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Age-related Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorder (LPD) occurs in elderly patients without immunodeficiency. An 81-year-old woman without any known immunodeficiency was examined for fever, rash, arthritis, thrombocytopenia, pleural and pericardial effusions, lymphadenopathy, and positive autoantibodies, which satisfied the classification criteria for systemic lupus erythematosus (SLE). However, a lymph node biopsy revealed EBV-LPD, and she was diagnosed with age-related EBV-LPD. In young individuals, EBV infection is a major differential diagnosis of SLE, but to our knowledge, this is the first reported case of age-related EBV-LPD mimicking SLE. We should therefore consider EBV-related disorders in the differential diagnosis of SLE even in elderly individuals.

Objectives This study evaluated the prognostic factors for acute exacerbation (AE), including sequential changes in Krebs von den Lungen-6 (KL-6) levels, in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) patients. Methods This was a retrospective observational study. We reviewed 125 patients diagnosed with RA-ILD between 2010 and 2019. We defined ΔKL-6 as the annual variation rate of KL-6 one visit before AE onset (or the last visit). The Cox regression analysis was used for evaluating significant variables associated with AE. We analysed the overall survival and respiratory-related death-free survival. Results Thirty-three patients (26.4%) developed AE during the observation period. The univariate analysis revealed that KL-6 levels at RA-ILD diagnosis [hazard ratio (HR), 1.11; 95% confidence interval (CI), 1.05–1.15; p Conclusion ΔKL-6 can be a prognostic marker for detecting AE in RA-ILD patients.

To analyse the protective effect of different doses of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis for early severe infections in antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV), considering time-varying changes.In this retrospective observational study, we assessed the protective effect of TMP/SMX within the first 6 months of diagnosis among Japanese patients with AAV. We included 250 consecutive patients with AAV who were admitted to our hospital. The protective effect of TMP/SMX against early severe infections was verified using Cox regression analysis along with potential confounding factors. Cox regression with inverse probability treatment weights for early severe infections was also performed as a sensitivity analysis.Cox regression analysis showed that the reduced TMP/SMX exposure group had a significant protective effect against early severe infections (standard-dose group versus no TMP/SMX group: hazard ratio [HR] 0.393, 95% confidence interval [CI]: 0.139-1.11, p=0.077; reduced-dose group versus no TMP/SMX group: HR 0.418, 95%CI: 0.216-0.807, p=0.009), even when considering time-dependent changes. In the sensitivity analysis, the reduced-dose group still had a significantly lower risk of early severe infections than the no TMP/SMX group (HR = 0.393, 95%CI: 0.177-0.873, p=0.022). During follow-up, 18.0% of the patients discontinued TMP/SMX due to side effects.TMP/SMX is highly effective in preventing severe infections among patients with AAV despite the high incidence of side effects. Further studies are needed to determine the optimal dose of TMP/SMX for preventing severe infections, especially considering renal impairment.

Supplemental Digital Content is available in the text, Recent large observational studies of antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) show that severe infection is a major cause of death and that the majority of infections occur during the early phase of initiating remission-induction therapy. Many risk factors for severe infection have been suggested, but these have been inconsistent. Nevertheless, infectious risk factors in elderly patients with AAV have not been adequately investigated in previous studies. In this retrospective observational study, we examined potential predictors of severe infection within 90 days (early severe infections) after remission-induction therapy in patients with AAV aged 65 years or older. We included 167 consecutive elderly patients with AAV admitted to our hospital. Data from medical history and remission-induction therapy were analyzed for predictive risk factors associated with early severe infections. The relationship between initial doses of corticosteroids and cumulative incidence of severe infections was also analyzed. A multivariate analysis of risk factors for early severe infections was performed using logistic regression analysis. The Kaplan–Meier method was used to estimate the overall survival, and the log-rank test was used to evaluate the differences between patients with and without early severe infections. Gray method was used to compare the cumulative incidence of severe infections in patients who did and did not receive initial high-dose corticosteroids. Logistic regression analysis showed that initial high-dose corticosteroid administration (prednisolone ≥0.8 mg/kg/d) (odds ratio [OR] 3.86, P = .030) and serum creatinine levels at diagnosis ≥1.5 mg/dL (OR 5.13, P = .003) were independent predictors of early severe infection although administration of cyclophosphamide or rituximab was not. The cumulative incidence of severe infections was also significantly higher in patients who received initial high-dose corticosteroids (P = .042), and patients with early severe infections exhibited a high mortality rate within 6 months (P

Background:Skeletal muscle is known as one of the organ involvements of primary systemic vasculitis.1,2 Muscle inflammation is detected by magnetic resonance imaging, and necrotizing vasculitis is proved by muscle biopsy.3 As with systemic vasculitis or single organ vasculitis, glucocorticoid (GC) and immunosuppressants are used in its treatment.4 There are not many reports about muscular vasculitis, and its long-term clinical course after initial treatment, including the rates of relapse and mortality, remains unclear.Objectives:To identify the predictors of relapse and mortality in patients with muscular vasculitis, especially focusing on the status of anti-neutrophil cytoplasmic antibody (ANCA).Methods:We retrospectively reviewed patients diagnosed with necrotizing vasculitis with muscle involvements in our hospital between 2004 and 2020. In all cases, muscular vasculitis was identified by muscle biopsy or magnetic resonance imaging. To focus on the clinical features of muscular vasculitis, we excluded patients with such severe organ involvements as cardiovascular, abdominal, cerebral, severe renal, and severe pulmonary involvements. We compared the 5-year cumulative incidence of relapse, the overall survival rate, and the dose of GC over 5 years between the ANCA-positive and ANCA-negative groups. A relapse was defined as any new or worsened state of disease activity requiring an escalation of GC dose. Gray’s method was used for assessing the cumulative incidence of relapse. The log-rank test was used for assessing overall survival. The Mann-Whitney U test was used for assessing the dose of GC. The possible factors for relapse in 5 years in a univariate analysis were selected for a multivariate analysis using the Cox proportional hazards model.Results:Forty-nine patients were enrolled. The median age of onset was 77 (69-82) years and 71.4% were women. There were 30 ANCA-positive patients (90.0% with anti-myeloperoxidase) and 19 ANCA-negative patients. The median age and the number of patients with renal involvements were higher in the ANCA-positive group than in the ANCA-negative group (73.0 ± 9.29 years vs. 79.5 ± 20.28 years, p=0.0062 and 7/30 [23.3%] vs. 0/19 [0.0%], p=0.034, respectively). The Birmingham Vasculitis Activity Score (ver. 3), the induction dose of GC, and the rate of immunosuppressants use were not significantly different between the two groups. During the observational period, 24 patients relapsed. The 5-year cumulative incidence of relapse was significantly higher in the ANCA-positive group than in the ANCA-negative group (p=0.026) (Figure 1). The Cox proportional hazards model revealed that the presence of ANCA was an independent risk factor for relapse (hazard ratio: 3.15; 95% confidence interval 1.06–9.38; p=0.040). During the observational period, 9 patients died (3 died from cancer, 1 from interstitial pneumonia, 1 from cerebral hemorrhage, 1 from infection, and 3 from unknown reasons). The ANCA-positive group exhibited a higher mortality rate than the ANCA-negative group without a statistical significance (p=0.12). The 5-year cumulative dose of GC was larger in the ANCA-positive group than in the ANCA-negative group without a statistical significance (14786 [11246–19138] mg vs. 10088 [7129–12634] mg, p=0.12).Conclusion:In muscular vasculitis, the presence of ANCA is an independent risk factor for long-term relapse. Stratified treatment depending on the ANCA status may reduce the relapse rate and the occurrence of side effects of GC in patients with muscular vasculitis.References:[1]Kitching AR et al. Nat Rev Dis Primers 2020; 6(1): 71.[2]Hernández-Rodríguez J et al. J Autoimmun 2014; 48-49: 84-9.[3]Ushiyama S et al. Rheumatol Int 2020; 40(10): 1667-74.[4]Ganeshanandan LR et al. Semin Arthritis Rheum 2020; 50(3): 503-8.Disclosure of Interests:None declared

