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Essence of chicken (EOC), a hot water extract of chicken, is widely consumed in Southeast Asia as a beverage. EOC has an inhibitory effect on the elevation of blood glucose levels and a secretagogue effect on insulin. However, the mechanism by which EOC promotes insulin secretion is unknown. We aimed to verify the postprandial hyperglycemic inhibitory effect and the insulin secretory effect of EOC in healthy adults under appropriate placebo settings. In addition, we aimed to understand the mechanism underlying the insulin secretory effect of EOC.Thirty-four healthy Japanese adults were fed 68 mL of EOC or control food, followed by 200 g of cooked rice. Blood glucose and plasma insulin levels were measured at 30, 45, 60, 90, and 120 min after the participants ate cooked rice. The trial had a randomized, double-blind, crossover, placebo-controlled design.The ingestion of EOC induced an increase in the maximum blood concentration (Cmax) of insulin and shortened the time required to reach the maximum blood concentration following rice consumption. Ingestion of the test beverage resulted in a significantly higher insulinogenic index than that obtained after ingestion of the control beverage. No side effects were observed in this study. Mechanistic experiments revealed that EOC stimulated significant (p0.05) secretion of GLP-1 from NCI-H716 human intestinal L cells at 0.1, 1, and 10 mg/mL.Consuming EOC when eating rice supports pancreatic function. Daily consumption of EOC could elevate the early-phase insulin response; therefore, it could prevent diabetes in Asians with low insulin secretion.

BackgroundAntineutrophil cytoplasmic antibody -associated vasculitis (AAV) is usually treated with combination of high-dose glucocorticoid (GC) and immunosuppressive agents, followed by tapering GC dose. Although the European League Against Rheumatism (EULAR) has specific recommendations for tapering the GC dose, clinicians often taper it slower than recommended due to concerns of potential disease relapse. However, such slower taper may prolong GC exposure for the patients, increasing the risk of adverse events, particularly infection.ObjectivesThe aims of our study were (1) to clarify GC dose tapering in the treatment of AAV in a real-world setting, in contrast to the EULAR recommendation of 2015 and (2) to compare the incidence of AAV relapse and severe infection between patients underdoing EULAR-recommended tapering and those undergoing slower tapering than the recommendation.MethodsIn this multicenter (25 sites in Japan), observational, retrospective study of AAV, 541 patients who had initial or severe relapse were enrolled between January 2017 and June 2020. Of these, 349 patients with microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) who entered in GC tapering phase after successful induction treatment were included. These patients were then grouped on the pace of GC tapering, defined as the GC dose at 12 weeks after treatment initiation: (1) EULAR group: 7.5-10 mg/day of GC, according to the EULAR recommendation of 2015, and (2) SLOWER group: >10 mg/day of GC. Their baseline characteristics and clinical outcomes were compared. Primary outcome was defined as relapse-free days from treatment initiation, whereas secondary outcome included the incidence of infectious events requiring hospitalization within 48 weeks from treatment initiation. Multivariable analysis was performed to assess the relationship between tapering pace and clinical outcomes.ResultsThere were 44 patients (12.6%) in the EULAR group and 290 (83.2%) in the SLOWER group. Regarding baseline characteristics, compared with the EULAR group, the SLOWER group had significantly higher serum C-reactive protein level (EULAR, 5.89 ± 6.89 mg/dL vs SLOWER, 7.56 ± 6.01 mg/dL; p = 0.03), as well as a trend toward higher Birmingham Vasculitis Activity Score (version 3) (EULAR, 11.80 ± 7.01 SLOWER, 13.93 ± 7.06; p = 0.08) We did not observe any significant differences in the frequency of relapses between the two groups (EULAR, 8/44, 18.2% vs SLOWER, 55/290, 19.0%; p = 0.63). Multivariable Cox proportional hazard analysis revealed no relationship GC dose at 12 weeks from treatment initiation and incidence of relapse. However, upon logistic regression analysis, the SLOWER group was found to have significant higher risk of a severe infectious event within 48 weeks from treatment initiation (p = 0.046; hazard ratio, 1.27; 95% confidence interval, 1.004 – 1.601).ConclusionOur finding indicates that clinicians tended to taper GC slower for patients with higher disease activity. However, slower GC taper was not found to reduce the frequency of relapse. In addition, slower GC taper was found to increase the risk of a severe infection. Hence, clinicians should pay attention not only relapsing but also late GC taper resulting in the risk of serious infection, especially in patients with higher disease activity of AAV.References[1]Eur J Clin Invest 2015;45 (3): 346–368.[2]Rheumatology (Oxford). 2021 Dec 24;61(1):205-212.[3]Arthritis Res Ther. 2021 Mar 20;23(1):90.[4]Scand J Rheumatol. 2022 Jan 20;1-13.[5]J Rheumatol. 2018 Apr;45(4):521-528.[6]Rheumatol Adv Pract. 2021 Mar 9;5(3):rkab018.[7]Ann Rheum Dis. 2016 Sep;75(9):1583-94.Figure 1.AcknowledgementsWe would like to thank Editage (www.editage.com) for English language editing.Disclosure of InterestsNone declared

