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Background Data on real-world use of everolimus (EVR) in Japanese maintenance kidney transplant (KTx) patients are limited. This post-marketing surveillance study was conducted to assess the safety and effectiveness of EVR, and identify factors affecting renal impairment. Methods Adult maintenance KTx patients were enrolled within 14 days of initiating EVR. Patient medical data were collected using electronic data capture case report forms at 6 months, 1, and 2 years after initiating EVR, or at discontinuation. Results All patients receiving EVR in Japan during the surveillance period were enrolled (N = 263). Mean time from transplantation to EVR initiation was 75.7 months. Decreased renal function (31.56%) was the primary reason for initiating EVR. In combination with EVR, the mean daily dose of tacrolimus and cyclosporine could be reduced to ~ 79 and ~ 64%, by 2 years, respectively. Incidences of serious adverse events and adverse drug reactions were 15.97 and 49.43%, respectively. Two-year graft survival rate was 95.82% and low in patients with baseline estimated glomerular filtration rate (eGFR; modification of diet in renal disease) 2 (69.57%; P P = 0.0206). Throughout the survey, mean eGFR values were stable (> 55 mL/min/1.73 m2). Renal impairment was influenced by patient and donor age, eGFR, and UPCR at baseline. Conclusions No new safety concerns for the use of EVR in adult maintenance KTx patients were identified. Early EVR initiation may be considered in these patients before renal function deterioration occurs.

Purpose Optic nerve damage leads to impairment of visual functions. We previously demonstrated that apolipoprotein E-containing lipoproteins (E-LPs) protect retinal ganglion cells (RGCs) from degeneration in a glaucoma model of glutamate/aspartate transporter-deficient mice. This study aimed to determine whether E-LPs protect RGCs from N-methyl-D-aspartate (NMDA)-induced excitotoxicity, and to investigate the details of an indirect neuroprotective mechanism of E-LPs by reducing α2-macroglobulin, which interferes with the neuroprotective effect of E-LPs, in Muller glia. Methods Excitotoxicity was caused by intravitreal injection of NMDA, and then retinae were subjected to immunoblotting or quantitative reverse transcription-PCR. Primary cultures of mouse mixed retinal cells and mouse Muller glia were used for evaluating the effects of E-LPs on the expression of α2-macroglobulin. Results Intravitreal injection of E-LPs protected the optic nerve from degeneration and attenuated the increase in α2-macroglobulin in aqueous humor and retina of rats. E-LPs directly decreased the expression and secretion of α2-macroglobulin in primary cultures of Muller glia; this decrease in production of α2-macroglobulin was blocked by knockdown of the low-density lipoprotein receptor-related protein 1 (LRP1) with small interfering RNA. E-LPs promoted the phosphorylation of STAT3, whereas Stattic, an inhibitor of STAT3, restored the expression of α2-macroglobulin decreased by E-LPs. Conclusions In addition to our previous findings of the protection of RGCs by E-LPs, the new observations in Muller glia indicate that a reduction of the intraocular α2-macroglobulin, regulated by the E-LP-LRP1-STAT3 pathway, might be an additional protective mechanism against excitotoxicity in the retina.

BACKGROUND Left ventricular function has been shown to be an important prognostic indicator in patients with repaired tetralogy of Fallot (rTOF) and tends to decrease with age. In recent years, left atrial (LA) function was reported to be a useful prognostic indicator more than or equal to left ventricular function in acquired heart diseases. However, atrial function in rTOF has not yet been sufficiently examined. PURPOSE The aim of this study was to investigate the relationship between LA dysfunction and age in rTOF using strain analysis. METHODS In order to assess the relationship between LA function and age, we recruited 59 patients with rTOF ranging in age from 5-40 years. We stratified the patients into 3 groups (T1: 5-10 years, T2: 11-20 years, T3: 21-40 years) and divided 54 controls of similar age into 3 corresponding groups (N1, N2, and N3). Two-dimensional speckle tracking images (2D-STI) obtained from four- and two-chamber views were used to assess LA functions by measuring reservoir, conduit, and pump strain. Additionally, we measured the strain rate (SR) in the systole, early diastole, and late diastole. RESULTS LA reservoir strain (37.4 ± 2.2% vs. 47.9 ± 1.7%, P= 0.004), LA pump strain (8.3 ± 1.4% vs. 14.1 ± 2.7%, p Early diastole SR was significantly decreased in the T1 and T3 groups compared with the N1 and N3 groups (T1 vs N1, 3.00 ± 0.63% vs. 4.03 ± 0.0.80%, p CONCLUSIONS In rTOF, most of the LA functions assessed by strain analysis decreased compared to normal controls in over 20 years old age. Furthermore, all measured functions decreased with age in rTOF while only two parameters decreased with age in normal controls. These results suggest that LA function may be an important indicator in long-term rTOF follow-up. These are new insights into LA function in patients with rTOF.

