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Objective: The optimal strategy for difficult-to-treat (D2T) rheumatoid arthritis (RA) has not been identified, and the ultrasound characteristics of D2T RA have not been reported. We investigated the clinical characteristics and factors contributing to the outcome in D2T RA in a multicentre RA ultrasound observational cohort. Method: We reviewed 307 Japanese patients diagnosed with RA who underwent treatment with biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). We compared the differences in patient characteristics between the D2T RA and non-D2T RA groups. We examined the factors contributing to a good response [defined as b/tsDMARD continuation and Clinical Disease Activity Index (CDAI) ≤ 10 at 12 months] in the D2T RA patient group. Results: Forty-three patients (14%) were categorized as D2T RA and the remaining 264 (86%) as non-D2T RA at baseline. The grey-scale (GS) score, disease duration, and CDAI at the initiation of treatment were significantly higher in the D2T RA group than in the non-D2T RA group. In contrast, the power Doppler (PD) score was not significantly different between the two groups. Of the 43 D2T RA patients, 20 achieved a good response. The introduction of CTLA4-Ig (n = 5) was significantly associated with a good response in analysis based on inverse probability weighting with propensity score. GS and PD scores at baseline were not significantly associated with therapeutic response at 12 months in D2T RA patients. Conclusions: Patients with D2T RA had high clinical and ultrasound activity and poor responses to treatment with b/tsDMARDs. CTLA4-Ig was associated with a good response at 12 months in D2T RA patients. [ABSTRACT FROM AUTHOR]

This study investigated the effectiveness of treatment with Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) assessed by ultrasonography (US) activity, and the influence of patient characteristics and previous treatments. This prospective study assessed 60 treatment initiations among 53 Japanese patients diagnosed with RA who underwent treatment with JAK inhibitors during June 2013 to February 2020. Of the 53 patients, seven patients were enrolled in duplicate because they were treated with two different JAK inhibitors at different periods. For each case, the improvement rate on the power Doppler (PD) score was assessed at 6 month follow-up. Median improvement rate of PD score was used to classify cases as either US responders or non-responders, and patient characteristics were compared between the two groups. All indicators of clinical disease activity and US activity showed a significant improvement at 3 months compared with baseline. Although the JAK inhibitor-cycler group and the interleukin-6 (IL-6) inhibitor inadequate response (IR) group tended to show a later improvement for US activity, all indicators of clinical disease activity and US activity showed a significant improvement at 6 months compared with baseline for both groups. Multivariate analysis showed that concomitant methotrexate use and an IR to the previous biologic or targeted-synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) treatment were independently and significantly associated with US responders. Use of a JAK inhibitor in combination with methotrexate and an absence of IR to any previous b/tsDMARDs demonstrated superior effectiveness for patients with RA. [ABSTRACT FROM AUTHOR]