Mutations in the Matrin 3 (MATR3) gene have been identified as a cause of amyotrophic lateral sclerosis (ALS) or vocal cord and pharyngeal weakness with distal myopathy (VCPDM). This study investigated the mechanism by which mutant MATR3 causes multisystem proteinopathy (MSP) including ALS and VCPDM. We first analyzed the muscle pathology of C57BL/6 mice injected with adeno-associated viruses expressing human WT or mutant (S85C) MATR3. We next generated transgenic mice that overexpress mutant (S85C) MATR3, driven by the CMV early enhancer/chicken β-actin promoter, and evaluated their clinicopathological features. Intramuscular injection of viruses expressing WT and mutant MATR3 induced similar myogenic changes, including smaller myofibers with internal nuclei, and upregulated p62 and LC3-II. Mutant MATR3 transgenic mice showed decreased body weight and lower motor activity. Muscle histology demonstrated myopathic changes including fiber-size variation, internal nuclei and rimmed vacuoles. Spinal cord histology showed a reduced number of motor neurons, and activation of microglia and astrocytes. Comprehensive proteomic analyses of muscle demonstrated upregulation of proteins related to chaperones, stress response, protein degradation, and nuclear function. Overexpression of WT and mutant MATR3 similarly caused myotoxicity, recapitulating the clinicopathological features of MSP. These models will be helpful for analyzing MSP pathogenesis and for understanding the function of MATR3. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Type I X-ray bursts are thermonuclear explosions on the neutron star (NS) surface caused by mass accretion from a companion star. Observations of X-ray bursts provide valuable information on X-ray binary systems, e.g., binary parameters, the chemical composition of accreted matter, and the nuclear equation of state (EOS) of NSs. There have been several theoretical studies to constrain the physics of X-ray bursters. However, they have mainly focused on the burning layers above the solid crust of the NS, which brings up issues of the treatment of NS gravitation and internal energy. In this study, focusing on the microphysics inside NSs, we calculate a series of X-ray bursts using a general-relativistic stellar-evolution code with several NS EOSs. We compare the X-ray-burst models with the burst parameters of a clocked burster associated with GS 1826-24. We find a monotonic correlation between the NS radius and the light-curve profile. A larger radius shows a higher recurrence time and a large peak luminosity. In contrast, the dependence of light curves on the NS mass becomes more complicated, where the neutrino cooling suppresses the efficiency of nuclear ignition. We also constrain the EOS and mass of GS 1826-24, i.e., stiffer EOSs, corresponding to larger NS radii, are not preferred due to too-high peak luminosity. The EOS and the cooling and heating of NSs are important to discuss the theoretical and observational properties of X-ray bursts., 19 pages, 16 figures, 3 tables, updated to match published version (ApJ)

BackgroundHypertrophic pachymeningitis (HP), characterized by an inflammatory disorder indicating intracranial or spinal thickening of dura mater, is found to develop as a neurological involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Meanwhile, the previous studies focusing on HP in AAV have been reported as a single-institution study, and the analyses were performed in a small number of patients because HP is a rare neurological disorder. Therefore, neither etiological nor clinical characteristics of HP in AAV have been adequately elucidated.ObjectivesThis study clarified the characteristics of HP in AAV by analyzing the information of multicenter study in Japan (Japan collaborative registry of ANCA-associated vasculitis: J-CANVAS).MethodsWe analyzed the clinical information from 541 Asian patients with AAV enrolled in J-CANVAS. Of them, newly diagnosed and relapsed AAV were included in 448 and 93, respectively. The epidemiological and clinical findings were compared between patients with and without HP. Clinical manifestations related to AAV were evaluated based on the Birmingham Vasculitis Activity Score version 3. To elucidate independent factors in HP development, logistic regression analyses were additionally performed.ResultsOf the total 541 patients (mean age: 71±14 years, M:F = 1:1.2), HP was demonstrated in 28 (5.17%), including 17 (3.79%) in newly diagnosed AAV and 11 (11.8%) in relapsed AAV. The classification of granulomatosis with polyangiitis (GPA) was significantly higher in patients with HP than those without HP (50% vs. 21%, p = 0.0007). In newly diagnosed AAV, patients with HP significantly had higher GPA classification and higher positivity for PR3-ANCA than those without HP (53% vs. 17%, p = 0.001; 29% vs. 9%, p = 0.015, respectively). Conversely, positivity for MPO-ANCA was significantly higher in patients with HP than those without HP in relapsed AAV (91% vs. 55%, p = 0.025), despite not significantly different in the classification of AAV. Headache and cranial neuropathies were significant neurological symptoms in patients with HP compared to those without HP (82% vs. 6.6%, p < 0.0001; 32% vs. 2.9%, p < 0.0001, respectively). Besides, ear, nose and throat (ENT) and mucous membranes/eyes were significantly higher involvements in patients with HP than in those without HP (54% vs. 26%, p = 0.003; 29% vs. 9%, p = 0.003, respectively). Moreover, higher complications of “conjunctive hearing loss” and “sudden visual loss”, which are included in the categories of ENT and mucous membranes/eyes involvement, respectively, were significantly indicated in patients with HP than those without HP (39% vs. 7.2%, p < 0.0001; 21% vs. 1.2%, p < 0.0001, respectively). Multivariable logistic regression analysis identified that ENT (odds ratio [OR] 1.28, 95% confident interval [CI] 1.09 to 1.49, p = 0.002) and mucous membranes/eyes involvement (OR 1.37, CI 1.14 to 1.65, p = 0.0006), as well as conjunctive hearing loss (OR 4.52, CI 1.56 to 13.05, p = 0.005) and sudden visual loss (OR 1.84, CI 1.12 to 3.00, p = 0.015), were independent related factors in patients with HP.ConclusionGPA could be significantly classified in patients with HP. Notably, patients with HP significantly showed higher positivity for PR3-ANCA than those without HP in newly diagnosed AAV. Furthermore, sudden visual loss and conjunctive hearing loss might be implicated in HP development.Disclosure of InterestsNone declared