Thalidomide was originally used as a sedative and found to be a teratogen, but now thalidomide and its derivatives are widely used to treat haematologic malignancies. Accumulated evidence suggests that thalidomide suppresses nerve cell death in neurologic model mice. However, detailed molecular mechanisms are unknown. Here we examined the molecular mechanism of thalidomide’s neuroprotective effects, focusing on its target protein, cereblon (CRBN), and its binding protein, AMP-activated protein kinase (AMPK), which plays an important role in maintaining intracellular energy homeostasis in the brain. We used a cerebral ischemia rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Thalidomide treatment significantly decreased the infarct volume and neurological deficits of MCAO/R rats. AMPK was the key signalling protein in this mechanism. Furthermore, we considered that the AMPK–CRBN interaction was altered when neuroprotective action by thalidomide occurred in cells under ischemic conditions. Binding was strong between AMPK and CRBN in normal SH-SY5Y cells, but was weakened by the addition of H2O2. However, when thalidomide was administered at the same time as H2O2, the binding of AMPK and CRBN was partly restored. These results suggest that thalidomide inhibits the activity of AMPK via CRBN under oxidative stress and suppresses nerve cell death.

Background Anthracycline cardiotoxicity affects clinical outcomes, and its early detection using methods that rely on conventional echocardiography, such as left ventricular ejection fraction (LVEF) is difficult. This study aimed to evaluate the characteristics and the differences in cardiac dysfunction among childhood cancer survivors in 3 age groups using layer-specific strain analysis in a wide age range.Methods and Results:The 56 patients (median age: 15 [range: 6.8-40.2] years) who had been treated with anthracycline for childhood cancer were divided into 3 age groups (C1: 6-12 years, C2: 13-19 years, C3: 20-40 years) after anthracycline treatment, and 72 controls of similar ages were divided into 3 corresponding groups (N1, N2, and N3). Layer-specific longitudinal strain (LS) and circumferential strain (CS) of 3 myocardial layers (endocardium, midmyocardium, and epicardium) were determined using echocardiography. Myocardial damage had not occurred yet in C1. Endocardial CS at the basal level was less in C2 than in N2. Endocardial CS at all levels and midmyocardial CS at the basal and papillary levels were lower in C3 than in N3. LVEF and LS were not significantly different between patients and controls. Conclusions Among survivors of childhood cancer, impaired myocardial deformation starts in adolescence and extends from the endocardium towards the epicardium and from the base towards the apex with age. These findings are a novel insight into the time course of anthracycline cardiotoxicity.

Background Left ventricular (LV) dysfunction in patients with repaired tetralogy of Fallot (rTOF) is an important risk factor for adverse outcomes. The aim of this study was to assess the details and time course of such LV dysfunction using layer-specific strain analysis by echocardiography.Methods and Results:The 66 patients with rTOF (mean age, 16.3±9.3 years) were divided into 3 groups (T1: 4-10 years, T2: 11-20 years, T3: 21-43 years), and 113 controls of similar age (mean age, 17.2±9.3 years) were divided into 3 corresponding groups (C1, C2, and C3). Layer-specific longitudinal strain (LS) and circumferential strain (CS) of 3 myocardial layers (endocardial, midmyocardial, and epicardial) were determined by echocardiography. Basal and papillary endocardial CS values were decreased in T1 compared with C1. With the exception of papillary epicardial CS, basal/papillary CS and LS of all 3 layers decreased in T2 compared with C2. Excepting papillary epicardial CS, all other values were decreased in T3 compared with C3. Conclusions Potential myocardial damage was found in the endocardium at the basal and papillary levels of the LV in young patients with rTOF, extending from the endocardium to the epicardium and from the base to the apex. This is the possible time course of LV dysfunction in patients with rTOF.