Rationale: Eosinophilic granulomatosis with polyangiitis (EGPA) is belongs to the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) subgroups. EGPA, unlike other subgroups of AAV, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis, has the unique feature that both ANCA and eosinophilic inflammation are involved in its pathogenesis. Although AAV often relapses, there are currently no reports of EGPA developing during other subgroups of AAV. Herein, we document a case of EGPA that developed during the clinical course of MPA., Patient Concerns: A 61-year-old Japanese woman was diagnosed with MPA based on interstitial lung disease and myeloperoxidase-ANCA positivity. After starting immunosuppression therapy, including prednisolone and tacrolimus, she was expected to achieve clinical remission. Nonetheless, she occasionally experienced MPA relapse, which required an increased prednisolone dose, rituximab, intravenous cyclophosphamide, and plasma exchange. Three years after MPA onset, she developed renal amyloidosis; thus, subcutaneous tocilizumab was added to her regimen. Following clinical remission, the administration interval of her subcutaneous tocilizumab therapy was extended and immunosuppressants were discontinued. She then developed bronchial asthma and mild eosinophilia (eosinophilic count: ~1000/μL). Further, a year later, she underwent total hip replacement using a titanium implant. Subsequently, she developed abnormal sensation in both hands, numbness, and muscle weakness, as well as palpable purpura and massive eosinophilia (eosinophilic count: ~8500/μL)., Diagnosis: We diagnosed the patient with EGPA based on 5 items (asthma, multiple mononeuropathies, sinus abnormality, and extravascular eosinophils) of the 1990 American College of Rheumatology classification criteria., Interventions: We administered 400 mg/kg intravenous immunoglobulin for 5 consecutive days, 300 mg mepolizumab subcutaneously every 4 weeks, and 40 mg/day prednisolone following pulsed methylprednisolone therapy (1000 mg/day for 3 consecutive days)., Outcomes: After these treatments, the patient's symptoms improved, and eosinophilic count and inflammatory markers declined., Lessons: The present case suggests that EGPA can be induced by the development of eosinophilic inflammation in other subgroups of AAV., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The aim of our study was to analyze the expressions of nuclear factor of activated T cells (NFAT)-related substances including long noncoding RNA NRON which participates in pathophysiology of Sjögren's syndrome (SS), and to assess the histologic findings in individuals with SS. In this study, the expressions of NRON, NFATc1, CD3/CD4, and proviral integration site for Moloney murine leukemia virus (PIM)-1 were examined by in situ hybridization, immunohistochemical analysis, and immunofluorescence in labial salivary glands (LSGs) obtained from 16 patients with SS and five controls. The microcell count method has been applied to calculate the NFATc1-positive area/infiltrating cell area in LSGs, and we compared those results to the infiltrating cell area, focus score, serum immunoglobulin G, and the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index. The NRON expression in the nuclei of cell-infiltration lesions of the SS patients were prominent. The NFATc1 expression was strong in the cytoplasm of infiltrating mononuclear cells and weak in ducts of both SS and controls. In SS, the NFATc1-positive area/infiltrating cell area was positively correlated with the infiltrating cell area and focus score. CD3/CD4 was expressed in infiltrating mononuclear cells, and PIM-1 colocalized with NFATc1 in the cytoplasm. These results suggest NRON along with NFATc1/PIM-1 in SS LSGs might participate in SS pathophysiology., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: To investigate the utility of 18F-FDG PET/CT in the diagnostic procedure of IgG4-related disease (IgG4-RD), we analysed the association between quantitative method of 18F-FDG PET/CT and histological findings., Methods: Twenty-one patients with IgG4-RD in whom 18F-FDG PET/CT was performed at the time of diagnosis were enrolled. Tissue biopsy was performed at 24 sites in 21 patients. To perform quantitative analysis of 18F-FDG PET/CT imaging, the highest standardised uptake value (SUV) of the pixels (SUVmax) and the average SUV (SUVmean) within the biopsied lesion were measured. The SUVmean of the liver was also measured as a reference., Results: The mean age at diagnosis was 64.6±11.9 years, and the median serum IgG4 level was 650 mg/dl. Histological findings were consistent with IgG4-RD (histopathology-positive) at 19 out of 24 sites. Although there was no significant difference in the values of SUVmax between histopathology-positive and histopathology-negative tissues, the values of SUVmean were significantly higher in the histopathology-positive tissue (4.98 and 3.54, respectively p<0.05). The values of SUVmean/liver were also higher in the histopathology-positive tissue (2.17 and 1.52, respectively p<0.05). To establish a cut-off value of SUVmean to determine which of multiple lesions should be biopsied, a ROC curve was constructed. ROC curve analysis indicated SUVmean=4.07 or SUVmean/liver=1.66 as a cut-off value., Conclusions: Our present study suggested that quantitative analysis of 18F-FDG-PET/CT imaging might be useful for selecting the biopsy site in IgG4-RD. The calculation of SUVmean, not of SUVmax, is important for evaluating IgG4-RD-related lesions in 18F-FDG PET/CT imaging.