Adrenal cortex and medulla are derived from mesoderm and ectoderm, respectively. Mixed corticomedullary tumors (MCMTs), comprising an intimately admixed population of both adrenal cortical cells and pheochromocytes in a single adrenal tumor, are extremely rare and its pathogenesis has remained unknown. Here, we report a case of MCMT whose cells co-expressed cortical and medullary antigens in the same tumor cells.[Case description]A 40-year-old woman was referred to our hospital for investigating Takotsubo cardiomyopathy following resection of uterine fibroids. An abdominal CT scan depicted a 24 mm tumor on her left adrenal gland. Her basal serum ACTH, cortisol levels and urinary cortisol were 13.8 pg/mL, 9.5 μg/dL, and 26.5 μg/day respectively. The cortisol level was normally suppressed by an administration of 1 mg dexamethasone (1.4 μg/dL). Plasma renin activity, aldosterone levels and urinary aldosterone were 15.0 ng/mL/h, 122 pg/mL, and 5.0 μg/day, respectively (with administration history of azosemide). On the other hand, her plasma adrenaline and noradrenaline levels were elevated as high as 177 pg/mL and 536 pg/mL, and urinary metanephrine and normetanephrine were 2.12 mg/day and 1.10 mg/day. A 123I-metaiodobenzylguanidine scan revealed high uptake in the tumor. After adequate adrenergic α-receptor blockage, left adrenalectomy was performed. Her postoperative endocrine and clinical findings were normalized without any further complications.[Pathology] Immunohistochemistry (IHC) revealed the presence of MCMT. Cells morphologically consistent with pheochromocytoma and adrenocortical cells were confirmed by immunostaining of chromogranin A and SF-1, respectively. Chromogranin A-positive medullary-derived and SF-1-positive cortical-derived tumor cells were intermixed in the chimeric fashion. In addition, some tumor cells were positive for both proteins, indicating hybrid nature of the cells. Tumor cells of cortical origin expressed CYP11β1, 3β-HSD, p450c21, and p450c17, but not CYP11β2. Non neoplastic adrenal cortex were atrophic, whereas the glomerulosa was hyperplastic positive for CYP11β2, consistent with diffuse hyperplasia and adrenal medullar unremarkable. [Conclusions:]The adrenal tumor was clinically diagnosed as pheochromocytoma, but the pathological findings did reveal cortisol production in the tumor and aldosterone overproduction in the accompanying cortex. This is the first case of MCMT co-expressing adrenal medullary and cortical antigens in the same tumor cells as hybrid cells.

Background:Acute exacerbation (AE) is a life-threatening complication in connective tissue disease (CTD) associated interstitial lung disease (ILD) (CTD-ILD), including rheumatoid arthritis (RA). Although several risk factors for AE in CTD-ILD have been suggested, these are inconsistent. Krebs von den Lungen-6 (KL-6) is reported as a useful blood marker to detect severe CTD-ILD and RA-ILD, and serum KL-6 levels are significantly higher in patients with AE than in those without AE in RA-ILD patients [1]. However, the predictive value of KL-6 for AE in CTD-ILD or RA-ILD has not been completely confirmed.Objectives:To investigate the predictive factors for AE including initial serum KL-6 levels at RA-ILD onset and sequential changes of KL-6. We also examined the causal relationship between AE and mortality of RA-ILD patients.Methods:We retrospectively reviewed 115 patients with RA-ILD treated in our hospital between 2005 and 2019. Suspected drug-induced pneumonia cases or patients with other coexisting CTD were excluded. Cox regression analyses was used for univariate analysis to detect predictors of AE. Overall survival rate, respiratory-related deaths-free survival rate and AE-free survival rate were analyzed using the Kaplan-Meier method. P < 0.05 was considered statistically significant.Results:Among 115 patients, 29 patients (25.2%) developed AE and 32 patients (27.8%) died. The median follow-up period (IQR) was 57 (25.0-91.5) months, 57.4% were female and the mean age at RA-ILD onset was 72.2 ± 7.9 years old throughout the whole cohort. Among the AE group, methotrexate (MTX), tumor necrosis factor α inhibitor (TNFi) and non TNFi biological-DMARDs were used at AE onset in 10.7%, 0.0%, and 3.6% of patients, respectively. There was a significant difference of serum KL-6 levels at AE onset between AE group and non-AE group (1081.9 ± 624.7 vs 556.1 ± 285.6 U/mL, p < 0.001). Initial serum KL-6 levels at RA-ILD onset in AE group were higher than those in non-AE group, without a significant difference (648.9 ± 325.7 vs 523.7 ± 276.8 U/mL, p = 0.050). The optimal cut-off level of initial serum KL-6 to predict AE was 551 U/mL according to ROC analysis. In univariate analysis, the following factors were significantly associated with AE; usual interstitial pneumonia (UIP) pattern on HRCT at AE onset (Hazard Ratio [HR]: 2.18; 95% confidence interval [CI]: 1.02-4.61; p = 0.045), initial serum KL-6 > 551 U/mL at RA-ILD onset (HR: 2.46; 95%CI: 1.17-5.43; p = 0.018), increasing serum KL-6 levels > 10% before AE onset compared to the previous year (ΔKL-6 > 10%/year) (HR: 4.98; 95%CI: 2.17-11.84; p < 0.001). Initial serum KL-6 > 551 U/mL at RA-ILD onset and ΔKL-6 > 10%/year before AE were also significant prognostic factors for AE when we analyzed only in non-UIP patients (HR: 2.84; 95%CI: 1.15-7.35; p = 0.024, HR: 9.49; 95%CI: 3.02-36.25; p < 0.001, respectively). Conversely, median age at RA-ILD diagnosis, positive ratio of anti-CCP antibody, smoking habits, respiratory comorbidities, SDAI score, and therapeutics at both RA-ILD and AE onset had no significant associations with AE. Patients with initial serum KL-6 > 551 U/mL at RA-ILD onset and ΔKL-6 > 10%/year before AE had a significantly worse AE-free survival rate compared to others (p < 0.001). (Figure 1). Moreover, patients with AE had significantly lower overall survival rate (p < 0.001) and respiratory-related deaths-free survival rate (p < 0.001) than those without AE.Figure 1.KL-6 was measured at RA-ILD onset. ΔKL-6 means the annual variation ratio of KL-6 before AE. The survival curve using the Kaplan Meier method (Log rank test).Conclusion:Serum KL-6 levels at the disease onset and its sequential changes may be able to predict AE in the near future and support the early detection of AE in RA-ILD patients.References:[1]Sarcoidosis Vasc Diffuse Lung Dis. 2016 Oct 7; 33 (3):216-223.Disclosure of Interests:Nozomi Tanaka: None declared, Keisuke Nishimura Speakers bureau: Mitsubishi Tanabe Pharma Corporation. Pfizer Inc. Kyowa Kirin Co., Ltd. Chugai Pharmaceutical Co., Ltd. ONO PHARMACEUTICAL CO., LTD. Japan Blood Products Organization. Kissei Pharmaceutical Co., Ltd. Astellas Pharma Inc. AYUMI Pharmaceutical Corporation. Eisai Co., Ltd. DAIICHI SANKYO COMPANY. Norvartis AG. Bayer AG. Sanofi K.K., Daisuke Waki Speakers bureau: Mitsubishi Tanabe Pharma, AbbVie Inc, eisai Co,. Ltd, ONO PHARMACEUTICAL CO., LTD, Keiichiro Kadoba: None declared, Tomohiro Yoshida: None declared, Hiroyuki Murabe: None declared, Toshihiko Yokota: None declared

