Optimal stimulation site of the femoral nerve to record F waves from the vastus lateralis muscle.

INTRODUCTION/AIMS: The conventional recording of F waves from the vastus lateralis muscle (VL) may not accurately measure the F-wave amplitude, as the F-wave latency is short and overlaps with the M wave. However, the optimal stimulation site of the femoral nerve for recording M and F waves separately from the VL remains unclear. In this study we aimed to determine the optimal stimulation site of the femoral nerve to record M and F waves separately from the VL. METHODS: Stimulating electrodes were placed medial and lateral to the VL (50%, 60%, 70%, and 80% of the distance along a line extending from the proximal to the distal thigh). Each site of the distal thigh was electrically stimulated at random and F waves were recorded from the VL. Each stimulation site was considered to be success if there was no severe pain or discomfort during electrical stimulation of the femoral nerve and no overlap between the recorded M and F waves; otherwise, it was determined as a failure. RESULTS: Thirteen healthy men participated in the study. F waves were successfully recorded in five participants at the 50% sites, eight participants at the 60% site, and 12 participants at the 70% and 80% sites. In cases of failed F-wave measurement, the participants experienced severe pain or discomfort due to electrical stimulation. DISCUSSION: M and F waves could be recorded separately from the VL when the relevant branch of the femoral nerve was stimulated in the distal thigh.

Home exercises after volar locking plate fixation for distal radius fracture in the elderly are as effective as supervised physiotherapy -multicenter retrospective study.

BACKGROUND: Although home exercises are used for postoperative rehabilitation of distal radius fractures (DRF), the superiority of home exercise over supervised physiotherapy rehabilitation is controversial. This study aimed to compare the function of home exercise and supervised physiotherapy rehabilitation during postoperative rehabilitation for DRF. METHODS: We conducted a multicenter, retrospective study in which we included 1949 patients over 65 years old who underwent volar locking plate fixation for DRF. After propensity score matching, 308 patients were assigned to each of an independent home exercise group (IHG) and supervised physiotherapy group (SPG). Wrist function was assessed after 3, 6, and 12 months postoperatively. RESULTS: The results showed that the Mayo Wrist Score did not differ significantly within the observation period. Range of motion of the wrist was better in the SPG up to 3 months postoperatively but was almost the same as that in the IHG at 6 months. However, the Numerical Rating Scale score was lower in the IHG during all observation periods. CONCLUSIONS: Home exercise may be as effective as supervised physiotherapy in the medium term, but supervised physiotherapy rehabilitation should be considered if early recovery and good wrist function are desired.

Excitability of anterior horn cells after periodic or discrete repetitive movements.

INTRODUCTION/AIMS: It has been well established that spasticity interferes with smooth joint movements. Although the degree of spasticity is related to the excitability of anterior horn cells and is thought to improve after repetitive movements, the effect of the rhythm of repetitive movements on the excitability of anterior horn cells remains unknown. Therefore, we investigated the excitability of anterior horn cells after periodic and discrete repetitive movements using F waves. METHODS: Right-handed, healthy subjects were recruited for this study. Subjects then performed periodic or discrete repetitive thumb abduction movements for 10 seconds, measuring the F waves before, immediately after, and then 2 and 4 minutes after performing these movements. Specifically, the F waves were recorded from the abductor pollicis brevis muscle, after median nerve stimulation at the wrist. Next, the F/M amplitude ratio, which was used to evaluate the excitability of anterior horn cells, was compared before, immediately after, and 2 and 4 minutes after each task. RESULTS: A total of 12 subjects participated in this study. In the periodic task, the F/M amplitude ratio was found to be significantly decreased immediately after the task compared with before the task, but there was no significant difference between the other trials. Conversely, in the discrete task, there was no significant difference in the F/M amplitude ratio between trials. DISCUSSION: Periodic repetitive movements were found to temporarily reduce the excitability of anterior horn cells.

Single-incision laparoscopic cholecystectomy with the right accessory hepatic duct diagnosed preoperatively: A case report.