BackgroundCytomegalovirus (CMV) has been associated with atherosclerosis in patients with chronic renal failure, and may cause secondary nephrotic syndrome. Therefore, we hypothesized that the reactivation of CMV by immunosuppressive therapy in patients with vasculitis may affect renal function.ObjectivesThe purpose of this study was to investigate relationships between CMV infection and renal function during ANCA-associated vasculitis remission induction therapy.MethodsThis retrospective cohort study enrolled microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis patients at 25 sites in Japan who had a first or severe relapse between January 2017 and June 2020. Of these, patients with MPA or GPA who had a positive renal lesion score on BVAS (version 3) at baseline, or vasculitis findings on renal biopsy, CMV assayed by 48 weeks of treatment, were included. Patients were divided into two groups based on the presence or absence of a positive CMV antigen test during the remission induction phase (0–48 weeks of treatment). Outcomes were the rate of change in estimated glomerular filtration rate (eGFR) at 48 weeks after initiation of treatment in both groups, as determined by (eGFR at 48 weeks - eGFR at the initiation of treatment)/eGFR at the initiation of treatment; where lower values were associated with worse renal function. General linear models adjusted for age, gender, presence of diabetes or chronic kidney disease, and the use of rituximab or cyclophosphamide were generated.ResultsA total of 387 patients had CMV antigen measured during ANCA-associated vasculitis treatment, of which 164 had renal involvement and eGFR measured at 48 weeks. Seventy-seven (47.0%) were male and the median age was 75 years (range 69–80 years). CMV reactivation was observed in 44 patients (26.8%). The beta coefficient of multiple regression analysis with CMV positive as 1 and negative as 0 was 0.08 (95% confidence interval -0.13 to 0.29) (p = 0.47). The rate of change in eGFR was higher in the CMV positive group, but not statistically significantly.ConclusionContrary to our hypothesis, renal prognoses tended to be better when CMV reactivation was observed. The patients in the CMV reactivation group may have been treated more aggressively, and some patients with a poor prognosis who were not followed up for 48 weeks dropped out. Further research investigating the adjustment of treatment methods is required.Disclosure of InterestsNone declared

Currently, preoperative chemotherapy is usually done for advanced esophageal cancer according to guidelines. It is still difficult to predict the effect of chemotherapy before the chemotherapy. If the effect would be poor, the patient may miss the possibility of treatment. We have been examining the possibility of predicting the chemotherapy effect based on test results before and during chemotherapy. In this study we used artificial intelligence to predict the effect of chemotherapy. Methods 80 patients who underwent preoperative chemotherapy for esophageal cancer in our department from 2012 to 2019. We predict the chemotherapy effect according to age, sex, type of chemotherapy (FP/DCF), number of chemotherapy, T, M, N, blood examination results before chemotherapy as WBC, neutrophil count, lymphocyte count, hemoglobin, platelets, total protein, Albumin, CRP, IgG, IgA, IgM, IL6, creatinine, lowest WBC, neutrophil and lymphocyte count, during chemotherapy. The effect of chemotherapy was classified: CR, PR, and PD. Prediction were performed using MatLab R2019b classification learner and Neural Net Pattern Recognition. Results The actual effect was CR/PR/SD/PD = 0/33/42/5 cases. The correct answer rate was 66.3% for the optimized tree model, 66.3% for the optimized Naïve Bayesian model, 67.5% for the optimized SVM model, and 56.3% for the optimized ensemble model. With optimized SVM, the sensitivity to predict PD was 20%, specificity was 94.5%, and AUC was 0.83. Moreover, the sensitivity to predict PR was 75.8%, and the specificity was 76.6%. With Neural Net Pattern Recognition, the correct answer rate was 90%, and the sensitivity to predict PD was 20%, specificity was 94.7%. Conclusion In this study, Neural Net Pattern Recognition as a deep learning model could predict the effect of preoperative chemotherapy more accurately than that of classification learner. The poor prediction of PD was due to the small number of teacher models, and the prediction of PR with many teacher models was more accurate. We will add more teacher models, and establish a prediction model that can be used clinically for both sensitivity and specificity.

