A Ubiquitously Expressed UDP-Glucosyltransferase, UGT74J1, Controls Basal Salicylic Acid Levels in Rice.

Salicylic acid (SA) is a phytohormone that regulates a variety of physiological and developmental processes, including disease resistance. SA is a key signaling component in the immune response of many plant species. However, the mechanism underlying SA-mediated immunity is obscure in rice (Oryza sativa). Prior analysis revealed a correlation between basal SA level and blast resistance in a range of rice varieties. This suggested that resistance might be improved by increasing basal SA level. Here, we identified a novel UDP-glucosyltransferase gene, UGT74J1, which is expressed ubiquitously throughout plant development. Mutants of UGT74J1 generated by genome editing accumulated high levels of SA under non-stressed conditions, indicating that UGT74J1 is a key enzyme for SA homeostasis in rice. Microarray analysis revealed that the ugt74j1 mutants constitutively overexpressed a set of pathogenesis-related (PR) genes. An inoculation assay demonstrated that these mutants had increased resistance against rice blast, but they also exhibited stunted growth phenotypes. To our knowledge, this is the first report of a rice mutant displaying SA overaccumulation.

Diagnostic Role and Feasibility of 18F-FDG PET for Assessing Takayasu Arteritis: Diagnostic Efficacy of Quantifying 18F-FDG Uptake.

Takayasu arteritis (TAK) is classified as large-vessel vasculitis caused by inflammation. It is often difficult to identify on clinical examination, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) plays an indispensable role in diagnosing TAK by detecting the location and grade of the inflammatory lesions. The clinical utility of 18F-FDG PET has been established by clinical evidence, and 18F-FDG PET was added to the Japanese national health insurance listing in April 2018. In TAK, 18F-FDG uptake shows typical findings and is easily distinguished, except from physiological uptake. Particularly, the clinical significance of 18F-FDG PET is that can present not only with stenosis but also without stenosis in the arteries, which means that therapeutic intervention is possible before irreversible stenosis develops in the arteries. Additionally, 18F-FDG PET has superior diagnostic accuracy because it allows quantitative analysis using the maximum standardized uptake value. The analysis is used for the assessment of disease activity of TAK and can be utilized for therapeutic intervention in case of repeating remission during the follow-up term.

Takayasu arteritis: clinical importance of extra-vessel uptake on FDG PET/CT.

BACKGROUND: [F-18]fluorodeoxyglucose positron emission tomography/computed tomography is routinely used for assessing Takayasu arteritis patients. However, extra-vessel [F-18]fluorodeoxyglucose uptake has not been evaluated in detail in these patients. We aimed to describe the extent and distribution of extra-vascular [F-18]fluorodeoxyglucose uptake on positron emission tomography/computed tomography in Takayasu arteritis patients. Seventy-three [F-18]fluorodeoxyglucose positron emission tomography/computed tomography scans from 64 consecutive Takayasu arteritis patients (59 women, mean age, 35.4 years; range, 13 to 71 years) and 40 scans from age-matched controls (36 women, mean age, 37.8 years; range, 13 to 70 years) were examined. We graded [F-18]fluorodeoxyglucose uptake in large vessels using a 4-point scale and evaluated extra-vessel findings. Factors correlated with disease activity were examined. We evaluated the relationship between disease activity according to the National Institutes of Health score with extra-vessel findings, as well as other inflammatory markers (e.g., white blood cell count and C-reactive protein level). RESULTS: Extra-vessel involvement was present in 50 of 73 (68.4%) scans, specifically at the following sites: lymph nodes, 1.4%; thyroid glands, 17.8%; thymus, 11.0%; spleen, 1.4%; vertebrae, 45.2%; and pelvic bones, 9.6%. Takayasu arteritis patients had higher [F-18]fluorodeoxyglucose uptake in the spine (P = 0.03) and thyroid glands (P = 0.003) than did controls; uptake in other regions was comparable between groups. Compared with inactive patients, those with active Takayasu arteritis had a higher number of [F-18]fluorodeoxyglucose uptake sites in the vasculature (P = 0.001). Finally, patients with a National Institutes of Health score of ≥ 1 had significantly higher extra-vascular involvement (P = 0.008). CONCLUSIONS: Extra-vessel [F-18]fluorodeoxyglucose uptake may be present in the context of Takayasu arteritis-related inflammatory processes. Information on extra-vascular [F-18]fluorodeoxyglucose uptake may be useful for detecting and evaluating inflammatory processes when interpreting positron emission tomography/computed tomography scans obtained from Takayasu arteritis patients.