The N-methyl-D-aspartate (NMDA) receptor has been implicated in several neurodegenerative diseases, including stroke. Low-density lipoprotein receptor-related protein 1 (LRP1) plays pivotal roles in endocytosis and signaling in the cell. Immature LRP1 is processed by furin in the trans-Golgi network (TGN) and transported to the cell surface as its mature form. Activation of mature LRP1 exerts a protective effect against glutamate-induced degeneration of the rat retinal ganglion cells, as was shown in our previous study. However, the roles of LRP1 in the pathogenesis of excitotoxic neuronal injuries remain to be determined. The aim of this present study was to achieve further insight into the pathophysiologic roles of LRP1 after excitotoxic neuronal injuries. Our findings are the first to demonstrate that LRP1 was significantly cleaved by furin after cerebral ischemia in rats as well as after exposure of cultured cortical neurons to NMDA. It was noteworthy that the intracellular domain (ICD) of LRP1 was co-localized with TGN and furin. Furthermore, a furin inhibitor inhibited the cleavage of LRP1 and co-localization of LRP1-ICD with TGN or furin. Our findings suggest that furin-mediated cleavage of LRP1 and changes in the localization of LRP1-ICD were involved in the excitotoxic neuronal injury.

The proprotein convertases (PCs) act as serine proteases and are known to convert diverse precursor proteins into their active forms. Among the PCs, furin has been considered to play a crucial role not only in embryogenesis, but also in the initiation and progression of certain pathologic conditions. However, the roles played by furin with respect to neuronal cell injuries remain to be determined. An excessive influx of Ca2+ through the N-methyl-d-aspartate (NMDA) receptor has been associated with diverse neurological and neurodegenerative disorders. The aim of this study was to achieve further insight into the pathophysiologic roles of furin in cultured cortical neurons. We demonstrated that furin inhibitors dose-dependently prevented neuronal injury induced by NMDA treatment. Neuronal injury induced by NMDA treatment was attenuated by the calpain inhibitor calpeptin. And the increase observed in the activity of calpain after NMDA treatment was significantly inhibited by these furin inhibitors. Furthermore, calpain-2 activity, which was evaluated by means of the immunoblotting assay, was increased by NMDA treatment. It was noteworthy that this increased activity was almost completely inhibited by a furin inhibitor. Our findings suggested that furin is involved in NMDA-induced neuronal injury by acting upstream of calpain.

The major mechanisms of gas permeation through solid membranes are described and the applicable equations describing the permeance are presented. The mechanisms depend on the relative size of the permeating molecules and the diameter of the pores. As pore size decreases the operable mechanisms are Hagen-Pouiselle flow, Knudsen diffusion, surface diffusion, gas-translation, and finally solid-state diffusion. The Hagen-Pouiselle mechanism involves flow through large pores, while the Knudsen mechanism involves collision of molecules with the walls of pores of intermediate size. Surface diffusion deals with movement of molecules trapped in the potential field of the walls of pores of relatively small size, while gas-translation involves molecules that can escape the field, but are constrained by the small pores. Finally, solid-state transport comprises dissolution and transport by diffusion within the solid. These mechanisms are illustrated for hydrogen permeance with the use of two membranes, an alumina membrane with intermediate sized pores and a silica on alumina membrane of dense structure.