Background IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition characterized by tumefactive lesions and, often but not always, elevated serum IgG4 levels [1]. Glucocorticoids (GC) are usually used as induction therapy for IgG4-RD. However, relapse often occurs following GC tapering, and predictors of relapse remain unclear. Objectives To identify predictors of relapse of IgG4-RD after induction therapy. Methods We retrospectively reviewed 57 patients diagnosed with IgG4-RD and treated with GC in our hospital between January 2004 and November 2018. Clinical features at baseline, including organ involvement and blood markers (total hemolytic complement [CH50], its fractions [C3 and C4], IgG4, IgG, IgE, anti-nuclear antibody, rheumatoid factor, C-reactive protein, soluble interleukin-2 receptor, eosinophils), were collected. We divided patients into 2 groups on the basis of clinical features and examined whether they relapsed. In this study, hypocomplementemia was defined as decreased serum C3, C4, or CH50 less than the lower limit of normal. A relapse was defined as any new or worsened state of disease activity that required an escalation in treatment (immunosuppressants and/or GC). The follow-up period was defined as 182 days. Results Forty-three men and 14 women (mean age 68.1 ± 10.9 years) were included. Both serum IgG4 and IgG were measured at baseline in all patients (mean IgG4 798.8 ± 873.1 mg/dL and mean IgG 2874.0 ± 1934.1 mg/dL, respectively). All of the serum C3, C4, and CH50 were measured at baseline in 34/57 patients (mean C3 75.7 ± 33.3 mg/dL; mean C4 14.8 ± 11.5 mg/dL; and mean CH50 37.0 ± 23.1 U/mL). Fifteen patients had at least one episode of hypocomplementemia, and 19 patients did not. Most patients had multiple organ lesions. The details of dominant lesions were as follows: Dacryoadenitis and/or sialadenitis (Mikulicz disease), 36/57 patients (63.2%); biliary or pancreatic lesion, 29/57 (50.1%); retroperitoneal fibrosis, 22/57 (38.6%); and renal lesion 16/57 (28.1%). All patients were given prednisolone and gradually reduced (mean induction dose 31.7 ± 9.8 mg/day). No patients received immunosuppressant as induction therapy. During the follow-up period, 6 patients relapsed, and the dose of prednisolone was increased immediately. Relapsed lesions were as follows: Mikulicz disease, 3/6 patients (50.0%); biliary or pancreatic lesion, 1/6 (16.7%); retroperitoneal fibrosis 1/6 (16.7%); and pulmonary lesion 1/6 (16.7%). Patients with hypocomplementemia had significantly shorter relapse-free survival than those without (p=0.039, Figure 1). Patients with decreased serum C4 or CH50 (less than the lower limit of normal) also had significantly shorter relapse-free survival than those without, but those with decreased serum C3 did not. Such a tendency was not seen in other blood markers (IgG4, IgG, IgE, anti-nuclear antibody, rheumatoid factor, C-reactive protein, soluble interleukin-2 receptor, eosinophils). Conclusion Hypocomplementemia at baseline in patients with decreased serum C4 or CH50 may predict relapse of IgG4-RD after prednisolone therapy. References [1] Stone JH, et al. N Engl J Med2012; 366: 539-51. Disclosure of Interests None declared

BACKGROUND: Thyroid storm (TS) is a life-threatening condition requiring emergency treatment. The reported mortality of TS is 10-20%, but there have not been many large clinical studies regarding the severity and prognosis of TS. The 2017 Guidelines for the Management of Thyroid Storm (The Japan Thyroid Association (JTA) and The Japan Endocrine Society) indicate that there is a significant correlation between TS mortality and the Acute Physiology and Chronic Health Evaluation (APACHE II) score (Odds ratio: 1.15), as well as between TS mortality and the Sequential Organ Failure Assessment (SOFA) score (Odds ratio: 1.33). In this report, we examined which severity score is a prognostic predictor of TS severity, in a comparison between the JTA score and the Burch-Wartofsky point scale (BWPS). CLINICAL CASES: In a retrospective chart review of patients diagnosed and treated at the Kurashiki Central Hospital (Kurashiki City, Japan) from 2005 to 2017, 3361 patients were diagnosed with Graves' disease, but only 5 developed TS (0.14%). TS was defined using the JTA and BWPS criteria; based on the use of either diagnostic criteria, the diagnosis of TS did not differ. Its severity was defined using the SOFA and APACHE II scores. The median age was 56 years [49-77 years]; females comprised 3 of the 5 patients (60%). Only 1 patient experienced a fatal case of TS. All 5 cases met the JTA criteria for definite diagnosis of TS; the median BWPS score was 80 points [55-85 points]. The median SOFA score was 3 points [0-5 points] and the media APACHE II score was 16 points [10-20 points]. The APACHE II score of the fatal case was 20 points, which was the highest among all 5 cases. Among the surviving cases, the periods of treatment in the Intensive Care Unit was less than 3 days. All survival cases were treated with antithyroid drugs, β-blockers, glucocorticoids, and acetaminophen. None of the patients in our report underwent hemodialysis. The APACHE II score is an accurate measure of severity of illness that correlates strongly with patient outcome. In our analysis, there was no difference between the survival cases and the fatal case, with respect to the JTA and BWPS criteria, or the SOFA score. However, the APACHE II score of the fatal case was higher than that of the survival cases. Notably, Aa-DO2/PaO2, arterial blood pH/venous blood HCO3-, and Glasgow Coma Scale were the major factors associated with mortality. CONCLUSION: Our data suggested that there was no difference in the diagnosis of TS, based on the diagnostic criteria of JTA and BWPS. The APACHE II score was helped to estimate the severity of multiple organ dysfunction of TS.