Albumin and globulin make up the majority of serum proteins and are strongly involved in inflammation. In recent years, reports on cancer and inflammation have been scattered, and there are reports indicating that the albumin / globulin ratio (A/G ratio) may be a predictor of prognosis in patients with cancer. Here, we examined the A/G ratio and clinicopathological factors in curative cases of esophageal cancer. Methods A retrospective study was conducted on 122 patients who underwent radical surgery for esophageal cancer in our department from January 2013 to December 2017. We analyzed the correlation between A/G ratio and blood biochemical test values, and the relationship between postoperative complications and prognosis. With respect to prognosis, the cut-off value was set to 1.6 from the ROC curve, and divided into a high-value group and a low-value group, and comparatively examined. Results There were 106 males and 16 females. The median age at surgery was 69 years. Neoadjuvant chemotherapy was performed in 65 patients. A negative correlation was found between the A/G ratio and inflammatory markers. On the other hand, a positive correlation was observed between the A/G ratio and the value of a marker for nutritional indicators. In the prognostic study, the low-value group had a significantly worse prognosis than the high-value group. The group with an A/G ratio of less than 1.6 after chemotherapy had a poor prognosis. The A/G ratio was lower in the group with pneumonia after surgery. Conclusion The A/G ratio reflects the preoperative inflammatory response and nutritional status, suggesting that it is a useful factor for predicting postoperative complications and prognosis in patients with curative esophageal cancer.

Muscle histology of sporadic inclusion body myositis (sIBM) demonstrates inflammatory findings and degenerative features including accumulation of TAR DNA-binding protein of 43 kDa (TDP-43). However, whether sarcoplasmic accumulation of TDP-43 is a primary trigger of muscle degeneration or a secondary event resulting from muscle degeneration in the pathophysiology of sIBM remained unclear. Our study aimed to discover whether muscle-dominant expression of TDP-43 is a primary cause of muscle degeneration. We generated several lines of wild-type TDP-43 transgenic mice driven by a creatine kinase 8 promoter, and analyzed the phenotypes via biochemical, histological, and proteomic techniques. The mice showed increased serum levels of myogenic enzymes. Muscle histology demonstrated myopathic changes including fiber size variation, abundant tubular aggregates, and TDP-43 aggregation with upregulation of endoplasmic reticulum (ER) stress. Proteomic analysis with aggregated materials in degenerative myofibers identified increased sarcoplasmic reticulum (SR)/ER-resident proteins that regulated calcium homeostasis, as well as cytosolic 5′-nucleotidase 1A. Muscle-dominant wild-type TDP-43 expression indeed caused myotoxicity featuring tubular aggregates and TDP-43-positive inclusions. Our observation suggested that TDP-43 aggregates might not be sufficient to trigger the pathogenesis of sIBM although myofiber sarcoplasmic aggregation of TDP-43 led to myofiber degeneration via ER stress and possibly calcium dysregulation, independently of inflammatory process.

Zn1-xMgxSeyTe1-y layers have been grown on (100) ZnTe substrates by low-pressure metalorganic vapor phase epitaxy using dimethylzinc, bis-methylcyclopentadienyl magnesium ((MeCp)2Mg), diethylselenide and diethyltelluride as source materials. The Mg mole fraction of Zn1-xMgxSeyTe1-y layer can be controlled successfully by varying (MeCp)2Mg transport rate. P-type doping of this material has been tried using tris-dimethylaminophosphorus as a dopant source. The influence of annealing temperature or dopant transport rate upon the electrical property has been investigated. All the layers show p-type conduction even without annealing. Through this study, a maximum carrier concentration of 2.5×1018 cm−3 is obtained.

Photoluminescence (PL) spectra and electrical properties of both as-grown and annealed phosphorus-doped ZnTe layers grown by low-pressure metalorganic vapor phase epitaxy have been clarified as a function of reactor pressure or dopant transport rate. The carrier concentration of as-grown layer increases with decreasing reactor pressure or increasing dopant transport rate, in good agreement with PL behavior. Similar tendency is also found for annealed layer. Annealing treatment induces the enhancement of the carrier concentration, independent of reactor pressure or dopant transport rate. Through this study, a high carrier concentration near 10 19 cm −3 has been attainable.

