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The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly of α‐synuclein into filaments is believed to underlie the prion‐like spreading of protein inclusions in a number of human neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We previously determined the atomic structures of α‐synuclein filaments from the putamen of five individuals with MSA. Here, we used filament preparations from three of these brains for the in vitro seeded assembly of recombinant human α‐synuclein. We find that the structures of the seeded assemblies differ from those of the seeds, suggesting that additional, as yet unknown, factors play a role in the propagation of the seeds. Identification of these factors will be essential for understanding the prion‐like spreading of α‐synuclein proteinopathies., The assembly of certain proteins into amyloids underlies multiple neurodegenerative diseases. The spreading of these assemblies through the brain is thought to occur through a prion‐like mechanism. We used filaments extracted from multiple system atrophy brains to seed recombinant α‐synuclein. The resulting structures differ from those of the seeds, indicating that seeded assembly does not necessarily replicate the seed structures.

The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

Although asthma attacks are known adverse events associated with nonsteroidal anti-inflammatory drug (NSAID) use, few studies have quantified these risks. The objectives of this study were to utilize an epidemiological approach to quantitatively evaluate the risk of acute asthma attacks associated with NSAID prescription in Japan and to compare the risks among NSAIDs according to their cyclooxygenase (COX)-2 selectivity.We conducted a self-controlled case series study using Japanese health insurance claims data. Exposed cases were identified as those who had experienced both NSAID prescription and acute asthma attack, which was defined as the combination of an inhalation procedure and the prescription of any inhaled βWe identified 9769 subjects, more than 95% of whom were younger than 60 years. There was a significantly higher risk of acute asthma attacks during the NSAID prescription period when compared with the baseline period. The quantified IRRs were, in descending order, 93.94 (95% CI, 90.10-97.95) for the prescription start date, 3.96 (95% CI, 3.63-4.33) for 1 to 9 days after the prescription start date, 3.01 (95% CI, 2.78-3.25) for 7 days after the prescription end date, 2.19 (95% CI, 1.82-2.65) for9 days after the prescription start date, and 1.44 (95% CI, 1.29 -1.61) for 7 days before the prescription start date. There were lower asthmatic risks for COX-2 selective NSAIDs compared with nonselective NSAIDs.The use of NSAIDs in Japan was associated with an increased risk of acute asthma attacks. However, this risk was lower in COX-2 selective NSAIDs.

We demonstrate a CMOS-compatible, metal-oxide based Electro-Chemical Random-Access Memory (MO- ECRAM) for high-speed, low-power neuromorphic computing. The device demonstrates symmetric and linear conductance update, large on/off ratio and good retention while also withstanding high temperature treatments necessary for BEOL compatibility. Resistive switching in MO-ECRAM is observed with voltage pulses down to 10 ns and scales exponentially with voltage pulse amplitude, enabling parallel array operations without any selector/access devices. For the first time, we experimentally demonstrate fundamental techniques for fully- parallel array operations, stochastic update scheme and zero-shifting technique, and show a successful stochastic gradient descent algorithm demonstration in hardware using a MO- ECRAM array.

IL-1β is one of the inflammatory cytokines and is cleaved from pro-IL-1β proteolytically by activated Caspase 1. For the activation of Caspase 1, inflammasome was formed by two signals, what is called, priming and triggering signals. In this study, it was found that mouse macrophage J774.1 cells, when treated by single large amount of lipopolysaccharide (LPS), produced a significant amount of IL-1β. On the other hand, IL-1β production was not detected when treated by a single, small amount of LPS. Then, focusing on endoplasmic reticulum (ER) stress response among stress responses induced by a large amount of LPS, when GSK2656157, a PERK inhibitor, was used for inhibition of ER stress, GSK2656157 reduced IL-1β production dose-dependently. Next, when Thapsigargin, an ER stress reagent, was added with LPS, IL-1β production increased more than by LPS alone. Thus, these results suggested that ER stress was involved in LPS-induced IL-1β production. When the activation of Caspase 1 was examined by fluorescence activated cell sorter analysis, it was found that GSK2656157 inhibited LPS-induced Caspase 1 activation. Further, it was confirmed that GSK2656157 did not affect LPS-induced TNF-α production and activation of NF-κB and specifically inhibited the PERK/eIF-2α pathway. Therefore, it was found that GSK2656157 specifically inhibited ER stress induced by large amount of LPS and reduced LPS-induced IL-1β production through inhibition of Caspase 1 activation.

