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BackgroundIn immunoglobulin G4-related kidney disease (IgG4-RKD), persistent renal insufficiency may be observed despite the good initial response to glucocorticoids[1, 2]. However, its long-term prognosis in relation to renal function as well as malignancy and mortality has not been well clarified.ObjectivesTo clarify the long-term renal prognosis, complications of malignancy, mortality, and factors related to those outcomes in IgG4-RKD.MethodsWe retrospectively reviewed the medical records of patients with IgG4-RKD diagnosed by the expert members of the IgG4-RKD working group in the Japanese Society of Nephrology. We investigated clinical, radiological, and histopathological features at baseline and course of renal function, complications of malignancy, and mortality during the long-term observation periods (median 71 months) in 75 patients. Using collected data, we calculated the crude incidence rates (IR) of chronic kidney disease (CKD) status, malignancy, and death. Cox regression analyses were performed to assess CKD-related factors. Additionally, we calculated the standardized incidence ratio (SIR) of malignancy and standardized mortality ratio (SMR) using national Japan statistics.ResultsFifty-nine patients were male, and 16 were female (median age 70 years). At diagnosis, their median eGFR was 45.1 mL/min/1.73m2 (interquartile range [IQR] 28.6-69.9). Seventy-two patients (96%) were treated with prednisolone at a median initial dose of 30 (IQR 30-39) mg/day, leading to a reasonable initial improvement of renal function. The IR of CKD was 30.2/100 person-years, and 66.7% (50/75) of the patients showed CKD at the last visit. Age- and sex-adjusted Cox regression analyses indicated that lower eGFR (per 10 mL/min/1.73m2, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.61-0.80), pre-existing hypertension (HR 2.39, 95% CI 1.32-4.34), and wider areas with inflammation (>50% vs. 50% vs. ConclusionThis study suggests that pre-treated renal insufficiency and extensive renal inflammatory and fibrotic lesions are related to CKD under glucocorticoid therapy in IgG4-RKD. Similarly with the whole IgG4-related disease, IgG4-RKD may have an increased incidence of malignancy but a mortality rate equivalent to the age- and sex-matched Japanese population.References[1]Saeki T et al. The clinical course of patients with IgG4-related kidney disease. Kidney Int. 2013 Oct;84(4):826-33.[2]Mizushima I et al. Factors related to renal cortical atrophy development after glucocorticoid therapy in IgG4-related kidney disease: a retrospective multicenter study. Arthritis Res Ther. 2016 Nov 25;18(1):273.Disclosure of InterestsNone declared

With a specially designed electrochemical cell, the changes in impedance behavior for Inconel 600 and aluminide diffusion coatings under molten sulfate film with thermal cycles (from 800 ˚C to 350 ˚C) were monitored with electrochemical impedance measurements. It was found that corrosion resistance for both materials increased with lower temperatures. At the same time, the state of molten salt was also monitored successfully by measuring the changes in impedance at high frequency, which generally represents the resistance of molten salt itself. After two thermal cycles, both Inconel 600 and aluminide diffusion coatings showed excellent corrosion resistance. The results from SEM observation and EDS analysis correlated well with the results obtained by electrochemical impedance measurements. It is concluded that electrochemical impedance is very useful for monitoring the corrosion resistance of materials under molten salt film conditions even with thermal cycles.

To investigate nitrogen circulation via subduction, we measured isotopic compositions of nitrogen and noble gases of mantle-derived xenoliths from Far Eastern Russia, where the tectonic setting is a plate convergence margin in the Mesozoic to Cenozoic era. Kinetic fractionation accompanies the extraction of volatiles from a subducting plate, engendering the infiltration of fluids with light isotopic compositions into mantle wedge. The δ 15 N values are −13.26 to +0.19‰, some of which are lower than those of air (0‰) and upper mantle (−5 ± 2‰). The 3He/4He and 40Ar/36Ar ratios are 0.2–5.6 Ra and 304–1156, respectively, which are common for the mantle xenoliths in eastern Asia, a representative subduction setting. The N2/36Ar are 1.5 × 104 – 4.5 × 104, which are much lower than the mantle value (6.7 × 106) and which are rather more similar to atmospheric (2.5 × 104) and deep seawater (1.1 × 104) values. Kinetic fractionation can lower the δ 15 N value to −15‰ without marked change of the N2/36Ar ratio. Therefore, the low δ 15 N values of the present xenoliths might be regarded as values of the fluid experiencing fractionation during infiltration of the fluid from the subducting oceanic plate into the mantle wedge.

