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This study was undertaken to investigate the age-related differences of monocyte chemotactic protein-1 (MCP-1) and matrix metalloproteinase-3 (MMP-3) expression in mouse intervertebral disc (IVD) and to determine whether MMP-3 plays a role in disc degeneration. Expression of MCP-1 and MMP-3 mRNA in mouse IVD was assessed by quantitative PCR. The ability of MCP-1 and MMP-3 expression in IVD to respond to TNF-α or TWEAK stimulation was examined by quantitative PCR, WB, ELISA, and immunohistochemistry. IVD derived from MMP-3-deficient and wild-type mice were compared using Safranin-O staining and immunohistochemistry. mRNA levels of MCP-1 and MMP-3 in IVD significantly diminished and the ability of MCP-1 or MMP-3 expression to respond to TNF-α or TWEAK stimulation was significantly reduced as age increased. IVD derived from 64-week-old wild-type mice showed clearly diffuse proteoglycan loss by Safranin-O staining and immunohistochemistry compared with younger mice. However, no loss of proteoglycan and typeII collagen were observed in IVD derived from 64-week-old MMP-3-deficient mice. MCP-1 and MMP-3 expression in mouse IVD showed age-related decreases. The response to inflammation in IVD also displayed age-related changes. Therefore, disc degeneration may vary with the patients' age and targeting MMP-3 may be a possible future therapeutic strategy for disc degeneration.

Danforth'sshort-tail (Sd) mouse is a semi-dominant mutation affecting the development of the vertebral column. Although the notochord degenerates completely by embryonic day 9.5, the vertebral column exists up to the lumber region, suggesting that the floor plate can substitute for notochord function. We previously established the mutant mouse line, Skt(Gt), through gene trap mutagenesis and identified the novel gene, Skt, which was mapped 0.95cM distal to the Sd locus. Taking advantage of the fact that monitoring notochordal development and genotyping of the Sd locus can be performed using the Skt(Gt) allele, we assessed the development of the vertebra, notochord, somite, floor plate and sclerotome in +-+/+-Skt(Gt), Sd-+/+-+, Sd-Skt(Gt)/+-+, Sd-Skt(Gt)/+-Skt(Gt), Sd-+/Sd-+ and Sd-Skt(Gt)/Sd-Skt(Gt) embryos. In Sd homozygous mutants with a C57BL/6 genetic background, the vertebral column was truncated in the 6th thoracic vertebra, which was more severe than previously reported. The floor plate and sclerotome developed to the level of somite before notochord degeneration and the number of remaining vertebrae corresponded well with the level of development of the floor plate and sclerotome. Defects to the sclerotome and subsequent vertebral development were not due to failure of somitogenesis. Taken together, these results suggest that the notochord induced floor plate development before degeneration, and that the remaining floor plate is sufficient for maintenance of differentiation of the somite into the sclerotome and vertebra in the absence of the notochord.

O2/CO2 combustion is a promising technology to facilitate carbon capture in pulverized coal-fired power plants. The reduction of recycled NO, influence of CO2 concentration on the conversion ratio ...

Cenospheres recovery is one of the coal fly ash beneficiations, providing economic as well as environmental benefits. Current techniques, such as lagoon or other wet-separation processes, consume large amounts of water and add to water pollution due to leaching of toxic materials from fly ash. The other possible disadvantage is the need for a wide operational area, which is unsuitable for densely populated countries. As wet-separation processes have some disadvantages, an improved and/or sustainable alternative recovery technique is required. An air classifier is one of the alternative techniques. In this study, two types of air classifiers, namely a closed-type pneumatic separator and a micron separator, have been investigated. In terms of separation efficiency, it was found that the micron separator has the potential to be applied in cenospheres recovery from coal fly ash, giving a Newton's efficiency of 0.44, as compared to a value of about 0.26 for the closed-type pneumatic separator. The cenospheres recoveries of both pieces of equipment at their optimum Newton's efficiencies were similar at over 60 wt.%. The separation performance was further assessed from the particle distributions of the overflow and underflow products obtained from both pieces of equipment, as well as from SEM images. It was found that the lower Newton's efficiency of the closed-type pneumatic separator was due to the re-concentration of fine particles in the underflow product at air-flow rates higher than 2.2 m/s (the underflow product yield was about 55 wt.%). In order to further confirm the applicability of this technique, the micron separator, which had provided higher separation efficiency and cenospheres recovery, was deployed in a cenospheres recovery unit prior to the use of a wet-separation process (float and sink tank). About 80% of the cenospheres was recovered, with an 87.8% reduction in the total mass of fly ash to be separated in the float and sink tank. Consequently, much less water was needed for the process of cenospheres recovery. Moreover, it was also confirmed that the micron separator could yield higher quality fly ashes, that is, fly ash types I and II, from lower feed quality of fly ash type IV, which is the lowest category in commercial classification of fly ash according to JIS A6201.

Common iliac artery (CIA) thrombosis is a rare surgical complication which may cause serious leg damage and may occasionally be fatal. We experienced two cases of CIA thrombosis in nephroureterectomy with the pluck technique for upper tract urothelial carcinoma. Patients were treated using emergent femoro–femoral bypass, and one patient was treated with fasciotomy of the lower extremity for compartment syndrome. CIA thrombosis is considered a possible complication of nephroureterectomy, particularly with the pluck technique in open surgery. Arterial thrombosis in intrapelvic surgery including nephroureterectomy should be carefully considered for patients at risk.