We aimed to investigate the efficacy of plasma exchange on severe anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Of 182 patients with AAV in our hospital, 12 patients with life-threatening organ damage (rapidly progressive glomerulonephritis and/or diffuse alveolar hemorrhage) underwent centrifuge-based therapeutic plasma exchange and immunosuppressive therapy. Twenty-four patients matched for age, serum creatinine, and severity of vasculitis, who received high-dose glucocorticoids with or without immunosuppressants, were included in the nonplasma exchange group. Renal survival rate at 2 years from induction treatment was not significantly different between the plasma and nonplasma exchange groups (P = 0.524). Mortality rate at 5 years from induction treatment was not significantly different between the plasma and nonplasma exchange groups (P = 0.631). In this retrospective study, we could not show the significant differences in the renal survival rate and survival rate between the two groups.

Rationale: Thrombocytepenia, anasarca, fever, renal insufficiency, and organomegaly (TAFRO) syndrome is a novel disease entity characterized by a constellation of symptoms (thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly). Here, we describe the development of TAFRO syndrome-like features during the treatment of rheumatoid arthritis with a Janus kinase (JAK) inhibitor. Patient concerns: In this report, a 74-year-old woman treated with a JAK inhibitor (tofacitinib) for rheumatoid arthritis was admitted because of fever and thrombocytopenia. Diagnoses: On laboratory examination, marked thrombocytopenia and elevated creatinine and C-reactive protein levels were present. A computed tomography scan revealed lymphadenopathy, hepato-splenomegaly, and anasarca. A left axillary lymph node biopsy revealed Castleman's disease-like features. These clinical features satisfied the proposed diagnostic criteria for TAFRO syndrome. Since autoimmune disorders should be excluded when diagnosing TAFRO syndrome, it is not strictly correct to diagnose her as TAFRO syndrome. Therefore, we diagnosed her as rheumatoid arthritis complicated by TAFRO syndrome-like features. Interventions: The patient was treated with high-dose glucocorticoid, tacrolimus, eltrombopag, intravenous immunoglobulin, and rituximab. Outcomes: Her condition was refractory to the above-mentioned treatment, and she eventually died because of multi-organ failure 6 months after the first admission. Lessons: TAFRO syndrome-like features can develop during treatment with a JAK inhibitor for rheumatoid arthritis. Patients with autoimmune diseases complicated by TAFRO syndrome-like features can follow a fatal clinical course, and thus, an intensive combined treatment is warranted for such patients, especially in cases refractory to glucocorticoid.

Background:There are several reports that cytomegalovirus (CMV) reactivation resulted in more co-infections affecting survival in rheumatic disease, and CMV reactivation can lead to infections in granulomatosis with polyangiitis patients by inducing CD4+CD28- T cell and depressing naïve T cell populations.1-4Despite this evidence, the prognostic value of CMV reactivation for severe infections in patients with connective tissue disease are still unknown.Objectives:The aim of this study was to examine prognostic factors for severe infection during the early phase of treatment, especially in CMV reactivation, in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) who received initial high dose corticosteroid therapy (prednisolone > 0.8mg/kg/day).Methods:We analyzed the data of 88 consecutive hospitalized patients newly diagnosed with AAV at our hospital from January 2006 to March 2019 in this retrospective cohort study. There were 32 patients with CMV reactivation during remission induction therapy compared to 56 patients without CMV reactivation. CMV reactivation was defined by the detection of CMV pp65 antigen in blood samples, and CMV positive cells ≥ 5 per 3.0 × 105polymorphonuclear neutrophils (PMNs). The variable for severe infections within 180 days with apvalue < 0.1 in univariate analysis were selected for multivariate analysis using the Cox regression model. The positive predictive value (PPV) and positive likelihood ratio (PLR) of CMV reactivation for subsequent severe infections were also analyzed.Results:Patients with CMV reactivation, compared to those without, had a higher prevalence of MPO-ANCA, renal manifestation and renal impairment at diagnosis, received hemodialysis (HD), higher revised five factor score (FFS), older age, higher Birmingham Vasculitis Activity Score at diagnosis, and higher initial doses of corticosteroids (CS) at baseline. Revised FFS ≥ 2, renal involvement, high initial serum creatinine (≥ 1.5 mg/dl) at diagnosis, received HD, and CMV reactivation were associated with severe infections in the univariate analysis, although receiving cyclophosphamide or rituximab was not. Among these variables, CMV reactivation (Hazard ratio [HR] 3.50; 95% confidence interval [CI]: 1.22-10.10;p= 0.02) and high initial serum creatinine at diagnosis (HR 8.09; 95%CI: 2.00-32.73;p< 0.01) were independent risk factors for severe infections within 180 days. (Table 1) The PPV and PLR of CMV reactivation for subsequent severe infections were 35% and 1.91. When including higher initial serum creatinine, PPV and PLR for subsequent severe infections was 67% and 7.26.Table 1.Cox regression analysis for severe infections within 180 days.Univariate analysisMultivariate analysisPotential prognostic factorsHR (95% CI)P valueHR (95% CI)P valueAge ≥ 651.36 (0.48-3.71)0.580Male1.23 (0.50-3.04)0.648Past history of lung disease0.39 (0.11-1.36)0.140Past history of diabetes mellitus0.64 (0.15-2.77)0.550Lung involvement1.76 (0.67-4.62)0.254Renal involvement†3.68 (1.22-11.10)0.021Serum Cr ≥ 1.5 at diagnosis9.50 (3.40-26.49)< 0.0018.09 (2.00-32.73)0.003Hemodialysis4.85 (1.73-13.54)0.0030.96 (0.31-2.97)0.950BVAS ≥ 201.50 (0.59-3.81)0.393Revised FFS ≥ 24.40 (1.28-15.13)0.0180.83 (0.16-4.27)0.818MPSL pulse therapy1.16 (0.47-2.86)0.746Received CYC or RTX1.54 (0.55-4.27)0.409CMV reactivation5.10 (1.93-13.48)0.0013.50 (1.22-10.06)0.020† “Renal involvement” was excluded in the multivariate analysis to avoid multicollinearity.Conclusion:Our study shows that there should be focus on subsequent severe infections when CMV reactivation is detected during early phase of treatment, especially in renal-impaired patients with ANCA-associated vasculitis.References:[1]Gardiner BJ et al. Rheumatol Int. 2019;39:1229-40[2]Hung M et al. J Microbiol Immunol Infect. 2019;52:114-21.[3]Hanaoka R et al. Mod Rheumatol. 2012;22:438-45.[4]Morgan MD et al. Arthritis Rheum. 2011;63:2127-37.Disclosure of Interests:Daisuke Waki Speakers bureau: Mitsubishi Tanabe Pharma, AbbVie Inc, eisai Co,. Ltd, ONO PHARMACEUTICAL CO., LTD,, Keisuke Nishimura Speakers bureau: Mitsubishi Tanabe Pharma Corporation. Pfizer Inc. Kyowa Kirin Co., Ltd. Chugai Pharmaceutical Co., Ltd. ONO PHARMACEUTICAL CO., LTD. Japan Blood Products Organization. Kissei Pharmaceutical Co., Ltd. Astellas Pharma Inc. AYUMI Pharmaceutical Corporation. Eisai Co., Ltd. DAIICHI SANKYO COMPANY. Norvartis AG. Bayer AG. Sanofi K.K., Tomohiro Yoshida: None declared, Keiichiro Kadoba: None declared, Nozomi Tanaka: None declared, Hiroyuki Murabe: None declared, Toshihiko Yokota: None declared

