Publications by authors named "Hiroshi Fujii"

327 Publications

Synthesis, characterization, and reactivity of oxoiron(IV) porphyrin π-cation radical complexes bearing cationic N-methyl-2-pyridinium group.

J Inorg Biochem 2021 Oct 15;223:111542. Epub 2021 Jul 15.

Department of Chemistry, Biology, and Environmental Sciences, Graduate School of Humanities and Sciences, Nara Women's University, Nara 630-8506, Japan. Electronic address:

Electronic charge near the active site is an important factor for controlling the reactivity of metalloenzymes. Here, to investigate the effect of the cationic charge near the heme in heme proteins, we synthesized new iron porphyrin complexes (1 and 2) having cationic 3-methyl-N-methyl-2-pyrdinium group and N-methyl-2-pyridinium group at one of the four meso-positions, respectively. The N-methyl-2-pyridinium groups could be introduced by Stille coupling used palladium catalysts. Oxoiron(IV) porphyrin π-cation radical complexes (Compound I) of 1 (1-CompI) and 2 (2-CompI) are soluble in most organic solvents, allowing direct comparison of their electronic structure and reactivity with Compound I of tetramesitylporphyrin (3-CompI) and tetrakis-(2,6-dichlorophenyl)porphyrin (4-CompI) under the same conditions. Spectroscopic data for 1-CompI are close to those for 3-CompI, but the redox potential for 1-CompI is close to that of 4-CompI. Kinetic analysis of the epoxidation reactions shows that 1-CompI and 2-CompI are (~250-fold) more reactive than 3-CompI, and comparable to 4-CompI. DFT calculations allow to propose that the positive shift of the redox potential and the enhanced reactivity of 1-CompI and 2-CompI is induced by the intramolecular electric field effect of N-methyl-2-pyridinium cation, not by the electron-withdrawing effect.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111542DOI Listing
October 2021

Multi-targeted therapy for refractory eosinophilic granulomatosis with polyangiitis characterized by intracerebral hemorrhage and cardiomyopathy: a case-based review.

Rheumatol Int 2021 Jul 21. Epub 2021 Jul 21.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic autoimmune disorder classified under anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, predominantly affecting small- to medium-sized vessels, characterized by asthma, eosinophilia, and necrotizing granulomatous inflammation. Most patients with EGPA experience peripheral neuropathy, whereas intracerebral hemorrhage is rare as EGPA-related presentation in central nervous system involvement, causing severe morbidity and mortality. Here, we present a 45-year-old man with refractory EGPA who developed intracerebral hemorrhage as the first manifestation, followed by cardiac involvement. This patient with a history of bronchial asthma developed a right putaminal hemorrhage caused by EGPA. Although intravenous cyclophosphamide (IVCY) and mepolizumab (MPZ) induced remission, relapse was frequently observed. Subsequently, he developed cardiomyopathy despite administration of rituximab (RTX) substituted from IVCY and MPZ. Combined immunosuppressive therapy, including IVCY, MPZ, and RTX was required to inhibit vascular inflammation, leading to sustained remission. We review previously published literature while focusing on the clinical features of patients with intracerebral hemorrhage caused by EGPA and describe clinical characteristics for detecting EGPA in patients with intracerebral hemorrhage, emphasizing rapid evaluation and recognition of EGPA and adequate intervention in the early vasculitic phase of this disease. We also refer to the immunological aspects of this case. It is important to consider "multi-targeted therapy" through interleukin-5 suppression and B cell depletion in the management of refractory EGPA.
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http://dx.doi.org/10.1007/s00296-021-04950-zDOI Listing
July 2021

Serum IgG4 levels at diagnosis can predict unfavorable outcomes of untreated patients with IgG4-related disease.

Sci Rep 2021 Jun 25;11(1):13341. Epub 2021 Jun 25.

Department of Rheumatology, Kanazawa University Hospital, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.

The outcomes of patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) who are not treated are unclear. This study aimed to clarify these outcomes and identify the factors related to them. We retrospectively evaluated various clinical features including laboratory data and involved organs at diagnosis in 107 patients with IgG4-RD, who were followed up for more than 6 months, at a single center in Japan. We compared the clinical features of the 27 untreated patients with those of the 80 patients treated with glucocorticoid. The patient outcomes were investigated, and logistic regression analysis was performed to identify factors related to them. The patients comprised 73 men and 34 women (median age 67 years). The untreated patients had significantly lower IgG4-RD responder index (9 vs. 12) and fewer affected organs (1 vs. 3) than did those treated with glucocorticoid. Of these 27 patients, 8 experienced deterioration of IgG4-RD after the diagnosis. In the age- and sex-adjusted logistic regression analysis, serum IgG4 elevation (per 100 mg/dL, odds ratio 1.194, 95% confidence interval 1.017-1.402) was the only significant factor related to disease deterioration in untreated patients with IgG4-RD, whereas not serum IgG4 levels (per 100 mg/dL, odds ratio 0.995, 95% confidence interval 0.921-1.075) but history of allergy (OR 3.134, 95% confidence interval 1.094-8.977, P = 0.033) related to deterioration in patients who underwent treatment. Serum IgG4 levels may be a useful predictor of unfavorable outcomes in untreated patients with IgG4-RD, who tend to have fewer affected organs and lower IgG4-RD responder index.
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http://dx.doi.org/10.1038/s41598-021-92814-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233326PMC
June 2021

Significant Solvent Effect on Reactivity of Oxoiron(IV) Porphyrin π-Cation Radical Complex: Activation in -Alkane Solvent.