Deposition conditions of cuprous oxide (Cu2O) thin films on glass substrates and nitrogen doping into Cu2O were studied by using reactive radio-frequency magnetron sputtering method. The effects of defect passivation by crown-ether cyanide treatment, which simply involves immersion in KCN solutions containing 18-crown-6 followed by rinse, were also studied. By the crown-ether cyanide treatment, the luminescence intensity due to the near-band-edge emission of Cu2O at around 680 nm was enhanced, and the hole density was increased from 1016 to 1017 cm−3. Finally, polycrystalline p-Cu2O/n-ZnO heterojunctions were grown for use in solar cells. Two deposition sequences were studied, ZnO deposited on Cu2O and Cu2O deposited on ZnO. It was found that the crystallographic orientation and current–voltage characteristics of the heterojunction were significantly influenced by the deposition sequence, both being far superior for the heterojunction with structure Cu2O on ZnO than for the inverse structure. We successfully obtained a photoresponse for the first time in the deposited thin film of Cu2O/ZnO.

Polycrystalline n-ZnO/p-Cu2O heterojunctions were fabricated by reactive sputtering for photovoltaic applications. Although electrical rectification was not reproducibly obtained in the as-grown samples, rectification was observed in the samples fabricated with cyanide treated Cu2O. We have previously shown that cyanide treatment has an effective role in passivation of defects in Cu2O, in analogy to hydrogen passivation. It is, therefore, believed that the observed improvement in the electrical rectification of the ZnO/Cu2O heterojunctions is attributable to the defect passivation near the hetero-interface. The effectiveness of the cyanide treatment and the importance of defect passivation in ZnO/Cu2O heterojunctions are presented. (© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

To investigate the antibacterial activity of mucosal Th1 and Th2 immune responses induced nasally and orally, mice were immunized with mucosal vaccine containing fimbrial protein of Porphyromonas gingivalis, a causative agent for a destructive chronic inflammation in the periodontium, and cholera toxin (CT) as mucosal adjuvant. Nasal vaccine containing low doses of fimbriae (10 μg) and CT (1 μg) induced Ag-specific Th1/Th2-type response in CD4+ T cells in mucosal effector tissues, including nasal passage and submandibular glands, which accounted for the generation of Ag-specific IgA-producing cells. In contrast, oral immunization required higher amounts of fimbriae and CT for the induction of Ag-specific IgA responses. Fimbriae-specific IgA mAbs generated from submandibular glands of nasally immunized mice inhibited P. gingivalis attachment to and reduced subsequent inflammatory cytokine production from epithelial cells. These findings suggest that nasal vaccination is an effective immunization regimen for the induction of Ag-specific Th1 and Th2 cell-driven IgA immune responses that possess the ability to inhibit bacterial attachment to epithelial cells and subsequent inflammatory cytokine production.

Bone marrow stromal cell Ag-1 (BST-1; CD157)-deficient mice were generated to examine the immunologic roles of the molecule in vivo. In BST-1−/− mice, the development of peritoneal B-1 cells was delayed, and CD38low/− B-lineage cells were increased in the bone marrow and spleen. Partial impairment of thymus-independent (TI-2) and thymus-dependent (TD) Ag-specific immune responses was noted in the systemic and mucosal compartments of BST-1−/− mice, respectively. Although serum Ig levels as well as TD and TI-1 Ag-specific systemic immune responses were normal, the TI-2 Ag-induced IgG3 response was selectively impaired. Oral immunization of BST-1−/− mice with cholera toxin, a potent TD Ag for the induction of IgA response, resulted in the poor production of Ag-specific Abs at the intestinal mucosa accompanied by the reduced number of Ag-specific IgA-producing cells in the lamina propria. These results indicate that BST-1 has roles in B cell development and Ab production in vivo.