Background Colour doppler ultrasonography (CDU) in temporal arteries (TA) is useful for diagnosis and follow-up of giant cell arteritis (GCA).1 However, the usefulness of CDU in carotid arteries (CA) for follow-up of GCA is not fully understood. 2 Objectives We investigated retrospectively relationship between clinical features and vessel wall thickness of TA and CA on CDU at baseline and during follow-up. Methods We recruited patients with newly diagnosed GCA in our hospital from January in 2004 to July in 2017. Among 35 patients, both of TA and CA were evaluated by CDU before and after treatment in 14 patients (four male and 10 female). Trained ultrasonographers and rheumatologists evaluated the CDU findings. Vessel wall thickness was evaluated at thickest portion of parietal or frontal ramus of TA, where biopsy was often performed. Intima-media thickness (IMT) of CA was also evaluated at thickest portion in each carotid artery. Results Average age was 73.2±11.3 years old. Follow-up periods after starting treatment were 244±149 weeks. All patients were diagnosed as GCA according to ACR criteria (1990) or temporal artery biopsy. Twelve patients were complicated with polymyalgia rheumatica (PMR) meeting EULAR/.ACR classification criteria (2012). All patients were treated with oral glucocorticoids (0.2 to 1.0 mg/kg prednisolone, 0.886 mg/kg on average). Immunosuppressants were added in four patients (methotrexate; n=3, tacrolimus; n=1). Aspirin was prescribed in nine patients. Eleven patients (78.6%) had circumferential hypoechoic vessel wall thickness (halo sign) of TA at baseline, and halo signs dissapeared in eight patients during follow-up. Average of vessel wall thickness significantly decreased from 0.665 mm to 0.311 mm (p=0.0016). The vessel wall thickness apparently increased in two patients out of three on clinical relapse, but it didn’t increase in those who kept remission. Graphical changes consistent with vasculitis in CA were observed in six patients, who showed hypoechoic thick intima and media on ultrasound or integration of FDG on PET/CT. Average of IMT in CA decreased from 1.167 mm to 0.883 mm (p=0.090) during follow-up in patients with vasculitis on CA. IMT changed little in patients without vasculitis on CA. Improvement rate was significantly higher in CA-involved patients than in CA-non-involved patients (p=0.043). IMT increased during follow-up in two CA-non-involved patients. Difference in B/A between CA involved and non-involved: p=0.043 (Mann-Whitney U test) Conclusions CDU of temporal arteries is useful for follow-up of GCA. CDU of carotid arteries has limited usefulness only in CA-involved patients. References [1] Suelves AM, et al. Clin Ophthalmol. 2010; Nov 25;4:1383–4. [2] Hafner F, et al. Eur J Clin Invest2014; 44(3):249–256. Disclosure of Interest None declared

Background The introduction of treatment regimens comprising of cyclophosphamide or rituximab combined with corticosteroids has brought about dramatic improvements in the prognosis of ANCA-associated vasculitis. 1 Severe infectious events, especially in the early phase of treatment, associated with risk of death have been reported in the past several studies. 2,3 Objectives We retrospectively investigated the association between mortality and early severe infection in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), and we also attempted to identify the potential predictors for early severe infection. Methods We recruited 182 consecutive hospitalised patients newly diagnosed with AAV at our hospital, from January 2000 to June 2017, in this retrospective cohort study. All cause mortality, relapse, and severe infections within six months after starting treatment (early severe infection) were analysed. Results The mean age was 70 years at diagnosis, and the classification according to the Chapel Hill Conference definition were microscopic polyangiitis (MPA) in 82 patients (45.1%), granulomatosis with polyangiitis (GPA) in 36 patients (19.8%), eosinophilic granulomatosis with polyangiitis (EGPA) in 24 patients (13.2%), and renal-limited vasculitis in 32 patients (17.6%). 4 Median follow up was 158 weeks (range 0–182 w). Using Cox regression analysis, elderly onset (age ≥75 years) AAV (p = 0.027) and early severe infection (p ≤ 0.001) were independent predictors of all cause mortality (table 1). Early severe infection tended to increase among patients who received immunosuppressive therapy of a corticosteroid combined with cyclophosphamide or rituximab (conventional treatment), and this trend was significant in non-severe (BVAS = 0.030) (table 2). Treatment response rate (p=0.058) and relapse rate (p = 0.137) were not significant between the different treatment groups. Conclusions Early severe infection is an independent predictor of death in patients with AAV, and conventional treatment has a potential risk of death due to severe infection. This study supports the current EULAR recommendation that several treatment strategies are recommended according to the disease severity of vasculitis. 5 AAV patients who receive conventional treatment should be carefully monitored to reduce the occurrence of severe infection, especially in early phase of treatment. References [1] Little MA, et al. Ann Rheum Dis2010;69:1036–43. [2] Lai QY, et al. J Rheumatol2014;41(9):1849–55. [3] Solans-Laque R, et al. Medicine2017;96(8):e6083. [4] Janette JC, et al. Arthritis Rheum2013;65:1–11. [5] Yates M et al. Ann Rheum Dis 2016;75(9):1583–94. Disclosure of Interest None declared

Silicone (polydimethylsiloxane) sheets and tubes were irradiated with Ar ions using plasma-based ion implantation (PBII). The roughness of the surface increased dramatically with increasing applied high voltage. The Raman spectra showed a destruction of methyl groups and the formation of amorphous carbon structures. The RBS measurements indicated an enrichment of carbon atoms and the presence of implanted ions at the surface. Owing to the irradiation, the adhesive strength of the fibrin glue (a biological tissue adhesive) improved from 0.08 to 0.57 N/mm 2 and the cell attachment percentage increased from 50 to 85% in a sample irradiated at 5 kV.