Inorg Chem 2021 Jul 14;60(13):9243-9247. Epub 2021 Jun 14.

Department of Chemistry, Graduate School of Humanities and Sciences, Nara Women's University, Kitauoyanishi, Nara 630-8506, Japan.

The solvent effect on the reactivity of high-valent metal oxo complexes has not been studied well, because of their solubility and stability. We synthesize oxoiron(IV) porphyrin π-cation radical complexes ( and ) having the -hexyl side chains. and are soluble in various solvents, even in hexane, at -80 °C, allowing for the study of their reactivity in various organic solvents. We show that pentane, hexane, heptane, and -butyl methyl ether significantly increase the reactivity of and , but dichloromethane, the most frequently used solvent in previous studies, is the worst for increasing the reactivity among the solvents. H NMR and EPR spectroscopies show no significant change in hexane, but the Eyring plots for the epoxidation reactions indicate that the entropies of activation in -alkane solvents are larger than those in dichloromethane. The observed solvent effect can be rationalized with reorganization energy of the solvent in the reaction.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01018DOI Listing
July 2021

Cyclophosphamide-associated enteritis presenting with severe protein-losing enteropathy in granulomatosis with polyangiitis: A case report.

World J Gastroenterol 2021 May;27(20):2657-2663

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai 9808574, Japan.

Background: Although cyclophosphamide (CPA) is the key drug for the treatment of autoimmune diseases including vasculitides, it has some well-known adverse effects, such as myelosuppression, hemorrhagic cystitis, infertility, and infection. However, CPA-associated severe enteritis is a rare adverse effect, and only one case with a lethal clinical course has been reported. Therefore, the appropriate management of patients with CPA-associated severe enteritis is unclear.

Case Summary: We present the case of a 61-year-old woman diagnosed with granulomatosis with polyangiitis based on the presence of symptoms in ear, lung, and, kidney with positive myeloperoxidase-antineutrophil cytoplasmic antibody. She received pulsed methylprednisolone followed by prednisolone 55 mg/d and intravenous CPA at a dose of 500 mg/mo. Ten days after the second course of intravenous CPA, she developed nausea, vomiting, and diarrhea, and was admitted to the hospital. Laboratory testing revealed hypoalbuminemia, suggesting protein-losing enteropathy. Computed tomography revealed wall thickening of the stomach, small intestine, and colon with contrast enhancement on the lumen side. Antibiotics and immunosuppressive therapy were not effective, and the patient's enteritis did not improve for > 4 mo. Because her condition became seriously exhausted, corticosteroids were tapered and supportive therapies including intravenous hyperalimentation, replenishment of albumin and gamma globulin, plasma exchange, and infection control were continued. These supportive therapies improved her condition, and her enteritis gradually regressed. She was finally discharged 7 mo later.

Conclusion: Immediate discontinuation of CPA and intensive supportive therapy are crucial for the survival of patients with CPA-associated severe enteritis.
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http://dx.doi.org/10.3748/wjg.v27.i20.2657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160622PMC
May 2021

Bisphosphonate-related atypical insufficiency fracture of the tibial plateau : A case report.

J Med Invest 2021 ;68(1.2):186-188

Department of Orthopedic Surgery, Ogori Daiichi General Hospital, Yamaguchi, Japan.

Objective : Only a few cases of insufficiency fractures of the tibial plateau following bisphosphonate use have been reported. The authors report a case with bisphosphonate (BP) -related atypical insufficiency fracture of tibial plateau, which developed delayed union. Patient : A 65-year-old Japanese woman presented with left knee pain without any trauma. She had a 5-year history of risedronate use for primary osteoporosis. Initial X-rays were unremarkable, but magnetic resonance imaging (MRI) confirmed an insufficiency fracture at the left tibial plateau at 3 weeks after the initial visit. Risedronate treatment was stopped because we diagnosed her with a BP-related atypical insufficiency fracture of the tibial plateau. She was treated with rest, a lateral wedge insole and protective weight-bearing with a T-cane for 3 months. Result : At 3-month follow-up, the patient still had a pain and a delayed healing on radiographs. Six months later, X-rays showed that the fracture site had a sclerotic change, but MRI revealed delayed union. At 8-month follow-up, the fracture was healed without any symptoms. Conclusion : All clinicians need to be aware of the delayed healing of atypical insufficiency fracture related with prolonged BP use. J. Med. Invest. 68 : 186-188, February, 2021.
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http://dx.doi.org/10.2152/jmi.68.186DOI Listing
January 2021

Factors contributing to discrepant estimated glomerular filtration values measured by creatinine and cystatin C in patients with rheumatoid arthritis.

Sci Rep 2021 05 10;11(1):9884. Epub 2021 May 10.

Department of Rheumatology, Kanazawa University Hospital, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.