Strain engineering for pFETs has been conventionally enabled utilizing embedded SiGe in the source/drain regions to continuously boost the transistor current drive and transconductance [1]. Historically, for planar technologies, transconductance was monotonically improved by advancing the technology generations. However, this trend for transconductance, when properly normalized to the effective device width (fin perimeter) is no longer observed when FinFETs were introduced to the mainstream CMOS to improve the short channel effects for sub 30nm gate lengths [2]. The FinFET transconductance saturation or drop be attributed to ineffectiveness of the embedded SiGe stressors (in spite of higher mobility near-(110) surfaces) and/or increased contribution of the S/D resistance as the contacted gate pitch size aggressively scales down. Unless there is a strong and reliable method to externally apply gigantic strain to the Si fin channel, using strained SiGe (s-SiGe) channel, with built-in uniaxial compression, is a strong option to overcome this issue. In fact, SiGe has been utilized in CMOS industry as a knob to control the threshold voltage (Vth) and in part to boost the pFET reliability and transport [3]. Moreover, introduction of SiGe channel for planar pFET has improved reliability, resulting in further Capacitance-Equivalent-oxide-Thickness (CET) scaling over Si. For s-Si1-xGex FinFETs, choice of Ge content (x) is not trivial. Adding more Ge can ideally build in more channel stress resulting increased hole mobility and current drive. However, epitaxial-defect-driven fin height control due to the critical thickness constraints, process thermal budget, bandgap reduction and gate-induced drain leakage (GIDL) control remain challenging. In particular, High-Ge-Content (HGC) s-SiGe FinFETs are of great interest for two reasons, from the transport point of view: First, very high level of strain (close to 3GPa) can be achieved when lattice matched to Si [4]. Second, if strain-relaxed buffer (SRB) SiGe with moderate Ge % is used to tensily strain Si nFET, higher Ge is required to compressively strain the pFET [5]. The GIDL issue can be mitigated by operating the high-performance (HP) device at a lower VDD, i.e. below 0.6V, in line with logic roadmap [4]. Controlling the HFIN, to be competitive with the state-of-the-art Si FinFETs, remains challenging. Above all, a major challenge is associated with the gate stack and interface trap control which is more pronounced in HGC SiGe than Si and pure Ge. In this talk, key process details to enable relatively tall fins and optimized replacement high-k metal gate (RMG) stacks in high-Ge-content SiGe will be discussed and their impact on key device characteristics will be presented. In particular, we review our recent advancement to achieve optimized RMG IL and passivation [6], high hole mobility and record performing short channel pMOS FinFETs. In additions, a metal gate work-function tuning solution will be presented utilizing an ultra-thin replacement metal-gate scheme to achieve target high-performance off current down to 15nm gate lengths. References: [1] T. Ghani et al., IEDM, 2003, p. 197. [2] P. Hashemi, et al., IEDM, 2017, p. 824. [3] S. Krishnan et al., IEDM, 2011, p. 634. [4] P. Hashemi et al., IEDM, 2014, p. 402. [5] R. Xie et al., IEDM, 2016, p. 47. [6] P. Hashemi et al., VLSI Tech. Symp., 2017, p. 120.

The degree of separation in the recovery of cenospheres from coal fly ash has been estimated for both wet and dry separation processes by applying the terminal velocity concept of particles. Particle diameter and density were determined by sieving industrial cenospheres and coal fly ash type IV, the model particles. This information was then utilized to calculate the terminal velocity needed to estimate the separation performances of both the wet and dry separation processes. Based on this estimation, the dry separation process performed similarly to the wet separation process, with an optimum Newton's efficiency of 0.54, only slightly lower than that of the wet separation process of 0.6. Moreover, it was observed that the cenospheres were concentrated in the underflow product, whereas for the wet separation process the reverse was true. The findings of this assessment were verified using a micron separator. Similar tendencies in the concentration of cenospheres in the underflow products were obtained. An optimum Newton's efficiency as high as 0.44 was achieved, with 66% recovery of the cenospheres. The recovery of the cenospheres was only 4% lower than the estimated value (70%), from which we conclude that dry separation processes are interesting technologies to apply to the recovery of cenospheres from coal fly ash because of their high efficiencies.

Background. We previously established a treatment protocol for conventional cyclosporine (Sandimmune, Novartis, Basel, Switzerland) in children with frequently relapsing nephrotic syndrome; ~50% of patients remained relapse free for 2 years, without serious adverse events. Recently, microemulsified cyclosporine (Neoral, Novartis), which has a more stable absorption profile than conventional cyclosporine, has been developed. We tested the hypothesis that microemulsified cyclosporine is at least as effective as conventional cyclosporine. Methods. To evaluate the safety and efficacy of microemulsified cyclosporine, a prospective, multicentre trial was conducted according to the previously established protocol, using microemulsified cyclosporine instead of conventional cyclosporine. The duration of treatment was 24 months. During the first 6 months, patients received microemulsified cyclosporine in a dose that maintained the trough level between 80 and 100 ng/mL of cyclosporine. For the next 18 months, the dose was adjusted to maintain a level between 60 and 80 ng/mL. Results. A total of 62 patients (median age, 5.4 years; 48 males, 14 females) were studied. The frequency of relapse decreased from 4.6 ± 1.4 to 0.7 ± 1.5 times per year (P

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...