Objective: To compare the efficacy and safety of tofacitinib and baricitinib in patients with RA in a real-world setting., Methods: A total of 242 patients with RA who were treated with tofacitinib (n = 161) or baricitinib (n = 81) were enrolled. We evaluated efficacy and safety between tofacitinib and baricitinib using multivariable analyses to avoid confounding. Their clinical disease activity and AEs were evaluated for 24 weeks., Results: The mean (SD) DAS28-ESR change from baseline to 24 weeks was 1.57 (1.55) (tofacitinib) and 1.46 (1.36) (baricitinib). There was no significant difference in the clinical response between the two groups (adjusted mean difference, 0.04; 95% CI, -0.35 to 0.28). The efficacy was not significantly changed in the patients without concomitant MTX use in both groups, but the concomitant MTX use showed better clinical efficacy in the cases of baricitinib treatment. In both groups, the most common AE was herpes zoster infection, and the AE rates were similar between the two groups. However, the predictive factors contributing to clinical response as revealed by a multivariable logistic analysis differed. The concomitant oral steroid use was independently associated with the achievement of DAS-low disease activity in the tofacitinib group, whereas in the baricitinib group, the number of biological and/or targeted synthetic DMARDs previously used was associated., Conclusions: Our findings indicate that tofacitinib and baricitinib had comparable continuing efficacies and safety profiles. However, there is a possibility that the influence of clinical characteristics on the treatment response differs. The comparison provides useful information to the optimal use of JAK inhibitors in real-world settings., (© 2021. The Author(s).)

Background: Bradyrhizobium diazoefficiens USDA110 nodulates soybeans for nitrogen fixation. It accumulates poly-3-hydroxybutyrate (PHB), which is of physiological importance as a carbon/energy source for survival during starvation, infection, and nitrogen fixation conditions. PHB accumulation is orchestrated by not only the enzymes for PHB synthesis but also PHB-binding phasin proteins (PhaPs) stabilizing the PHB granules. The transcription factor PhaR controls the phaP genes., Results: Inactivation of phaR led to decreases in PHB accumulation, less cell yield, increases in exopolysaccharide (EPS) production, some improvement in heat stress tolerance, and slightly better growth under microaerobic conditions. Changes in the transcriptome upon phaR inactivation were analyzed. PhaR appeared to be involved in the repression of various target genes, including some PHB-degrading enzymes and others involved in EPS production. Furthermore, in vitro gel shift analysis demonstrated that PhaR bound to the promoter regions of representative targets. For the phaP1 and phaP4 promoter regions, PhaR-binding sites were determined by DNase I footprinting, allowing us to deduce a consensus sequence for PhaR-binding as TGCRNYGCASMA (R: A or G, Y: C or T, S: C or G, M: A or C). We searched for additional genes associated with a PhaR-binding sequence and found that some genes involved in central carbon metabolism, such as pdhA for pyruvate dehydrogenase and pckA for phosphoenolpyruvate carboxykinase, may be regulated positively and directly by PhaR., Conclusions: These results suggest that PhaR could regulate various genes not only negatively but also positively to coordinate metabolism holistically in response to PHB accumulation.

Background: In Escherichia coli, nagD, yrfG, yjjG, yieH, yigL, surE, and yfbR encode 5'-nucleotidases that hydrolyze the phosphate group of 5'-nucleotides. In Bacillus subtilis, genes encoding 5'-nucleotidase have remained to be identified., Results: We found that B. subtilis ycsE, araL, yutF, ysaA, and yqeG show suggestive similarities to nagD. Here, we expressed them in E. coli to purify the respective His 6 -tagged proteins. YcsE exhibited significant 5'-nucleotidase activity with a broader specificity, whereas the other four enzymes had rather weak but suggestive activities with various capacities and substrate specificities. In contrast, B. subtilis yktC shares high similarity with E. coli suhB encoding an inositol monophosphatase. YktC exhibited inositol monophosphatase activity as well as 5'-nucleotidase activity preferential for GMP and IMP. The ycsE, yktC, and yqeG genes are induced by oxidative stress and were dispensable, although yqeG was required to maintain normal growth on solid medium. In the presence of diamide, only mutants lacking yktC exhibited enhanced growth defects, whereas the other mutants without ycsE or yqeG did not., Conclusions: Accordingly, in B. subtilis, at least YcsE and YktC acted as major 5'-nucleotidases and the four minor enzymes might function when the intracellular concentrations of substrates are sufficiently high. In addition, YktC is involved in resistance to oxidative stress caused by diamide, while YqeG is necessary for normal colony formation on solid medium.