This study aimed to clarify the factors underlying the discrepancy that has been noted between estimated glomerular filtration ratio (eGFR) measured using serum creatinine (Cr) and eGFR using serum cystatin C (CysC) in patients with rheumatoid arthritis (RA) and to identify those patients whose renal function should be evaluated using CysC. We retrospectively evaluated clinical features, disease activity, Steinbrocker radiological staging, and co-morbidities (diabetes mellitus, hypertension, dyslipidemia) in 238 RA patients. eGFR using serum creatinine (eGFR-Cr) and eGFR using serum cystatin C (eGFR-CysC) were calculated using the new Japanese coefficient-modified Modification of Diet in Renal Disease study equation. To clarify the cause(s) of differences of 20% or more between the two eGFRs, we divided our RA patients into Group A (eGFR-Cr/eGFR-CysC ≥ 1.2) and Group B (eGFR-Cr/eGFR-CysC < 1.2), and searched for factors independently related to Group A. Forty-five patients (18.9%) were assigned to Group A, and 193 (81.1%) to Group B. BMI (Odds Ratio [OR] 0.820, 95% confidence interval [CI] 0.675-0.996), Hb (OR 0.633, 95% CI 0.433-0.926), CK (OR 0.773 per 10 units, 95% CI 0.644-0.933), NSAID use (OR 0.099, 95% CI 0.020-0.494), diabetes mellitus (OR 6.024, 95% CI 1.508-24.390) and stage 4 Steinbrocker radiological stage (OR 10.309, 95% CI 2.994-35.714) were identified as independent relevant factors for Group A by a multifactorial analysis. Renal function in RA patients with low BMI, diabetes, anemia and low CK may be overestimated using eGFR-Cr alone, and such patients need to be evaluated using eGFR-CysC.
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http://dx.doi.org/10.1038/s41598-021-89303-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110572PMC
May 2021

Biological and molecular characterization of linalool-mediated field resistance against Xanthomonas citri subsp. citri in citrus trees.

Tree Physiol 2021 May 7. Epub 2021 May 7.

Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan.

The biological and molecular traits of the Ponkan mandarin (Citrus reticulata Blanco) were characterized in an investigation of the mechanisms of field resistance against citrus canker disease caused by the bacterial pathogen, Xanthomonas citri subsp. citri (Xcc). Various conventional citrus varieties that show diverse responses to Xcc were investigated, and the temporal changes in Xcc titer in response to linalool concentrations among the varieties revealed differences in Xcc proliferation trends in the inoculated leaves of the immune, field-resistant, and susceptible varieties. In addition, increased linalool accumulation was inversely related to Xcc titers in the field-resistant varieties, which is likely caused by host-pathogen interactions. Quantitative trait locus (QTL) analysis using the F1 population of the resistant Ponkan mandarin and susceptible 'Harehime' ('E-647' × 'Miyagawa-wase') cultivar revealed that linalool accumulation and Xcc susceptibility QTLs overlapped. These results provide novel insights into the molecular mechanisms of linalool-mediated field resistance to Xcc, and suggest that high linalool concentrations in leaves has an antibacterial effect and become a candidate-biomarker target for citrus breeding to produce seedlings with linalool-mediated field resistance against Xcc.
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http://dx.doi.org/10.1093/treephys/tpab063DOI Listing
May 2021

Association of various myositis-specific autoantibodies with dermatomyositis and polymyositis triggered by pregnancy.

Rheumatol Int 2021 Apr 10. Epub 2021 Apr 10.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

Although pregnancy is an important risk factor for autoimmune rheumatic diseases, little is known regarding the association between pregnancy and dermatomyositis (DM) or polymyositis (PM). Herein, we present two patients with DM that developed during the perinatal period. The first patient was positive for anti-aminoacyl synthetase (ARS) antibody and developed DM in the 14th week of pregnancy. Despite treatment, her foetus died of intrauterine growth restriction in the 27th week. The second patient was positive for anti-melanoma differentiation-associated gene 5 (MDA-5) antibody and developed DM 1 week after miscarriage at 9 weeks of gestation. The patient developed severe interstitial pneumonia, and intensive therapy including tofacitinib and rituximab administration was required. Our cases and a literature review revealed that various myositis-specific autoantibodies, including anti-ARS, anti-Mi-2, anti-TIF-1γ, and anti-MDA-5, are associated with DM and PM triggered by pregnancy. We also found that delay in commencing treatment in case of active disease including myositis and interstitial pneumonia, and poor response to corticosteroids were related to poor foetal outcomes in DM and PM. Although rare in pregnant women, it is critical to consider the possibility of DM and PM in patients presenting with rash, fever, weakness, and cough, and testing for myositis-specific autoantibodies is recommended.
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http://dx.doi.org/10.1007/s00296-021-04851-1DOI Listing
April 2021

Distinct Autoantibodies against Endothelial Protein C Receptor in Ulcerative Colitis.

Gastroenterology 2021 Mar 24. Epub 2021 Mar 24.

Department of Rheumatology, Tohoku University Hospital, Sendai, Japan.

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http://dx.doi.org/10.1053/j.gastro.2021.03.037DOI Listing
March 2021

Non-immunoglobulin G4-related multifocal fibrosclerosis presenting generalized morphea-like skin lesions.