To identify proteins related to the pathophysiology of aortic valve stenosis (AS), we investigated the protein profiles of AS aortic valves. Specifically, proteins were extracted from a thickened and calcified area (AS-C) and an apparently non-thickened and non-calcified area (AS-N) in an identical aortic valve leaflet in each of 6 AS patients. The proteins were then separated by 2-dimensional gel electrophoresis (2DE). Protein spots detected by 2DE were compared between the AS-C and AS-N samples. Protein spots of interest were subjected to protein identification by mass spectrometry.In total, 670 protein spots were detected by 2DE, 28 of which showed more than 1.5-fold different intensity (P < 0.05) between the AS-C and AS-N samples. Proteins were identified in 17 out of the 28 spots. Fibrinogen and lumican were identified in 9 and 3 spots, respectively. Intensity of these 12 spots was lower in the AS-C samples than in the AS-N samples. In the 1D-Western blot analysis, 4 lumican bands (80 kDa, 75 kDa, 65 kDa, and 53 kDa) were detected, of which 2 bands with 80 kDa and 75 kDa showed lower intensity in the AS-C samples than in the AS-N samples. When de-glycosylated protein samples were used in the 1D-Western blot, only a single lumican band with ~40 kDa was detected, indicating that lumican was variously glycosylated and that highly glycosylated lumican molecules were decreased in AS-C.Collectively, insufficient glycosylation of lumican in the thickened and calcified areas of AS aortic valves may be involved in the pathophysiology of AS.

We developed an Al2O3/HfO2 bi-layer gate dielectric with an in-situ O3 treatment for interface state density (Dit) and gate leakage current density (Jg) reductions on SiGe channels. We observed Ge-content dependent equivalent oxide thickness (EOT) scaling and EOT 0.44 nm was achieved with an MOS capacitor with a Si0.05Ge0.95 substrate. The O3 treatment enabled application to non-planar device structures and we demonstrated five orders of magnitude lower off currents (IOFF), a sub-threshold slope of 68 mV/decade, and a very high hole mobility of 457 cm $^{2}\text{V}^{\mathrm {-1}}\text{s}^{\mathrm {-1}}$ at an inversion carrier density (Ninv) of $1\times 10^{13}$ cm $^{\mathrm {-2}}$ for asymmetrically strained SiGe PMOSFETs with Ge% of 65%–70%.

Background The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, as the current standard sequence for metastatic colorectal cancer patients. Patients and methods Patients with KRAS exon 2 wild-type metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence [cetuximab ± irinotecan followed by regorafenib (C-R arm)]. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. Exploratory end points included serial biomarker analyses, including oncogenic alterations from circulating tumor DNA or multiple serum or plasma proteins. Results One-hundred one patients were randomized and eligible for efficacy analysis. Sequential treatment was successful in 86% patients in both arms. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (P = 0.0293), with a hazard ratio (HR) of 0.61 for OS [95% confidence interval (CI) 0.39–0.96]. The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI 0.61–1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI 0.17–0.50). No unexpected safety signals were observed. The quality of life scores during the entire treatment period was not significantly different between the two arms. Circulating biomarker analyses showed emerging oncogenic alterations in RAS, BRAF, EGFR, HER2, and MET, which were more commonly detected after cetuximab than after regorafenib. Conclusions The therapeutic sequence of regorafenib followed by cetuximab suggests a longer OS than the current standard sequence.

Strained-SiGe, with high-Ge-content, has recently drawn significant attention as an alternate p-channel option for advance FinFETs. Among various technological challenges, gate stack is so critical to enable high-performance FETs. In this paper, key process details of the optimized gate stacks in high-Ge SiGe, such as IL formation and passivation, are disclosed and feasibility of Vth tuning by an ultra-thin replacement metal-gate scheme down to 15nm LG is demonstrated, for the first time. Moreover, near ideal SS, excellent reliability and mobility at scaled EOTs are achieved, which has led to high transconductance devices with proper junction engineering. In addition, we demonstrate the most aggressively-scaled SiGe fins reported to date formed by 3D-Ge-condensation, exhibiting excellent short-channel characteristics.

In this paper, we report multi-threshold-voltage (multi-Vt) options for stacked Nanosheet gate-all-around (GAA) transistors. V t can be modulated through workfunction metal (WFM) thickness as well as the inter-nanosheet spacing (T sus ), the combination of which may be leveraged to increase the number of undoped V t offerings within a CMOS device menu relative to a FinFET CMOS device menu, which fundamentally does not have T sus as a V t tuning option. Hence we propose our multi-V t scheme by taking advantage of the unique structure of stacked GAA transistor.

In this paper, we discuss a technique for selective GeO x -scavenging which creates a GeO x -free interfacial layer (IL) on Si 1−x Ge x substrates. This process reduces interface trap density (N it ) and increases high-field hole mobility in Si 1−x Ge x pFETs. In addition, we identify the existence of electronic defect levels close to the Si 1−x Ge x band edges associated with the Ge surface concentration at the Si 1−x Ge x /IL interface. These electronic defects act as carrier scattering centers severely degrading the channel mobility and modulate the device threshold voltage. By successfully eliminating the GeO x component in the IL and electronic defects states at the Si 1−x Ge x /IL interface, high channel carrier mobility over a wide range of inversion carrier density in compressively-strained Si 1−x Ge x channel pFETs is demonstrated.