Background and Aims: MicroRNA (miRNA) are endogenous, approximately 22-nucleotide non-coding RNA that suppress gene expression at post-transcriptional levels by binding to the 3′-untranslated region of specific mRNA targets through base-pairing. It has been recently reported that miRNA have critical functions in key biological processes such as cell proliferation and cell death in various cancer cells. However, the relationship between intestinal inflammation and miRNA expression remains unclear. In the present study, we used microarray technology to identify miRNA induced in the colonic mucosa of patients with active ulcerative colitis (UC). Methods: Two colonic biopsy specimens from patients with active stage (>Matts grade 2) of UC under colonoscopy and two colonic biopsy specimens from healthy volunteers were obtained for gene expression profiles. Total RNA was extracted, and miRNA expression profiles were investigated using miRNA Microarray. Subsequently, to confirm the result of the Microarray investigation, we checked the expression of several selected miRNA using real-time polymerase chain reaction (PCR) in 12 colonic biopsy specimens from patients with active UC under colonoscopy and 12 specimens from the healthy volunteers. Results: In the microarray study, the expression of several miRNA was upregulated in the colonic mucosa of patients with active UC. Furthermore, two miRNA (miR-21, miR-155) were selected in the study using real-time PCR. Conclusion: Upregulated miRNA may be responsible for the development of intestinal inflammation in UC.

We demonstrate a novel remote interfacial layer (IL) scavenging technique yielding a record-setting equivalent oxide thickness (EOT) of 0.42 nm using a HfO2-based high-k gate dielectric. The remote IL scavenging shows advantages in carrier mobility and gate leakage current over conventional IL scaling schemes. Moreover, this method enables intrinsic EOT scaling without introducing additional charges and interface degradation. It is shown that the mobility degradation observed for a La-containing high-k is not due to the La-induced dipole but due to the intrinsic IL scaling effect, whereas an Al-induced dipole brings about additional mobility degradation. This unique nature of the La-induced dipole in conjunction with the IL scaling enables aggressive EOT scaling toward the end of the road map.

舌下投与は痛みを伴わないため, 内服不能で他の投与経路確保が困難な終末期患者に有用な方法である. われわれは, がん性疼痛に対するブプレノルフィン(0.1～0.2mg/回), フェンタニル(0.05～0.2mg/回)注射剤舌下投与, および不眠時のミダゾラム(0.1mg・kg‾¹)注射剤舌下投与の有効性と安全性について検討した. 3剤は口腔内よりすみやかに吸収され, 約90％の症例に効果があった. 眠気, 嘔気のほか, 嚥下障害を有する例で痰の増加がみられた以外は, 特に大きな副作用はなかった. 注射剤の舌下投与は, 緩和ケアにおける代替投与経路として患者のQOLのために有用な手段である. Palliat Care Res 2010; 5(1): 201-205

A 63-year-old patient presented with cerebral hyperperfusion manifesting as transient aphasia and general tonic convulsions 3 and 4 days after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. Diffusion-weighted magnetic resonance (MR) imaging revealed a focal low-intensity area at the site of anastomosis in the left temporal lobe, with high apparent diffusion coefficient, together with focal intense increase in cerebral blood flow in the same region. This lesion was considered to be pure vasogenic edema caused by cerebral hyperperfusion. Additional treatment with intravenous drip infusion of free radical scavenger and reduction in blood pressure with nicardipine improved the patient's symptoms and brain edema. The brain edema gradually decreased on MR imaging and completely disappeared at 3 months after bypass surgery. Cerebral hyperperfusion is often encountered after recanalization of occlusive arteries, removal of arteriovenous malformations, and carotid endarterectomy, but may also occur after STA-MCA anastomosis.

A record high electron mobility (248 cm2/V middots at E eff of 1 MV/cm) was obtained at T inv of 1.47 nm, with a band-edge effective work function, by a Hf-Si/HfO2 stack using gate-last process, resulting in I ON of 1178 muA/mum (I OFF of 100 nA/ mum ) at V dd of 1.0 V for a 45-nm gate nMOSFET without strain-enhanced technology.

Transforming growth factor-beta (TGFbeta) is abundant in mammalian milk in a latent form. However, whether the latent form of TGFbeta in human milk is converted to the active form in vivo remains uncertain. To address this issue, we first investigated whether latent TGFbeta or human milk-borne latent TGFbeta was activated in an in vitro assay, simulating the effects of gastric acid. We then tested whether gastric acid was necessary for the activation of orally administered latent TGFbeta or human milk-borne latent TGFbeta in mice by inhibiting gastric acidity with cimetidine, an antagonist of H2-receptors. Latent TGFbeta or human milk-borne latent TGFbeta increased Smad-responsive promoter activity in MFB-F11 reporter cells at pH 1.2, but not at pH 7.0, regardless of the presence or absence of the gastric protease pepsin. In mice treated orally with latent TGFbeta (5 microg/mouse), the phosphorylation of Smad2 and TGFbeta target gene mRNA expression (TGFbeta and Smad7) was increased in the small intestine (P < 0.05) and this effect was inhibited by cimetidine (100 mg/kg, intraperitoneally). Similarly, mice treated orally with 1200 microL/d of human milk containing latent TGFbeta (3 microg/L) for 2 wk had increased TGFbeta and Smad7 mRNA expression in the small intestine (P < 0.05) and this was inhibited by the antiacid treatment. Therefore, the latent form of TGFbeta, such as TGFbeta in human milk, can be activated by gastric acid following oral administration in mice. This process may be involved in the conversion of human milk-borne latent TGFbeta to the active form in vivo.

