Loss of the DNA-binding domain of the farnesoid X receptor gene causes severe liver and kidney injuries.

Farnesoid X receptor (FXR) regulates bile acid synthesis, lipid metabolism, and glucose homeostasis in metabolic organs. FXR-knockout (FXR-KO) mice lacking the last exon of the FXR gene develop normally and display no prenatal and early postnatal lethality, whereas human patients with mutations in the DNA-binding domain of the FXR gene develop severe hepatic dysfunction. In this study, we generated novel FXR-KO mice lacking the DNA-binding domain of the FXR gene using CRISPR-Cas9 technology and evaluated their phenotypes. Similar to the aforementioned FXR-KO mice, our novel mice showed elevated serum levels of total bile acids and total cholesterol. However, they were obviously short-lived, showing severe liver and renal pathologies at an early age. These results indicate that FXR, including its unknown isoforms, has more significant functions in multiple organs than previously reported. Thus, the novel FXR-KO mice could lead to a new aspect that requires reworking of previous knowledge of FXR in the liver and renal function.

Enthesitis as an initial presentation of vascular Behçet's syndrome: a case-based review.

Enthesitis is a characteristic manifestation of spondyloarthropathy (SpA). Historically, Behçet's syndrome (BS) was classified within SpA. Although they are now classified separately, the association between BS and SpA remains controversial. The concept of MHC-I (major histocompatibility complex class I)-opathy has been proposed based on the overlap in immunopathological mechanisms among diseases associated with human leukocyte antigen (HLA) class I. Enthesitis is a frequent complication in patients with BS who also have acne and arthritis. However, information regarding enthesitis in patients with BS without arthritis (BS-WA) is limited. Herein, we report a case of vascular BS complicated by enthesitis. In this case, heel pain was the dominant symptom at presentation. Laboratory tests revealed chlamydia antibody positivity, leading to a tentative diagnosis of reactive arthritis. Despite treatment, C-reactive protein (CRP) levels remained elevated. Imaging revealed numerous aneurysmal lesions in the large vessels. Based on these findings and other symptoms, patient was diagnosed with vascular BS. He tested positive for HLA-B15 and HLA-B46, which are associated with peripheral SpA. Subsequent remission induction therapy for BS was effective and the patient was discharged without complications. Our case and a literature review suggest that there exists a subgroup of BS-WA with a complication of enthesitis, possibly belonging to the spectrum of MHC-I-opathies. It is important to consider BS as a differential diagnosis in patients presenting with enthesitis and to conduct a precise medical history review regarding the symptoms of BS.

Novel Diagnostic Autoantibodies Against Endothelial Protein C Receptor in Patients With Ulcerative Colitis.

There have been many reports on serologic autoantibodies in inflammatory bowel diseases (IBD),1 consisting of ulcerative colitis (UC) and Crohn's disease (CD), and recently Kuwada et al2 reported a new autoantibody against integrin αvß6 with high sensitivity and specificity for UC. Concurrently, we had discovered autoantibodies against endothelial protein C receptor (EPCR) in Takayasu arteritis (TAK), which is sometimes complicated by UC.3 Interestingly, this autoantibody was found in most patients with TAK associated with UC, and we found that the positivity rate in patients with UC without TAK was also high, suggesting that anti-EPCR antibody is a candidate autoantibody useful for the diagnosis of UC.4 To clarify the diagnostic usefulness of anti-EPCR antibodies in patients with IBD and their relationship to several disease subphenotypes and their disease activities, we analyzed the serum samples from patients with IBD and non-IBD control subjects in Japan and the United States.

Myeloid immune checkpoint ILT3/LILRB4/gp49B can co-tether fibronectin with integrin on macrophages.