Pinus trifolia Miki 1939 (Pinaceae) was originally proposed based on seed cones from the upper Miocene of Aichi and Gifu Prefectures, central Japan. However, before the publication of P. trifolia, a different name (Pinus fujiii (Yasui) Miki) was given to a female cone with the same morphology. On the other hand, P. fujiii auct. non (Yasui) Miki has been used for seed cones with different morphologies from Yasui's holotype, i.e., apophyses arranged in 5:8 parastichies and a perexcentromucronate slightly-pointed umbo. As a result of re-examination on the Miki and Yasui specimens, we concluded that P. trifolia was a synonym for P. fujiii and proposed here Pinus mikii sp. nov. for cones assigned to P. fujiii auct. non (Yasui) Miki. We also emended the diagnosis of P. fujiii based on these specimens. Pinus fujiii is characterized by a large female cone in which the apophyses with a centromucronate prickle-like umbo are arranged in 8:13 parastichies, and deciduous seed wings. These characters suggest that P. fujiii belongs to the section Trifoliae of the subgenus Pinus, which is now restricted to North and Central America and the Caribbean islands. Fossil data suggest that the P. fujiii lineage firstly appeared in Japan around the Eocene/Oligocene boundary. We speculate that the P. fujiii lineage might have moved southward to Japan from a refugium located elsewhere in high-latitude areas in response to the late Eocene cooling event, as occurred with other Trifoliae species in North America. © 2015 Yamada et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

To investigate the clinical outcome of double balloon enteroscopy (DBE)-assisted endoscopic retrograde cholangiopancreatography (DB-ERCP) in patients with altered gastrointestinal anatomy.Between September 2006 and April 2011, 47 procedures of DB-ERCP were performed in 28 patients with a Roux-en-Y total gastrectomy (n = 11), Billroth II gastrectomy (n = 15), or Roux-en-Y anastomosis with hepaticojejunostomy (n = 2). DB-ERCP was performed using a short-type DBE combined with several technical innovations such as using an endoscope attachment, marking by submucosal tattooing, selectively applying contrast medium, and CO₂ insufflations.The papilla of Vater or hepaticojejunostomy site was reached in its entirety with a 96% success rate (45/47 procedures). There were no significant differences in the success rate of reaching the blind end with a DBE among Roux-en-Y total gastrectomy (96%), Billroth II reconstruction (94%), or pancreatoduodenectomy (100%), respectively (P = 0.91). The total successful rate of cannulation and contrast enhancement of the target bile duct in patients whom the blind end was reached with a DBE was 40/45 procedures (89%). Again, there were no significant differences in the success rate of cannulation and contrast enhancement of the target bile duct with a DBE among Roux-en-Y total gastrectomy (88 %), Billroth II reconstruction (89%), or pancreatoduodenectomy (100%), respectively (P = 0.67). Treatment was achieved in all 40 procedures (100%) in patients whom the contrast enhancement of the bile duct was successful. Common endoscopic treatments were endoscopic biliary drainage (24 procedures) and extraction of stones (14 procedures). Biliary drainage was done by placement of plastic stents. Stones extraction was done by lithotomy with the mechanical lithotripter followed by extraction with a basket or by the balloon pull-through method. Endoscopic sphincterotomy was performed in 14 procedures with a needle precutting knife using a guidewire. The mean total duration of the procedure was 93.6 ± 6.8 min and the mean time required to reach the papilla was 30.5 ± 3.7 min. The mean time required to reach the papilla tended to be shorter in Billroth II reconstruction (20.9 ± 5.8 min) than that in Roux-en-Y total gastrectomy (37.1 ± 4.9 min) but there was no significant difference (P = 0.09). A major complication occurred in one patient (3.5%); perforation of the long limb in a patient with Billroth II anastomosis.Short-type DBE combined with several technical innovations enabled us to perform ERCP in most patients with altered gastrointestinal anatomy.

The toluene-degrading bacterium Acinetobacter sp. Tol 5 is highly adhesive through cell-surface nanofibers. Previously, we identified two morphologically distinct nanofibers on Tol 5 cells, namely, nonperitrichate anchor-like and peritrichate pilus-like nanofibers. In the present study, the application of improved electron microscopy techniques enabled discrimination of three distinct types of peritrichate nanofibers on Tol 5 cells. Interestingly, production of these nanofibers was affected by the available growth substrate. Thick, long, straight nanofibers a, which were present on cells grown on toluene, lactate, and ethanol, were not observed on cells grown on triacylglycerol (TAG). In contrast, cells grown on TAG were covered with long, curved nanofibers c , which only existed sparsely on cells grown on toluene, lactate, and ethanol. Thin, short, straight nanofibers b were found densely covering the margin of cells grown on all four growth substrates. SDS-PAGE of Tol 5 cell-surface proteins detected a protein of 17.5 kDa that was expressed at a high level on ethanol, but was undetectable on TAG. Conversely, a 26 kDa protein was identified that was exclusively expressed on TAG, but was only faintly expressed by cells grown on the other substrates. Based on N-terminal amino acid sequences, the 17.5 and 26 kDa proteins were identified as the major subunits of type 1 and Fil pili, respectively, which are typical bacterionanofibers. From these results, we deduced that nanofibers a and c are type 1 and Fil pili, respectively. The adhesiveness of Tol 5 cells was low only when they were grown on TAG.