A 64-year-old man was admitted to our hospital for the hormonal evaluation of a right adrenal adenoma. He had been diagnosed with severe proteinuria and hypertension, and antihypertensive treatment was started at the age of 60. His renal function gradually declined, and hemodialysis was begun at the age of 64. Since his blood pressure was uncontrollable and resistant to antihypertensive treatment, an endocrinological examination was performed for an incidental right adrenal mass detected by computed tomography. The results of screening, including captopril challenge and an adrenocorticotropin stimulation test for primary aldosteronism, and adrenal venous sampling suggested excessive aldosterone secretion from the right adrenal gland. Adrenalectomy was performed; his blood pressure decreased and became well-controlled with a reduced antihypertensive regimen. Furthermore, he received renal transplantation which resulted in normalization of his serum potassium level, improvement of renal function and hormonal levels such as plasma renin activity and aldosterone concentration, and satisfactory blood pressure without any antihypertensive medications. This case is extremely important to demonstrate the effects of adrenalectomy for primary aldosteronism in a hemodialysis patient. It is possible that adrenalectomy may be a useful treatment for primary aldosteronism even in patients undergoing hemodialysis. Careful long-term follow-up of our case and investigations of the efficacy of adrenalectomy in similar cases are needed to address this issue.

We demonstrate scaled high-Ge-content (HGC) strained SiGe pMOS FinFETs with very high short channel (SC) performance using a Replacement High-K/Metal Gate (RMG) flow, for the first time. A novel RMG gate stack process was introduced to create Ge-free interface-layer (IL) with excellent reliability and sub-threshold swing (SS) as low as 62mV/dec, the best reported to date for Si-cap-free SiGe FinFETs. We also present some structural details of the gate stack, for the first time. Short channel characteristics of HGC SiGe FinFETs have also been studied for various fin widths. Compared to our earlier RMG work, improved I/I free process with ultra-thin spacers has led to considerable R on and R ext reduction. As a result, we have demonstrated very high SiGe performance with I on =0.45mA/μm at I off =100nA/μm at V dd =0.5V for L G =25nm, matching our record for gate-first SiGe FinFETs and outperforming the gate-first results at such LG.

Osteoarthritis (OA) is a group of common, chronic, and painful inflammatory joint diseases. One important finding in OA patients is a remarkable decrease in the molecular weight of hyaluronic acid (HA) in the synovial fluid of affected joints. Therapeutic HA is available to patients in most parts of the world as a viscosupplementation product for the treatment of OA. Previous clinical reports show that high molecular weight HA (HMWHA) more effectively relieves pain than low molecular weight HA (LMWHA). However, the mechanism behind this finding remains unclear. In this study, we investigated whether a LMWHA (Low-0.9 MDa) and two types of HMWHA (High-1.9 MDa and 6 MDa) differentially affected chondroregulatory action. We tested this using ATDC5 cell, a murine chondrocytic cell line widely used in culture systems to study chondrogenic differentiation. We found that HMWHA, especially hylan G-F 20 (High-6 MDa), significantly induced aggrecan and proteoglycan accumulation, nodule formation, and mRNA expression of chondrogenic differentiation markers in a time- and dose-dependent manner. In addition, we showed that HMWHA prevented TNF-α induced inhibition of chondrogenic differentiation, with no effect on cell proliferation or viability. These results reveal that HMWHA significantly promotes chondrogenic differentiation of ATDC5 cells in vitro, and suggest that HMWHA plays a significant chondroregulatory role in vivo. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1619–1627, 2014.

The (pro)renin receptor ((P)RR) is expressed in several tissues including kidney, heart and brain, and is thought to regulate the tissue renin–angiotensin system (RAS) through the non-proteolytic activation of prorenin. (P)RR is cleaved by furin to generate soluble (P)RR (s(P)RR), which is secreted into the extracellular space. s(P)RR is a candidate biomarker reflecting the status of the tissue RAS. Here, we investigated the relationship between background factors and serum s(P)RR levels. We measured s(P)RR levels in 122 patients with essential hypertension (EH) and assessed the relationships between background factors and s(P)RR levels. Serum s(P)RR levels were 19.0 ± 4.9 ng ml−1. Single regression analyses showed that age (r =0.251, P

Intratumoural dihydrotestosterone (DHT) synthesis could be an explanation for castration resistance in prostate cancer (PC). By using liquid chromatography-mass spectrometry, we evaluated the intratumoral DHT synthesis from 5α-androstane-3β,17β-diol (3β-diol), which is inactive androgen metabolized from DHT. 3β-diol had biochemical potential to be converted to DHT via three metabolic pathways and could stimulate PC cell growth. Especially, 3β-diol was not only converted back to upstream androgens such as dehydroepiandrosterone (DHEA) or Δ5-androstenediol but also converted directly to DHT which is the main pathway from 3β-diol to DHT. Abiraterone had a significant influence on the metabolism of DHEA, epiandrosterone and 3β-diol, by the inhibition of the intratumoural 3β-hydroxysteroid dehydrogenase (3β-HSD) activities which is one of key catalysts in androgen metabolic pathway. The direct-conversion of 3β-diol to DHT was catalysed by 3β-HSD and abiraterone could inhibit this activity of 3β-HSD. These results suggest that PC had a mechanism of intratumoural androgen metabolism to return inactive androgen to active androgen and intratumoural DHT synthesis from 3β-diol is important as one of the mechanisms of castration resistance in PC. Additionally, the inhibition of intratumoural 3β-HSD activity could be a new approach to castration-resistant prostate cancer treatment.