Cow milk contains a large amount of an immunoregulatory cytokine, transforming growth factor-beta (TGFbeta). The present study investigated whether commercially available pasteurized cow milk retains TGFbeta activity both in vitro and in vivo. Some commercial cow milk increased TGFbeta/Smad-responsive reporter activity and induced Smad2 phosphorylation and the transcription of the TGFbeta/Smad target genes TGFbeta itself and Smad7 in vitro. Mice treated orally with 500 microL of cow milk containing TGFbeta (3 microg/L) daily for 2 wk had increased phosphorylation of Smad2 and TGFbeta and Smad7 mRNA expression in the intestine. These mice also had significantly greater serum TGFbeta concentrations than the mice treated orally with PBS. Furthermore, oral administration of 500 microL of cow milk containing TGFbeta (3 microg/L) daily for 2 wk before the induction of dextran sodium sulfate colitis and lipopolysaccharide-induced endotoxemia ameliorated tissue damage and mortality, respectively, in mice. These in vivo effects of cow milk were abrogated by the simultaneous administration of TGFbeta type I receptor kinase inhibitor with the cow milk, and they were not observed after the oral administration of cow's milk containing little TGFbeta. In humans, 1 oral challenge of 10 mL/kg cow milk containing TGFbeta (3 microg/L) increased the plasma TGFbeta concentrations at 4 h after the challenge. Thus, some commercially available pasteurized cow milk retains TGFbeta activity, which may be able to provide protection against experimental colitis and endotoxemia associated with increased intestinal and circulating TGFbeta levels.

Patients with diseases characterized by chronic inflammation, caused by infection or cancer, have T cells and NK cells with impaired function. The underlying molecular mechanisms are diverse, but one of the major mediators in this immune suppression is oxidative stress caused by activated monocytes, granulocytes, or myeloid-derived suppressor cells. Reactive oxygen species can seriously hamper the efficacy of active immunotherapy and adoptive transfer of T and NK cells into patients. In this study, we have evaluated whether enhanced expression of the antioxidant enzyme catalase in human T cells can protect them against reactive oxygen species. Human CD4+ and CD8+ T cells retrovirally transduced with the catalase gene had increased intracellular expression and activity of catalase. Catalase transduction made CD4+ T cells less sensitive to H2O2-induced loss-of-function, measured by their cytokine production and ability to expand in vitro following anti-CD3 stimulation. It also enhanced the resistance to oxidative stress-induced cell death after coculture with activated granulocytes, exposure to the oxidized lipid 4-hydroxynonenal, or H2O2. Expression of catalase by CMV-specific CD8+ T cells saved cells from cell death and improved their capacity to recognize CMV peptide-loaded target cells when exposed to H2O2. These findings indicate that catalase-transduced T cells potentially are more efficacious for the immunotherapy of patients with advanced cancer or chronic viral infections.

Background Both active and passive smoking are considered to be risk factors for asthma development. However, the precise mechanisms involved remain elusive. Recently, thymic stromal lymphopoietin (TSLP) has been shown to play a key role in the development of T H 2-type allergic inflammation in patients with asthma. Objective The aim of this study was to investigate whether there was a causal relationship between cigarette smoke exposure and TSLP expression in the lung. Methods We examined the effects of repeated intranasal exposure of cigarette smoke extract (CSE) on TSLP mRNA and protein expression in the mouse lung by means of real-time PCR, Western blotting, and immunohistochemistry. We also examined the effects of intranasal exposure of CSE plus ovalbumin (OVA) on T H 2-type immune responses and lung pathology. Results Repeated exposure of CSE induced TSLP mRNA and protein expression, which was inhibited by treatment with antioxidative N-acetylcysteine and by TNF-α receptor I deficiency. In addition, the intranasal exposure of CSE simultaneously with OVA induced OVA-specific T H 2-type immune responses and airway inflammation, which were inhibited by the blockade of the TSLP activity. Conclusion CSE induced TSLP expression in the mouse lung in an oxidative stress–dependent and TNF-α receptor I–dependent manner, and when challenged simultaneously with an antigen, CSE promoted the development of airway inflammation in association with T H 2-type immune responses.

This is a report of posterior interosseous nerve palsy caused by solitary and nerve-derived tumor. Magnetic resonance imaging is beneficial in the preoperative diagnosis and the localization of tumor.