J Dermatol 2021 Jun 25;48(6):e271-e272. Epub 2021 Mar 25.

Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

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http://dx.doi.org/10.1111/1346-8138.15867DOI Listing
June 2021

Interferon Enhances B Cell Activation Associated With FOXM1 Induction: Potential Novel Therapeutic Strategy for Targeting the Plasmablasts of Systemic Lupus Erythematosus.

Front Immunol 2020 3;11:498703. Epub 2021 Feb 3.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Systemic lupus erythematosus (SLE) is an autoimmune disease. It is characterized by the production of various pathogenic autoantibodies and is suggested to be triggered by increased type I interferon (IFN) signature. Previous studies have identified increased plasmablasts in the peripheral blood of SLE patients. The biological characteristics of SLE plasmablasts remain unknown, and few treatments that target SLE plasmablasts have been applied despite the unique cellular properties of plasmablasts compared with other B cell subsets and plasma cells. We conducted microarray analysis of naïve and memory B cells and plasmablasts (CD38CD43 B cells) that were freshly isolated from healthy controls and active SLE (n = 4, each) to clarify the unique biological properties of SLE plasmablasts. The results revealed that all B cell subsets of SLE expressed more type I IFN-stimulated genes. In addition, SLE plasmablasts upregulated the expression of cell cycle-related genes associated with higher FOXM1 and FOXM1-regulated gene expression levels than that in healthy controls. This suggests that a causative relationship exists between type I IFN priming and enhanced proliferative capacity through FOXM1. The effects of pretreatment of IFN on B cell activation and FOXM1 inhibitor FDI-6 on B cell proliferation and survival were investigated. Pretreatment with IFN promoted B cell activation after stimulation with anti-IgG/IgM antibody. Flow cytometry revealed that pretreatment with IFN preferentially enhanced the Atk and p38 pathways after triggering B cell receptors. FDI-6 inhibited cell division and induced apoptosis in activated B cells. These effects were pronounced in activated B cells pretreated with interferon . This study can provide better understanding of the pathogenic mechanism of interferon-stimulated genes on SLE B cells and an insight into the development of novel therapeutic strategies.
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http://dx.doi.org/10.3389/fimmu.2020.498703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902015PMC
April 2021

-Substitution Activates Oxoiron(IV) Porphyrin π-Cation Radical Complex More Than Pyrrole-β-Substitution for Atom Transfer Reaction.

Inorg Chem 2021 Mar 15;60(5):3207-3217. Epub 2021 Feb 15.

Department of Chemistry, Graduate School of Humanities and Sciences, Nara Women's University, Kitauoyanishi, Nara 630-8506, Japan.

There have been two known categories of porphyrins: a -substituted porphyrin like -tetramesitylporphyrin (TMP) and a pyrrole-β-substituted porphyrin like native porphyrins and 2,7,12,17-tetramethyl-3,8,13,18-tetramesitylporphyrin (TMTMP). To reveal the chemical and biological function of native hemes, we compare the reactivity of the oxoiron(IV) porphyrin π-cation radical complex (Compound I) of TMP () with that of TMTMP () for epoxidation, hydrogen abstraction, hydroxylation, sulfoxidation, and demethylation reactions. Kinetic analysis of these reactions indicated that is much more reactive than when the substrate is not sterically bulky. However, as the substrate is sterically bulkier, the difference of the reactivity between and becomes smaller, and the reactivity of is comparable to that of for a sterically hindered substrate. Since the redox potential of is almost the same as that of , we conclude that is intrinsically more reactive than for these atom transfer reactions, but the steric effect of is stronger than that of . This is contrary to the previous result for the single electron transfer reaction: is faster than . DFT calculations indicate that the orbital energies of the Fe═O moiety for are higher than those for . The difference in steric effect between and is explained by the distance from the mesityl group to the oxo ligand of Compound I. Significance of the pyrrole-β-substituted structure of the hemes in native enzymes is also discussed on the basis of this study.
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http://dx.doi.org/10.1021/acs.inorgchem.0c03548DOI Listing
March 2021

Allelic composition of carotenoid metabolic genes in 13 founders influences carotenoid composition in juice sac tissues of fruits among Japanese citrus breeding population.

PLoS One 2021 4;16(2):e0246468. Epub 2021 Feb 4.

National Agriculture and Food Research Organization Institute of Fruit and Tea Tree Science, Shimizu, Shizuoka, Japan.