The (pro)renin receptor [(P)RR] is cleaved by furin to generate soluble (P)RR [s(P)RR], which reflects the status of the tissue renin-angiotensin system. Hemodialysis patients have advanced atherosclerosis. The aim of this study was to investigate the relationships between serum s(P)RR levels and background factors, including indices of atherosclerosis, in hemodialysis patients. Serum s(P)RR levels were measured in hemodialysis patients and clearance of s(P)RR through the membrane of the dialyzer was examined. Furthermore, relationships between serum s(P)RR levels and background factors were assessed. Serum s(P)RR levels were significantly higher in hemodialysis patients (30.4 ± 6.1 ng/ml, n = 258) than those in subjects with normal renal function (21.4 ± 6.2 ng/ml, n = 39, P < 0.0001). Clearance of s(P)RR and creatinine were 56.9 ± 33.5 and 147.6 ± 9.50 ml/min, respectively. Serum s(P)RR levels were significantly higher in those with ankle-brachial index (ABI) of < 0.9, an indicator of severe atherosclerosis, than those with ABI of ≥ 0.9 (32.2 ± 5.9 and 30.1 ± 6.2 ng/ml, respectively, P < 0.05). An association between low ABI and high serum s(P)RR levels was observed even after correction for age, history of smoking, HbA1c, and LDL-C. Serum s(P)RR levels were significantly higher in hemodialysis patients when compared with subjects with normal renal function, although s(P)RR is dialyzed to some extent, but to a lesser extent than creatinine. High serum s(P)RR levels may be associated with atherosclerosis independent of other risk factors, suggesting that serum s(P)RR could be used as a marker for atherosclerotic conditions in hemodialysis patients.

Objective To investigate the relation between functional impairments of cancer patients and circulating cytokines using a multiplex technique. Design and methods 50 patients with cancer were assessed using the quality of life (QOL) questionnaire. 27 plasma cytokine levels were determined by using the Bio-Plex array system. The relation to QOL scores was assessed using Chi-square test for categorical variables and univariate linear regression analysis for cytokine levels. Results Multivariate analysis showed that interleukin-6 (IL-6) level is a significant independent determinant of physical (β = − 0.238, P = 0.0126) and cognitive functioning (β = − 0.462, P = 0.0006) and that vascular endothelial growth factor (VEGF) level is a significant independent determinant of emotional functioning (β = − 0.414, P = 0.039). Conclusion This study, in which 27 cytokines are simultaneously tested with cutting edge technology, demonstrates that plasma IL-6 and VEGF are significant independent determinants of functional impairments in patients with cancer.

3510Background: REVERCE demonstrated longer overall survival (OS) with the therapeutic sequence of regorafenib (R) followed by cetuximab (C) ± irinotecan (R-C arm) compared with that of C ± irinote...

The 78-kDa glucose-regulated protein (GRP78) is an important molecular chaperone in the endoplasmic reticulum (ER) induced by various stresses. This study showed that stimulation with anti-CD3 mAb, PMA plus ionomycin, or an antigen increased the levels of GRP78 mRNA in primary T cells, which was inhibited by Ca(2+) chelators EGTA and BAPTA-AM and by an inhibitor of calcineurin FK506. In addition, the specific knockdown of GRP78 protein expression induced apoptosis in mouse EL-4 T cell line associated with CHOP induction and caspase-3 activation. Furthermore, overexpression of GRP78 inhibited PMA/ionomycin-induced cell death in EL-4 cells. Collectively, GRP78 expression is induced by TCR activation via a Ca(2+)-dependent pathway and may play a critical role in maintaining T cell viability in the steady and TCR-activated states. These results suggest a novel regulatory mechanism and an essential function of GRP78 in T cells.

In this paper, we demonstrate a wet treatment for the HfSix/HfO2 gate stack of n-type metal oxide semiconductor field effect transistor (nMOSFET) fabricated by a gate-last process in order to scale down the electrical thickness at inversion state Tinv value and reduce the gate leakage Jg. As a result, we succeeded in scaling down Tinv to 1.41 nm without mobility or Jg degradation by ozone–water-last treatment. We found that a high-density interfacial layer (IFL) is formed owing to the ozone–water-last treatment, and Hf diffusion to the IFL is suppressed, which was analyzed by high-resolution angle-resolved spectroscopy.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is associated with joint destruction. Imatinib mesylate (imatinib) is an inhibitor that specifically targets a set of protein tyrosine kinase, such as abl, c-kit, and platelet-derived growth factor receptor (PDGFR) and it is widely used to treat chronic myeloid leukemia (CML). The purpose of the present study is to determine whether imatinib can provide benefit in the arthritis induced by anti-collagen type II antibody (CAIA) in mice, a model that provides an opportunity to study the effector inflammatory phase of arthritis without involving the priming phase of the immune responses. Mice treated with intraperitoneal administration of imatinib (1 or 10 mg/kg) prior to the development of CAIA displayed significant reductions in the severity of CAIA as assessed by arthritis score, histology, and synovial PDGF and vascular endothelial growth factor expression. In addition, treatment of the mice that had developed CAIA with intraperitoneal administration of imatinib (1 or 10 mg/kg) inhibited the progression of arthritis as assessed by those parameters. These results suggest that imatinib prevents and treats CAIA. Imatinib may thus have both a preventive and therapeutic potential for the joint inflammation at the effector stage of RA.