Diamond-like carbon (DLC) is a kind of carbon materials and it is considered to have an excellent biocompatibility. DLC coating to the surface of various materials was proposed to improve the biocompatibility of materials. It is possible that DLC is able to apply to biomaterials such as artificial vessel, tooth root and joint in the future. However, the relationship between fine structure, morphology, element doping, etc. in DLCs and the biocompatibility is not clear yet. As a kind of barometer of the biocompatibility, in this study, we have investigated the cell adhesion to nitrogen-doped DLCs fabricated by the PBIID method using toluene gas. The cell adhesion percentage for a non-doped DLC was 75.6%. That for nitrogen-doped DLCs increased monotically from 78.3% to 87.6% with an increasing nitrogen concentration, up to 0.7%. However, when the nitrogen concentration was more than 0.7%, the adhesion percentage saturated at about 87%. As a result, the cell adhesion percentage for nitrogen-doped DLCs was enhanced more than 10% in comparison with that for a non-doped DLC. It is considered that the cell adhesion percentage is improved due to C–N and N–H bonds that promoted the protein adsorption on the surface of the sample, and that the surface became hydrophilic excessively at the nitrogen concentration more than 0.7% and the electrostatic effects were cancelled.

Silicone (polydimethylsiloxane) sheets and tubes for medical use were irradiated with inert gas ions using plasma-based ion implantation (PBII). The affinity of the surface with tissue examined by an animal test was improved by the irradiation at optimal conditions. The cell attachment percentage increased at an applied voltage of less than −7.5 kV; however, it decreased at higher voltage. The specimens irradiated at higher voltages were more hydrophobic than unirradiated specimens. The surface became rough with increasing voltage and textures, and small domains appeared. This effect was caused by different etching speeds in the amorphous and crystalline areas.

A 21-year-old man presented persistent dry cough, general malaise, loss of appetite, decreased sexual desire and double vision. Chest radiograph revealed a mass shadow in the left upper lobe. Histopathological diagnosis of the tumor was squamous cell carcinoma. Brain computed tomography and magnetic resonance imaging revealed a metastasis to the pituitary gland. Hypopituitarism was diagnosed by pituitary function tests. Diabetes insipidus was absent and the function of the posterior lobe of the pituitary gland was preserved. Hypopituitarism due to pituitary metastasis is a rare complication of lung cancer, and has never been reported in a patient as young as 21 years old.

In the present study, the work function change of Li 2 O due to change of oxygen potential of sweep gas was investigated by measuring the contact potential difference (CPD) between Li 2 O and Pt electrodes with a so-called `high temperature Kelvin probe'. The CPD change for Li 2 O was generally insensitive to the oxygen partial pressure in the sweep gas. A similar insensitivity was also observed for LiAlO 2 . Although the CPD change of Li 2 O was about 200 mV when the oxygen partial pressure was changed by as much as 15 orders of magnitude, such was not the case for LiAlO 2 . By comparing with the results obtained for other Li-bearing ceramics, it was estimated to be caused by the adsorption/desorption processes of water vapor contained in the sweep gas.

Diamond-like carbon (DLC) has excellent mechanical properties and chemical stability. Several techniques have been proposed for DLC fabrication. The plasma-based ion implantation and deposition (PBIID) method has several advantages, such as few limitations in sample shape, in comparison with conventional PVD or CVD methods. We have investigated the cell adhesion to nitrogen-doped DLCs fabricated by the PBIID method. The cell adhesion percentage for a non-doped DLC was 67% and for nitrogen-doped DLCs the adhesion increased by more than 10%. The cell adhesion percentage was 85% for a sample with a ratio of nitrogen to carbon of 0.2. We consider the possibility that the cell adhesion percentage is improved due to C–N and N–H bonds that promote the protein adsorption on the surface of the sample.

PATIENT: Male, 66. FINAL DIAGNOSIS: Hypercalcemic crisis. SYMPTOMS: Near drowning state. MEDICATION: - CLINICAL PROCEDURE: - SPECIALTY: Critical care medicine. OBJECTIVE: Challenging differential diagnosis. BACKGROUND: Hypercalcemic crisis, generally caused by malignancy or primary hyperparathyroidism, is a life-threatening emergency that can result in multi-organ failure. Lowering the patient's calcium level immediately and determining the correct etiology are essential. CASE REPORT: We report a case of hypercalcemic crisis with a novel etiology. A 66-year-old male presented to the emergency room in cardiac arrest with a ventricular arrhythmia after being discovered submerged in an indoor public bath. He underwent cardioversion and was emergently intubated. Computed tomography showed bilateral pulmonary edema, suspected from water aspiration. Laboratory data revealed severe hypercalcemia and mild hypernatremia. Following three days of continuous hemodiafiltration, serum Ca decreased to and remained within normal limits. We concluded the etiology of hypercalcemia was absorption of Ca resulting from aspirated water. CONCLUSIONS: Near drowning can be a cause of hypercalcemic crisis. For cases of near drowning, it is important to investigate the source of the aspirated water and consider electrolyte abnormalities in the diagnosis. Language: en

Prolonged hypoglycemia induced by acetohexamide (AH) in a patient with noninsulin dependent diabetes mellitus accompanied by primary hypothyroidism was presented. A 74-year-old man who had been treated with AH (500mg, daily) for diabetes mellitus since 1973 was admitted to our hospital in Oct. 1988 because of hypoglycemic coma. On admission, the level of blood glucose was 20mg/dl. Continuous intravenous administration of 10 per cent glucose solution led to improvement in the mental state on the second day. However, the level of blood glucose remained between 30 to 45mg/dl for four days after admission. On the fifth day, a fasting blood glucose level finally reached 75mg/dl. In a thyroid function test, the serum levels of thyroid hormone showed the following decreases: T3 68ng/dl, T4 2.8 micrograms/dl, free T4 0.3ng/dl, while basal TSH levels increased to 50.3 microU/ml. Since anti-thyroid microsomal antibody was positive and thyroid 99mTc-pertechnetate uptake was slightly elevated, the hypothyroidism in this patient was considered to be caused by chronic thyroiditis. Urinalysis was positive for protein. In a renal function test, the blood urea nitrogen was 26.7mg/dl and creatinine 1.7mg/dl, and creatinine clearance decreased to 22ml/min. After thyroid function returned to euthyroid, creatinine clearance improved (41 ml/min). To clarify the relationship between hypothyroidism and the metabolism of AH, the serum levels of AH and its metabolite hydroxyhexamide (HH) following oral administration of AH (500mg) were evaluated before and after thyroxine replacement therapy. The blood glucose level before therapy was lower than that after therapy, and hypoglycemic symptoms were observed early in the second and third morning after AH administration.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of metastatic thyroid cancer from sigmoid colon cancer is presented. A 52-year-old woman had a sigmoidectomy due to adenocarcinoma of the sigmoid colon in April 1988. Serum carcinoembryonic antigen (CEA) levels gradually rose from July 1990 along with multiple metastatic lesions which appeared in the lung. They were resected in January 1991. Two months later the subject noticed a painless and firm lump on the left anterior neck. She was found to have a solitary mass in the left thyroid lobe. Thyroid function remained within normal range. Cytological findings obtained by fine-needle aspiration biopsy showed tall columnar carcinoma cells with an acinar pattern. Subtotal thyroidectomy was performed, and histological examination revealed metastatic adenocarcinoma from colon cancer. Immunohistochemical staining by anti-CEA was positive but anti-thyroglobulin was negative.