Objective Sporadic inclusion body myositis (sIBM), an intractable progressive muscle disease, frequently occurs in older persons. sIBM pathogenesis may involve protein degradation dysfunction and immune abnormalities. Autoantibodies recognizing cytosolic 5′-nucleotidase 1A (cN1A) were found in plasma and serum from sIBM patients. However, whether anti-cN1A autoantibodies play a pathogenic role in sIBM is controversial. This study investigated the pathogenic properties of anti-cN1A autoantibodies in sIBM pathogenesis. Methods We developed a cell-based assay to detect anti-cN1A autoantibodies, which we found in serum from patients with neuromuscular diseases including sIBM. We also investigated the clinicopathological differences between sIBM patients with and without the autoantibodies. We used passive in vitro and in vivo immunization models to evaluate the pathogenic role of the autoantibodies. Results Of 67 patients with sIBM, 24 (35.8%) possessed anti-cN1A autoantibodies as determined via our cell-based assay. In the anti-cN1A–positive group, the percentage of patients with hepatitis C virus antibodies was significantly lower and the mean area of type 2 myofibers was significantly smaller compared with the autoantibody-negative group. In the in vitro passive immunization model, p62/SQSTM1 significantly increased in anti-cN1A–positive sIBM immunoglobulin G (IgG)-supplemented cells. In the in vivo passive immunization model, anti-cN1A–positive sIBM IgG-injected mice demonstrated p62/SQSTM1-positive sarcoplasmic aggregates in myofibers, associated with macrophage infiltration. Interpretation Our cell-based assay is useful for anti-cN1A autoantibodies detection. Patients with anti-cN1A autoantibodies demonstrated unique clinicopathological features. In vitro and in vivo passive immunization model results suggest that anti-cN1A autoantibodies may affect protein degradation in myofibers. Ann Neurol 2017;81:512–525

Amyotrophic lateral sclerosis (ALS) is a progressive disease characterised by degeneration of upper and lower motor neurons. The histological feature of skeletal muscles in ALS is the presence of denervated and reinnervated myofibres including small angulated fibres, grouped atrophy and fibre type grouping. Moreover, target/targetoid fibres (TFs) are frequently observed as abnormal structures of myofibres in ALS. A classic study revealed TFs in 50% of cases of biopsy-proven motor neuron diseases.1 The target fibre was first described as a sign of muscle fibre denervation in 1961.1 The name ‘target fibre’ is derived from its appearance on the transverse section that contains three more or less distinct concentric zones,1 and the central zone contains longitudinally oriented wavelike threads, possibly derived from Z-disc and bundles of myofilaments.2 The components of TFs have been identified as LC3, desmin, αB-crystallin, dystrophin, filamin C and Hsp27.2 However, the biological significance of TFs remains unclear. In contrast to the neuropathological changes in motor neurons that are assessable at autopsy, histological evaluation of skeletal muscles can be conducted before the death of the patients, which may contribute to diagnosis at an early-stage disease and evaluation of therapeutic efficacy. The present study aimed to determine the biological significance of the formation of TFs in neurogenic muscular atrophy in ALS. ### Patients and clinical assessments We retrospectively analysed the medical records of 17 consecutive patients with ALS who were admitted to the Department of Neurology, Kumamoto University Hospital, from January 2005 to December 2017, and who underwent muscle biopsy to exclude myopathies because they lacked upper motor neuron (UMN) signs and/or showed elevation of serum creatine kinase (CK) levels. We recorded the clinical characteristics as shown in online supplementary table 1. ### Supplementary data [jnnp-2020-324151supp001.pdf] ### Histological analyses Muscle biopsy samples had been examined by routine histochemical techniques including a series of myofibrillar adenosine triphosphatase …

Background. The presence of patent foramen ovale (PFO) has been linked to many illness, including cryptogenic stroke, transient ischemic attack, migraine, platypnea-orthodeoxia syndrome and decompression sickness in scuba divers. Transesophageal echocardiography is the gold standard technique for the visualization of atrial septal anatomy, but it is a secondary level exam, not always available, with additional associated costs and not completely free from procedural risks. Standard transthoracic echocardiography (TTE) has a too low sensitivity for PFO screening. Purpose. The aim of the study was to assess the role of TTE associated with agitated saline contrast injection (contrast-TTE) as a gatekeeper for the identification of PFO in a large cohort of patients undergoing selection for percutaneous closure. Methods. A total of 200 patients undergoing a diagnostic work-up for the identification of PFO was imaged by contrast-TTE at rest and after provocative maneuvers (PM: Valsalva in all cases). Contrast TTE was graded from 0 to 4 on the bases of bubbles counting (0: no bubbles; 1: 30 bubbles; 4: complete LV opacification). PFO closure was performed after a consensual clinical decision by the cardiologist and the neurologist taking into account comprehensive imaging, clinical evaluation and thrombophilia screening. PFO closure was always monitored by intracardiac echocardiography. Results. At baseline contrast TTE was positive (≥2) in 34 patients (17%) while contrast TTE with PM was positive in 94 cases (47%). 27 out of 200 patients (14%) had an interatrial septal aneurysms. PFO closure was performed in 34 cases (17%). All of these had severe right-to-left shunting (≥3) at contrast TTE and 9 cases had also an interatrial septal aneurysms. The procedure was aborted in only 1 patient due to a complex defect anatomy. Conclusion. Contrast TTE with PM may be not only considered an accurate tool for the detection of PFO but may be also inserted in the diagnostic work- up as a primary gatekeeper for percutaneous closure. Severe shunting at contrast TTE influences final decision making in a large cohort of cases undergoing screening for PFO closure.