Functional identification of a rice trehalase gene involved in salt stress tolerance.

Trehalose is a disaccharide with a pivotal role in plant growth and development. In contrast to the recent advances in understanding trehalose biosynthesis in plants, their catabolism of trehalose is poorly understood. Here, we isolated and characterized a trehalase gene, OsTRE1, in rice (Oryza sativa L.). An expression analysis in young seedlings revealed that OsTRE1 is induced by stresses such as salt, drought, and chilling. ABA treatment also transiently upregulated OsTRE1 expression. The accumulation of OsTRE1 mRNA in response to 150 mM NaCl was consistent with an increased trehalase activity in the roots. Transgenic rice plants overexpressing OsTRE1 showed remarkable increases in trehalase activity and dramatic decreases in trehalose abundance compared with the wild type, with little change in the levels of other soluble sugars, such as glucose, fructose, and sucrose. Callus cells generated from the transgenic lines overexpressing OsTRE1 were able to grow using trehalose as their sole carbon source. These data indicated that OsTRE1 is a functional trehalase gene in rice. The OsTRE1 overexpressors did not have notable morphological alterations or growth defects but exhibited enhanced salt tolerance, suggesting the involvement of OsTRE1 in salt stress tolerance in rice.

The rice ethylene response factor OsERF83 positively regulates disease resistance to Magnaporthe oryzae.

Rice blast caused by Magnaporthe oryzae is one of the most destructive diseases of rice (Oryza sativa) worldwide. Here, we report the identification and functional characterization of a novel ethylene response factor (ERF) gene, OsERF83, which was expressed in rice leaves in response to rice blast fungus infection. OsERF83 expression was also induced by treatments with methyl jasmonate, ethephon, and salicylic acid, indicating that multiple phytohormones could be involved in the regulation of OsERF83 expression under biotic stress. Subcellular localization and transactivation analyses demonstrated that OsERF83 is a nucleus-localized transcriptional activator. A gel-shift assay using recombinant OsERF83 protein indicated that, like other ERFs, it binds to the GCC box. Transgenic rice plants overexpressing OsERF83 exhibited significantly suppressed lesion formation after rice blast infection, indicating that OsERF83 positively regulates disease resistance in rice. Genes encoding several classes of pathogenesis-related (PR) proteins, including PR1, PR2, PR3, PR5, and PR10, were upregulated in the OsERF83ox plants. Taken together, our findings show that OsERF83 is a novel ERF transcription factor that confers blast resistance by regulating the expression of defense-related genes in rice.

Myocardial perfusion reserve quantified by cardiac magnetic resonance imaging is associated with late gadolinium enhancement in hypertrophic cardiomyopathy.

Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) imaging has demonstrated the capability of stratifying hypertrophic cardiomyopathy (HCM). Stress perfusion test of CMR can quantify myocardial perfusion reserve (MPR), but its clinical role is not determined. The purpose of this study was to investigate the relationship between MPR and LGE in patients with HCM. A total of 61 consecutive cases underwent complete evaluation with electrocardiography and CMR [cine imaging, coronary MR angiography (MRA), and stress perfusion testing with LGE]. HCM cases were diagnosed by the Japanese conventional guideline prior to this CMR study. Mild LVH was defined as more than 13 mm in maximum LV wall thickness at end diastole on the cine imaging of the CMR. MPR was calculated as the ratio of stress/rest myocardial blood flow using an intensity curve on the stress perfusion test. Cases with ischemic heart disease were excluded from the study based on clinical history and coronary MRA. There were 37 HCM and 24 mild LVH cases (average age: 60.5 ± 10.9 vs. 64.8 ± 10.8; male: 62.2 vs. 75.0%, respectively, non-significant). MPR in HCM was lower than in LVH (1.5 ± 0.5 vs. 2.2 ± 0.9, p < 0.001) and normal subjects (2.4 ± 0.9, p < 0.001). MPR in HCM with LGE (N = 34) was lower than in HCM without LGE (N = 3) (1.4 ± 0.5 vs. 2.1 ± 0.2, p = 0.014). Multiple regression analysis verified that LGE was the strongest predictor of MPR among multiple clinical parameters, including LVH, LV dysfunction (ejection fraction < 50%), and the presence of negative T wave (p < 0.001). MPR was impaired in HCM with LGE compared with HCM without LGE. The clinical role of MPR on CMR needs to be clarified by further research.