Accessory hepatic duct or gallbladder duplication is considered to be a risk factor for bile duct injuries and open conversion during laparoscopic cholecystectomy (LC). A 32-year-old woman with epigastric pain was referred to our department. Gallstone disease in the gallbladder was diagnosed by ultrasonography and magnetic resonance cholangiopancreatography. The involvement of an accessory hepatic duct was suspected during endoscopic retrograde cholangiography. Drip infusion cholangiography with computed tomography showed that the cystic duct merged with the accessory right hepatic duct. Single-incision LC (SILC) was successfully performed without bile duct injury. The operative time and intraoperative blood loss were 145 min and 1 mL, respectively. The patient was discharged 3 days' postoperatively, without complications. The involvement of the accessory right hepatic duct is a rare anomaly and is considered to be a risk factor for bile duct injuries. However, obtaining pre-operative images enabled us to perform SILC successfully.

Induction of human pluripotent stem cell-derived natural killer cells for immunotherapy under chemically defined conditions.

Natural killer (NK) cells are innate lymphocytes and show cytotoxicity against tumor cells without prior antigen specific stimulation. Because of their innate properties, NK cells are being considered for immunotherapies against various malignancies or leukemia. Human pluripotent stem cells (hPSCs) are capable of inducing enough NK cells for allogeneic transplantation. However, current induction protocols require feeder cells or human or bovine serum for the differentiation and expansion of NK cells, which incurs potential risk for contamination and may cause lot dependency in the cells. To address these issues, here we established a differentiation protocol for developing functional NK cells from hPSCs under a completely chemically-defined condition. The resultant PSC-derived NK cells show comparable phenotypes to those produced under serum-containing condition, exerting strong killing potential against a leukemia cell line in vitro and resistance to tumor growth in vivo. Our protocol can be a useful tool for applying PSC-derived NK cells to future cellular cancer immunotherapies.

Small Imaging Depth LIDAR and DCNN-Based Localization for Automated Guided Vehicle.

We present our third prototype sensor and a localization method for Automated Guided Vehicles (AGVs), for which small imaging LIght Detection and Ranging (LIDAR) and fusion-based localization are fundamentally important. Our small imaging LIDAR, named the Single-Photon Avalanche Diode (SPAD) LIDAR, uses a time-of-flight method and SPAD arrays. A SPAD is a highly sensitive photodetector capable of detecting at the single-photon level, and the SPAD LIDAR has two SPAD arrays on the same chip for detection of laser light and environmental light. Therefore, the SPAD LIDAR simultaneously outputs range image data and monocular image data with the same coordinate system and does not require external calibration among outputs. As AGVs travel both indoors and outdoors with vibration, this calibration-less structure is particularly useful for AGV applications. We also introduce a fusion-based localization method, named SPAD DCNN, which uses the SPAD LIDAR and employs a Deep Convolutional Neural Network (DCNN). SPAD DCNN can fuse the outputs of the SPAD LIDAR: range image data, monocular image data and peak intensity image data. The SPAD DCNN has two outputs: the regression result of the position of the SPAD LIDAR and the classification result of the existence of a target to be approached. Our third prototype sensor and the localization method are evaluated in an indoor environment by assuming various AGV trajectories. The results show that the sensor and localization method improve the localization accuracy.

Predictors of biologic discontinuation due to insufficient response in patients with rheumatoid arthritis who achieved clinical remission with biologic treatment: A multicenter observational cohort study.

OBJECTIVE: This study aimed to investigate predictors of biologic discontinuation due to insufficient response as a surrogate for relapse in patients with rheumatoid arthritis (RA) who achieved clinical remission with biologic treatment. METHODS: This study was performed based on data from a multicenter registry, and included 404 patients who achieved clinical remission within the first year of treatment with their first biologic. Cumulative retention rate of the first biologic was estimated using Kaplan-Meier curves, and the impact of patient characteristics on biologic discontinuation was assessed with Cox proportional hazards models. RESULTS: During follow-up, 50 patients discontinued their first biologic due to insufficient response. Overall discontinuation rates due to insufficient response after achieving remission were 6%, 11%, and 19% at 1, 2, and 5 years, respectively. Multivariate analysis revealed that concomitant glucocorticoids at achieving remission [hazard ratio (HR): 3.80, 95% confidence interval (CI): 1.89-7.64)] and a higher level of C-reactive protein (CRP) at achieving remission (HR: 1.47 per 1 mg/dL, 95% CI: 1.09-1.99) independently predict discontinuation due to insufficient response after achieving remission. CONCLUSION: Patients with RA who achieved remission with concomitant glucocorticoid treatment and a higher level of CRP are at high risk of subsequent biologic discontinuation due to insufficient response.

Single-Photon Avalanche Diode with Enhanced NIR-Sensitivity for Automotive LIDAR Systems.