This paper presents an industry-ready PVT-robust 12-bit 1 MS/s untrimmed SAR ADC IP operating from 0.5/0.9V supply voltage for a sub-threshold sensor interface. The ADC exploits Fujitsu's 55 nm Deeply Depleted Channel (DDC) technology to dynamically regulate the bulk voltage of the NMOS and PMOS transistors to compensate for the PVT variations. This dynamic regulation of the the bulk voltage is enabled by a technology-assisted replica-biasing based design strategy. This enables a PVT-robust comparator operation up to 14MHz frequency from a 0.5V supply voltage to allow the ADC to achieve 68 $\mathrm{dB}\pm 1.1\mathrm{dB}$ SNDR and 88 $\mathrm{dB}+3.5\mathrm{dB}$ THD over P(SS,TT,FF) - V(0.45V to 0.55V) - T(-40°C to 90°C) variations at an average 12fJ/CS efficiency at $1/10^{th}$ of the sampling frequency.

Purpose Papillary muscle ischemia (PMI) is caused by micro-vessels' occlusion in the broad endocardium because papillary muscle perfusion is supply from micro-vessels of peripheral coronary arteries and is easy to fail by the increase in peripheral vascular resistance. However, the clinical significant is not understood because PMI could not be detected by existing perfusion imaging such as SPECT and MRI. We propose the detection method of PMI using 13N-ammonia PET (NH3-PET), and investigate the association with the global myocardial flow reserve (Global-MFR) reflecting coronary microvascular dysfunction. Methods Data of adenosine-stress NH3-PET for consecutive 260 patients with coronary artery disease (CAD) or suspected CAD was retrospectively analyzed. Using high-resolution cine imaging derived from NH3-PET, PMI was defined as the absence of the PM accumulation at stress conditions. Myocardial flow was generated from the time activity curve of left ventricle input and myocardial uptake using 3-compartment model and the first 2 minutes' dataset of list mode images. Global-MFR was calculated by stress to rest flow ratio. Summed stress score (SSS) was used as an estimate of the extent of myocardial ischemia. 150 out of 260 patients (58%) with SSS ≥4 or with the past history of coronary artery diseases were classified as ischemic group, and 110 patients (42%) with SSS Results PMI was seen in 68 of 260 patients (26.6%). The frequency of PMI was higher in the ischemic group than the non-ischemic group (37.8% vs. 10.1%, p Typical case of PMI Conclusion High-resolution cine imaging derived from NH3-PET makes it possible to detect PMI in about a quarter of patients with CAD or suspected CAD. PMI associates with reduced Global-MFR regardless of the presence of myocardial ischemia, suggesting that PMI is an important sign of early ischemia confined to the papillary muscle or the broad microvascular injury.

We report the clinical features of a patient with hereditary transthyretin (ATTR) amyloidosis associated with a novel mutation (Y114S, p.Y134S). A 65-year-old Japanese man was admitted to our hospital after a 3-year history of progressive dyspnea on exertion. Five years previously, he presented dysesthesia in both hands caused by carpal tunnel syndrome. A genetic analysis revealed a base pair substitution of adenine to cytosine in the second codon of exon 4, residue 114, in the TTR gene (c.401A>C). The clinical characteristics were progressive cardiomyopathy with a poor vital prognosis, late onset, sporadic case, bilateral carpal tunnel syndrome, hypothyroidism, and small fiber neuropathy.

We report on a new in situ laser spectroscopy technique using superfluid helium and a highly energetic ion beam. In taking advantage of superfluid helium as a host matrix for laser spectroscopy, we were able to develop an extremely low background detection system. The first demonstration using Rb-85(31+) ion beam (66 MeV/nucleon) accelerated at the RIKEN accelerator facility shows improvement of detection limit by two orders of magnitude. A quantitative evaluation of Rb atoms in the observation region enables an analysis of their optical absorption cross-section in superfluid helium from the fluorescence intensity dependence on ion-beam intensity and applied laser power. (C) 2018 The Japan Society of Applied Physics