To enrich carotenoids, especially β-cryptoxanthin, in juice sac tissues of fruits via molecular breeding in citrus, allele mining was utilized to dissect allelic variation of carotenoid metabolic genes and identify an optimum allele on the target loci characterized by expression quantitative trait (eQTL) analysis. SNPs of target carotenoid metabolic genes in 13 founders of the Japanese citrus breeding population were explored using the SureSelect target enrichment method. An independent allele was determined based on the presence or absence of reliable SNPs, using trio analysis to confirm inheritability between parent and offspring. Among the 13 founders, there were 7 PSY alleles, 7 HYb alleles, 11 ZEP alleles, 5 NCED alleles, and 4 alleles for the eQTL that control the transcription levels of PDS and ZDS among the ancestral species, indicating that some founders acquired those alleles from them. The carotenoid composition data of 263 breeding pedigrees in juice sac tissues revealed that the phenotypic variance of carotenoid composition was similar to that in the 13 founders, whereas the mean of total carotenoid content increased. This increase in total carotenoid content correlated with the increase in either or both β-cryptoxanthin and violaxanthin in juice sac tissues. Bayesian statistical analysis between allelic composition of target genes and carotenoid composition in 263 breeding pedigrees indicated that PSY-a and ZEP-e alleles at PSY and ZEP loci had strong positive effects on increasing the total carotenoid content, including β-cryptoxanthin and violaxanthin, in juice sac tissues. Moreover, the pyramiding of these alleles also increased the β-cryptoxanthin content. Interestingly, the offset interaction between the alleles with increasing and decreasing effects on carotenoid content and the epistatic interaction among carotenoid metabolic genes were observed and these interactions complexed carotenoid profiles in breeding population. These results revealed that allele composition would highly influence the carotenoid composition in citrus fruits. The allelic genotype information for the examined carotenoid metabolic genes in major citrus varieties and the trio-tagged SNPs to discriminate the optimum alleles (PSY-a and ZEP-e) from the rest would promise citrus breeders carotenoid enrichment in fruit via molecular breeding.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246468PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861536PMC
July 2021

Pneumonia and central nervous system infection caused by reactivation of varicella-zoster virus in a living-donor kidney transplantation patient: case report and review of the literature.

CEN Case Rep 2021 08 27;10(3):370-377. Epub 2021 Jan 27.

Department of Rheumatology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.

Varicella-zoster virus (VZV) typically causes herpes zoster in the elderly due to reactivation, but immunocompromised individuals may develop organ damage such as pneumonia with a poor prognosis. We herein report a case of pneumonia and central nervous system (CNS) infection caused by reactivation of VZV in a 50-year-old man who had received a living-donor kidney transplant. We also conducted a literature review of adult cases with pneumonia or CNS infection caused by VZV after kidney transplantation. It showed that there are cases in which eruptions appeared upto 21 days after the onset of the disease and others in which eruptions did not appear at any time during the clinical course. Furthermore, there may be a wide variety of intervals from kidney transplantation to VZV infection (including both primary infection and reactivation of VZV), ranging from 2 weeks to 11 years. Therefore, it should be kept in mind that kidney transplant patients are always at high risk of VZV infection, as early recognition and treatment of the disease improves its prognosis. Although the diagnosis of varicella pneumonia is generally made by PCR test of bronchoalveolar lavage fluid, our case experience suggests that the less invasive PCR test of sputum may be useful for rapid and accurate diagnosis. The efficacy of inactivated recombinant zoster vaccine in immunocompromised individuals at high risk of reactivation of VZV also needs to be examined in the future.
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http://dx.doi.org/10.1007/s13730-021-00576-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838850PMC
August 2021

Involvement of two or more sets of lacrimal glands and/or major salivary glands is related to greater systemic disease activity due to multi-organ involvement in IgG4-related dacryoadenitis/sialadenitis.

Mod Rheumatol 2021 Feb 11:1-10. Epub 2021 Feb 11.

Department of Rheumatology, Kanazawa University Hospital, Kanazawa, Japan.

Objectives: In IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), involvement of two or more sets of lacrimal glands (LGs) and/or major salivary glands (MSGs) is regarded as a specific finding with diagnostic significance. This study aimed to clarify the influence of this factor on the overall clinical picture of IgG4-DS.

Methods: We retrospectively reviewed the medical records of 130 patients with IgG4-related disease, 97 of whom were diagnosed with IgG4-DS. We determined their clinical features according to the presence/absence of involvement of ≥2 sets of LGs and/or MSGs and compared the results with those obtained in 33 DS-limited patients.

Results: The IgG4-DS patients comprised 60 men and 37 women (median age 65 years). The median serum IgG4 level at diagnosis was 548 mg/dL. The patients with involvement of ≥2 sets ( = 44) had significantly more affected organs, lower serum C3 and C4 levels, and a tendency to have higher serum IgG levels and IgG4-RD responder index than did those without it ( = 53). In the 33 DS-limited patients, these two groups had no significant differences in clinical features.

Conclusions: Involvement of ≥2 sets of LGs and/or MSGs suggests greater systemic disease activity mainly reflected by involvement of more organs.
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http://dx.doi.org/10.1080/14397595.2021.1878623DOI Listing
February 2021

Positive disease-specific autoantibodies have limited clinical significance in diagnosing IgG4-related disease in daily clinical practice.

Rheumatology (Oxford) 2021 07;60(7):3317-3325

Department of Rheumatology, Kanazawa University Hospital, Kanazawa, Japan.

Objectives: The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results.

Methods: We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases.

Results: Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels.

Conclusions: The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.
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http://dx.doi.org/10.1093/rheumatology/keaa783DOI Listing
July 2021

Asymmetrical Interstitial Lung Disease Suggested to Be Due to Hypoplasia of the Unilateral Pulmonary Artery: A Case Report with a 20-year Follow-up.

Intern Med 2021 Apr 16;60(8):1265-1270. Epub 2020 Nov 16.