A single-photon avalanche diode (SPAD) with enhanced near-infrared (NIR) sensitivity has been developed, based on 0.18 µm CMOS technology, for use in future automotive light detection and ranging (LIDAR) systems. The newly proposed SPAD operating in Geiger mode achieves a high NIR photon detection efficiency (PDE) without compromising the fill factor (FF) and a low breakdown voltage of approximately 20.5 V. These properties are obtained by employing two custom layers that are designed to provide a full-depletion layer with a high electric field profile. Experimental evaluation of the proposed SPAD reveals an FF of 33.1% and a PDE of 19.4% at 870 nm, which is the laser wavelength of our LIDAR system. The dark count rate (DCR) measurements shows that DCR levels of the proposed SPAD have a small effect on the ranging performance, even if the worst DCR (12.7 kcps) SPAD among the test samples is used. Furthermore, with an eye toward vehicle installations, the DCR is measured over a wide temperature range of 25-132 °C. The ranging experiment demonstrates that target distances are successfully measured in the distance range of 50-180 cm.

The relationship between trans-femoral prosthesis alignment and the center trajectory of plantar pressure in the frontal plane.

[Purpose] It is difficult to identify by visual observation whether alignment abnormalities in trans-femoral prostheses in the frontal plane are attributable to the adduction angle or the abnormal alignment of the positions of the medial and lateral sides of the socket in relation to the foot. Therefore, we focused on the trajectory of the center of plantar pressure during walking, and we proposed a method for differentiating these two alignment abnormalities. [Subjects and Methods] We recruited 4 trans-femoral unilateral amputees. Bench alignment was achieved initially. We compared the amplitude of the trajectory of the center of plantar pressure when walking under 2 conditions: 1) when changing the adduction angle and 2) when changing the positional relationship between the socket and the foot. [Results] It was not possible to distinguish between the 2 types of malalignment on the prosthesis side. There was a significant difference when changing the positional relationship on the contralateral side. Thereby, the plantar pressure of the contralateral side could be used to distinguish between the 2 types of malalignment. [Conclusion] The results of this study suggested that trans-femoral prosthesis malalignment could be evaluated through the plantar pressure of the contralateral side in amputees.

Development of an algorithm to predict comfort of wheelchair fit based on clinical measures.

[Purpose] The purpose of this study was to develop an algorithm to predict the comfort of a subject seated in a wheelchair, based on common clinical measurements and without depending on verbal communication. [Subjects] Twenty healthy males (mean age: 21.5 ± 2 years; height: 171 ± 4.3 cm; weight: 56 ± 12.3 kg) participated in this study. [Methods] Each experimental session lasted for 60 min. The clinical measurements were obtained under 4 conditions (good posture, with and without a cushion; bad posture, with and without a cushion). Multiple regression analysis was performed to determine the relationship between a visual analogue scale and exercise physiology parameters (respiratory and metabolism), autonomic nervous parameters (heart rate, blood pressure, and salivary amylase level), and 3D-coordinate posture parameters (good or bad posture). [Results] For the equation (algorithm) to predict the visual analogue scale score, the adjusted multiple correlation coefficient was 0.72, the residual standard deviation was 1.2, and the prediction error was 12%. [Conclusion] The algorithm developed in this study could predict the comfort of healthy male seated in a wheelchair with 72% accuracy.

[Hepatic resection for local recurrence after radiofrequency ablation therapy for colorectal liver metastases].

Patients who underwent hepatic resection of locally recurrent tumors after radiofrequency ablation(RFA)for colorectal liver metastases (CRLM) were retrospectively investigated. Among 12 patients who underwent RFA as first-line treatment for CRLM, 7 experienced local recurrence, 5 of whom (6 nodules) underwent hepatic resection. The mean diameter (range) of the tumors was 9.5(5-16) mm, and they were located at S2, S7 (adjacent to the right hepatic vein), S5/6 (between the root of the anterior and the posterior Glisson's pedicle), S1r (right paracaval portion), S6, and S3. No local recurrence was observed after hepatic resection. In conclusion, hepatic resection must be the initial therapeutic strategy for CRLM, and the indication for RFA must be considered carefully.

Clinical efficacy of abatacept in Japanese rheumatoid arthritis patients.