Early Detection and Intervention of Coronary Artery Involvement in Immunoglobulin G4-related Disease.

A 59-year-old man with swollen submandibular glands developed an aortic aneurysm requiring aortic prosthesis implantation. Echocardiography performed to evaluate the cardiac function before the surgery incidentally revealed masses around the coronary arteries. The serum IgG4 levels were increased. A post-operational pathological examination of the abdominal aneurysms revealed infiltration of plasma cells, with the ratio of IgG4/IgG-positive cells being >80%. The patient was diagnosed with IgG4-related disease (RD) with coronary artery involvement. He was treated successfully with corticosteroid before any associated cardiovascular events occurred. Given the poor prognosis of IgG4-RD-associated coronary artery involvement, this case emphasizes the importance of the early assessment with echocardiography, even if patients have no cardiovascular symptoms.

Profiles of serum cytokine levels in Takayasu arteritis patients: Potential utility as biomarkers for monitoring disease activity.

BACKGROUND: Takayasu arteritis (TA) is an autoimmune arteritis of unknown etiology. Currently, the erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) levels are widely used to monitor disease activity of TA. However, sometimes it is difficult to reflect inflammatory symptoms in either CRP or ESR values, especially in TA patients with immunosuppressive therapies. Therefore, higher-accuracy biomarkers for evaluating disease activity need to be explored. METHODS AND RESULTS: We examined 21 Japanese patients diagnosed with TA; 17 TA patients were treated with prednisone with or without additional immunosuppressive therapies and the remaining 4 patients were treated with infliximab, a human monoclonal anti-tumor necrosis factor (TNF)-α antibody. In active phase, the serum levels of both TNF-α and interleukin (IL)-6 were significantly higher than in healthy subjects, as is the case with both the levels of CRP and ESR. In contrast, the levels of both IL-12 and IL-23 remained in the normal range. Both TNF-α and IL-6 levels were markedly decreased in response to therapies, on equality with both CRP and ESR levels. Regarding the TA patients treated with infliximab, both CRP and IL-6 levels tended to be decreased after infliximab therapy. Conversely, TNF-α level after infliximab therapy was higher than before therapy. CONCLUSION: Both TNF-α and IL-6 levels, but not IL-12 or IL-23 levels, in the serum could be potent biomarkers that can reflect the activity of TA.

The rice ent-KAURENE SYNTHASE LIKE 2 encodes a functional ent-beyerene synthase.

The rice genome contains a family of kaurene synthase-like (OsKSL) genes that are responsible for the biosynthesis of various diterpenoids, including gibberellins and phytoalexins. While many OsKSL genes have been functionally characterized, the functionality of OsKSL2 is still unclear and it has been proposed to be a pseudogene. Here, we found that OsKSL2 is drastically induced in roots by methyl jasmonate treatment and we successfully isolated a full-length cDNA for OsKSL2. Sequence analysis of the OsKSL2 cDNA revealed that the open reading frame of OsKSL2 is mispredicted in the two major rice genome databases, IRGSP-RAP and MSU-RGAP. In vitro conversion assay indicated that recombinant OsKSL2 catalyzes the cyclization of ent-CDP into ent-beyerene as a major and ent-kaurene as a minor product. ent-Beyerene is an antimicrobial compound and OsKSL2 is induced by methyl jasmonate; these data suggest that OsKSL2 is a functional ent-beyerene synthase that is involved in defense mechanisms in rice roots.

Isolated cardiac sarcoidosis: clinical characteristics, diagnosis and treatment.