No large cohort study has yet determined the incidence of acute kidney injury (AKI) in children with heart failure treated with renin-angiotensin system (RAS) inhibitors. We thus retrospectively analyzed the incidence and risk factors for severe AKI (stages 2-3 according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines) at our institutions from 2008 to 2011. Among 312 children (162 boys; median age, 7.3 months), 59 cases of AKI occurred in 45 children. The incidence of AKI was 14.3 cases per 100 person-years overall (follow-up 413.6 person-years), or 27.3, 16.8, and 4.5 cases per 100 person-years in children aged1, 1-3, and ≥4 years, respectively. Among them, 23 (39.0 %) children had metabolic acidosis and 14 (23.7 %) had hyperkalemia. Younger age, myocardial disease, cyanotic congenital heart disease, use of spironolactone, and cardiac surgery were independent risk factors for AKI. Furthermore, 37.3 % of children suffered dehydration during AKI.AKI incidence is relatively high in children, particularly younger children, with heart failure treated using RAS inhibitors. Careful monitoring of renal function and serum electrolytes is essential. Proper management of fluid balance after infection and cardiac surgery may reduce the risk of AKI. Temporary discontinuation in RAS inhibitors should be considered during dehydration or surgery.• Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the two main classes of renin-angiotensin system (RAS) inhibitors used to treat hypertension, heart failure, and chronic kidney disease. Acute kidney injury (AKI) and hyperkalemia are potentially life-threatening complications associated with the use of ACEIs and ARBs. Some reports have suggested that dehydration and cardiac surgery are risk factors for AKI in children. However, no large-scale cohort studies have determined the incidence of AKI, its risk factors, and its outcomes in children with heart failure treated with ACEIs and/or ARBs. What is new: • In this retrospective cohort study, we determined the incidence, severity, and risk factors for severe AKI in children with heart failure treated with ACEIs and/or ARBs. The incidence of AKI in these children was relatively high (14.3 episodes per 100 person-years). In addition, younger age, myocardial disease, cyanotic congenital heart disease, concomitant use of spironolactone, and cardiac surgery were risk factors for AKI. Furthermore, 37.3 % of children had dehydration during AKI episodes. • Our results suggested that appropriate fluid balance after infection and cardiac surgery might reduce the risk of AKI and its complications. Temporary discontinuation or reductions in the levels of ACEIs and/or ARBs during dehydration or before surgery may also be warranted in these patients.

Rheumatoid arthritis (RA) is characterized by hypertrophic synovial tissues comprising excessively proliferating synovial fibroblasts and infiltrating inflammatory cells. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates cell growth, inflammation and angiogenesis by acting on various cell types. In RA synovial tissues, TGF-beta is expressed at high levels. However, the precise role of TGF-beta in RA remains unclear. We herein demonstrated a causal link between the TGF-beta-induced RA synovial cell proliferation and induction of platelet-derived growth factor (PDGF)-AA. In addition, TGF-beta induced IL-6 and vascular endothelial growth factor (VEGF) production by RA synovial fibroblasts associated with nuclear factor-kappa B activation. These effects of TGF-beta on RA synovial fibroblasts were suppressed by TGF-beta type I receptor kinase inhibitor HTS466284. Furthermore, HTS466284 significantly prevented anti-collagen type II antibody-induced arthritis in mice according to the clinical manifestations, histology, tumor necrosis factor-alpha, PDGF and VEGF expression and 5-bromo-2'-deoxyuridine incorporation. These in vitro and in vivo results suggest that TGF-beta plays a role in the development of synovial hyperplasia consisting of synovial cell proliferation, inflammation and angiogenesis. The blockade of TGF-beta signaling may thus become an additional strategy for the treatment of RA.

Sonochemical reactions of alkyl and aryl thiols in water–organic mixed solvent systems were kinetically investigated. The reaction in the liquid–liquid interface apparently depends on the polarities, surface activities, vapor pressures and hydrophobicities of organic solvents and thiols. Interestingly, the rate jump in sonochemical disappearance of alkyl thiols was observed under emulsified conditions.

The ability of various tea catechins to generate H2O2 and the hydroxyl radical in the presence of the Cu2+ ion was investigated and compared with the effect of iron ions. The presence of Cu2+ accelerated the generation of H2O2 by EGC, while EGCg with Cu2+ generated a little H2O2. The presence of iron ions inhibited the generation of H2O2 by EGC. EGC and EC with Cu2+ generated the hydroxyl radical, while EGCg and ECg with Cu2+ did not. The fact that EGCg showed less prooxidative activity than EGC can be explained by the chelating ability of catechin gallates to metal ions under the experimental conditions.