OBJECTIVES: The purpose of this study was to examine the treatment retention and efficacy of abatacept, the first member of a new class of biologic agents, in Japanese rheumatoid arthritis (RA) patients during clinical practice. METHODS: A retrospective multicenter study was conducted with patients who underwent abatacept therapy for 24 weeks (n = 143). RESULTS: Patients at baseline had a mean age of 63.5 years, a mean disease duration of 11.3 years, and a mean disease activity score in 28 joints (DAS28) of 4.5. Overall retention of abatacept treatment was 83.2 % at 24 weeks, when 46.2 % of patients achieved DAS28-defined low disease activity (LDA; DAS28 <3.2) and 26.6 % achieved DAS28-defined remission (DAS28 <2.6). LDA was achieved in a significantly higher proportion of patients without prior biologics therapy compared to those with prior biologics (60.9 vs. 34.2 %, p = 0.001). There was no significant difference between patients with or without concomitant methotrexate (MTX) therapy (45.2 vs. 47.5 %). CONCLUSIONS: Abatacept therapy appears to be highly effective and well tolerated during clinical treatment of RA. Abatacept was particularly effective in patients with no history of biologics use, and did not appear to be dependent on concomitant MTX therapy.

Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis.

OBJECTIVES: The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C-reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks. METHODS: One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels. RESULTS: Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks. CONCLUSIONS: Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice.

Efficacious Combination Drug Treatment for Colorectal Cancer That Overcomes Resistance to KRAS G12C Inhibitors.

Recent advances in combinatorial chemistry led to the discovery of inhibitors targeting the KRAS G12C-mutant protein. However, efficacy of its monotherapy on colorectal cancer is limited. Thus, effective combination drugs should be explored for applicable patients with colorectal cancer to fully benefit from the KRAS G12C inhibitor treatment. Here we used a patient-derived colorectal cancer stem cell (PD-CRC-SC) spheroid culture and showed that three-drug combination of inhibitors against KRAS G12C, EGFR, and FGFR synergistically suppressed the growth of colorectal cancer cells carrying the KRAS G12C mutation. Likewise, a combination of KRAS G12C and SHP2 inhibitors was also effective. Importantly, activation of the PI3K/AKT pathway in heregulin-responsive colorectal cancer cells canceled out the effect of KRAS G12C inhibition, which was largely overcome by PI3K inhibitors. These results reveal that evaluating efficacy of combination therapies with PD-CRC-SC spheroids can be a promising strategy to find the best regimen for patients with colorectal cancer.

Crystal structures of protein glutaminase and its pro forms converted into enzyme-substrate complex.

Protein glutaminase, which converts a protein glutamine residue to a glutamate residue, is expected to be useful as a new food-processing enzyme. The crystal structures of the mature and pro forms of the enzyme were refined at 1.15 and 1.73 Å resolution, respectively. The overall structure of the mature enzyme has a weak homology to the core domain of human transglutaminase-2. The catalytic triad (Cys-His-Asp) common to transglutaminases and cysteine proteases is located in the bottom of the active site pocket. The structure of the recombinant pro form shows that a short loop between S2 and S3 in the proregion covers and interacts with the active site of the mature region, mimicking the protein substrate of the enzyme. Ala-47 is located just above the pocket of the active site. Two mutant structures (A47Q-1 and A47Q-2) refined at 1.5 Å resolution were found to correspond to the enzyme-substrate complex and an S-acyl intermediate. Based on these structures, the catalytic mechanism of protein glutaminase is proposed.

A selective estrogen receptor modulator inhibits tumor necrosis factor-α-induced apoptosis through the ERK1/2 signaling pathway in human chondrocytes.

Tumor necrosis factor α (TNF-α) is a pleiotropic cytokine mediating inflammatory as well as cell death activities, and is thought to induce chondrocytic chondrolysis in inflammatory and degenerative joint diseases. Selective estrogen receptor modulators (SERMs), such as raloxifene, which are commonly used in clinical settings act as estrogen agonists or antagonists. It is assumed that estrogens have a potential role in cartilage protection; however, the precise molecular mechanism for the protective effects of estrogens is unclear. This study was designed to examine whether raloxifene inhibits TNF-α-induced apoptosis in human chondrocytes and to clarify the mechanisms involved. We also investigated the signaling pathways responsible for the anti-apoptotic effect of raloxifene. Apoptosis in chondrocytes was determined by DNA fragmentation assay and caspase-3 activation. Raloxifene significantly inhibited TNF-α-induced caspase-3 activation and cell DNA fragmentation levels in chondrocytes. The inhibitory effect of raloxifene was abolished by the estrogen receptor antagonist ICI 182,780. Extracellular signal-regulated kinase 1/2 (ERK1/2) regulates apoptosis, acting as an apoptotic or anti-apoptotic signal. TNF-α-induced apoptosis was significantly enhanced by the ERK1/2 pathway inhibitor PD98059. Raloxifene stimulated a further increase in ERK1/2 phosphorylation in TNF-α-treated chondrocytes. Furthermore, the anti-apoptotic effects of raloxifene were inhibited by PD98059. In addition, the anti-apoptotic effects of raloxifene were completely abolished in ERK1/2 siRNA-treated chondrocytes. These results suggest that raloxifene prevents caspase-3-dependent apoptosis induced by TNF-α in human chondrocytes by activating estrogen receptors and the ERK1/2 signaling pathway.