Pollen from Japanese cedar (sugi) and cypress (hinoki) trees is responsible for the growing prevalence of allergic rhinitis, especially pollinosis in Japan. Previous studies have suggested that air pollutants enhance the allergic response to pollen in susceptible individuals. We conducted a time-stratified case-crossover study to examine the potential modifying effects of PM2.5 and suspended particulate matter (SPM) on the association between pollen concentration and daily consultations for pollinosis. A total of 11,713 daily pollinosis cases (International Classification of Diseases, ICD-10, J30.1) from January to May, 2001-2011, were obtained from a clinic in Chiyoda, Tokyo. Daily pollen counts and the daily mean values of air pollutants (PM2.5, SPM, SO2, NO2, CO, and O3) were collected from monitoring stations across Tokyo. The effects of pollen were stratified by the level of PM2.5 and SPM to examine the interaction effect of pollen and particulate pollutants. We found a statistically significant interaction between pollen concentration and PM2.5/SPM. On days with a high level of PM2.5 (>95th percentile), an interquartile increase in the mean cumulative pollen count (an average of 28 pollen grains per cm(2) during lag-days 0 to 5) corresponded to a 10.30% (95%CI: 8.48%-12.16%) increase in daily new pollinosis cases, compared to 8.04% (95%CI: 7.28%-8.81%) on days with a moderate level of PM2.5 (5th-95th percentile). This interaction persisted when different percentile cut-offs were used and was robust to the inclusion of other air pollutants. A similar interaction pattern was observed between SPM and pollen when a less extreme cut-off for SPM was used to stratify the effect of pollen. Our study showed the acute effect of pollen was greater when the concentration of air particulate pollutant, specifically PM2.5 and SPM, was higher. These findings are consistent with the notion that particulate air pollution may act as an adjuvant that promotes allergic disease (i.e. pollinosis)., (Copyright © 2014 Elsevier B.V. All rights reserved.)

To determine the consultation patterns of Japanese cedar pollinosis subjects during the pollen dispersal season, we surveyed those treated at a private clinic in Chiyoda Ward, Tokyo, from 1990 to 2009. We also studied the relationship between subject numbers and pollen count. The above relationship correlated highly with linear regression equation y = 0.0897x + 627.47 with R² = 0.7851 (p < 0.001). The relationship from 1994 to 2009, when the study began in early January, correlated highly with logarithmic regression equation y = 257.43Ln(x) - 1014.8 with R² = 0.9542 (p < 0.001). Based on these results, we concluded that estimated pollen count helps predict the year's Japanese cedar pollinosis subject numbers very highly accurately. Numbers of subjects returning did not correlate well with pollen count, and continued to decrease each year. Return visits averaging 2.6 in 1990 gradually decreased to 0.73 in 2006--a reduction we attributed to long-term medication and the increased self-payment proportion in medical expenditures.

