Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation.

OBJECTIVES: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis. METHODS: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. RESULTS: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. CONCLUSIONS: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

Incidence and risk of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) after tooth extraction in patients with autoimmune disease.

INTRODUCTION: Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a rare but serious complication in patients receiving antiresorprtive agents (AR). However, the incidence of ARONJ after tooth extraction in patients with autoimmune disease (AID) remains unclear. The present study aimed to clarify the high-risk population of ARONJ in patients with AID. MATERIALS AND METHODS: The study population comprised 232 patients treated with AR, AID or non-AID, who had undergone dental extraction from January 2011 to September 2017. The incidence and risk factors of ARONJ were analysed retrospectively. Additionally, the relationship between ARONJ and osteoporotic fracture (OF) and AR discontinuation during dental procedures was investigated. RESULTS: Of 232 patients, 10 developed ARONJ within 1 year of dental extraction. The incidence of ARONJ in patients with AID was higher than that in non-AID patients (2.0/100 person-year vs 0.5/100 person-year; p = 0.03). Among the AID patients, RA patients had strikingly high incidence of ARONJ (3.6/100 person-year). The incidence of neither ARONJ nor OF significantly differed between patients who continued and discontinued AR in the perioperative period. CONCLUSION: Patients with AID who undergo dental extraction are at high risk of ARONJ. Discontinuation of AR would not significantly contribute to reduce the incidence of ARONJ in those patients.

Clinically amyopathic dermatomyositis manifested after the allogeneic haematopoietic stem cell transplantation: Case presentation and literature review.

Clinically amyopathic dermatomyositis (CADM) lacks muscle symptoms, associated with rapidly progressive interstitial lung disease. Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody has been identified as a disease-labelling autoantibody. We report two cases of CADM manifested after the allogeneic haematopoietic stem cell transplantation (allo-HSCT)-Case 1: a 56-year-old man with acute leukaemia received the allo-HSCT and Case 2: a 45-year-old female patient with lymphoma received the allo-HSCT. She received donor lymphocyte infusion because of a post-transplant relapse. After allo-HSCT or donor lymphocyte infusion, Gottron papules emerged, and both patients were diagnosed as CADM based on dermatological findings coupled with the positivity of anti-MDA-5 antibody, accompanied by interstitial shadows consistent with ILD on chest computed tomography. Case 2 was initially diagnosed as a kind of chronic graft versus host disease. Their symptoms were improved by the combination of immunosuppressive agents with a concomitant decrease in anti-MDA-5 antibody levels. For Case 2, rituximab was subsequently started for relapse of lymphoma, resulting in a substantial decrease in the level of anti-MDA-5 antibody and improvement in rash and ILD. Our cases raise a possibility that CADM emerges after the HSCT, highlighting the importance of early diagnosis to avoid fated progression into ILD.

Comprehensive molecular motion capture for sphingomyelin by site-specific deuterium labeling.

Lipid rafts have attracted much attention because of their significant functional roles in membrane-associated processes. It is thought that sphingomyelin and cholesterol are essential for forming lipid rafts; however, their motion characteristics are not fully understood despite numerous studies. Here we show accurate local motions encompassing an entire sphingomyelin molecule, which were captured by measuring quadrupole splittings for 19 kinds of site-specifically deuterated sphingomyelins (that is, molecular motion capture of sphingomyelin). The quadrupole splitting profiles, which are distinct from those reported from perdeuterated sphingomyelins or simulation studies, reveal that cholesterol enhances the order in the middle parts of the alkyl chains more efficaciously than at the shallow positions. Comparison with dimyristoylphosphocholine bilayers suggests that cholesterol is deeper in sphingomyelin bilayers, which likely explains the so-called umbrella effect. The experiments also demonstrate that (i) the C2'-C3' bond predominantly takes the gauche conformation, (ii) the net ordering effect of cholesterol in sphingomyelin bilayers is not larger than that in phosphatidylcholine bilayers, (iii) cholesterol has no specific preference for the acyl or sphingosine chain, (iv) the acyl and sphingosine chains seem mismatched by about two methylene lengths, and (v) the motion of the upper regions of sphingomyelin chains is less temperature dependent than that of lower regions probably due to intermolecular hydrogen bond formation among SM molecules. These insights into the atomic-level dynamics of sphingomyelin provide critical clues to understanding the mechanism of raft formation.