Alternative oxidase (AOX) catalyzes the four-electron reduction of dioxygen to water as an additional terminal oxidase, and the catalytic reaction is critical for the parasite to survive in its bloodstream form. Recently, the X-ray crystal structure of trypanosome alternative oxidase (TAO) complexed with ferulenol was reported and the molecular structure of the non-heme diiron center was determined. The binding of O2 was a unique side-on type compared to other iron proteins. In order to characterize the O2 binding state of TAO, the O2 binding states were searched at a quantum mechanics/molecular mechanics (QM/MM) theoretical level in the present study. We found that the most stable O2 binding state is the end-on type, and the binding states of the side-on type are higher in energy. Based on the binding energies and electronic structure analyses, O2 binds very weakly to the TAO iron center (ΔE =6.7 kcal mol−1) in the electronic state of Fe(II)…O O, not in the suggested charge transferred state such as the superoxide state (Fe(III) O O· –) as seen in hemerythrin. Coordination of other ligands such as water, Cl−, CN−, CO, N3− and H2O2 was also examined, and H2O2 was found to bind most strongly to the Fe(II) site by ΔE = 14.0 kcal mol−1. This was confirmed experimentally through the measurement of ubiquinol oxidase activity of TAO and Cryptosporidium parvum AOX which was found to be inhibited by H2O2 in a dose-dependent and reversible manner.

Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi). It was originally a Latin American endemic health problem, but now is expanding worldwide as a result of increasing migration. The currently available drugs for Chagas disease, benznidazole and nifurtimox, provoke severe adverse effects, and thus the development of new drugs is urgently required. Ubiquinone (UQ) is essential for respiratory chain and redox balance in trypanosomatid protozoans, therefore we aimed to provide evidence that inhibitors of the UQ biosynthesis have trypanocidal activities. In this study, inhibitors of the human COQ7, a key enzyme of the UQ synthesis, were tested for their trypanocidal activities because they were expected to cross-react and inhibit trypanosomal COQ7 due to their genetic homology. We show the trypanocidal activity of a newly found human COQ7 inhibitor, an oxazinoquinoline derivative. The structurally similar compounds were selected from the commercially available compounds by 2D and 3D ligand-based similarity searches. Among 38 compounds selected, 12 compounds with the oxazinoquinoline structure inhibited significantly the growth of epimastigotes of T. cruzi. The most effective 3 compounds also showed the significant antitrypanosomal activity against the mammalian stage of T. cruzi at lower concentrations than benznidazole, a commonly used drug today. We found that epimastigotes treated with the inhibitor contained reduced levels of UQ9. Further, the growth of epimastigotes treated with the inhibitors was partially rescued by UQ10 supplementation to the culture medium. These results suggest that the antitrypanosomal mechanism of the oxazinoquinoline derivatives results from inhibition of the trypanosomal UQ synthesis leading to a shortage of the UQ pool. Our data indicate that the UQ synthesis pathway of T. cruzi is a promising drug target for Chagas disease.

Introduction V117957 is a recently described investigational oral, potent, and selective nociceptin/orphanin-FQ peptide (NOP) receptor partial agonist which was previously evaluated in ~200 healthy subjects. Its satisfactory safety/tolerability profile has been established with the top doses at 30mg following a single oral administration and 10mg once daily for 2 weeks. V117957 demonstrated favorable drug-like properties for insomnia treatment, including oral bioavailability, fast absorption, and rapid elimination. Methods A total of 52 patients with insomnia disorder have been evaluated in two separate randomized, double-blind, crossover, placebo-controlled sleep studies. Insomnia disorder was confirmed by screening polysomnography (PSG). All subjects received orally, for two consecutive nights, either V117957 10mg or placebo in Study #1 or 0.5, 1, 3, 6mg or placebo in Study #2. Efficacy was measured via PSG for the primary endpoint of sleep efficiency (SE) and secondary endpoints of sleep onset (latency to persistent sleep [LPS]) and maintenance (wakefulness after sleep onset [WASO]). Efficacy also was measured by patient diary (subjective sleep latency [sSL], subjective total sleep time [sTST], sWASO). Pharmacodynamics (PD) on next-day residual effects were also measured, including cognitive, psychomotor and mood effects. Results V117957 showed statistically significant greater sleep efficiency and less WASO in a dose-dependent manner (0.5-10 mg) and a statistically significant reduction in LPS at 10mg, as compared to placebo. V117957 at 0.5mg and 1mg exhibited next-day residual effects similar to placebo. At doses of 3mg or higher, V117957 showed dose-dependent next-day residual effects. V117957 was safe and well-tolerated across all doses tested with no serious adverse events, with somnolence being the most frequent treatment-emergent adverse event. No concerning laboratory findings and no clinically significant findings on vital signs and electrocardiograms have been attributed to V117957 in these subjects. Conclusion V117957 was safe and well-tolerated in patients with insomnia disorder. These results demonstrated that NOP receptors represent a novel mechanistic treatment for insomnia disorder and support continued evaluation of V117957. Support Funded by Shionogi and Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.

