Hepatocyte growth factor ameliorates dermal sclerosis in the tight-skin mouse model of scleroderma

The tight-skin (TSK/+) mouse, a genetic model of systemic sclerosis (SSc), develops cutaneous fibrosis and defects in pulmonary architecture. Because hepatocyte growth factor (HGF) is an important mitogen and morphogen that contributes to the repair process after tissue injury, we investigated the role of HGF in cutaneous fibrosis and pulmonary architecture defects in SSc using TSK/+ mice. TSK/+ mice were injected in the gluteal muscle with either hemagglutinating virus of Japan (HVJ) liposomes containing 8 μg of a human HGF expression vector (HGF-HVJ liposomes) or a mock vector (untreated control). Gene transfer was repeated once weekly for 8 weeks. The effects of HGF gene transfection on the histopathology and expression of tumor growth factor (TGF)-β and IL-4 mRNA in TSK/+ mice were examined. The effect of recombinant HGF on IL-4 production by TSK/+ CD4(+ )T cells stimulated by allogeneic dendritic cells (DCs) in vitro was also examined. Histologic analysis revealed that HGF gene transfection in TSK/+ mice resulted in a marked reduction of hypodermal thickness, including the subcutaneous connective tissue layer. The hypodermal thickness of HGF-treated TSK/+ mice was decreased two-fold to three-fold compared with untreated TSK/+ mice. However, TSK/+ associated defects in pulmonary architecture were unaffected by HGF gene transfection. HGF gene transfection significantly inhibited the expression of IL-4 and TGF-β1 mRNA in the spleen and skin but not in the lung. We also performed a mixed lymphocyte culture and examined the effect of recombinant HGF on the generation of IL-4. Recombinant HGF significantly inhibited IL-4 production in TSK/+ CD4(+ )T cells stimulated by allogeneic DCs. HGF gene transfection inhibited IL-4 and TGF-β mRNA expression, which has been postulated to have a major role in fibrinogenesis and reduced hypodermal thickness, including the subcutaneous connective tissue layer of TSK/+ mice. HGF might represent a novel strategy for the treatment of SSc

Prediction of Optimal Reversal Dose of Sugammadex after Rocuronium Administration in Adult Surgical Patients

The objective of this study was to determine the point after sugammadex administration at which sufficient or insufficient dose could be determined, using first twitch height of train-of-four (T1 height) or train-of-four ratio (TOFR) as indicators. Groups A and B received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as a first dose when the second twitch reappeared in train-of-four stimulation, and Groups C and D received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as the first dose at posttetanic counts 1–3. Five minutes after the first dose, an additional 1 mg/kg of sugammadex was administered and changes in T1 height and TOFR were observed. Patients were divided into a recovered group and a partly recovered group, based on percentage changes in T1 height after additional dosing. T1 height and TOFR during the 5 min after first dose were then compared. In the recovered group, TOFR exceeded 90% in all patients at 3 min after sugammadex administration. In the partly recovered group, none of the patients had a TOFR above 90% at 3 min after sugammadex administration. An additional dose of sugammadex can be considered unnecessary if the train-of-four ratio is ≥90% at 3 min after sugammadex administration. This trial is registered with UMIN000007245

Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) induced in (C57BL/6 × DBA/2) F1 (BDF1) mice by the injection of DBA/2 mouse spleen cells represents histopathological changes associated with systemic lupus erythematosus (SLE), primary biliary cirrhosis (PBC) and Sjogren's syndrome (SS), as indicated by glomerulonephritis, lymphocyte infiltration into the periportal area of the liver and salivary glands. We determined the therapeutic effect of hepatocyte growth factor (HGF) gene transfection on lupus using this chronic GVHD model. Chronic GVHD mice were injected in the gluteal muscle with either HVJ liposomes containing 8 μg of the human HGF expression vector (HGF-HVJ liposomes) or mock vector (untreated control). Gene transfer was repeated at 2-week intervals during 12 weeks. HGF gene transfection effectively prevented the proteinuria and histopathological changes associated with glomerulonephritis. While liver and salivary gland sections from untreated GVHD mice showed prominent PBC- and SS-like changes, HGF gene transfection reduced these histopathological changes. HGF gene transfection greatly reduced the number of splenic B cells, host B cell major histocompatibility complex class II expression, and serum levels of IgG and anti-DNA antibodies. IL-4 mRNA expression in the spleen, liver, and kidneys was significantly decreased by HGF gene transfection. CD28 expression on DBA/2 CD4+ T cells was decreased by the addition of recombinant HGF in vitro. Furthermore, IL-4 production by DBA/2 CD4+ T cells stimulated by irradiated BDF1 dendritic cells was significantly inhibited by the addition of recombinant HGF in vitro. These results suggest that HGF gene transfection inhibited T helper 2 immune responses and reduced lupus nephritis, autoimmune sialoadenitis, and cholangitis in chronic GVHD mice. HGF may represent a novel strategy for the treatment of SLE, SS and PBC