Orange and yellow crystals of copper(I) complexes bearing 8-(diphenylphosphino)quinoline: a pair of distortion isomers of an intrinsic tetrahedral complex.

The tetrafluoroborate salt of bis{8-(diphenylphosphino)quinoline}copper(I), [Cu(Ph(2)Pqn)(2)]BF(4), afforded orange prismatic (2O) or yellow columnar (2Y) crystals, dependent on the solvent and concentration of the recrystallization solution used. X-ray analysis revealed that crystals of 2O and 2Y had the same composition and exhibited different crystal systems: 2O was triclinic, with space group P ̅1 and Z = 2, and 2Y was monoclinic with space group P2(1)/c and Z = 4. In these crystals, the tetrahedral copper(I) complex exhibited a strong "rocking distortion" toward a trigonal pyramidal coordination geometry (by a slide translation of one of the unsymmetrical bidentate chelating ligands along the tetrahedral edge). In addition, both the 2O and 2Y complexes showed a "flattening distortion", meaning that the dihedral angle between the two chelate planes were off-perpendicular and oriented toward opposite directions, which resulted in a pair of distortion isomers: syn clinal (sc: 2O) and anti clinal (ac: 2Y). (31)P CP-MAS NMR spectroscopy indicated that 2O and 2Y could be distinguished. Both isomers exhibited inequivalent P atoms, but a larger difference in chemical shift was observed in 2Y. TD-DFT calculations reproduced the difference in spectra between the orange- and yellow-colored complexes, which originated from metal-to-ligand charge-transfer transitions.

Direct interaction between amphotericin B and ergosterol in lipid bilayers as revealed by 2H NMR spectroscopy.

Although amphotericin B (AmB) is thought to exert its antifungal activity by forming transmembrane ion-permeable self-assemblies together with ergosterol, no previous study has directly proven AmB-ergosterol interaction. To establish the interaction, we measured (2)H NMR using deuterium-labeled sterols and AmB. The (2)H NMR spectra of deuterated ergosterol in palmitoyloleoylphosphatidylcholine (POPC) bilayers showed that fast axial diffusion of erogosterol was almost completely inhibited by the coexistence of AmB. Conversely, cholesterol mobility in POPC membrane was essentially unchanged with or without AmB. These results unequivocally demonstrate that ergosterol has significant interaction with AmB in POPC bilayers. In addition, we examined the mobility of AmB using deuterium-labeled AmB, and found that, although AmB is almost immobilized in sterol-free and cholesterol-containing POPC membranes, a certain ratio of AmB molecules acquires mobility in the presence of ergosterol. The similar mobility of AmB and ergosterol in POPC bilayers confirmed the idea of the direct intermolecular interaction between ergosterol and AmB.

Highly oriented aragonite nanocrystal-biopolymer composites in an aragonite brick of the nacreous layer of Pinctada fucata.

13C CP/MAS NMR and FE/TEM measurements of the aragonite brick of the nacreous layer of Pinctada fucata indicate that it assembles with highly oriented aragonite nanocrystals, which are regulated by biopolymers.

Lipid deposition in various sites of the skeletal muscles and liver exhibits a positive correlation with visceral fat accumulation in middle-aged Japanese men with metabolic syndrome.

Objective In addition to excess visceral fat, lipid deposition in the liver and skeletal muscle has been implicated in the pathophysiology of type 2 diabetes and metabolic syndrome. This study was designed to explore the relationship between hepatic and muscular lipid deposition and visceral fat accumulation in 105 middle-aged men with metabolic syndrome. Methods Abdominal computed tomography (CT) was used to simultaneously evaluate the visceral fat area (VFA) and CT Hounsfield unit (HU) values of three different portions of skeletal muscle and the liver. Results A significant inverse correlation was observed between the VFA and the CT HU values of the iliopsoas muscle, back muscle, rectus abdominis muscle and liver. Three types of interventions, i.e., lifestyle modification and treatment with antidiabetic drugs, such as Pioglitazone or Miglitol, caused significant decreases in visceral fat accumulation. The extent of lipid deposition in the liver was strongly correlated with the levels of glucose-lipid metabolic markers, which decreased significantly following Pioglitazone treatment. On the other hand, the amount of lipid deposition in the three skeletal muscles and the liver did not decrease after Miglitol treatment. Conclusion Visceral fat accumulation is accompanied by excess lipid deposition in skeletal muscle and the liver in patients with metabolic syndrome. The CT-based simultaneous, concise evaluations of ectopic lipid deposition and visceral fat mass used in the present study may provide unique information for assessing cardiometabolic risks and the therapeutic impact in patients with diabetes-obesity syndrome.