Design and characterization of a 256 x 64-pixel single-photon imager in CMOS for a MEMS-based laser scanning time-of-flight sensor.

We introduce an optical time-of-flight image sensor taking advantage of a MEMS-based laser scanning device. Unlike previous approaches, our concept benefits from the high timing resolution and the digital signal flexibility of single-photon pixels in CMOS to allow for a nearly ideal cooperation between the image sensor and the scanning device. This technique enables a high signal-to-background light ratio to be obtained, while simultaneously relaxing the constraint on size of the MEMS mirror. These conditions are critical for devising practical and low-cost depth sensors intended to operate in uncontrolled environments, such as outdoors. A proof-of-concept prototype capable of operating in real-time was implemented. This paper focuses on the design and characterization of a 256 x 64-pixel image sensor, which also comprises an event-driven readout circuit, an array of 64 row-level high-throughput time-to-digital converters, and a 16 Gbit/s global readout circuit. Quantitative evaluation of the sensor under 2 klux of background light revealed a repeatability error of 13.5 cm throughout the distance range of 20 meters.

Effect of total arthroplasty combined with anti-tumor necrosis factor agents in attenuating systemic disease activity in patients with rheumatoid arthritis.

We assessed the effect of total large-joint arthroplasty combined with anti-tumor necrosis factor (TNF) therapy for rheumatoid arthritis (RA). We studied 45 RA patients (age 57.91 ± 12.74 years, RA duration 13.43 ± 8.28 years) who underwent total arthroplasty (35 knees, 19 hips, 3 elbows, and 1 ankle) between August 2002 and November 2009. All patients received anti-TNF agents (infliximab, 22; etanercept, 33; adalimumab, 3) during the period of the study (that is, they were being treated with the agents when operated on and postoperatively). The disease activity score 28 (DAS28)-erythrocyte sedimentation rate (mean ± standard deviation) in all patients improved significantly from baseline (just before the operation; 4.32 ± 0.99) to 1 year after the operation (3.35 ± 0.93) in contrast with the finding that the mean DAS28-ESR values had remained unchanged from 1 year before the operation to the baseline. Changes in clinical variables in the 58 cases were investigated at baseline, and at 4, 12, and 52 weeks after the operation. The patients were divided by a median split of baseline demographics into 2 groups for further evaluation. Compared with the high-value groups, those with low C-reactive protein and matrix metalloproteinase-3 values showed better results and had lower disease activity. Overall, the DAS28-ESR in both groups had improved 1 year after the operation. In RA patients who are being treated with anti-TNF agents, large-joint arthroplasty may be beneficial, not only for the relief of pain arising from joint destruction, but also for the systemic reduction of RA activity.

Early aggressive intervention with tocilizumab for rheumatoid arthritis increases remission rate defined using a Boolean approach in clinical practice.

The goal of treating rheumatoid arthritis (RA) should be remission, for which a new definition was proposed in 2011. To determine which patients can achieve the new Boolean-based definition of remission in clinical practice, we analyzed factors associated with remission in 123 patients who received tocilizumab for 52 weeks. We found that patients with short disease duration (<4.8 years) had a significantly higher rate of remission (31.7%) than those with longer disease duration, and patient global assessment was the most important factor for achieving remission. Multivariate analysis revealed the following predictors of remission: short disease duration [<4.8 years; odds ratio (OR) 2.5, 95% confidence interval (CI) 1.4-4.7] and lower disease activity [28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR) <5.23; OR 2.5, 95% CI 1.2-5.1). In this study, we showed that remission, as newly defined using a Boolean approach, is a realistic goal for patients treated with tocilizumab with short disease duration in real-world clinical practice.