Division of Diagnostic Pathology, Saitama Prefectural Cardiovascular and Respiratory Center, Japan.

We herein report a case of asymmetrical interstitial lung disease (ILD) that remained almost completely asymmetrical over time on chest computed tomography (CT). An open lung biopsy from the right lung showed severe pleural adhesion, obstruction of the pulmonary artery, and dilated systemic arteries in addition to the usual interstitial pneumonia pattern. Three-dimensional CT angiography showed partial defects of pulmonary arteries on the affected side. After excluding other known causes of ILD and gastroesophageal reflux, we suspected that decreased pulmonary artery perfusion in the present case may have been responsible for the observed asymmetrical unilateral fibrosis.
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http://dx.doi.org/10.2169/internalmedicine.5753-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112992PMC
April 2021

Calcification of the Anterior Acromial Insertion of the Deltoid Muscle.

Case Rep Orthop 2020 10;2020:8895801. Epub 2020 Oct 10.

Department of Orthopedic Surgery, Ogori Daiichi General Hospital, Yamaguchi, Japan.

A 45-year-old man presented with severe left shoulder pain that was not associated with trauma. Plain radiography with the arm in an elevated position and ultrasonography demonstrated calcium deposits at the anterior acromial insertion site of left deltoid muscle. Conservative management could successfully relieve pain. At the 3-year follow-up, the calcification completely disappeared. To the best of our knowledge, calcium deposits at the acromial insertion site of the deltoid have not been reported in the literature. Clinicians who suspect calcific tendinitis but do not observe calcification around the rotator cuff should carefully palpate and examine other sites, such as the deltoid origin, and use ultrasonography or radiography.
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http://dx.doi.org/10.1155/2020/8895801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576339PMC
October 2020

JAK2 mutation-positive polycythaemia vera associated with IgA vasculitis and nephrotic syndrome: a case report.

Mod Rheumatol Case Rep 2020 07 13;4(2):289-295. Epub 2020 Feb 13.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

We report a case of polycythaemia vera (PV) associated with IgA vasculitis. A 45-year-old man was admitted for evaluation of abdominal pain and palpable purpura. IgA vasculitis was diagnosed, and oral prednisolone therapy (30 mg/day) was initiated. On day 6, the patient developed left hemiparesis, and magnetic resonance imaging revealed acute cerebral infarction. Bone marrow biopsy results and the identification of a Janus kinase 2 () mutation led to the diagnosis of PV. Despite steroid therapy, urine protein levels increased to 15 g/g・Cre. Renal biopsy demonstrated mild mesangial proliferation with IgA deposits, but immunosuppressive therapy was partially effective. This case suggests that PV can be a complication of IgA vasculitis and that preventive measures for thrombosis should be taken in such cases.
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http://dx.doi.org/10.1080/24725625.2020.1728061DOI Listing
July 2020

Unique Electronic Structures of the Highly Ruffled Hemes in Heme-Degrading Enzymes of , IsdG and IsdI, by Resonance Raman and Electron Paramagnetic Resonance Spectroscopies.

Biochemistry 2020 10 29;59(40):3918-3928. Epub 2020 Sep 29.

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira, Aoba, Sendai 980-8577, Japan.

uses IsdG and IsdI to convert heme into a mixture of staphylobilin isomers, 15-oxo-β-bilirubin and 5-oxo-δ-bilirubin, formaldehyde, and iron. The highly ruffled heme found in the heme-IsdI and IsdG complexes has been proposed to be responsible for the unique heme degradation products. We employed resonance Raman (RR) and electron paramagnetic resonance (EPR) spectroscopies to examine the coordination and electronic structures of heme bound to IsdG and IsdI. Heme complexed to IsdG and IsdI is coordinated by a neutral histidine. The trans ligand is hydroxide in the ferric alkaline form of both proteins. In the ferric neutral form at pH 6.0, heme is six-coordinated with water as the sixth ligand for IsdG and is in the mixture of the five-coordinated and six-coordinated species for IsdI. In the ferrous CO-bound form, CO is strongly hydrogen bonded with a distal residue. The marker lines, ν and ν, appear at frequencies that are distinct from other proteins having planar hemes. The EPR spectra for the ferric hydroxide and cyanide states might be explained by assuming the thermal mixing of the -electron configurations, ()(,) and (,)(). The fraction for the latter becomes larger for the ferric cyanide form. In the ferric neutral state at pH 6.0, the quantum mechanical mixing of the high and intermediate spin configurations might explain the peculiar frequencies of ν and ν in the RR spectra. The heme ruffling imposed by IsdG and IsdI gives rise to unique electronic structures of heme, which are expected to modulate the first and subsequent steps of the heme oxygenation.
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http://dx.doi.org/10.1021/acs.biochem.0c00731DOI Listing
October 2020

One after another retinal involvement in lupus.

Eur J Rheumatol 2020 Sep 3. Epub 2020 Sep 3.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

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http://dx.doi.org/10.5152/eurjrheum.2020.20022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133891PMC
September 2020

Blue LED light induces regreening in the flavedo of Valencia orange in vitro.

Food Chem 2021 Jan 25;335:127621. Epub 2020 Jul 25.