Four epicatechins [(−)-epicatechin (EC), (−)-epicatechin gallate (ECg), (−)-epigallocatechin (EGC), (−)-epigallocatechin gallate (EGCg)] and their corresponding copper complexes were compared with regard to their effect on the viability of Caco-2 colon cancer cells in vitro, measured by 3-(4,5-dimethylthyazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. The viability of Caco-2 cells exposed to EC (1 mM), ECg (1 mM) or EGC (1mM) respectively, for 30 min, was comparable to that of the saline control group, while EGCg (1 mM) apparently enhanced cellular activity. in contrast, the cells treated with epicatechin-copper complexes were killed. Bivalent copper 91 mM), in similar conditions, did not affect the cells. No cell leakage or other histological differences were observed, implying a rapid cell death. The suggested mechanism of killing is by OH radical attack, produced in the presence of epicatechin-copper complexes, but not in the presence of either of the epicatechins or copper alone. The reaction sites are discussed.

Toxic effects of dichloromethane and trichloroethylene on the growth of three planktonic green algae, Chlorella vulgaris NIES227, Selenastrum capricornutum NIES35, and Volvulina steinii NIES545, were examined. The two organic solvents at concentrations of up to a hundred-fold the Japanese national effluent standards did not affect the growth of the former two algae, but at just a tenth of the concentration of the standards were fatal to the latter. Even water with a relatively low concentration of pollutants, which meets the effluent standards for human health, is not necessarily harmless to the natural ecosystem.

Osteosarcoma is the most common primary bone malignancy and accounts for more than half of primary skeletal malignancies in children and young adults. Although vascular endothelial growth factor (VEGF) expression in osteosarcoma has been associated with poor outcome, its role in the pathogenesis of osteosarcoma remains controversial. Here, VEGF and VEGFR1 expression in both human and murine osteosarcoma cells associated with increasing malignant potential. Autocrine VEGF/VEGFR1 signaling resulted in constitutive activation of VEGFR1 in highly aggressive osteosarcoma cells. In addition, survival and proliferation of highly aggressive osteosarcoma cells was dependent on autocrine VEGF/R1 signaling in vitro. The effect of VEGFR1 expression on in vivo tumor growth and angiogenesis was evaluated by immunoselecting subpopulations of osteosarcoma cells that express high or low levels of VEGFR1. Cell enriched for high VEGFR1 expression showed increased VEGF production, tumor growth, tumor angiogenesis, and osteolysis in vivo. In addition, it was demonstrated that VEGF and VEGFR1 are coexpressed by a subset of tumor cells in human osteosarcoma, similar to what was observed in the murine osteosarcoma cells. These results suggest that autocrine VEGF/VEGFR1 signaling in a subpopulation of tumor cells plays a pivotal role in osteosarcoma progression. Implications: Aggressive osteosarcoma phenotypes are mediated by autocrine VEGF/VEGFR1 signaling and improved stratification measures and novel anti-angiogenic strategies may benefit this specific tumor type. Mol Cancer Res; 12(8); 1100–11. ©2014 AACR.

Enantioselective synthesis and absolute configuration of (-)-1-(benzofuran-2-yl)-2-propylaminopentane ((-)-BPAP), which is a highly potent and selective catecholaminergic activity enhancer (CAE) substance, are described. The synthetic approach consists of the coupling reaction of benzofuran with (R)-N-tosyl-2-propylazirizine or (R)-N-methoxy-N-methylnorvaliamide, followed by appropriate modifications of the resulting coupling products. As the results, (-)-BPAP turned out to have the R configuration, which was finally confirmed by X-ray crystallographic analysis.

Background. Urinary mononuclear cells (UMCs) were studied in IgA nephropathy (IgAN) in relation to clinical and histopathological parameters. Methods. A two-color flow-cytometry analysis was used to phenotype and quantitate UMCs in patients with IgAN (n = 37) and those with other kidney diseases (n = 27). Results. The IgAN patients had higher numbers of UMCs than the patients with other kidney diseases. Macrophages (CD14+; P < 0.0001) and T lymphocytes (CD3+; P = 0.0001; CD4+, P < 0.0001) were predominantly found. In the IgAN patients, the quantities of urinary CD3+, CD14+ cells correlated with impaired renal function; namely, serum creatinine, creatinine clearance, and urinary protein excretion. The UMCs were associated with histopathological changes such as glomerular segmental lesions (r = 0.511; P < 0.01 for CD3+; r = 0.623, P < 0.0001 for CD4+, and r = 0.552; P < 0.001 for CD14+) and the index of glomerular hypercellularity (r = 0.405; P = 0.01 for CD3+ T cells and r = 0.392, P = 0.01 for CD14+ macrophages). Moreover, the UMCs reflected the severity of pathology, as estimated by the glomerular score (r = 0.424; P < 0.01 for CD3+; r = 0.458; P < 0.01 for CD4+; r = 0.500, P = 0.001 for CD14+ cells). UMCs were weakly correlated with tubulointerstitial changes. Conclusion. UMCs were associated with the clinical stage of IgAN and mirrored the extent of histopathology in the kidney. Flow-cytometry analysis of UMCs may help to predict the course of the disease.