To clarify medical consultation dynamics in Japanese cedar pollinosis patients visiting an office building clinic in an office block in central Tokyo, we surveyed number of patient at a private ENT clinic in Chiyoda-ku, Tokyo, during the Japanese cedar pollen season from 1990 to 1999. Based on questionnaires and CAP RAST tests in 1995, we studied the profiles of Japanese cedar pollinosis patients and determined positive rates of noncedar antigens. The gender ratio in 1995 was 674 men versus 501 women, most frequently men in their 40s and women in their 20s. Of these, 79.2% worked in Chiyoda-ku and Chuo-ku, but only 1.9% lived in these districts. Positive rates of noncedar antigens in 232 who received simultaneous CAP RAST tests were 64.7% for Japanese cypress, 38.3% for house dust, 35.3% for Dermatophagoides pteronyssinus, 34.4% for Epidermoptidae spp, 19.8% for mixed grasses, and 10.3% for mixed weeds (asteraceous plants). Patients positive for cedar alone were 19.0% and positive for both cedar and cypress but negative for other antigens were 23.3%; about 60% of these were suspected of multiple sensitization to antigens other than cedar and cypress. The number of pollens and patients were summarized weekly and compared. Those paying a first visit were peaked with an increase in pollen in the first week of March almost every year; second visits peaked 1 or 2 weeks later than the first visit. Little increase in first visit was noted even with increasing pollen dissemination from the latter half of March. The relationship between the number of pollen and patients each year from 1990 to 1999 correlated highly with the linear regression equation y = 0.1005x + 547.07 with R2 = 0.7562. The relationship between square roots of the number of pollen and patients each year for 5 year from 1995 to 1999 correlated very highly with the linear regression equation y = 11.167x + 376.72 with R2 = 0.9941. We concluded that the number of patients may be predicted with substantially higher accuracy based on the estimated amount of pollen in a given year.

Prevalence rate of allergy to Japanese cedar pollen was investigated by means of questionnaires and immunological examinations in residents of 3 regions in Tokyo (Akiruno city, Chofu city, and Ota ward). The results were as follows: 1) the prevalence rate of allergy to Japanese cedar pollen in Tokyo was 25.7% in Akiruno city, 21.1% in Chofu city, and 17.7% in Ota ward in 1996; 2) stratification by the age reveal that the prevalence rate was the highest in the age group of 30 to 44, and the group showed prevalence rate of above 40% in Akiruno city; 3) overall prevalence rate of Tokyo was 19.4% in 1996, which was approximately twice as much as that in 1985; 4) increase in prevalence rate in the recent decade was most significant in Akiruno city where the largest number of Japanese cedar pollen was detected in the air, and prevalence rate tended to rise in the young group of 14 or less.

A 17-year-old woman was referred to our hospital because of cough and fever. The chest X-ray films revealed an anterior mediastinal mass shadow. Steroid drugs and antibiotics were administered and the shadow diminished slightly. To confirm diagnosis, open thoracotomy was performed. The tumor was extended to the mediastinum, thymus and heart as well as the right middle lobe and right lower lobe. Microscopic findings of the resected tumor showed proliferation of histiocytes with infiltration by inflammatory cells, lymphocytes and fibrous tissue.

The nuclear DNA contents of paraffin-embedded specimens of 41 cases of a hepatocellular carcinoma have been measured by means of flow cytometry. Results have indicated that 25 cases (61%) were diploid and 16 cases (39%) were aneuploid. In the aneuploid cases, the serum AFP level was found to be higher and stage more advanced. We also found that patients with aneuploid tumors had a poorer prognosis than those with diploid tumors, this fact uncovered by means of a Cox's proportional hazard model. In conclusion, the ploidy pattern of the nuclear DNA may serve as a useful prognostic marker for a hepatocellular carcinoma.

2,5-Dihydroxy-1,4-dithiane (I) and its derivatives (II-IV) showed rather marked inhibitory activities on the growth of the roots of two plant species. All compounds tested had phytogrowth-inhibitory activities. These compounds markedly inhibited the growth of the two plant species at the concentration of 1.0 x 10(-3) M. Seeds of Brassica rapa treated with 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane (III) and its diacetate (IV) at the same concentration failed to germinate. Among these compounds, IV showed the most potent inhibitory activity on the two plant species. The radicles of both plant species treated with these compounds at concentrations higher than 1.0 x 10(-4) M showed negative geotropism, even though germination occurred. The compounds except for 2,5-diacetoxy-1,4-dithiane (II) also had antibacterial activities. In particular, III had rather marked antibacterial activity and its minimal inhibitory concentration (MIC) for Staphylococcus aureus IFO-3060 and Escherichia coli IFO-12734 was 4.0 micrograms/ml.