Sarcoidosis is a systemic disease characterized by the development of noncaseating epithelioid granulomas in multiple organs. Despite extensive investigations over a long period of time, the etiology of this disease remains unknown. Cardiac involvement of this disease is the most ominous complication leading to fatal outcome. Recently, attention has been focused on isolated cardiac sarcoidosis, which exists without clinically apparent sarcoidosis elsewhere. One of the critical issues of isolated cardiac sarcoidosis is difficulty in diagnosis, since existence of the cardiac lesion should be detected from cardiac manifestations alone. Because specificity of biomarkers or sensitivity of histological examination of biopsied sample is very low, diagnosis of isolated cardiac sarcoidosis mainly depends on imaging modalities. In this review article we summarized current knowledge on the pathogenesis of sarcoidosis, clinical features of cardiac sarcoidosis especially that isolated to the heart by showing some typical cases. Utilities and problems of diagnostic imaging tests for this condition including echocardiography, cardiac magnetic resonance imaging, and fluorodeoxyglucose-positron emission tomography are discussed. Advances in pharmacological and nonpharmacological treatment for cardiac sarcoidosis have improved the prognosis of cardiac sarcoidosis to a great deal; however, there are many issues that remain to be solved in the management of isolated cardiac sarcoidosis.

Vessel Wall Inflammation of Takayasu Arteritis Detected by Contrast-Enhanced Magnetic Resonance Imaging: Association with Disease Distribution and Activity.

AIMS: The assessment of the distribution and activity of vessel wall inflammation is clinically important in patients with Takayasu arteritis. Magnetic resonance imaging (MRI) is a useful tool, but the clinical utility of late gadolinium enhancement (LGE) in Takayasu arteritis has yet to be determined. The aim of the present study was to evaluate the utility of LGE in assessing vessel wall inflammation and disease activity in Takayasu arteritis. METHODS AND RESULTS: We enrolled 49 patients with Takayasu arteritis who had undergone 1.5 T MRI. Patients were divided into Active (n = 19) and Inactive disease (n = 30) groups. The distribution of vessel wall inflammation using angiography and LGE was assessed by qualitative analysis. In 79% and 63% of patients in Active and Inactive groups, respectively, greater distribution of vessel wall inflammation was observed with LGE than with conventional angiography. MRI values of pre- and post-contrast signal-to-noise ratios (SNR), SNR increment (post-SNR minus pre-SNR), pre- and post-contrast contrast-to-noise ratios (CNR), and CNR increment (post-CNR minus pre-CNR) were evaluated at arterial wall sites with the highest signal intensity using quantitative analysis of post-contrast LGE images. No statistically significant differences in MRI parameters were observed between Active and Inactive groups. Contrast-enhanced MRI was unable to accurately detect active disease. CONCLUSION: Contrast-enhanced MRI has utility in detecting the distribution of vessel wall inflammation but has less utility in assessing disease activity in Takayasu arteritis.

Clinical characteristics of definite or suspected isolated cardiac sarcoidosis: application of cardiac magnetic resonance imaging and 18F-Fluoro-2-deoxyglucose positron-emission tomography/computerized tomography.

BACKGROUND: Isolated cardiac sarcoidosis (iCS) is difficult to diagnose in patients without histologic evidence of sarcoidosis. We aimed to clarify the clinical characteristics of iCS, including imaging features on cardiac magnetic resonance imaging (MRI) and (18)F-fluoro-2-deoxyglucose positron-emission tomography/computerized tomography (FDG-PET/CT) scans. We also reviewed the therapeutic effect of corticosteroids and determined the long-term prognosis. METHODS AND RESULTS: We retrospectively reviewed 83 consecutive patients with suspicious CS from 1997 to 2013. Systemic sarcoidosis with CS (sCS, n = 30) and iCS (n = 11) were diagnosed according to clinical criteria. In iCS cases, sarcoidosis was not detected in any other organs. The clinical features did not significantly differ between sCS and iCS cases, except for ejection fraction, which was lower in iCS (P = .025). Nine sCS and 4 iCS cases showed late gadolinium enhancement, and the lesions tended to be on the epicardial side (76.9% P = .011) and septal wall (52.9% P < .001). The coefficient of variance for the myocardial standardized uptake value of FDG-PET/CT was higher in sCS (0.32 ± 0.13; n = 19) and iCS (0.32 ± 0.09; n = 7) than in control cases (n = 31; P < .001). B-Type natriuretic peptide level was improved after prednisolone treatment in both groups. Kaplan-Meier curve indicated that prognosis was not different between sCS and iCS cases. CONCLUSIONS: The clinical cardiac characteristics of iCS cases were similar to those of sCS. Cardiac MRI and FDG-PET, noninvasive imaging modalities, could be useful modalities to detect myocardial involvement in the cases with definite or suspected iCS.

Diagnosis and assessment of Takayasu arteritis by multiple biomarkers.