びまん浸潤型大腸癌(4型大腸癌)の壁内浸潤様式の特異性についての検討を行った.対象は4型大腸癌4例でリンパ管浸潤を主体とする型Lymphangiosis type(LA)と,印環細胞が間質に線維化を伴って浸潤性に増生する型Linitis plastica type(LP)の二群に分けられた.対照としてLAでは組織型が同一で脈管侵襲度も大腸癌取扱い規約のly3に相当する症例を,またLPでも組織型,脈管侵襲度が同一でありながら2または3型を示す症例の壁内浸潤様式を比較検討した.対照群と比較するとLAは(1)垂直方向で塊状の浸潤像を示さず,線維化が軽度で,固有筋層を破壊せずに深部浸潤し,(2)水平方向へ左右幅広くリンパ管内進展を示していた。LPは(1)垂直方向で大粘液結節による腫瘍塊を形成せずに浸潤し,固有筋層の破壊もなく,(2)水平方向で印環細胞が小粘液結節を伴い幅広い進展を示していた.4型大腸癌の壁内浸潤様式について,LAではリンパ管内という進展経路に特異性があり,癌細胞の特殊な接着性などが要因として考えられた.LPでは印環細胞型粘液癌という組織型に特異性があり,大腸の印環細胞は胃のそれとは異なる形質により4型癌に至ると思われた.

大腸ポリープのうち腺管内腔側に上皮鋸歯状増殖を示す病変〔Colorectal Polyp with Epithelial Serrated Proliferation(CP-ESP)〕を組織学的に核形態計測を用いて分類することで以下の知見を得た.対象はCP-ESP60病変,ポリープ最大割面で3～6陰窩を選び全上皮細胞核の長短径を実測し,π/4×長径×短径(楕円面積近似式)および長径/短径を求め核サイズ,紡錘化の指標とした.陰窩3等分による底部〔Bottom(B)〕,中間部〔Middle(M)〕,上方部〔Upper(U)〕のうちB-UおよびM-Uの2領域間で,核サイズ平均値の差を検定した.CP-ESPはB,Mに比しUで有意に核サイズが減少するZone形成(+)群〔Z(+)〕と,いずれも有意差のないZone形成(-)群〔Z(-)〕に分類された.Z(+)のうち腺管分枝のないものは従来のHyperplastic Polyp(HP)に相当し,腺管分枝を示すものの中にはB～Mで大きな核をもつ異常増殖性病変が含まれた.Z(-)のうち腺管分枝のないものにはLongacreらのSerrated Adenoma(SA)に,腺管分枝を示すものはTubulovillous Adenoma(TVA)に相当した.従来のHP,LongacreらのSA,鋸歯状腺管を有するTVAは核サイズ,核形,Zone形成の有無腺管分枝の有無により,それぞれ鑑別し得るものと考えられた.

Adiponectin is a cytokine constitutively produced by adipocytes and exhibits multiple biological functions by targeting various cell types. However, the effects of adiponectin on primary gingival fibroblasts and periodontal ligament cells are still unexplored. Therefore, we investigated the effects of adiponectin on gingival fibroblasts and periodontal ligament cells.The expression of adiponectin receptors (AdipoR1 and AdipoR2) on human gingival fibroblasts (HGFs), mouse gingival fibroblasts (MGFs) and human periodontal ligament (HPDL) cells was examined using RT-PCR and western blotting. HGFs and MGFs were stimulated with interleukin (IL)-1β in the presence or absence of adiponectin, and the expression of IL-6 and IL-8 at both mRNA and protein levels was measured by real-time PCR and ELISA, respectively. Furthermore, small interfering RNAs (siRNAs) in MGFs were used to knock down the expression of mouse AdipoR1 and AdipoR2. The effects of adiponectin on the expression of alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2) genes were evaluated by real-time PCR. Mineralized nodule formation of adiponectin-treated HPDL cells was revealed by Alizarin Red staining.AdipoR1 and AdipoR2 were expressed constitutively in HGFs, MGFs and HPDL cells. Adiponectin decreased the expression of IL-6 and IL-8 in IL-1β-stimulated HGFs and MGFs. AdipoR1 siRNA in MGFs revealed that the effect of adiponectin on reduction of IL-6 expression was potentially mediated via AdipoR1. Adiponectin-treated HPDL cells promoted the expression of ALP and Runx2 mRNAs and up-regulated ALP activity. Furthermore, adiponectin enhanced mineralized nodule formation of HPDL cells.Our observations demonstrate that adiponectin exerts anti-inflammatory effects on HGFs and MGFs, and promotes the activities of osteoblastogenesis of HPDL cells. We conclude that adiponectin has potent beneficial functions to maintain the homeostasis of periodontal health, improve periodontal lesions, and contribute to wound healing and tissue regeneration.