Using [125I] bTSH, labeled TSH binding (LTB) in sera from 203 patients with various thyroid disorders was studied. Four of them with known potent anti-TSH antibody showed extremely high LTB, as has been reported previously. Excluding these 4 sera, the mean ± s.d. of serum LTB from 199 patients was calculated to be 8.6 ± 2.1%. LTB exceeding 10.7% (mean + 1 s.d.) was observed in 16 sera; these weretaken as increased. LTB measured by polyethyleneglycol (PEG) precipitation correlated significantly with the serum IgG concentration; however, sera with increased LTB had high values irrespective of the serum IgG concentration. Specificities of increased LTB in 13 sera were further analyzed by means of binding to Protein A-sepharose and displacement studies using bTSH and nonradioactively iodinated bTSH. A significant correlation was observed between the LTB obtained by PEG and those by Protein A-sephrose. BTSH specificity was confirmed in 5 of the 13 sera; 7 of the remaining 8 sera showed displacement only by iodinated bTSH. None of the control Graves' sera showed any significant displacement. Comparisons of the results of measurement of LTB by Protein A-sephrose and those by the displacement studies disclosed that most of displaced sera had increased LTB to the IgG fraction. Disease distributions of 203 overall cases and 20 increased LTB cases revealed that apparently higher incidence (22.9%) of increased LTB in untreated Graves' patients than the others, though some increased LTB cases were also observed in patients with inactive Graves' or other thyroid disorders. In conclusion, increased LTB was observed in sera from approximately 10% of the patients with various thyroid disorders; most of them were found to be specific to either bTSH or iodinated bTSH. A frequent association of increased LTB with active Graves disease suggests a significance of these antibody like products to the disease process.

To clarify magnesium metabolism in thyroid dysfunction, plasma and erythrocyte magnesium concentrations (P-Mg, E-Mg) were determined in patients with untreated thyroid diseases and their relations to thyroid hormone levels and the duration of illness were examined. P-Mg was significantly lower in hyperthyroid patients than in euthyroid or hypothyroid individuals. E-Mg was significantly higher in hypothyroid patients than in hyperthyroid or euthyroid individuals. In the entire series of 84 subjects, both P-Mg and E-Mg showed significant negative correlations with thyroid hormone levels, but the correlations were greater in P-Mg than E-Mg. In hyperthyroid patients, both P-Mg and E-Mg were negatively correlated with the duration of illness, but this correlation was greater in E-Mg than P-Mg. Also, both P-Mg and E-Mg were significantly higher in patients with destructive thyroiditis with a short duration (0.5 months) such as subacute or painless thyroiditis than in patients with Graves' disease (4.9 months). These results suggest that magnesium metabolism in thyroid dysfunction is affected not only by thyroid hormone levels but also by the duration of illness.

The effect of T3 was studied on phosphorylation of cytosolic proteins in rat anterior pituitary. Cytosols obtained from hypothyroid (H) and T3 (50 μg/100 g body weight) injected H rats (T) were phosphorylated in vitro. Although total incorporation of 32P into proteins did not differ between H and T, analysis of phosphoproteins by SDS polyacrylamide gel electrophoresis and autoradiography revealed that T3 injection significantly increased phosphorylation of 2 proteins within 1 h. These results and our previous demonstration of T3 effects on phosphorylation in rat liver cytosol and cultured human skin fibroblasts suggest that protein phosphorylation is an important early intracellular process in T3 action.

Decreased serum T3 concentrations in elderly subjects and their possible relationship with the development of dementia have been indicated. To see the effects of a passive increase in the serum T3 concentration, low dose T3 administration was undertaken. Forty-four subjects from 65 to 93 years of age (average 81.0 +/- 7.8) were divided into 2 groups. The grade of dementia was determined by Hasegawa's dementia rating scale (DR score). In 22 subjects, 25 micrograms per day of T3 was administered for 4 W, while the control group was given a placebo. The DR score was measured before and immediately after the study. Changes in behaviour were monitored in a double-blind fashion. The administration of T3 induced a 0.65 nmol/l increase in serum T3 in 2 W and 0.36 nmol/l in 4 W. These T3 increases were not associated with significant changes in the DR score but 7 of 22 subjects showed apparent improvement in behaviour. TSH was suppressed to less than 1 mU/l in 2 W and then slightly increased by the 4th week, but T4, rT3 and fT4 all showed significant and progressive decreases. The DR score after T3 correlated significantly with the rT3/T4 ratio (before T3: -0.55, changes: +0.50) and also with changes in rT3 (r = 0.49). In conclusion, T3 administration to the elderly subjects was associated with behavioural improvement in some individuals, but the intellectual ability as assessed by the DR score in those with low T3 or elevated rT3 were hardly improved by passive T3 elevation.

In our previous study, we observed a tendency towards an age-related increase in the serum thyrotropin (TSH) concentration. Regulatory mechanisms TSH secretion in elderly subjects were studied. In 43 elderly subjects, serum TSH did not correlate significantly with serum T4, T3 free T4 or rT3. Further, those with increased TSH (>5 mU/l, 9 subjects) did not overlap with those with low T3 (

Our previous study demonstrated that a high level of nuclear triiodothyronine receptors (NT3R), which are identical to the hepatic NT3R, exists in neuronal nuclei of the cerebral cortex from an adult rat brain. To investigate whether thyroid hormone acts through binding to nuclear receptors, we measured RNA polymerase activities in isolated neuronal and glial nuclei of cerebral cortices prepared from three groups of rats with different T3 levels: T3 (20 micrograms/100 g BW/d, for three days)-injected hyperthyroid rats, control normal rats, and thyroidectomized rats. The enzyme activities in both nuclear fractions were assayed under the condition of dose-response linearity. When RNA polymerase I activity in neuronal nuclei from control rats was expressed as 100%, the activities from T3-injected and hypothyroid rats were 112.3 +/- 3.4% (n = 5, P less than .05) and 86.9 +/- 3.5% (n = 5, P less than .05), respectively. The increase in the enzyme activities were parallel to the increase in T3 content in neuronal nuclei among the groups. Glial nuclear RNA polymerase I showed the same tendency in response to T3, although the enzyme activity was smaller than from neuronal nuclei. RNA polymerase II, however, showed no significant change in response to altered T3 levels. The existence of numerous receptors and an induction of increased RNA polymerase I activity by T3 in neuronal nuclei raise the possibility that thyroid hormone through a NT3R pathway in the cerebral cortex of even the mature rat brain.