Background & Aim: In the enteric-infection-induced model of inflammation, Th1 and Th2 cytokines have opposing effect on intestinal muscle function and 5-HT signaling (Motomura et al. Gut 2008; Gastroenterology 128;Suppl A 626,2005), but the role of Th1 and Th2 dominant environments for non-infective post-inflammatory (PI) gut dysfunction remains to be determined. Here we investigated the mechanism for gut dysfunction that persists after acute inflammation in Th1 and Th2 dominant environments utilizing mouse model of T cell-induced enteropathy. Methods: BALB/c (Th2 dominant response) and AKR (Th1 dominant response) mice were treated with an anti-CD3 antibody (100 μg), and sacrificed at days 0, 1, 3, 7, and 14 post-treatment to investigate the histological changes, longitudinal smooth muscle cell contraction, various cytokines (Th1, Th2, Th17 cytokines), chemokines, and mediators mRNA /protein expressions and 5-HT-expressing enterochromaffin (EC) cells numbers in the small intestine. Results: In BALB/c mice small intestinal tissue damage was observed from 24 hours after the anti-CD3 antibody injection, but had resolved by day 5. Carbachol-induced smooth muscle cell contractility was significantly increased (p

フッ化チタンアンモニウム溶液作用によリ, エナメル質表面に生成するglazeの耐久性を検索する目的で, in vitroで7日間の蒸留水水洗実験を行い, X線マイクxアナライザ分析ならびに走査電子顕微鏡による観察を行った。フッ化物溶液はフッ化チタンアンモニウム溶液 (フッ素濃度9000ppm, pH 3.4) とリン酸酸性フッ化ナトリウム溶液 (フッ素濃度9000ppm, pH 3.4) で, controlには蒸留水を用いた。Intact enamelに各溶液を20℃にて60分間作用させ, 直後, 水洗24時間後および7日後にエナメル質表層の元素分析を行った。形態的観察は上記試料のほかに, 0.5M過塩素酸処理後の試料についても行った。その結果APF溶液作用群ではエナメル質表層に高濃度に取り込まれたフッ素は水洗により急激に減少するのに対し, フッ化チタンアンモニウム溶液作用群ではエナメル質表層にチタンとフッ素が取り込まれ, 水洗後も安定に存在することが示された。両フッ化物溶液作用群ともに, エナメル質表面に沈着物を認めたが, APF溶液作用群では水洗により速やかに溶出するのに対し, フッ化チタンアンモニウム溶液作用群ではglaze様の変化を示し, 水洗後もglazeは残留した。また, glazeの耐酸性は水洗後も変らず, 持続することが認められた。

モヤシを市販次亜塩素酸ナトリウム液 (アンチホルミン液) に浸漬した場合の, ビタミンC含量の変化を調べた。その結果, アンチホルミン液処理により, モヤシ中の総ビタミンCは, 未処理とくらべ実験室処理では85% (5～120分浸漬の平均), 工場処理では76%に減少した。この減少のおもな原因は, 浸漬液中へのビタミンCの溶出と考えられる。また, 工場処理では, 水洗中にモヤシの機械的攪拌が行なわれるために, 実験室処理にくらべその溶出量も多くなったと思われる。1/500アンチホルミン液は, モヤシ中のビタミンCに対して酸化剤として作用し, モヤシ中の還元型ビタミンCを酸化型ビタミンCに変化させるが, この液のもつ高いpHの影響によるビタミンCの分解はあまり起こらないと推察された。