STUDY DESIGN Molecular biologic and immuno-histologic analyses using in vitro murine intervertebral disc tissue culture. OBJECTIVE To investigate the role of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in matrix metalloproteinase 3 (MMP-3) pathway induction, and the effect of TWEAK to induce other cytokines or angiogenesis factors in disc tissues. SUMMARY OF BACKGROUND DATA We previously demonstrated that TWEAK and its receptor Fn14 were expressed in murine disc tissues. TWEAK induced MMP-3 upregulation and aggrecan downregulation in disc tissues. METHODS Enzyme-Linked ImmunoSorbent Assay (ELISA), western blot, and immuno-histologic analyses were used to assess the role of TWEAK-induced MMP-3, using murine disc tissue culture. RESULTS TWEAK induced disc cells to generate MMP-3 as did TNF-alpha and IL-1beta. MMP-3 activity was detectable in murine disc cells. MMP-3 induction was markedly inhibited with a c-Jun N-terminal kinase (JNK) inhibitor. Phosphorylation of JNK was also confirmed. Introduction of TWEAK resulted in the degradation of disc matrix in organ disc culture, whereas proteoglycan degradation was markedly abrogated in the presence of an MMP-3 specific inhibitor or a JNK inhibitor. In addition, TWEAK also induced monocyte chemotactic protein (MCP)-1 via the NF-kappaB pathway, as phosphorylation of NF-kappaB was confirmed by western blotting. CONCLUSION TWEAK plays an important role in MMP-3 induction in murine disc cells via JNK that results in degradation of disc matrix. TWEAK also induces MCP-1, which belongs to the chemokine family that recruits inflammatory cells via the NF-kappaB pathway.

Objective To determine whether thymic stromal lymphopoietin (TSLP) plays a role in the resorption of herniated disc tissue. Methods The expression of TSLP messenger RNA (mRNA) and protein in mouse intervertebral disc cells was assessed by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), and immunohistochemical analysis. The ability of mouse intervertebral disc cells to respond to TSLP stimulation was examined by Western blot analysis, ELISA, and protein array analysis. Intracellular signaling pathways involved in TSLP signaling in mouse intervertebral disc cells were investigated using several chemical inhibitors. The role of TSLP in macrophage migration into the intervertebral disc was assessed by in vitro migration assay. Finally, TSLP expression in clinical specimens derived from patients with a herniated disc was examined by immunohistochemistry. Results Mouse intervertebral disc cells expressed TSLP mRNA and protein upon stimulation with NF-κB–activating ligands such as tumor necrosis factor α. In addition, the mouse intervertebral disc cells expressed the TSLP receptor and produced monocyte chemotactic protein 1 (MCP-1; CCL2) and macrophage colony-stimulating factor in response to TSLP stimulation. Both anulus fibrosus and nucleus pulposus intervertebral disc cells expressed MCP-1 upon TSLP stimulation, which was mediated via the phosphatidylinositol 3-kinase/Akt pathway. Consistently, the supernatants of TSLP-activated intervertebral disc cultures had the capacity to induce macrophage migration in an MCP-1–dependent manner. Finally, TSLP and MCP-1 were coexpressed in human herniated disc specimens in which macrophage infiltration into the tissue was observed. Conclusion TSLP induced by NF-κB–activating ligands in intervertebral discs may contribute to the recruitment of macrophages to the intervertebral disc by stimulating MCP-1 production and may be involved in the resorption of herniated disc tissue.

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.

Epithelial cell-derived thymic stromal lymphopoietin (TSLP) is a master switch for asthma or atopic dermatitis by inducing a dendritic cell-mediated Th2-type allergic inflammation. Allergic rhinitis is also pathologically characterized by Th2-type allergic inflammation. This study demonstrates that mast cells regulate the epithelial TSLP expression in allergic rhinitis. TSLP expression was found to be up-regulated predominantly in the nasal epithelium in the ovalbumin (OVA)-sensitized and -nasally challenged mouse model of allergic rhinitis, which was abolished in mast cell-deficient WBB6F1-W/W(v) in comparison with control WBB6F1-+/+ mice. Similarly, the epithelial TSLP expression was reduced in Fc receptor gamma chain (FcgammaR)-deficient mice, where the high-affinity IgE receptor (FcepsilonRI) is not expressed on mast cells, in comparison with control C57BL/6 mice. Furthermore, the administration of neutralizing TSLP antibody during the challenge phase of OVA inhibited the development of allergic rhinitis. These results suggest that the direct stimulation of epithelial cells by antigens alone may not be sufficient to induce TSLP expression in the nasal epithelium, and that mast cell regulation of epithelial TSLP expression, possibly via FcepsilonRI, plays an important role in the development of allergic rhinitis.

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.

We propose a fluorine (F) treatment technique that is suitable for threshold voltage (Vth) modulation in p-channel metal–oxide–semiconductor field-effect transistors (PMOSFETs) with the atomic layer deposition (ALD) TiN/HfO2 gate structure. A work function near the band edge is achieved using the F treatment technique without the degradation of hole mobility in PMOSFETs. Vth shift value is almost the same regardless of gate length. The barrier height shift attributable to the F treatment corresponds closely to the Vth shift. It is found that the F treatment technique modulates the effective work function. No Vth shift in n-channel MOSFET (NMOSFETs), namely, the ALD-TiN/HfSix/HfO2 gate stack structure, is observed with F treatment. It is confirmed that F treatment is a suitable technique for complementary MOSFET (CMOSFETs) due to the confinement of Vth shift only to PMOSFETs.