LILRB4 (B4, also known as ILT3/CD85k) is an immune checkpoint of myeloid lineage cells, albeit its mode of function remains obscure. Our recent identification of a common ligand for both human B4 and its murine ortholog gp49B as the fibronectin (FN) N-terminal 30 kDa domain poses the question of how B4/gp49B regulate cellular activity upon recognition of FN in the plasma and/or the extracellular matrix. Since FN in the extracellular matrix is tethered by FN-binding integrins, we hypothesized that B4/gp49B would tether FN in cooperation with integrins on the cell surface, thus they should be in close vicinity to integrins spatially. This scenario suggests a mode of function of B4/gp49B by which the FN-induced signal is regulated. The FN pull-down complex was found to contain gp49B and integrin ß 1 in bone marrow-derived macrophages. The confocal fluorescent signals of the three molecules on the intrinsically FN-tethering macrophages were correlated to each other. When FN-poor macrophages adhered to culture plates, the gp49-integrin ß 1 signal correlation increased at the focal adhesion, supporting the notion that gp49B and integrin ß 1 become spatially closer to each other there. Adherence of RAW264.7 and THP-1 cells to immobilized FN induced phosphorylation of spleen tyrosine kinase, whose level was augmented under B4/gp49B deficiency. Thus, we concluded that B4/gp49B can co-tether FN in cooperation with integrin in the cis configuration on the same cell, forming a B4/gp49B-FN-integrin triplet as a regulatory unit of a focal adhesion-dependent pro-inflammatory signal in macrophages.

Intensive induction therapy combining tofacitinib, rituximab and plasma exchange in severe anti-melanoma differentiation-associatedprotein-5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-melanoma differentiation-associated protein-5 (MDA5) autoantibodies (Abs) are associated with rapidly progressive interstitial lung disease (RP-ILD) in dermatomyositis (DM). Because the addition of plasma exchange (PE) and rituximab (RTX) to triple therapy is inadequate in severe cases, we treat such cases with intensive induction therapy (IIT) combining all these options with tofacitinib (TOF). In this study, we investigated the poor prognostic factors and the efficacy and safety of IIT. METHODS: Thirty-three patients diagnosed with anti-MDA5 Ab-positive DM in our institution between 2014 and 2021 were included. The clinical characteristics of poor prognosis were retrospectively analysed using principal component analysis (PCA), and the outcomes of IIT were analysed in terms of survival, assessed using the Kaplan-Meier test, and adverse events. RESULTS: Although triple therapy with RTX, PE, or intravenous immunoglobulin was administered before the introduction of IIT, eight of 12 RP-ILD cases with a ferritin level >400 ng/mL (mean, 2,342) died within a median of 2.5 months. PCA revealed distinct clusters for prognosis, and age and serum ferritin were leading predictors of the prognosis. IIT, consisting of combinations of triple therapy with higher doses of methylprednisolone, PE, RTX, and TOF, was applied to eight patients (mean ferritin, 3,558). Although two patients died even with these regimens, a significant improvement in survival was documented. Several IIT-related adverse events were observed, including viral and fungal infections and cytopenia. CONCLUSIONS: IIT significantly improved the survival of patients with severe anti-MDA5 Ab-positive RP-ILD. Although infections are noted, their benefits outweigh the risks in younger patients with high serum ferritin levels.

Successful management of interstitial lung disease in dermatomyositis complicated by malignancy: a case-based review.

Dermatomyositis (DM) is associated with interstitial lung disease (ILD) and malignancy. However, the coexistence of ILD and malignancy (DM-ILD-malignancy) is rare, and limited information exists regarding its management. Herein, we report the case of a 70-year-old man who developed DM with rapidly progressive ILD and advanced gastric cancer and provide a literature review of managing DM-ILD-malignancy. The patient presented with typical DM skin rashes and shortness of breath, which worsened within 1 month, without muscular symptoms. Additionally, the patient tested negative for myositis-specific autoantibodies (MSAs). Computed tomography revealed ILD and advanced gastric cancer, which was confirmed on endoscopic examination to be a poorly differentiated adenocarcinoma. Although the patient's ILD progressed rapidly, surgical treatment of the cancer was prioritized. Prednisolone (PSL) 0.5 mg/kg was initiated 3 days before surgery and increased to 1 mg/kg at 7 days postoperative. Remarkable improvement in the skin rash and ILD was observed, and the PSL dose was tapered without immunosuppressants. A literature review revealed that anti-melanoma differentiation-associated gene 5 and anti-aminoacyl transfer RNA synthetase antibodies are the predominant MSAs in DM-ILD-malignancy, and the optimal treatment should be determined based on several factors, including ILD patterns, and malignancy type and stage. In particular, lung cancer may be a risk factor for the acute exacerbation of ILD, and preceding immunosuppression would be useful. Furthermore, prioritizing surgery for gastric cancer is effective because of its paraneoplastic nature.