In a patient with active Graves' disease an infiltrative ophthalmopathy developed during antithyroid drug therapy. Her eye symptoms were effectively treated with a large dose of prednisolone (PD), plasma exchanges (PE), cyclophosphamide, orbital irradiation, antithyroid drug and a supplemental dose of triiodothyronine. Before, during and after these treatments thyrotropin binding inhibitor immunoglobulin (TBII) activities in a unit serum immunoglobulin (IgG) were measured after adjusting the IgG concentration by adding normal IgG. Relative TBII concentrations were calculated by extrapolating individual data on a standard curve constructed from serial dilutions of the most potent IgG. Approximately a 5 fold increase in the TBII concentration was observed during the 2 months of progression of the ophthalmopathy, while TBII activity revealed only a 13.3% increase. After treatment TBII concentrations decreased gradually showing a close relation with the severity of the eye symptoms. Every PE was found to remove 48.5 +/- 7.9 (s.e.m.) % of TBII. After PE TBII returned to the preexchange level very rapidly and then overshot it in 2 to 3 weeks. Sixty mg of PD failed to prevent the overshoot but a 100 mg initial dose of PD after 5 PEs inhibited it to some extent. The effectiveness of combined therapy with PE, PD and cyclophosphamide appeared to confirm a role of humoral factors in the pathogenesis of Graves' ophthalmopathy. Serial determinations of TBII in a relative concentration were considered quite useful in analyzing the effectiveness of treatment in Graves' ophthalmopathy.

Many studies have shown alterations in the number of nuclear triiodothyronine receptor (NT3R) under pathophysiologic situations. Most of these studies were performed on the rat liver and it is not known whether NT3R in different tissues exhibits an alteration similar to that in the liver. We compared the change of nuclear receptor capacity for T3 in the liver and kidney during starvation and after T3 injection. Fasting for 72 h decreased maximal binding capacity (Cmax) in the rat liver receptor to 67% of the control, while it did not significantly change Cmax in the kidney. These changes in Cmax were parallel to those of nuclear protein concentrations in both tissues. Daily sc injection of T3 (20 μg/100 g body weight) for 3 days also caused the different alteration of Cmax in the liver and kidney. After T3, hepatic NT3R increased to 182% of the control, but renal NT3R increased only to 136%. Association constants were the same in all groups. These results show that changes of NT3R capacity under some conditions vary in different tissues.

To elucidate the mechanism of thyroid hormone action in the mature brain, we analyzed nuclear T3 receptors (NT3R) in neuronal and glial nuclei. Neuronal and glial nuclear fractions were prepared from mature rat brains with about 80% and 98% purity, respectively. Results from Scatchard analyses showed that NT3R capacity in neurons was 684.2 +/- 95.4 pg T3/mg DNA (mean +/- SD) in isolated nuclei and 345.6 +/- 77.6 pg T3/mg DNA in nuclear protein extracted with 0.4 M KCl. Glial NT3R had only one eighth the capacity of neuronal receptors. Displacement studies with several T3 analogs showed highly selective affinity of the receptors for L-T3. The relative affinities for several analogs were similar to those of liver NT3R. In addition, the elution profiles of the nuclear extracts through HPLC using gel filtration or diethylaminoethyl ion exchange columns exhibited similarity between neuronal and hepatic NT3R. The receptors in neuronal and glial nuclear fractions were analyzed in three groups of rats with different T3 levels: T3 (20 micrograms/100 g BW daily, for 3 days)-injected hyperthyroid rats, intact rats, and thyroidectomized rats. There were no significant alterations in capacity or affinity of the receptors among groups. The present studies demonstrate that numerous NT3R, which seem identical to hepatic NT3R, exist in neuronal nuclei. This raises the possibility that thyroid hormone acts through binding to NT3R in the cerebral cortex of the mature rat brain.

Labeled TSH binding (LTB) of individual serum samples was monitored simultaneously using the thyrotropin binding inhibitor immunoglobulin (TBII) assay. In 643 TBII determinations, 86 sera (13.4%) showed elevated LTB. The incidence of elevated LTB in active Graves’ patients (17.5%) was much higher than that of inactive Graves’ patients (6.7%). After TBII activities were corrected by LTB, 79% of the active Graves’ patients who had negative raw TBII were found to be positive. In patients with untreated active Graves’ disease, the detectability of TBII increased from 85% to 91% after LTB correction, while those in inactive Graves’ and other thyroid disorders did not increase so much (1.6 and 0%, respectively). Further, most of elevated LTB seen in other thyroid disorders were found to be different from those in Graves’ disease by heat stability experiment. Serial observations of LTB and TBII in 24 Graves’ patients showed 2 patterns. Parallel alterations were observed in 13 patients and reciprocal alterations in 11 patients. Patients showing parallel alteration had smaller goiter and were more sensitive to antithyroid drugs than those showing the latter pattern.

A patient with thyrotoxic Graves' disease had an apparent measurable level of serum TSH (2.5 microU/ml) by double-antibody radioimmunoassay (RIA). The serum IgG bound with both [125I]human(h)TSH and [125I]bovine(b)TSH. The [125I]hTSH binding was more effectively displaced by human than bovine TSH, whereas [125I]bTSH binding was displaced exclusively by bTSH. Scatchard analyses revealed that [125I]hTSH binding showed two components, whereas [125I]bTSH binding had only one component. Serum TSH determined by RIA became undetectable 21 months after antithyroid drug treatment with a parallel decrease of [125I]hTSH binding IgG activity. Four thyrotrophin binding inhibitory immunoglobulins (TBII) from other patients did not interfere with the binding of the patient's serum to [125I]h- or bTSH. Furthermore, the in-vitro thyroid stimulating activities of three thyroid stimulating antibodies (TSAb) were not affected by the addition of this patient's IgG. On the other hand, this patient's Ig (3 mg/ml) abolished the in-vitro thyroid stimulation by bTSH (100 microU/ml), but did not affect that by hTSH (100 microU/ml). The anti-hTSH antibody, TSH receptor antibody and anti-bTSH antibody in the serum, which contains TSAb as well as anti-TSH antibodies, could be partially purified by hTSH-agarose and subsequently by guinea pig fat cell membrane affinity absorptions. However, the anti-hTSH antibody fraction obtained had both hTSH binding activity and thyroid stimulating activity, and this fraction did not show any inhibitory effect on the in-vitro thyroid stimulation of autologous TSH receptor antibody or hTSH. The possible significance of anti-TSH antibodies is discussed.