Objective We previously reported that decrement of compound muscle action potential (CMAP) by repetitive nerve stimulation (RNS) was greater in the median nerves than in the ulnar nerves of patients with amyotrophic lateral sclerosis (ALS). The aim of this study was to evaluate whether CMAP decrement by RNS is a feasible marker for the differentiation of ALS from other diseases. Materials & methods We performed RNS in the median and ulnar nerves of 51 patients with ALS and 40 patients with other diseases. Results The CMAP decrement was significantly greater in the median nerves of patients with ALS, compared to the disease control patients. In the median nerves of patients with ALS, CMAP decrement was significantly greater in the cervical region-onset group than in the other region-onset group. Conclusions The finding of CMAP decrement in the median nerves can be useful for differentiating ALS patients with cervical region onset from other controls with active neuropathic diseases.

We report on the production of warm aluminum cluster anions, Al − (1 ≤ n ≤ 26), after femtosecond laser ablation of an aluminum nitride substrate. Large cluster anions of n ≥ 8 suffer metastable dissociation after their production, which indicates the internal energy of the cluster anions is high enough for the dissociation of an Al atom. We find that the efficiency of metastable dissociation is dependent on the size of cluster anions and the dependence can be rationalized by the dissociation energy of an Al atom from the cluster anions calculated with thermochemical data of the clusters.

Plasmodium falciparum is an apicomplexan parasite that causes the most severe malaria in humans. Due to a lack of effective vaccines and emerging of drug resistance parasites, development of drugs with novel mechanisms of action and few side effects are imperative. To this end, ideal drug targets are those essential to parasite viability as well as absent in their mammalian hosts. The mitochondrial electron transport chain (ETC) of P. falciparum is one source of such potential targets because enzymes, such as L-malate:quinone oxidoreductase (PfMQO), in this pathway are absent humans. PfMQO catalyzes the oxidation of L-malate to oxaloacetate and the simultaneous reduction of ubiquinone to ubiquinol. It is a membrane protein, involved in three pathways (ETC, the tricarboxylic acid cycle and the fumarate cycle) and has been shown to be essential for parasite survival, at least, in the intra-erythrocytic asexual stage. These findings indicate that PfMQO would be a valuable drug target for development of antimalarial with novel mechanism of action. Up to this point in time, difficulty in producing active recombinant mitochondrial MQO has hampered biochemical characterization and targeted drug discovery with MQO. Here we report for the first time recombinant PfMQO overexpressed in bacterial membrane and the first biochemical study. Furthermore, about 113 compounds, consisting of ubiquinone binding site inhibitors and antiparasitic agents, were screened resulting in the discovery of ferulenol as a potent PfMQO inhibitor. Finally, ferulenol was shown to inhibit parasite growth and showed strong synergism in combination with atovaquone, a well-described anti-malarial and bc1 complex inhibitor.

Purpose: We have recently developed a dynamic tumor tracking irradiation system using Vero4DRT (MHI‐Tm2000). It is needed to create a 4D correlation model between a fiducial marker implanted near a tumor and an external surrogate as a function of time by continuously acquiring both fluoroscopyimages and external surrogate signals. The purpose of this study was to propose a new dosimetry method using Gafchromic XR‐SP2 films to measuresurface dose by fluoroscopyimaging.Methods: First, half‐value layers (HVLs) were measured using aluminum(Al) thicknesses (15 mm) at 40125 kVp. Subsequently, several films were irradiated using various milliampere second values on a solid water phantom. The surface air kerma were also measured using the chamber to calculate the surface doses under the same condition. Then, the calibration curve of dose vs. pixel values was calculated. Finally, surface dose by fluoroscopyimaging was measured using several pieces of film taped on the chest phantom. Orthogonal X‐ray fluoroscopyimaging was simultaneously performed until completion of data acquisition for creating a 4D correlation model. Those films were scanned after irradiation using a flat‐bed scanner and converted to dose by calibration curve. Results: The HVLs for tube voltage within 40125 kVp ranged from 2.35 to 5.98 mm Al. The calibration curve between surface dose and pixel values was reasonably smooth. The differences between the measured and the calibrated doses were less than 3%. The hot spots with the maximum dose of 37.12 mGy were observed around the area overlapped by both fluoroscopic fields. Conclusions: We have proposed a new dosimetry method using Gafchromic XR‐SP2 films to measuresurface dose by fluoroscopyimaging. This phantom study has demonstrated that it may be feasible to assess surface dose to patients during dynamic tumor tracking irradiation in clinic with ease after further investigation. This research was supported by the Japan Society for the Promotion of Science (JSPS) through its Funding Program for World‐Leading Innovation R&D on Science and Technology (FIRST Program). Research sponsored in part by Mitsubishi Heavy Industries, Ltd.

Geometrical effects on the local heat transfer coefficient (HTC) and pressure drop for supercritical carbon dioxide in printed-circuit heat exchangers are numerically quantified. Combinations of di...