Upfront rituximab therapy for thrombotic thrombocytopenic purpura in systemic lupus erythematosus: a case-based review.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies and deposition of immune complexes on tissues. Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening hematological disorder that rarely develops in SLE, mainly caused by inhibitory or clearing autoantibody against ADAMTS13. Although B cells play critical roles in the pathogenesis of two diseases, the role of B-cell depletion therapy using rituximab (RTX), a chimeric monoclonal antibody targeting CD20, in the management of TTP associated with SLE remains unclear. We present a 27-year-old woman who manifested TTP and nephritis simultaneously at diagnosis of SLE. This patient successfully responded to high-dose glucocorticoids combined with plasma exchange, and early administration of RTX-induced sustained remission of TTP without relapse over 16 months. This literature review in light of our case demonstrates relationship between early intervention with RTX and better treatment response despite the degree of ADAMTS13 activity. Moreover, we discuss the clinical features in TTP associated with SLE, risk factors for the development of TTP in SLE, and possible outcomes based on RTX dose. It is important to consider upfront RTX as a promising treatment strategy for SLE-associated secondary TTP to improve short-term response and long-term prognosis.

"Coexistence of IgA nephropathy and renal artery stenosis in Takayasu arteritis: case report and literature review".

Although Takayasu arteritis (TAK) is a form of large vessel vasculitis, complications of glomerulonephritis have occasionally been observed, with mesangial proliferative glomerulonephritis as the most common. The aim of this work was to present a case-based review regarding the association of glomerulonephritis and IgA nephropathy (IgAN) with TAK. A literature search was carried out using the PubMed and Scopus databases for articles published in English, and the Ichu-shi Web for Japanese. A 34-year-old Japanese man was evaluated for proteinuria, and IgAN was diagnosed by renal biopsy. Simultaneously, aortic wall thickening and right renal artery stenosis confirmed a coexisting TAK. Prednisolone and methotrexate improved both diseases, and percutaneous transluminal renal angioplasty resulted in right renal artery reopening. Our case and literature review revealed that membranous proliferative glomerulonephritis and IgAN are common in eastern Asia, while focal segmental glomerulosclerosis and mesangial proliferative glomerulonephritis are common in other regions. The incidence of IgAN is higher in TAK cases and is mostly reported in Asia. Abdominal aortic involvement and renal artery stenosis are common in cases with preceding TAK. IgAN could be related to the cytokine network involving interleukin-6, suggesting the usefulness of tocilizumab in patients with TAK accompanied by IgAN. The type of glomerulonephritis complicated with TAK differs among regions, and patients with TAK are more likely to experience IgAN than the healthy population.

Severe Bone Marrow Aplasia Following Macrophage Activation Syndrome in Systemic Lupus Erythematosus.

Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases, characterized by activated macrophages with hemophagocytosis and multiple organ damage. We report a case of MAS associated with systemic lupus erythematosus that initially presented with severe liver dysfunction. Although it was improved with steroids and plasmapheresis, severe pancytopenia was subsequently experienced, and the bone marrow showed severe aplasia similar to aplastic anemia. Nevertheless, the administration of immunosuppressants resulted in the recovery of blood counts within two weeks. When severe MAS results in cytokine overproduction, bone marrow aplasia may occur, for which immunosuppressive therapy may be highly effective.

A target cultivar-specific identification system based on the chromatographic printed array strip method for eight prominent Japanese citrus cultivars.