Tobacco smoking has been suggested to be one of the important risk factors of developing periodontal disease. Although epidemiological studies have shown the detrimental effects of smoking on periodontal disease, the effects of smoke compounds on gingival tissue are not well understood. The aim of this study was to evaluate the effects of nicotine, which is the major component of the thousands of chemicals that constitute cigarette smoke, for cytodifferentiation of murine periodontal ligament (MPDL) cell.Expression of nAChR subunits on MPDL cells was examined using RT-PCR. The effects of nicotine on gene expression of extracellular matrices and osteoblastic transcription factors were evaluated by quantitative RT-PCR. Mineralized nodule formation of nicotine-treated MPDL cells was characterized by alizarin red staining.Murine periodontal ligament cells expressed several subunits of nAChR, which have functional calcium signals in response to nicotine. Gene expression of extracellular matrices and osteoblastic transcription factors were reduced in nicotine-treated MPDL cells. In addition, mineralized nodule formation was inhibited in MPDL cells in the presence of nicotine.Our findings indicate that nicotine may negatively regulate the cytodifferentiation and mineralization of MPDL cells.

We have investigated degradation of metamorphic In_Ga_As Esaki tunnel diodes. The degradation due to electrode diffusion and impurity interdiffusion is more prominent than that of lattice-matched In_Ga_As Esaki tunnel diodes., 2005 International Conference on Indium Phosphide and Related Materials : May 8-12, 2005, Glasgow, Scotland.

A 29-year-old male with Down's syndrome presented with severe headache and vomiting. Computed tomography demonstrated subarachnoid hemorrhage. Left carotid angiography showed severe stenosis of the middle cerebral artery 2 cm distal to its origin, as well as abnormal hyper-vascularization near the stenosis site similar to that seen in moyamoya disease. Right carotid angiography showed no abnormalities. However, slight stenosis of the distal part of the bilateral vertebral arteries was noted. There was no aneurysm. We judged that the subarachnoid hemorrhage had been caused by rupture of the moyamoya-like vessel. Some patients with Down's syndrome have anatomical vascular abnormality and vascular fragility. The cerebral vascular abnormality found in this case may be part of the systemic vascular abnormalities associated with Down's syndrome. The vascular changes in some adult patients with Down's syndrome may be a sign of premature aging, and long-term studies with periodic vascular examination of patients with Down's syndrome need to be performed.

Immunologic characterization of IgA-committed B-1 and B-2 cells, and unique subsets of T cells isolated from the murine lacrimal gland (LG), the primary exocrine tissue for the ocular surface, which is considered to be a part of the mucosal immune system.Single cells were obtained from LGs of C57BL/6 mice by the enzyme dissociation method using collagenase type IV. Samples underwent flow cytometric analysis to characterize the unique subsets of T and B cells. To test the effectiveness of ocular vaccination, mice were immunized ocularly or nasally with cholera toxin (CT; 10 microg/mouse) suspended in phosphate-buffered saline. Antigen-specific immune responses were determined by isotype and CT-specific enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot (ELISPOT) assay.When mononuclear cells (MC) isolated from LG samples were examined by flow cytometry, approximately 28% of cells were characterized as B220+ B cells. Because surface IgA+ (sIgA+) B cells develop from B-1 and B-2 lineages, it was important to examine which subset of B cells gives rise to LG sIgA+ B cells. Examination of the MC isolated from LG samples showed that approximately 4% of cells were sIgA+ B cells. Furthermore, nearly all these sIgA+ B cells (97.5%) belonged to the B-1 lineage, especially the B-1a cell line (B220low, CD5+). Of the isolated CD3+ T cells, 75% were alpha(beta) and 25% were gamma(delta)T-cell receptor positive. The proportion of NK1.1+ alpha(beta) T cells was higher (3%) in LG samples than in submandibular gland samples (0.5%). Ocular immunization with CT-induced antigen-specific mucosal (e.g., found in tear-wash and saliva samples) and systemic (e.g., serum) immune responses. The magnitude of antigen-specific antibody responses was comparable to those induced by nasal immunization.These results show that LG contains unique subsets of B (e.g., sIgA+ B-1 cells) and T (e.g., NK1.1+ alpha(beta)T cells) cells. Furthermore, as a part of the mucosal immune barrier, the LG is an important immunologic tissue for the ocular surface.