BACKGROUND: Patients with Takayasu arteritis (TA) often show recurrence under steroid treatment without an elevation of C-reactive protein (CRP). There is a report that matrix metalloproteinase (MMP)-2, MMP-3, MMP-9 and pentraxin3 (PTX3) could be sensitive biomarkers, but the characteristics of these biomarkers have not been established. METHODS AND RESULTS: We enrolled 45 consecutive patients; 28 were grouped in an active phase as evidenced by clinical recurrence within 2 years of blood sampling. Circulating levels of high-sensitivity (hs)CRP, MMPs, and PTX3 were determined. Patients in an active phase showed higher levels of hsCRP, MMP-9, and PTX3. Area under the receiving operating characteristics curves of hsCRP and PTX3 were significantly higher than that of MMP-9. Among the 28 patients with active TA, 71% was positive for hsCRP and 82% for PTX3. Patients without recurrence showed significantly higher plasma levels of MMP-9. There was a positive correlation between the plasma MMP-3 level and the prednisolone dose. However, PTX3 and MMP-9 levels did not have such a correlation. CONCLUSIONS: PTX3 and MMP-9, which are not affected by prednisolone, could be sensitive biomarkers for assessing TA activity. Evaluation of MMP-9 may suggest prior existence of TA.

Role of FDG PET-CT in Takayasu arteritis: sensitive detection of recurrences.

OBJECTIVES: The aim of this study was to investigate whether the maximum standardized uptake value (max SUV) of (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) provides a quantitative indication of disease activity in Takayasu arteritis (TA) cases. BACKGROUND: The clinical value of FDG-PET for assessing TA has been investigated. Clinical evaluation of disease activity is often difficult, because most patients develop recurrent inflammation while receiving corticosteroid treatment. METHODS: Thirty-nine TA patients underwent FDG-PET/CT at Tokyo Medical and Dental University from 2006 to 2010 (35 women and 4 men; median age, 30 years). Disease activity was defined according to National Institutes of Health criteria. Biomarkers including C-reactive protein and erythrocyte sedimentation rate were measured. Forty subjects without vasculitis served as control subjects. RESULTS: The max SUV was significantly higher in active than in inactive cases and control subjects (active [n = 27], median value, 2.7 vs. inactive [n = 12], 1.9; control [n = 40], 1.8; p < 0.001 each). Given a max SUV cutoff of 2.1, sensitivity for active-phase TA was 92.6%, specificity 91.7%, positive predictive value 96.2%, and negative predictive value 84.6%. In receiver-operating characteristic curves comparison, max SUV was superior to C-reactive protein (p < 0.05) and erythrocyte sedimentation rate (p < 0.05). Max SUV was significantly higher in relapsing on treatment cases (n = 17) than in stable on treatment cases (n = 12) (median value, 2.6 vs. 1.9; p < 0.001). CONCLUSIONS: FDG-PET/CT is useful for detection of active inflammation not only in patients with active TA before treatment but also in relapsing patients receiving immunosuppressive agents. The max SUV is useful for assessing subtle activity of TA with high sensitivity.

Improved prognosis of Takayasu arteritis over the past decade--comprehensive analysis of 106 patients.

BACKGROUND: We aimed to describe the recent clinical characteristics of Takayasu arteritis (TA). METHODS AND RESULTS: We enrolled 106 consecutive TA patients and compared the clinical characteristics of patients with TA onset before 1999 and after 2000, patients with onset at age less than 39 years and more than 40 years, patients with monophasic and relapsing-remitting clinical course, and patients with and without human lymphocyte antigen (HLA)-B52 allele. Among the patients with TA onset after 2000, the time from onset to diagnosis had decreased; the frequency of occlusion in aortic arch branches and the complication of moderate or severe aortic regurgitation (AR) had decreased, and the maximum dose of prednisolone and the use of immunosuppressive agents had increased. In patients with onset at age more than 40 years, the complications of coronary artery lesions and hypertension had increased, and the incidence of moderate or severe AR had decreased. In the relapsing-remitting group, the maximum dose of prednisolone and the use of immunosuppressive agents had increased, and the mean dose reduction rate of prednisolone was significantly high. There was no significant difference between patients with and without HLA-B52 allele. CONCLUSIONS: The prognosis of TA patients has improved over the past decade, which may be related to early diagnosis because of the development of noninvasive diagnostic imaging tools and improved medical treatments.