Citrus is a major cultivated crop in Japan, and new cultivars are of great interest in the Japanese and global market. Recently, the infringement of breeders' rights to citrus cultivars bred in Japan has become a problem related to the agricultural product export strategy promoted by the Japanese government. Cultivar identification systems using DNA markers are an effective tool for protecting breeders' rights. Here, a novel target cultivar-specific identification system using the chromatographic printed array strip method was developed for eight prominent Japanese citrus cultivars. A polymorphic InDel fragment specific to each cultivar was explored through the screening of published citrus InDel markers and next-generation sequencing of retrotransposon libraries. The cultivar-specific DNA marker set for each cultivar comprised 1-3 polymorphic InDel fragments in combination with a PCR-positive DNA marker for the ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit gene. The DNA markers were detected within 3 hours from DNA extraction to the detection by the C-PAS4 membrane stick following multiplex PCR. The developed system is superior as a convenient, rapid, and cost-effective DNA diagnostic method during inspection. The proposed target cultivar-specific identification system is expected to serve as an efficient tool for the injunction of suspicious registered cultivars, contributing to the protection of breeders' rights.

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

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.

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

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.

Sjögren's Syndrome Presenting with Temporary Hemiplegia Mimicking Transient Ischemic Attack.

Sjögren's syndrome manifests with a wide variety of neurologic symptoms. This case report presents a 53-year-old woman with Sjögren's syndrome associated with temporal hemiplegia, which was suspected to be a transient ischemic attack. After induction of immunosuppressive therapies [high-dose prednisolone (1 mg/kg/day) and intravenous cyclophosphamide (total 5 g)], the hemiplegia did not reappear and the blood flow abnormalities remarkably improved as depicted on electroencephalography and single photon emission computed tomography. This case suggests that temporal hemiplegia presenting with transient ischemia-like attack symptoms may be a neurologic manifestation of Sjögren's syndrome and responsive to immunosuppressive therapy.

Hypertrophic Pachymeningitis Development in Eosinophilic Granulomatosis with Polyangiitis at Relapse of Disease: A Case-Based Review.

Hypertrophic pachymeningitis (HP) presents with thickening of the dura mater in the cerebrum and spine, and its symptoms vary depending on the affected location. The association of HP with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis has been recognized, and most cases are complicated by granulomatosis with polyangiitis. We report the case of a 47-year-old man who presented with HP upon relapse of eosinophilic granulomatosis with polyangiitis (EGPA), with literature review. He presented with disturbance of consciousness, and magnetic resonance imaging (MRI) revealed thickening of the dura mater around the left parietal lobe. Although myeloperoxidase (MPO)-ANCA was positive on EGPA diagnosis, the elevation of MPO-ANCA was not documented at the onset of HP. Brain perfusion scintigraphy showed an increase in blood flow in the left parietal lobe and temporal lobe, and electroencephalogram (EEG) revealed slow waves in the left parietal lobe. He was treated with a high dose of corticosteroid and rituximab, and the slow waves on EEG and brain perfusion were normalized. Although the most frequent symptom of HP is headache, disturbance of consciousness can be the manifestation of HP, and inflammation of HP could affect the cerebral parenchyma, which can be documented as abnormal EEG and perfusion scintigraphy. Literature review revealed that most of the HP in EGPA developed when EGPA relapsed, and was observed in patients with MPO-ANCA positivity. HP develops without evidence of other clinical features of EGPA; therefore, adequate imaging, including contrast-enhanced MRI, is necessary. Rituximab may be effective for treating HP complicated with EGPA.

Diphtheria in Metro Manila, the Philippines 2006-2017: A Clinical, Molecular, and Spatial Characterization.

BACKGROUND: Diphtheria is a vaccine-preventable disease that persists as a global health problem. An understanding of the pattern of disease is lacking in low- and middle-income countries such as the Philippines. METHODS: We conducted a retrospective review of the clinical, microbiological, and epidemiological features of patients admitted with a clinical diagnosis of diphtheria to an infectious disease referral hospital in Metro Manila, the Philippines, between 2006 and 2017. Cases were mapped and the distribution was compared with population density. Corynebacterium diphtheriae isolates from between 2015 and 2017 were examined by multilocus sequence typing (MLST). RESULTS: We studied 267 patients (range:12-54 cases/year) admitted between 2006 and 2017. The case fatality rate (CFR) was 43.8% (95% confidence interval, 37.8-50.0%). A higher number of cases and CFR was observed among children <10 years. Mortality was associated with a delayed admission to hospital and a lack of diphtheria antitoxin. Between 2015 and 2017 there were 42 laboratory-confirmed cases. We identified 6 multilocus sequence types (STs). ST-302 was the most common (17/34, 48.6%), followed by ST67 (7/34, 20%) and ST458 (5/34, 14%). Case mapping showed a wide distribution of diphtheria patients in Metro Manila. Higher case numbers were found in densely populated areas but with no apparent clustering of ST types. CONCLUSIONS: Our analysis indicates that diphtheria remains endemic in Metro Manila and that the infection is frequently fatal in young children. Improved vaccine coverage and a sustainable supply of diphtheria antitoxin should be prioritized.