3,3'-Dihydroxy-alpha,beta-diethyldiphenylethane (I), an isomer of hexestrol (II), was found to have a strong hypotensive effect on rats and antifungal activity against some pathogenic fungi. The hypotensive effect of I (-100.0 +/- 21.0 mmHg, 10 mg/kg, i.v.) was stronger than that of II (-40.0 +/- 2.60 mmHg, i.v.). Unlike II and other oxystilbene-related compounds already tested, I showed prolonged hypotensive action at the dose of 10 mg/kg, and the blood pressure was not restored to the original level within 20 min. I also showed antifungal activity against all fungi tested (minimal inhibitory concentration: 10-120 micrograms/ml). It should be emphasized that by shifting the phenolic hydroxyl group to m-position, the biological activities were greatly increased.

Using anterior rhinomanometry, nasal resistance was measured in 397 Japanese children and students, aged 5 to 17 years. Thereafter the relationship between nasal resistance and age, sex, height and weight was studied. The results are as follows: 1. The nasal resistance of children and students significantly decreases with aging and it reaches almost the same as that of an adult at about 16 years of age. This decrease was confirmed statistically. However, the difference of sex was not significant in any age group. 2. There is no significant correlation among total nasal resistance, height and weight. So, it would be concluded that the growth of the frame-work of the nasal cavity does not follow the same course as that of the height or the weight. 3. Between ages 13 and 14, it seems that the nasal resistance increases slightly. The change in nasal resistance during this period may be attributed to unbalance of the growth between the nasal turbinates and the frame-work of the nasal cavity.

A 31-year-old man, suffering from Behçet disease, was admitted to our hospital because of a palpable mass in the right hypochondrium. On testing, laboratory data showed an abnormal liver function, positive HBs antigens, and a high AFP level. An abdominal CT and a SCAG revealed large tumors in the liver. The patient died of hepatic failure 6 months after the first admission and an autopsy was performed. At autopsy, hepatocellular carcinomas were found to occupy most of the entire liver. Histologically, the residual liver showed no remarkable changes, such as liver cirrhosis or chronic hepatitis. To date, few cases of Behçet disease complicating a malignant neoplasma have been reported. The possible relationship between Behçet disease and the occurrence of malignant tumors is described with a review of the literature.

Reexamination of conditions for processing and storing blood for plasma renin assay confirmed that plasma can be stored at -20 degrees C for at least 4 weeks without significant changes in active renin level. The active renin concentration is increased by storage at 4 degrees C because of conversion from inactive renin.

A 27-year-old woman, post parturition, was admitted to hospital because of epigastric pain. Ultrasonography and abdominal computerized tomography revealed a giant mass in the left lobe of the liver. Celiac angiography showed a hypervascular mass with irregular vascularity. Serum HBs antigen proved negative. A left hepatic lobectomy was performed in March, 1985. Histology of the tumor revealed the trabecular type of a hepatocellular carcinoma with Edmondson grade 2 atypism, whereas the non-cancerous region of the liver showed chronic inactive hepatitis. This case is presented, because of the rarity of a hepatocellular carcinoma developing in such a young patient. In addition, reported cases of a hepatocellular carcinoma in the young in Japan are reviewed.

In recent years, with the development of diagnostic procedures, the number of cases of early carcinoma of the gall bladder has been seen to gradually increase. In this paper, 8 cases of early gall bladder carcinoma have been evaluated, using a diagnostic approach. Cholecystolithiasis was the complication in 6 cases, and abdominal pain was seen as the most common symptom. Findings by various image diagnoses, such as ultrasonography, DIC, ERCP, and CT scan are described and discussed with a review of literature. Ultrasonography was considered to be the most useful tool for the detection and diagnosis of an early carcinoma of the gall bladder. A survey is thought to be required, involving the cases that have accumulated throughout the entire nation.