Gemcitabine (GEM) has improved both overall survival and tumor-related symptoms in patients with advanced pancreatic cancer when compared to 5-FU, and is a widely accepted treatment for such patients. However, pancreatic cancers remain extremely resistant to chemotherapy. Empiric chemotherapy based on GEM has had no major successes in treating patients with advanced disease. The objective of this study was to evaluate the response rate, survival, and toxicity of the sequential combination of GEM and hyperthermia. Between November 2005 and November 2007, 7 patients with unresectable pancreatic cancer received sequential combination therapy with GEM and hyperthermia at the Matsushita Memorial Hospital. Data were then compared with 7 historical controls treated with GEM alone at the same institution. There were no significant differences in age, performance status or UICC stage between the GEM plus hyperthermia and GEM monotherapy groups. The disease control rate (CR+PR+SD) was 14.3% for patients treated GEM alone and 57.1% for patients treated with GEM plus hyperthermia. The median survival time was 198 days for patients treated with GEM alone, and 327 days for patients treated with GEM plus hyperthermia. Combination therapy with GEM and hyperthermia thus improves overall survival when compared with GEM monotherapy (p=0.0275). The sequential combination of GEM plus hyperthermia showed a potential therapeutic effect, and was at least as effective as GEM monotherapy. To clarify the effects of this combination therapy, a larger prospective clinical trial is required.

The Japan Arteriosclerosis Longitudinal Study-Existing Cohorts Combine (JALS-ECC) is a pooled study based on individual participant data from existing prospective cohort studies in Japan. Its purpose was to consider associations between risk factors and cardiovascular disease (CVD) outcomes, as well as differences between subgroups, defined by age, gender or geographical region, which could not be detected in the smaller samples.Individual records for 66,691 participants in 21 cohort studies were pooled, accounting for a total of 575,628 person-years. From this data, there were 409 deaths attributed to stroke and 169 deaths attributed to coronary heart disease (CHD). Total stroke and CHD events were 1,478 and 178, respectively. Of the 1,424 total stroke events with a reported stroke subtype, 975 were classified as ischemic, 267 as hemorrhagic, and 178 as subarachnoid hemorrhage.The JALS-ECC collected data from existing cohort studies covering a diverse Japanese population, which has provided information about the effects of modifiable factors on the risks of the CVD. Such information should provide a reliable basis for establishing prevention strategies.

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.

Abdominal aortic aneurysm (AAA) is known to be rarely accompanied by disseminated intravascular coagulation (DIC). We report a case of AAA with DIC. An 81-year-old man with abdominal pain referred to our hospital. Computed tomography demonstrated an AAA (maximum diameter: 90 mm). The patient underwent a laparotomy, and an abdominal aorta replacement was performed. At the 3-month follow-up, the patient underwent Helicobacter pylori eradication treatment for 1 week. After treatment, the platelet count dramatically increased. The mechanism by which H. pylori eradication therapy improves hematological parameters has not been elucidated; however, this noninvasive treatment effectively resolved DIC associated with AAA.

Ménétrier's disease has been reported to be associated with Helicobacter pylori infection. The aim of this study was to investigate the genetic characteristics of various virulence factors and cytokine expression profiles in Helicobacter pylori isolated from patients with Ménétrier's disease. The genotyping of virulence factors was accomplished by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Induction of various cytokines in MKN45 cells or gastric fibroblasts by Helicobacter pylori stimulus was measured by real-time reverse transcription-PCR. We found that the Helicobacter pylori strain isolated from a patient with Ménétrier's disease was different from other strains in the MseI-RFLP pattern of the ureC gene. Helicobacter pylori isolated from a patient with Ménétrier's disease showed the highest hepatocyte growth factor (HGF) and TNF-alpha mRNA expressions from gastric fibroblasts, and the highest TNF-alpha expression from MKN45 cells. The results in this study suggest that the difference in cytokine production, depending on the difference in bacteria components, plays an important role in the development of Ménétrier's disease.

In Japanese healthy CYP2C19 extensive metabolizers, rabeprazole 10 mg shows a faster onset of action and stronger inhibition of acid secretion than does omeprazole 20 mg on the first 3 days of administration. We evaluated gastric ulcer improvement after 1 week's treatment with rabeprazole or omeprazole in relation to CYP2C19 polymorphism. A 6-mm rubber disc was placed temporarily at the side of the ulcer for measurement of the ulcer area. The improvement ratios of ulcer area in homozygous extensive metabolizers (homoEMs), heterozygous extensive metabolizers (heteroEMs) and poor metabolizers (PMs) treated with rabeprazole 10 mg were 60.8, 65.0 and 55.3%, respectively, and these values are not significantly different. Corresponding values with omeprazole 20 mg were 46.3, 61.7 and 63.2%, respectively, and the value of homoEMs was significantly smaller than that of heteroEMs. The improvement ratios with rabeprazole in homoEMs and heteroEMs were significantly greater than that with omeprazole in homoEMs.