In the presence of a nonlethal concentration of Cu(II), washed Escherichia coli ATCC11775 cells were killed by (-)-epigallocatechin (EGC) and (-)-epicatechin (EC). Cell killing was accompanied by a depletion in both the ATP and potassium pools of the cells, but the DNA double strand was not broken, indicating that the bactericidal activity of catechins in the presence of Cu(II) results from damage to the cytoplasmic membrane. Induction of endogenous catalase in E. coli cells increased their resistance to being killed by the combination of catechins and Cu(II). In all cases studied, EGC and EC with Cu(II) were found to generate hydrogen peroxide, but its concentration was too low to account for the bactericidal activity. The bactericidal activity of EGC in the presence of Cu(II) was completely suppressed by ethylenediaminetetraacetate, bathocuproine, catalase, superoxide disumutase (SOD), heated catalase, and heated SOD, but not by dimethyl sulfoxide. When catalase, either heated or unheated, was added to the cells incubated with EGC in the presence of Cu(II), it completely inhibited further killing of the cells. These findings suggest that recycling redox reactions between Cu(II) and Cu(I), involving catechins and hydrogen peroxide on the cell surface, must be important in the mechanism of the killing.

Pulverization-activation method was employed to accelerate solid-state organic reactions. Crushing and grinding of solid mixtures of hydrogen halide-treated silica gels, iodosobenzene and organic substrates in the absence of a solvent brought about smooth and rapid reactions to give halogenated and/or oxidized products in good yields. Various sulfides were smoothly converted to sulfonyl chlorides in one step in excellent yields. The surface of silica gel activated by pulverization serves as a reaction field on which reagent molecules can effectively encounter with each other.

Iodine was found to be an efficient catalyst for the aziridination of alkenes utilizing Chloramine-T (N-chloro-N-sodio-p-toluenesulfonamide) as a nitrogen source. For example, when two equivalents of styrene were added to Chloramine-T in the presence of a catalytic amount of iodine in a 1 : 1 solvent mixture of acetonitrile and neutral buffer, the corresponding aziridine 1 was obtained in 91% yield. The reaction could be applied to other acyclic and cyclic alkenes such as 1-octene and cyclohexene. The aziridination of p-substituted styrene derivatives 2–5 with Chloramine-T showed that electron-rich alkenes reacted faster than electron-poor ones. Several Chloramine-T analogs were also examined and were found to give the corresponding aziridines 8–10 in only moderate yields.

The effect of initial CO 2 concentration on NO destruction and regeneration was investigated as part of our ongoing research on NO emission from CO 2 recycled coal combustion, which could realize easy CO 2 recovery and drastic N() reduction simultaneously. Experiments were carried out in a flat flame burner for CH 4 /O 2 /Ar/NO/CO 2 flame at various excess oxygen ratios (from 0.6 to 1.2) and CO 2 concentrations (from 0% to 48%). It was found that CO 2 has a pronounced negative effect on the destruction of NO under fuel-rich condition. In contrast, under fuel- lean condition, the effect of CO 2 becomes smaller even at high CO 2 concentrations. Kinetic modeling showed that a large part of NO is regenerated through the reaction N+CO 2 = NO+CO at high CO 2 concentrations. The effect of CO 2 is not so significant under fuel-lean condition because this reaction is no longer competitive with other NO formation reactions in this case.

Aziridination of alkenes proceeds successfully using Chloramine-T (N-chloro-N-sodio-p-toluenesulfonamide). When anhydrous Chloramine-T was added to an acetonitrile solution of alkenes in the presence of various CuCl catalysts and MS-5A, the corresponding aziridines were obtained in moderate to good yields.

The mechanism of the generation and the quantitative analysis of singlet oxygen (1O2) formed by the exposure of a hematoporphyrin derivative (HpD) to light was re-evaluated by electron spin resonance (ESR) combined with 2,2,6,6,-tetramethyl-4-piperidine (TMPD). The change from TMPD to 2,2,6,6,-tetramethyl-4-piperidine-N-oxide (TAN) has been reported to depend on singlet oxygen. However, we confirmed that this reagent also react with superoxide anion (O2-) and hydroxyl radicals (OH). Therefore, the reactions between TMPD and 1O2, O2- and OH were re-examined using a kinetic approach. We found that the generation of TAN was proportional to the concentration of TMPD and HpD, as well as to the duration and strength of the illumination. The generation of TAN was not inhibited by dimethyl-sulfoxide (DMSO) or superoxide dismutase (SOD). The reaction rate between TMPD and 1O2 was determined to be 5.0 x 10(-7) M min-1. The generation of 1O2 from HpD was 2.7 x 10(-7) M min-1 under our conditions. The competitive reaction observed between 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and TMPD for O2- or OH shows that TMPD reacts with both forms of active oxygen, but gave no ESR signal. The second-order reaction rate constant of TMPD between O2- and OH was calculated as 73 M-1 s-1 and 1.5 x 10(9) M-1 s-1, respectively. The photochemical generation of 1O2 from methylene blue, another sensitizer, was also demonstrated by this method. These results show that ESR signal of TAN can be used for the highly selective monitoring of 1O2.