Department of Bioresource Sciences, Faculty of Agriculture, Shizuoka University, 836 Ohya, Suruga, Shizuoka 422-8529, Japan; Graduate School of Integrated Science and Technology, Shizuoka University, 836 Ohya, Suruga, Shizuoka 422-8529, Japan. Electronic address:

In the present study, the effects of blue LED light on the regreening of citrus fruit were investigated in an in vitro system of Valencia orange flavedos. The results showed that blue LED light irradiation induced regreening in the flavedos. After four-week culture in vitro, the flavedos exhibited obviously green color in the blue LED light treatment, while the flavedos in the control were still in orange color. During the regreening process, the blue LED light treatment induced chlorophyll accumulation, and substantially altered the carotenoid composition in the flavedos. Compared with the control, the content of 9-cis-violaxanthin was decreased, while the contents of lutein, β-carotene, and all-trans-violaxanthin were increased by blue LED light. In addition, gene expression results showed that the up-regulation of CitLCYe and down-regulation of CitLCYb2 by blue LED light led to a shift from β,β-branch to β,ε-branch of the carotenoid biosynthetic pathway.
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http://dx.doi.org/10.1016/j.foodchem.2020.127621DOI Listing
January 2021

Evaluation of risk factors of vertebral fracture in Japanese female patients with glucocorticoid-induced osteoporosis.

J Orthop Surg Res 2020 Jul 29;15(1):290. Epub 2020 Jul 29.

Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi, Aobaku, Sendai, Miyagi, 980-8574, Japan.

Background: Glucocorticoid-induced osteoporosis and vertebral fracture are common complications in patients on glucocorticoid treatment for rheumatological diseases. The present study aimed to identify the risk factors of vertebral fracture in Japanese female patients with glucocorticoid-induced osteoporosis.

Methods: This study included 225 Japanese women with glucocorticoid-induced osteoporosis and 72 patients with postmenopausal osteoporosis. All participants were treated with bisphosphonate or denosumab for osteoporosis with active form of vitamin D for at least 3 years. The differences of clinical parameters, including age, disease duration, body mass index (BMI), bone mineral density (BMD), and the dose and treatment duration of glucocorticoid were assessed between patients with and without vertebral fracture. Multivariate logistic regression analysis was also performed to evaluate the association of vertebral fracture with clinical parameters.

Results: The significant differences related to age, BMD of the hip, disease duration, glucocorticoid treatment duration between patients with and without vertebral fractures were demonstrated. The present study indicated that disease duration, BMI, and the total hip BMD were independent risk factors for vertebral fractures in patients with glucocorticoid-induced osteoporosis.

Conclusions: Prolonged disease duration, low BMI, and low total hip BMD could be risk factors of vertebral fracture in patients on glucocorticoid treatment for rheumatological diseases.
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http://dx.doi.org/10.1186/s13018-020-01813-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391489PMC
July 2020

TaqMan-MGB SNP genotyping assay to identify 48 citrus cultivars distributed in the Japanese market.

Breed Sci 2020 Jun 30;70(3):363-372. Epub 2020 May 30.

National Agriculture and Food Research Organization Institute of Fruit and Tea Tree Science, Shimizu, Shizuoka 424-0292, Japan.

A citrus cultivar identification system using CAPS marker has been developed on nursery trees, but this needs to be extended to include various product types, such as imported fruits and processed products. Here, we developed a new cultivar identification system using TaqMan-MGB SNP genotyping assay. Eight probe and primer sets were designed to amplify PCR fragments <100 bp to enable the genotyping of fresh and processed fruits in which predicted that insufficient quantities of DNA and residual impurities in the DNA extracts. The TaqMan-MGB SNP genotyping assay was stable and reproducible, and were confirmed to apply various sample sources, including leaves, fresh fruit, juice, canned fruit, and dry fruit. They could provide at least a single differentiating SNP to discriminate any paired combination among 48 citrus cultivars. Minimal marker subsets to identify the target cultivar were listed for each of 18 registered cultivars with valid patent. The allelic SNP genotypes of 48 citrus cultivars, which cover more than 98% of all citrus fruit shipment produced in Japan, is valuable for the referencing information in the DNA-based identification for fresh and processed fruits. This identification system will help protect registered cultivars and facilitate food fraud inspections.
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http://dx.doi.org/10.1270/jsbbs.19142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372028PMC
June 2020

Photo-biohydrogen Production by Photosensitization with Biologically Precipitated Cadmium Sulfide in Hydrogen-Forming Recombinant Escherichia coli.

Chembiochem 2020 12 31;21(23):3389-3397. Epub 2020 Aug 31.

Department of Chemistry, Biology, and Environmental Science, Faculty of Science, Nara Women's University, Kitauoyanishi-machi, Nara, 630-8506, Japan.