Background Epidemiologic studies suggest that TGF-β in breast milk provides protection against allergic disease during infancy. However, it is unclear whether orally administered TGF-β, such as TGF-β in human milk, retains and exerts its activity in the intestinal mucosa and can affect immune response (tolerance) to dietary antigens. Objective We sought to determine whether orally administered TGF-β is biologically active in intestinal mucosa and affects oral tolerance. Methods Activity of orally administered TGF-β in the intestinal mucosa was evaluated by means of in vivo imaging with transgenic mice expressing a Smad-responsive reporter construct (SBE-luc mice), by means of immunohistochemical staining with anti-phosphorylated Smad2 antibody, and by means of real-time RT-PCR analysis of TGF-β and Smad7 mRNA expression. The effects of orally administered TGF-β on oral tolerance induction were assessed in mice tolerized by means of high-dose ovalbumin (OVA) feeding. Results The oral administration of TGF-β increased Smad-responsive reporter activity in the intestines of SBE-luc mice and induced Smad2 phosphorylation and TGF-β and Smad7 mRNA expression in the intestines of BALB/c mice. Serum TGF-β levels were also increased after oral administration of TGF-β. BALB/c mice treated orally with OVA and TGF-β showed augmented reduction of OVA-specific IgE and IgG1 antibodies, T-cell reactivity, and immediate-type skin reactions when compared with the mice treated orally with OVA alone. Conclusions Orally administered TGF-β retains sufficient biologic activity in intestinal mucosa and enhances oral tolerance. Clinical implications Oral administration of TGF-β might become a potential strategy to prevent allergic diseases, such as food allergy.

Electron mobility, work function instabilities and re-growth of the thin SiO2 interfacial layer are main concerns for integrating metal/high-k stacks in high performance CMOS. High electron mobility has been obtained with both high (T~1000oC) and low (T~400oC) temperature processing but still the exact mechanism of the metal interaction with the gate stack is not fully understood. Threshold voltage control is also an open issue since metal/high-k stacks exhibit mid-gap work functions after high temperature annealing. Fixes have been proposed which require the introduction of positive (negative) charges near the Si/SiO2 interface to produce devices operating at the Si band edges.

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.

Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that triggers dendritic cell-mediated Th2-type inflammatory responses and is considered as a master switch for allergic inflammation. In this study, we found increased levels of TSLP and, also TNF-alpha as previously reported, in synovial fluid specimens derived from patients with rheumatoid arthritis (RA) when compared with those from patients with osteoarthritis (OA). In addition, TNF-alpha up-regulated TSLP expression in RA- and OA-derived synovial fibroblasts, which was inhibited by IFN-gamma. Furthermore, anti-TSLP neutralizing antibody ameliorated a TNF-alpha-dependent experimental arthritis induced by anti-type II collagen antibody in mice. Collectively, these results suggest that TSLP, as a downstream molecule of TNF-alpha, may be involved in the pathophysiology of inflammatory arthritis. TSLP might thus play a role not only in allergic diseases but also in inflammatory arthritis such as RA.

Multi-layered mirrors were fabricated by spin coating of two kinds of polymers. Optical thickness of each layer could be so controlled as to be equal to a quarter of a designed wavelength by adjusting the concentrations of the solutions and rotation speed of the spinner. Increase of the number of layers fabricated through a simple repetitive process of spin coating solutions and drying solvents resulted in the increase of the reflectivity at the designed wavelength. The mirrors possessed the reflectivity higher than 99%. The polymeric multi-layered mirrors were used for the first time as the output couplers of a microchip Nd 3+ :YVO 4 laser. The low-cost polymeric multi-layered films will be used for optically and electrically functional applications that cannot be realized by inorganic ones.

While lower serum albumin concentration is often found in the elderly, a relation between serum albumin and age has not been fully elucidated. We conducted population-based cross-sectional and 5-y longitudinal study to examine the relation. A total of 22,705 male and 40,149 female, aged 65 y and older, living in Gifu, participated in the health check service conducted by Gifu City Medical Association. They were self-supported in the activity of daily living and 3,438 of them were followed up every year from 1999 to 2003. Serum albumin levels decreased with age in both men and women. In the cross-sectional study, median value declined from 4.3 g/dL in males aged 65-69 y to 3.9 g/dL in 90< or = y, and 4.3 g/dL to 4.0 g/dL in females. Incidence of hypoalbuminemia (serum albumin < or =3.5 g/dL) increased in parallel with age from 1.2% (65-69 y) to 6.6% (85-89) in males, and 0.6% to 4.1% in females. In the longitudinal study, regression analysis showed a significant decline in serum albumin of 0.015 g/dL per year (r= -0.716) in males, and 0.012 g/ dL per year (r= -0.794) in females. Relative reduction of serum albumin in 5 y was larger in advanced age; 1.2% in females aged 65-69 y and 3.1% in 85-89 y (p

まれな上腕骨解剖頚骨折を伴った肩関節後方脱臼例を報告した．症例は21歳の男性であり，主訴は左肩痛，挙上困難であった．ラグビー試合中，タックルを受け転倒し，その上に他の選手が倒れてきて左肩を受傷した．直後より左肩の激痛が出現し当科受診となった．左肩は内転内旋位で上肢をかかえ，運動は困難であった．X線前後像で関節裂隙の消失を認め，腋窩撮影で上腕骨解剖頚骨折と肩関節後方脱臼を認めた．全麻下徒手整復を試みるも整復されず観血整復術を施行した．Delto-pectoral incisionで前方関節包を切開し，エレバトリウムにて上腕骨頭を整復後，K-wireにて経皮的に骨接合術を施行した．外固定を6週間施行し，術後2カ月のX線で骨癒合を認めK-wireを抜去した．術後1年のMRIで上腕骨頭壊死は認めなかった．術後11年のX線で変形性関節症は認めず，JOA scoreは100点であった．

We identified unique device width and length dependencies of Vt for FinFET Replacement Metal Gate (RMG). Choice of fill metal is important to obtain a flat Vt-Wdes trend. We proposed a new model for Vt-Lg roll-up for High-k last RMG and demonstrated a flat Vt-Lg trend via optimization of High-k and MOL films based on the understanding.