New metal-organic frameworks with large cavities: selective sorption and desorption of solvent molecules.

Five novel transition metal complexes [Cd(II) (3)(tpba-2)(2)(SCN)(6)].6 THF.3 H(2)O (1), [Cu(II) (3)(tpba-2)(2)(SCN)(6)].6 THF.3 H(2)O (2), [Ni(II) (3)(tpba-2)(2)(SCN)(6)].6 THF.3 H(2)O (3), [Cd(II) (2)(tpba-2)(SCN)(3)]ClO(4) (4), [Cu(I) (3)(SCN)(6)(H(3)tpba-2)] (5) [TPBA-2 = N',N'',N'''-tris(pyrid-2-ylmethyl)-1,3,5-benzenetricarboxamide, THF=tetrahydrofuran] were obtained by reactions of the corresponding transition metal salts with TPBA-2 ligand in the presence of NH(4)SCN using layering or solvothermal method, respectively. The results of X-ray crystallographic analysis showed that complexes 1, 2 and 3 are isostructural and have the same 2D honeycomb network structure with Kagomé lattice, in which all the M(II) (M = Cd, Cu, Ni) atoms are six-coordinated, and the TPBA-2 ligands adopt cis,cis,cis conformation while the thiocyanate anions act as terminal ligands. Capsule-like motifs are found in 1, 2 and 3, in which six THF molecules are hosted, and the results of XPRD and solid-state (13)C NMR spectral measurements showed that the compound 1 can selectively desorb and adsorb THF molecules occurring along with the re-establishment of its crystallinity. In contrast to 1, 2 and 3, complex 4 has different 2D network structure, resulting from TPBA-2 ligands with cis,trans,trans conformation, thiocyanate anions serving as end-to-end bridging ligands, and the incomplete replacement of perchlorate anions, which further link the 2D layers into 3D framework by the hydrogen bonds. In complex 5, the Cu(II) atoms are reduced to Cu(I) during the process of solvothermal reaction, and the Cu(I) atoms are connected by thiocyanate anions to form a 3D porous framework, in which the protonated TPBA-2 ligands are hosted in the cavities as templates.

Synthesis of zigzag-chain and cyclic-octanuclear calcium complexes and hexanuclear bulky aryl-phosphate sodium complexes with ortho-amide groups: structural transformation involving a network of inter- and intramolecular hydrogen bonds.

Three new polynuclear Ca(II)- and Na(I) phosphate complexes with two strategically oriented bulky amide groups, 2,6-(PhCONH)(2)C(6)H(3)OPO(3)H(2), were synthesized, including one with a zigzag-chain, [Ca(II)[O(3)POC(6)H(3)-2,6-(NHCOPh)(2)](H(2)O)(4)(EtOH)](n), a cyclic-octanuclear form, [Ca(II)(8)[O(3)POC(6)H(3)-2,6-(NHCOPh)(2)](8)(O=CHNMe(2))(8)(H(2)O)(12)], and a hexanuclear complex, (NHEt(3))[Na(3)[O(3)POC(6)H(3)-2,6-(NHCOPh)(2)](2)(H(2)O)(MeOH)(7)]. X-ray crystallography revealed that all have an unsymmetric ligand position due to the bulky amide groups. A dynamic transformation of the Ca(II) zigzag-chain structure to the cyclic-octanuclear complex was induced by changing coordination of DMF molecules, which caused a reorganization of the intermolecular/intramolecular hydrogen bond network.