An inorganic-biological hybrid system that integrates features of both stable and efficient semiconductors and selective and efficient enzymes is attractive for facilitating the conversion of solar energy to hydrogen. In this study, we aimed to develop a new photocatalytic hydrogen-production system based on Escherichia coli whole-cell genetically engineered as a biocatalysis for highly active hydrogen formation. The photocatalysis part was obtained by bacterial precipitation of cadmium sulfide (CdS), which is a visible-light-responsive semiconductor. The recombinant E. coli cells were sequentially subjected to CdS precipitation and heterologous [FeFe]-hydrogenase synthesis to yield a [email protected] coli hybrid capable of light energy conversion and hydrogen formation in a single cell. The [email protected] coli hybrid achieved photocatalytic hydrogen production with a sacrificial electron donor, thus demonstrating the feasibility of our system and expanding the current knowledge of photosensitization using a whole-cell biocatalyst with a bacterially precipitated semiconductor.
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http://dx.doi.org/10.1002/cbic.202000383DOI Listing
December 2020

ANCA-associated nephritis without crescent formation has atypical clinicopathological features: a multicenter retrospective study.

Clin Exp Nephrol 2020 Nov 10;24(11):999-1006. Epub 2020 Jul 10.

Department of Rheumatology, Kanazawa University Graduate School of Medicine, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.

Background: Although crescentic glomerulonephritis is a hallmark of ANCA-associated nephritis, the clinicopathological features of ANCA-associated nephritis without crescent formation remain to be elucidated.

Methods: We enrolled 146 Japanese ANCA-associated vasculitis (AAV) patients subjected to renal biopsy in 16 hospitals from 2001 to 2018, and compared those with and without crescent formation (C + and C- groups). The primary endpoint was end-stage renal disease (ESRD) and/or death.

Results: C- group comprised 25 (17.1%) subjects. They had better renal function at the time of renal biopsy [estimated glomerular filtration rate (eGFR); median 41.7 vs 27.5 ml/min/1.73 m, p < 0.01] with minor urinary abnormalities but had a higher serum C-reactive protein level (8.8 vs 5.4 mg/dl, p = 0.01) and frequency of extra-renal lesions of AAV (76.0% vs 48.8%, p = 0.02) than C + group. Pathologically, C- group had a higher frequency of arteritis (40.0% vs 16.5%, p < 0.01). Kaplan-Meier method with log-rank tests showed no significant difference in renal and life prognosis combined, regardless of crescent formation. Multivariate Cox regression analysis revealed baseline eGFR, sclerotic class, and extra-renal lesions to be risk factors of ESRD and death combined. Competing risk analysis showed baseline eGFR and sclerotic class to be associated with ESRD, whereas baseline eGFR and extra-renal lesions were associated with death.

Conclusion: ANCA-associated nephritis without crescent formation had different clinicopathological features from those with crescent formation, suggesting an atypical subtype of ANCA-associated nephritis. Despite the better renal function at the time of renal biopsy, these results suggest that this subtype requires especially careful attention, especially in the presence of extra-renal involvement.
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http://dx.doi.org/10.1007/s10157-020-01925-5DOI Listing
November 2020

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

Ann Rheum Dis 2020 11 9;79(11):1492-1499. Epub 2020 Jul 9.

Kazusa DNA Research Institute, Kisarazu, Chiba, Japan.

Objectives: To collect clinical information and mutation data on patients with Blau syndrome and to evaluate their prognosis.

Methods: Fifty patients with mutations were analysed. The activity of each 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 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.
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http://dx.doi.org/10.1136/annrheumdis-2020-217320DOI Listing
November 2020

High Relapse Rate in Patients with Polymyalgia Rheumatica despite the Combination of Immunosuppressants and Prednisolone: A Single Center Experience of 89 patients.

Tohoku J Exp Med 2020 06;251(2):125-133

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine.

Polymyalgia rheumatica (PMR) is an inflammatory disorder in the elderly and is characterized by pain in the shoulders and lower back. Previous studies from western countries have shown that relapse is frequent; however, there are only a few reports on the relapse rate in Japan. Here we examined the relapse rate, and sought to identify factors that predict recurrence in patients with PMR. Of 110 patients who fulfilled the Bird's criteria for PMR between May 2011 and June 2019, 21 patients were excluded, and the remaining 89 patients were followed up until July 2019. Relapse was defined when clinical symptoms were exacerbated and serum C-reactive protein level increased. The relapse-free survival curves were plotted using the Kaplan-Meier method, and log-rank test was used for statistical analysis. The mean age of the 89 patients (50 males and 39 females) was 71.8 years. The mean dose of initial prednisolone (PSL) was 11.8 mg/day. The 1-, 3-, and 5-year relapse-free survival rates were 81.6%, 58.0%, and 52.3% (N = 59, 21, and 7), respectively. In patients who experienced recurrence, the 1- and 3-year second relapse-free survival rates were 58.3% and 27.3% (N = 18 and 3), respectively. Immunosuppressants, such as methotrexate and tacrolimus, were added to PSL in 19 of 30 patients who experienced relapse at the discretion of the attending physicians; however, none of the immunosuppressants worked for preventing second relapses and had steroid-sparing effects. These results indicate that effective immunosuppressants are required to suppress relapse in the treatment of PMR.
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http://dx.doi.org/10.1620/tjem.251.125DOI Listing
June 2020

Rheumatoid Arthritis After Cord Blood Cell Transplantation.

J Clin Rheumatol 2021 Oct;27(7):e276-e277

From the Departments of Hematology and Rheumatology.

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http://dx.doi.org/10.1097/RHU.0000000000001430DOI Listing
October 2021
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