The antihistamine effects of olopatadine and levocetirizine, in standard-dose application described in their information (5 mg twice a day for olopatadine; 5 mg once daily for levocetirizine), were examined from 11.5 to 24 h after application. The test was designed in a double-blind, randomized, cross-over, placebo-controlled study of 12 healthy volunteers on histamine-induced flare and wheal response using an iontophoresis technique. The suppressive effect of olopatadine on the wheals induced by a 0.1-mA histamine iontophoresis lasted for 24 h after dosing. Both drugs inhibited flare induced by histamine iontophoresis almost completely until 24 h after the first administration. Suppression of the 0.2-mA-induced wheal response by levocetirizine, taken once daily, decreased with time, although 0.1-mA-induced flare was almost completely suppressed by the drug. Olopatadine completely suppressed even the wheal response induced by a 0.2-mA histamine iontophoresis. Compared with the placebo, the two drugs significantly suppressed the subjective itching assessed by visual analog scale at all intervals. There were no significant differences in subjective drowsiness and objective cognitive function between drug- and placebo-treated subjects. These results demonstrate that olopatadine seems to be more potent than levocetirizine when administrated in a standard dose. In conclusion, mild to moderate urticaria could be controlled by standard application as described in their information. On the other hand, severe urticaria could be managed by a standard application of olopatadine, but levocetirizine may need an additional dose to control severe urticaria.

Strikingly contrasting positive and negative sonochemical effects were observed in the reactions of lead tetraacetate with styrene and 2-octanol, respectively. The decomposition of lead tetraacetate itself in the absence of a substrate is not accelerated by ultrasound. These results are consistent with the idea that the radical chain reaction of lead tetraacetate and styrene involves the bimolecular initiation step of the two species; under ultrasonic irradiation, styrene is excited in the gas phase of the cavity. The efficiency of the sonochemical excitation must be decisively different between the gas phase and the liquid shell of the cavity. The importance of the boiling point of a substrate involved in the radical initiation step is proposed as a hypothetical guideline in homogeneous sonochemistry.

The methyl 1-thioglycoside derivative of 2-epi-, 2,4-di-epi-, 3-epi-, 4-epi, and 2-O-methyl- l -fucopyranose have been prepared as glycosyl donors for the synthesis of sialyl Lex ganglioside analogues containing modified α- l -fucopyranose residues.

Sialyl Le(x) ganglioside analogues containing 2-epi-, 2,3-di-epi-, 4-epi-, and 2-O-methyl-L-fucose in place of the L-fucose residue have been synthesized. Glycosylation of 2-(trimethylsilyl)ethyl O-(2-acetamido-4,6-O-benzylidene-2-deoxy-beta-D-glucopyranosyl)-(1--3)- 2,4,6- tri-O-benzyl-beta-D-galactopyranoside with the methyl 1-thioglycoside derivatives of the respective fucose analogues, using dimethyl(methylthio)sulfonium triflate (DMTST) as a promoter, gave the corresponding protected 2-(trimethylsilyl)ethyl deoxy-alpha-L-hexopyranosyl-(1--3)-O-(2- acetamido-2-deoxy-beta-D-glucopyranosyl)-(1--3)-beta-D-galactopyrano sid es. These were transformed by reductive ring-opening of their benzylidene acetal groups into the glycosyl acceptors. Dimethyl (methylthio)sulfonium triflate-promoted glycosylation of these compounds with methyl O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-alpha-D-galacto -2- nonulopyranosylonate)-(2--3)-2,4,6-tri-O-benzoyl-1-thio-beta-D- galactopyranoside afforded the desired pentasaccharides, which were converted via reductive removal of their benzyl groups, O-acetylation, selective removal of the 2-(trimethylsilyl)ethyl group, and reaction with trichloroacetonitrile, into the corresponding alpha-tri-chloroacetimidates. Glycosylation of (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol these in the presence of boron trifluoride etherate afforded the expected beta-glycosides, which were transformed in good yields, via selective reduction of the azido group, coupling with octadecanoic acid, O-deacylation, and deesterification, into the target gangliosides. The 2-(trimethylsilyl)ethyl glycosides of sialyl Le(x) oligosaccharides containing modified fucose were also prepared from the intermediates of the ganglioside synthesis.

Complexation of lanthanoid metal ions with 1,2-bis(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid and its two derivatives, in which the distance between the chelating functions is changed, has been studied by potentiometric pH titration. There are two complexation modes depending on the size of the metal ion. Structural flexibility of the chelator accounts for the change in the complexation mode.

Endoscopic mucosal resection (EMR) of colorectal polyps should be curative and safe. This study aimed to determine the efficacy and safety of colorectal EMR using 0.13 % hyaluronic acid (HA) solution. This was a single-armed multicenter prospective open trial conducted at 11 Japanese institutions. Lesion characteristics and various measures of clinical outcome, including en bloc resection, histopathologically complete resection, and postoperative bleeding were analyzed for 624 consecutive patients who underwent EMR of colorectal polyps at ≤20 mm in size from August 2010 to September 2011. En bloc and complete resection were achieved in 93.3 and 78.3 % of 624 lesions. The median EMR procedure time was 2.1 ± 1.5 min. The rates of postoperative bleeding and perforation were 1.1 and 0 %. The rate of en bloc resection was higher for polyps at 5–10 mm than for polyps at 11–20 mm (95.1 vs. 85.1 %; P

Iodination of unactivated aliphatic hydrocarbons with iodoform (CHI3) and solid NaOH were greatly accelerated under ultrasonic irradiation. The mechanism of the sonochemical acceleration was studied.