Background: (Pro)renin receptor[(P)RR] is a single trans-membrane receptor that binds to both renin and its precursor prorenin to activate tissue renin-angiotensin system (RAS). (P)RR is cleaved by furin to generate soluble (pro)renin receptor [s(P)RR], which is secreted into the extracellular space. Blood s(P)RR level is a candidate biomarker reflecting the status of the tissue RAS, and we have reported that serum s(P)RR levels are associated with renal function. Endocrine or metabolic factors contribute to progression of endorgan damages in hypertensive patients. Therefore, in the present study, we investigated the relationships between serum s(P)RR levels and endocrine or metabolic factors in patients with essential hypertension. Methods: We measured serum s(P)RR levels and assessed the relationships between serum s(P)RR levels and background factors including endocrine or metabolic factors such as age, body mass index (BMI), abdominal circumference, hemoglobin, uric acid, HbA1c, LDL-cholesterol (C), HDL-C, triglyceride (TG), high-sensitivity (hs) CRP, plasma renin activity, aldosterone concentration, noradrenaline, adrenaline, thyroid stimulating hormone, free T3, and free T4 in essential hypertensive patients. Results: A total of 302 patients (138 males) were enrolled. The mean value for age was 57±12 y.o., BMI was 24.9±5.1 Kg/m2, blood pressure was 140±16/85±12 mmHg, hemoglobin was 14.0±1.3 g/dl, estimated glomerular filtration rate (eGFR) was 75.2±20.6 ml/min/1.73 m2, HbA1c was 5.7±0.7%, and serum s(P)RR level was 21.0±5.8 ng/ml. Serum s(P)RR levels were significantly positively correlated with age (r=0.209, p Conclusion: In patients with essential hypertension, serum s(P)RR levels were shown to be associated with endocrine or metabolic factors in addition to renal function, suggesting serum s(P)RR level as a useful biomarker that reflects the status of endocrine or metabolic disorders.

Background: The (pro)renin receptor [(P)RR] plays an important role in regulating the tissue renin-angiotensin system (RAS) through the non-proteolytic activation of prorenin, the precursor of renin. (P)RR is cleaved by furin to generate soluble (P)RR [s(P)RR], which is secreted into the extracellular space, and serum s(P)RR has been reported to reflect the status of tissue RAS. Hemodialysis (HD) patients have poor prognosis due to increased prevalence of cardiovascular diseases resulting from severe atherosclerosis. It is speculated that activation of tissue RAS by (P)RR may be associated with this condition, it remains speculative. In the present study, we investigated the relationships between serum s(P)RR levels and background factors including indices of atherosclerosis in HD patients. Methods: Serum s(P)RR levels were measured in 258 maintenance HD patients and these values were compared with 25 subjects with normal renal function. Western blot analysis was done using HD waste water samples, and clearance of s(P)RR through the membrane of dialyzer was examined. Furthermore, relationships between serum s(P)RR levels and background factors were assessed in HD patients. Results: Serum s(P)RR levels were significantly higher in HD patients (30.4±6.1 ng/ml) than those in subjects with normal renal function (16.5±4.3, P

It has been known that LPS activates macrophages and induces IFN-β production from macrophages. The endogenous IFN-β produced by LPS stimulates the cells, which plays a role in innate immune. However, it was not elucidated yet if the signaling by exogenous IFN-β was influenced by LPS stimulation. In this study, it was found pretreatment of LPS interrupted IFN-β-induced JAK1/STAT1 phosphorylation. LPS pretreatment also reduced IFN-β-induced ISG54, one of IFN-β-inducible genes. Pretreatment with LPS for more than 2h shows inhibitory effect on IFN-β-induced STAT1 phosphorylation but simultaneous treatment or post-treatment of LPS with IFN-β did not show the inhibitory effect. The study using a neutralizing antibody to IFN-β indicated that IFN-β produced by LPS does not take part in the inhibitory effect of LPS. Furthermore, LPS did not affect the expression of IFN αβ receptor. A previous report has shown that LPS-induced SOCS3 inhibited IFN-γ-induced STAT1 phosphorylation, likewise, it was also shown in this study that LPS induced SOCS3 expression and its expression inhibited IFN-β-induced STAT1 phosphorylation which was confirmed by the knockdown study by the siRNA of SOCS3. The real-time PCR and immune-blot studies of SOCS3 indicated that LPS induced SOCS3 is independent of IL-6, IL-10, TNF-α and STAT3, and might depend on p38 activation by LPS. It was suggested that bacterial LPS rather interfere with IFN-β actions, dependent on the timing of LPS stimulation.