on ischemic edema may rescue the secondary damages around the infarct area. Keywords:: mannitol, ischemia, brain edema, hippocampus, image analysis

ABSTRACT: Since voltage-sensitive dyes (VSDs) change their optical properties in response to membrane potential changes, non-invasive optical measurements of membrane excitation using VSDs have been applied to various types of excitable tissue. This article deals with the authors' recent work using this technique in addition to basic and technical information about VSD imaging. By applying this technology to hippocampal brain slices, we have found that astrocytes play indispensable roles in sequestering glutamate, maintenance of synaptic transmission, and neuronal survival. Finally, the potential of VSD imaging for drug development was discussed.

OBJECTIVE: To assess the separate effects of thumb and finger extension/flexion on median nerve position and cross-sectional area. METHODS: Ultrasonography was used to assess median nerve transverse position and cross-sectional area within the carpal tunnel at rest and its movement during volitional flexion of the individual digits of the hand. Both wrists of 165 normal subjects (11 men, 4 women, mean age, 28.6, range, 22 to 38) were studied. RESULTS: Thumb flexion resulted in transverse movement of the median nerve in radial direction (1.2 ± 0.6 mm), whereas flexion of the fingers produced transverse movement in ulnar direction, which was most pronounced during flexion of the index and middle fingers (3.2 ± 0.9 and 3.1 ± 1.0 mm, respectively). Lesser but still statistically significant movements were noted with flexion of the ring finger (2.0 ± 0.8 mm) and little finger (1.2 ± 0.5 mm). Flexion of the thumb or individual fingers did not change median nerve cross-sectional area (8.5 ± 1.1 mm(2)). CONCLUSIONS: Volitional flexion of the thumb and individual fingers, particularly the index and middle fingers, produced significant transverse movement of the median nerve within the carpal tunnel but did not alter the cross-sectional area of the nerve. The importance of these findings on the understanding of the pathogenesis of the carpal tunnel syndrome and its treatment remains to be investigated.

The use of exocytosis for membrane expansion at nerve growth cones is critical for neurite outgrowth. TC10 is a Rho family GTPase that is essential for specific types of vesicular trafficking to the plasma membrane. Recent studies have shown that TC10 and its effector Exo70, a component of the exocyst tethering complex, contribute to neurite outgrowth. However, the molecular mechanisms of the neuritogenesis-promoting functions of TC10 remain to be established. Here, we propose that GTP hydrolysis of vesicular TC10 near the plasma membrane promotes neurite outgrowth by accelerating vesicle fusion by releasing Exo70. Using Förster resonance energy transfer (FRET)-based biosensors, we show that TC10 activity at the plasma membrane decreased at extending growth cones in hippocampal neurons and nerve growth factor (NGF)-treated PC12 cells. In neuronal cells, TC10 activity at vesicles was higher than its activity at the plasma membrane, and TC10-positive vesicles were found to fuse to the plasma membrane in NGF-treated PC12 cells. Therefore, activity of TC10 at vesicles is presumed to be inactivated near the plasma membrane during neuronal exocytosis. Our model is supported by functional evidence that constitutively active TC10 could not rescue decrease in NGF-induced neurite outgrowth induced by TC10 depletion. Furthermore, TC10 knockdown experiments and colocalization analyses confirmed the involvement of Exo70 in TC10-mediated trafficking in neuronal cells. TC10 frequently resided on vesicles containing Rab11, which is a key regulator of recycling pathways and implicated in neurite outgrowth. In growth cones, most of the vesicles containing the cell adhesion molecule L1 had TC10. Exocytosis of Rab11- and L1-positive vesicles may play a central role in TC10-mediated neurite outgrowth. The combination of this study and our previous work on the role of TC10 in EGF-induced exocytosis in HeLa cells suggests that the signaling machinery containing TC10 proposed here may be broadly used for exocytosis.

BACKGROUND: Inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) are intracellular Ca2+ release channels that regulate various vital processes. Although the ryanodine receptor type 2, another type of intracellular Ca2+ release channel, has been shown to play a role in embryonic cardiomyocytes, the functions of the IP3Rs in cardiogenesis remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: We found that IP3R1(-/-)-IP3R2(-/-) double-mutant mice died in utero with developmental defects of the ventricular myocardium and atrioventricular (AV) canal of the heart by embryonic day (E) 11.5, even though no cardiac defect was detectable in IP3R1(-/-) or IP3R2(-/-) single-mutant mice at this developmental stage. The double-mutant phenotype resembled that of mice deficient for calcineurin/NFATc signaling, and NFATc was inactive in embryonic hearts from the double knockout-mutant mice. The double mutation of IP3R1/R2 and pharmacologic inhibition of IP3Rs mimicked the phenotype of the AV valve defect that result from the inhibition of calcineurin, and it could be rescued by constitutively active calcineurin. CONCLUSIONS/SIGNIFICANCE: Our results suggest an essential role for IP3Rs in cardiogenesis in part through the regulation of calcineurin-NFAT signaling.

Advances in time-lapse fluorescence microscopy have enabled us to directly observe dynamic cellular phenomena. Although the techniques themselves have promoted the understanding of dynamic cellular functions, the vast number of images acquired has generated a need for automated processing tools to extract statistical information. A problem underlying the analysis of time-lapse cell images is the lack of rigorous methods to extract morphodynamic properties. Here, we propose an algorithm called edge evolution tracking (EET) to quantify the relationship between local morphological changes and local fluorescence intensities around a cell edge using time-lapse microscopy images. This algorithm enables us to trace the local edge extension and contraction by defining subdivided edges and their corresponding positions in successive frames. Thus, this algorithm enables the investigation of cross-correlations between local morphological changes and local intensity of fluorescent signals by considering the time shifts. By applying EET to fluorescence resonance energy transfer images of the Rho-family GTPases Rac1, Cdc42, and RhoA, we examined the cross-correlation between the local area difference and GTPase activity. The calculated correlations changed with time-shifts as expected, but surprisingly, the peak of the correlation coefficients appeared with a 6-8 min time shift of morphological changes and preceded the Rac1 or Cdc42 activities. Our method enables the quantification of the dynamics of local morphological change and local protein activity and statistical investigation of the relationship between them by considering time shifts in the relationship. Thus, this algorithm extends the value of time-lapse imaging data to better understand dynamics of cellular function.

We have analytically calculated and measured the amplitude-dependent shift of the betatron oscillation center at the electron storage ring, NewSUBARU. The shift is due to nonzero average horizontal deflections at the normal sextupole magnets. The shifted center forms a displaced closed orbit and is measured by a closed orbit distortion measurement system, although no single electron runs on this orbit. The measured shifts by betatron oscillations agreed with the theoretical calculation except the variation of data points, which did not obey the ring symmetry. Additional measurements, whose results included the effect of the circumference shift, experimentally proved the amplitude dependent circumference shift for the first time. We also discuss some applications of the shift, which has never been previously analyzed.