SIGMA: Scala Internal Domain-Specific Languages for Model Manipulations

International audienceModel manipulation environments automate model operations such as model consistency checking and model transformation. A number of external model manipulation Domain-Specific Languages (DSL) have been proposed, in particular for the Eclipse Modeling Framework (EMF). While their higher levels of abstraction result in gains in expressiveness over general-purpose languages, their limitations in versatility, performance, and tool support together with the need to learn new languages may significantly contribute to accidental complexities. In this paper, we present Sigma, a family of internal DSLs embedded in Scala for EMF model consistency checking, model-to-model and model-to-text transformations. It combines the benefits of external model manipulation DSLs with general-purpose programming taking full advantage of Scala versatility, performance and tool support. The DSLs are compared to the state-of-the-art Epsilon languages in non-trivial model manipulation tasks that resulted in 20% to 70% reduction in code size and significantly better performance

Tensile Properties of Forged Mg-Al-Zn-Ca Alloy

Continuously-casted Mg-9Al-1Zn-1Ca (in mass%) alloy (Mg-Ca alloy) and Mg-9Al-1Zn alloys (Ca-free Mg alloy) were forged at 573 K and their mechanical properties were investigated by tension tests at ambient temperature and 573 K. The forged Mg-Ca alloy showed higher 0.2% proof stress than the forged Ca-free Mg alloy. The high strength for the Mg-Ca alloy was attributed not only to grain refinement by hot forging, but also to the strengthening mechanisms arising from the difference in thermal expansion and geometrical incompatibility between Mg matrix and second phase. The Ca addition decreased the elongation to failure; however, the decrease was reduced for the forged specimens, compared to the unforged specimen. This results from segmentation of the second phases by the hot forging. Also, the forged Mg-Ca alloy showed a large elongation of 284% at 573 K

Effects of Homogenization Annealing on Dynamic Recrystallization

Compression tests were conducted at the temperature of 573 K with the true strain rates of 10 À3 -1 s À1 on as-cast and homogenized Mg6Al-2Ca-2RE (RE = rare earth) (in mass%) alloy specimens, and their dynamic recrystallization (DRX) behaviors were investigated. Strain hardening occurred after yielding, followed by strain softening. The flow stress of the as-cast specimen was higher than that of the homogenized specimen. The DRX grain size depended minimally on the Z-parameter in both of the as-cast and homogenized specimens. This is likely to be due to the particle-stimulated nucleation mechanism involving the second-phase particles. When the specimens were deformed to the true compressive strain of 1.6, non-recrystallized regions were not observed in the homogenized specimen; however, they were partially observed in the as-cast specimen. The grain size in the recrystallized region in the as-cast specimen was smaller than that in the homogenized specimen. Elemental analyses revealed Al segregation around the second-phase particles in the as-cast specimen. Therefore, it is suggested that DRX in the present Mg-Al-Ca-RE alloy is affected by not only the second-phase particles, but also the Al segregation

Development of a Vertex Finding Algorithm using Recurrent Neural Network

Deep learning is a rapidly-evolving technology with possibility to significantly improve physics reach of collider experiments. In this study we developed a novel algorithm of vertex finding for future lepton colliders such as the International Linear Collider. We deploy two networks; one is simple fully-connected layers to look for vertex seeds from track pairs, and the other is a customized Recurrent Neural Network with an attention mechanism and an encoder-decoder structure to associate tracks to the vertex seeds. The performance of the vertex finder is compared with the standard ILC reconstruction algorithm.Comment: 8 pages, 8 figures, preliminary version currently under review by IL

Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis

INTRODUCTION: Hepatocyte growth factor (HGF) is a potent proangiogenic molecule that induces neovascularization. The HGF antagonist, NK4, competitively antagonizes HGF binding to its receptor. In the present study, we determined the inhibitory effect of NK4 in a rheumatoid arthritis (RA) model using SKG mice. METHODS: Arthritis was induced in SKG mice by a single intraperitoneal injection of β-glucan. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was also injected intravenously at the time of or 1 month after β-glucan injection. Ankle bone destruction was examined radiographically. The histopathologic features of joints were examined using hematoxylin and eosin and immunohistochemical staining. Enzyme-linked immunosorbent assays were used to determine the serum levels of HGF, interferon γ (IFN-γ, interleukin 4 (IL-4) and IL-17 production by CD4(+ )T cells stimulated with allogeneic spleen cells. RESULTS: The intravenous injection of AdCMV.NK4 into SKG mice suppressed the progression of β-glucan-induced arthritis. Bone destruction was also inhibited by NK4 treatment. The histopathologic findings of the ankles revealed that angiogenesis, inflammatory cytokines and RANKL expression in synovial tissues were significantly inhibited by NK4 treatment. Recombinant NK4 (rNK4) proteins inhibited IFN-γ, IL-4 and IL-17 production by CD4(+ )T cells stimulated with allogeneic spleen cells. CONCLUSIONS: These results indicate that NK4 inhibits arthritis by inhibition of angiogenesis and inflammatory cytokine production by CD4(+ )T cells. Therefore, molecular targeting of angiogenic inducers by NK4 can potentially be used as a novel therapeutic approach for the treatment of RA

Comparison of intrathecal morphine with continuous patient-controlled epidural anesthesia versus intrathecal morphine alone for post-cesarean section analgesia: a randomized controlled trial

Background Several neuraxial techniques have demonstrated effective post-cesarean section analgesia. According to previous reports, it is likely that patient-controlled epidural analgesia (PCEA) without opioids is inferior to intrathecal morphine (IM) alone for post-cesarean section analgesia. However, little is known whether adding PCEA to IM is effective or not. The aim of this study was to compare post-cesarean section analgesia between IM with PCEA and IM alone. Methods Fifty patients undergoing elective cesarean section were enrolled in this prospective randomized study. Patients were randomized to one of two groups: IM group and IM + PCEA group. All patients received spinal anesthesia with 12 mg of 0.5% hyperbaric bupivacaine, 10 μg of fentanyl, and 150 μg of morphine. Patients in IM + PCEA group received epidural catheterization through Th11–12 or Th12-L1 before spinal anesthesia and PCEA (basal 0.167% levobupivacaine infusion rate of 6 mL/h, bolus dose of 3 mL in lockout interval of 30 min) was commenced at the end of surgery. A numerical rating scale (NRS) at rest and on movement at 4,8,12,24,48 h after the intrathecal administration of morphine were recorded. In addition, we recorded the incidence of delayed ambulation and the number of patients who requested rescue analgesics. We examined NRS using Bonferroni’s multiple comparison test following repeated measures analysis of variance; p < 0.05 was considered as statistically significant. Results Twenty-three patients in each group were finally analyzed. Mean NRS at rest was significantly higher in IM group than in IM + PCEA group at 4 (2.7 vs 0.6), 8 (2.2 vs 0.6), and 12 h (2.5 vs 0.7), and NRS during mobilization was significantly higher in IM group than in IM + PCEA group at 4 (4.9 vs 1.5), 8 (4.8 vs 1.9), 12 (4.9 vs 2), and 24 h (5.7 vs 3.5). The number of patients who required rescue analgesics during the first 24 h was significantly higher in IM group compared to IM + PCEA group. No significant difference was observed between the groups in incidence of delayed ambulation. Conclusions The combined use of PCEA with IM provided better post-cesarean section analgesia compared to IM alone. Trial registration UMIN-CTR (Registration No. UMIN000032475). Registered 6 May 2018 – Retrospectively registered

Nesfatin-1 evokes Ca2+ signaling in isolated vagal afferent neurons via Ca2+ influx through N-type channels

金沢大学医薬保健研究域医学系Nesfatin-1, processed from nucleobindin 2, is an anorexigenic peptide expressed in the brain and several peripheral tissues including the stomach and pancreas. Peripheral, as well as intracerebroventricular, administration of nesfatin-1 suppresses feeding behavior, though underlying mechanisms are unknown. In this study, we examined effects of nesfatin-1 on cytosolic Ca2+ concentration ([Ca2+]i) in the neurons isolated from the vagal afferent nodose ganglion of mice. Nesfatin-1 at 10-10-10-8 M increased [Ca2+]i in the isolated neurons in a concentration-dependent manner, and at 10-8 M it increased [Ca2+]i in 33 out of 263 (12.5%) neurons. These responses were inhibited under Ca2+-free conditions and by N-type Ca2+ channel blocker, ω-conotoxin GVIA. All the nesfatin-1-responsive neurons also exhibited [Ca2+]i responses to capsaicin and cholecystokinin-8. These results provide direct evidence that nesfatin-1 activates vagal afferent neurons by stimulating Ca2+ influx through N-type channels, demonstrating the machinery through which peripheral nesfatin-1 can convey signals to the brain. © 2009 Elsevier Inc. All rights reserved