Deletion of IL-5R alpha-chain (IL-5R alpha-/-) selectively influenced the mucosal IgA responses in vivo. While levels of IgA in mucosal secretions were more reduced in IL-5R alpha-/- mice than in wild-type mice, the levels of IgA in serum were not changed. The frequency of IgA-producing cells was reduced in mucosal effector sites (e.g., intestinal lamina propria and nasal passage), but not in inductive sites such as Payer's patches and nasal-associated lymphoreticular tissues in IL-5R alpha-/- mice. IgA-committed (surface IgA+; sIgA+) B-1 cells mainly resided in mucosal effector tissues, while conventional sIgA+ B (B-2) cells formed in mucosal inductive sites of wild-type mice. In contrast, in the effector tissue of IL-5R alpha-/- mice, sIgA+ B-1 cells, but not sIgA+ B-2 cells in the inductive site, were significantly reduced. IL-5R alpha was more expressed on sIgA+ B-1 cells than was IL-6R, while both IL-5R alpha and IL-6R were expressed on sIgA+ B-2 cells in wild-type mice. sIgA+ B-1 cells produced high levels of IgA with rIL-5 rather than of rIL-6 in vitro. Taken together, the findings suggest that the IL-5/IL-5R signaling pathway is critically important for the development of common mucosal immune system independent sIgA+ B-1 cell in mucosal effector tissues in vivo.

The nasal mucosa, an important arm of the mucosal immune system, is the first site of contact with inhaled antigens to induce an IgA response. A major aim of this study was to characterize the Th1 and Th2 cytokine expression of mucosal T cells residing in nasal-associated lymphoid tissue (NALT) and nasal passages (NP) as IgA inductive and effector sites, respectively, at the transcription and cellular levels. An application of single-cell reverse transcription-PCR for analysis of Th1 (IFN-gamma) and Th2 (IL-4 and IL-6) cytokine-specific mRNA revealed the presence of CD4+ T cells with a Th0 profile in NALT, while high numbers of Th2 cytokine-specific mRNA expressed by CD4+ T cells were noted in NP followed by Th1-type cells. NALT CD3+ CD4+ T cells of Th0 type have the capacity to become Th1- and/or Th2-type cells since their activation via the TCR-CD3 complex resulted in the expression of an array of Th1 and Th2 cytokines. CD3+ CD4+ T cells from NP, but not NALT, provide a helper function for the induction of antibody-forming cells including IgA isotype in B cell cultures. These findings suggest that NALT is characterized by a Th0 environment which can gain a Th1 and/or Th2 phenotype. In contrast, NP is considered to be a Th2 dominant site with some Th1 cells that can support the induction of IgA-producing cells.

A 61-year-old male had nephrotic syndrome in association with minimal renal amyloidosis. The amyloid deposits were inconspicuous and had been initially overlooked, and the biopsy specimen was thought to show minimal glomerular changes. Accordingly he was diagnosed as having minimal change nephrotic syndrome (MCNS). Thereafter, administration of 40 mg/day of prednisolone was started. A few weeks after treatment, proteinuria decreased, but did not disappear. Four years later, he was readmitted for the treatment of the nephrotic syndrome. The second biopsy at 65 years of age revealed typical renal amyloidosis by light microscopy. Congo red staining and electron microscopy confirmed the presence of amyloid deposits. The serum A protein (SAA) level was 328 micrograms/ml. Furthermore, the first biopsy specimen revealed minimal renal amyloidosis by Congo red staining. At the time, 40 mg/day of prednisolone proved ineffective for the proteinuria. However, after methylprednisolone pulse therapy, the proteinuria decreased and the nephrotic syndrome improved. After discharge, administration of 20 mg/day of prednisolone was maintained. One year later, the patient showed no evidence of recurrence of the nephrotic syndrome and the SAA level decreased (from 328 micrograms/ml to 74.4 micrograms/ml). Prednisolone proved to have a beneficial effect on the reduction of proteinuria and SAA levels. We strongly recommend careful examination for amyloid deposits in all kidney biopsy specimens with the appearance of MCNS on older patients whose proteinuria does not respond to the administration of prednisolone.

In the recent years, mucosal immune system is recognized as the new world in the area of immunology. The host is continuously exposed to the numerous numbers of environmental antigens via the mucosa and the skin. A total surface area of the mucosa is approximately 200 times larger than that of the skin, and the former surface area contains a large numbers of lymphoid cells (10(11)). In order to provide an effective defence for the host by vaccine, it is logical to consider the mucosal immune system. According to the new informations obtained by the modern cellular and molecular immunobiological knowledges and approaches, the concept of the mucosal immune system has been rapidly proceeded to apply for the development of mucosal vaccine. In this report, we have reviewed and discussed the recent progress in the characterization of mucosal immune system and the development of mucosal vaccine.