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

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.

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

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 (1-CompI and 2-CompI) having the n-hexyl side chains. 1-CompI and 2-CompI 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 tert-butyl methyl ether significantly increase the reactivity of 1-CompI and 2-CompI, but dichloromethane, the most frequently used solvent in previous studies, is the worst for increasing the reactivity among the solvents. 1H 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 n-alkane solvents are larger than those in dichloromethane. The observed solvent effect can be rationalized with reorganization energy of the solvent in the reaction.

Rate-Limiting Step of Epoxidation Reaction of the Oxoiron(IV) Porphyrin π-Cation Radical Complex: Electron Transfer Coupled Bond Formation Mechanism.

Epoxidation reactions catalyzed by high-valent metal-oxo species are key reactions in various biological and chemical processes. Because the redox potentials of alkenes are higher than those of most high-valent metal-oxo species, the electron transfer (ET) from the alkene to the high-valent metal-oxo species in the epoxidation reaction is endergonic and must be coupled with another exergonic process. To reveal the mechanism of the ET, we performed a Marcus plot analysis for the epoxidation reaction of the oxoiron(IV) porphyrin π-cation radical complex (compound I) with alkene. The Marcus plots can be simulated with a linear line with the gradient of 0.50 when the redox potential of compound I varies and 0.07 when the redox potential of alkene varies. These results indicate that the ET process is involved in the rate-limiting step and coupled with the following O-C bond formation process: ET coupled bond formation mechanism. The DFT calculations support this conclusion and disclose the details of the mechanism. As the alkene comes close to the oxo ligand, the energy of the highest occupied molecular orbital (HOMO) of the alkene increases and the energy for the ET becomes small enough to allow the ET. Finally, the ET occurs from the HOMO of the alkene to the porphyrin π-radical orbital. The shift of one electron from the HOMO of the alkene by the ET simultaneously results in the O-C half bond formation between the oxo ligand and the alkene. The ET process itself is still endergonic and reversible, but the bond formation coupled with the ET changes the overall process to exergonic and irreversible. We also discuss the similarity with the aromatic hydroxylation reaction and the relevance to the epoxidation reactions of other metal-oxo complexes and peracid.

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

There have been two known categories of porphyrins: a meso-substituted porphyrin like meso-tetramesitylporphyrin (TMP) and a pyrrole-ß-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 (TMP-I) with that of TMTMP (TMTMP-I) for epoxidation, hydrogen abstraction, hydroxylation, sulfoxidation, and demethylation reactions. Kinetic analysis of these reactions indicated that TMP-I is much more reactive than TMTMP-I when the substrate is not sterically bulky. However, as the substrate is sterically bulkier, the difference of the reactivity between TMP-I and TMTMP-I becomes smaller, and the reactivity of TMP-I is comparable to that of TMTMP-I for a sterically hindered substrate. Since the redox potential of TMP-I is almost the same as that of TMTMP-I, we conclude that TMP-I is intrinsically more reactive than TMTMP-I for these atom transfer reactions, but the steric effect of TMP-I is stronger than that of TMTMP-I. This is contrary to the previous result for the single electron transfer reaction: TMTMP-I is faster than TMP-I. DFT calculations indicate that the orbital energies of the Fe═O moiety for TMTMP-I are higher than those for TMP-I. The difference in steric effect between TMP-I and TMTMP-I is explained by the distance from the mesityl group to the oxo ligand of Compound I. Significance of the pyrrole-ß-substituted structure of the hemes in native enzymes is also discussed on the basis of this study.

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.

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 (n = 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 (n = 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.