Nobuko Sera

Incidence and Prognostic Value of Early Repolarization Pattern in the 12-Lead Electrocardiogram

Background— Early repolarization pattern is a common ECG finding characterized by J-point elevation and QRS notching or slurring in the inferior and/or lateral leads, yet little is known about its incidence and long-term prognosis in Asian populations. Methods and Results— We reviewed all the ECG records of the 5976 atomic-bomb survivors who were examined at least once during our biennial health examination in Nagasaki, Japan, between July 1958 and December 2004. We defined early repolarization pattern as ≥0.1-mV elevation of the J point or ST segment, with notching or slurring in at least 2 inferior and/or lateral leads. We assessed unexpected, cardiac, and all-cause death risk by Cox analysis. We identified 1429 early repolarization pattern cases (779 incident cases) during follow-up, yielding a positive rate of 23.9% and an incidence rate of 715 per 100 000 person-years. Early repolarization pattern had an elevated risk of unexpected death (hazard ratio, 1.83; 95% confidence interval, 1.12 to 2.97; P=0.02) and a decreased risk of cardiac (hazard ratio, 0.75; 95% confidence interval, 0.60 to 0.93; P<0.01) and all-cause (hazard ratio, 0.85; 95% confidence interval, 0.78 to 0.93; P<0.01) death. In addition, both slurring and notching were related to higher risk of unexpected death (hazard ratio, 2.09; 95% confidence interval, 1.06 to 4.12; P=0.03), as was early repolarization pattern manifestation in both inferior and lateral leads (hazard ratio, 2.50; 95% confidence interval, 1.29 to 4.83; P<0.01). Conclusions— Early repolarization pattern is associated with an elevated risk of unexpected death and a decreased risk of cardiac and all-cause death. Specific early repolarization pattern morphologies and location are associated with an adverse prognosis.

Fatty liver incidence and predictive variables

Although fatty liver predicts ischemic heart disease, the incidence and predictors of fatty liver need examination. The objective of this study was to determine fatty liver incidence and predictive variables. Using abdominal ultrasonography, we followed biennially through 2007 (mean follow-up, 11.6±4.6 years) 1635 Nagasaki atomic bomb survivors (606 men) without fatty liver at baseline (November 1990 through October 1992). We examined potential predictive variables with the Cox proportional hazard model and longitudinal trends with the Wilcoxon rank-sum test. In all, 323 (124 men) new fatty liver cases were diagnosed. The incidence was 19.9/1000 person-years (22.3 for men, 18.6 for women) and peaked in the sixth decade of life. After controlling for age, sex, and smoking and drinking habits, obesity (relative risk (RR), 2.93; 95% confidence interval (CI), 2.33–3.69, P<0.001), low high-density lipoprotein-cholesterol (RR, 1.87; 95% CI, 1.42–2.47; P<0.001), hypertriglyceridemia (RR, 2.49; 95% CI, 1.96–3.15; P<0.001), glucose intolerance (RR, 1.51; 95% CI, 1.09–2.10; P=0.013) and hypertension (RR, 1.63; 95% CI, 1.30–2.04; P<0.001) were predictive of fatty liver. In multivariate analysis including all variables, obesity (RR, 2.55; 95% CI, 1.93–3.38; P<0.001), hypertriglyceridemia (RR, 1.92; 95% CI, 1.41–2.62; P<0.001) and hypertension (RR, 1.31; 95% CI, 1.01–1.71; P=0.046) remained predictive. In fatty liver cases, body mass index and serum triglycerides, but not systolic or diastolic blood pressure, increased significantly and steadily up to the time of the diagnosis. Obesity, hypertriglyceridemia and, to a lesser extent, hypertension might serve as predictive variables for fatty liver.

Association of human T lymphotropic virus type I with Sjögren syndrome

Sjogren syndrome (SS) is an autoimmune disease caused by a combination of genetic and environmental factors. The most important environmental factor is viral infection. The retrovirus human T lymphotropic virus type I (HTLV-I) is deemed as an SS pathogen, because anti-HTLV-I antibodies were positive in 23% of patients with SS but only in 3.4% of control subjects (blood donors).1 The patients with SS in that study, however, were limited to those who visited the hospital, and the control is not screened for SS, a bias may have been present. Thus, in the present study, we measured anti-HTLV-I antibodies in 852 Nagasaki atomic bomb survivors who had previously been screened for SS. Between November 2002 and October 2004, 1008 Nagasaki atomic bomb survivors who had been followed biennially since 1958 at the Radiation Effects Research Foundation (RERF),2 answered a questionnaire concerning ocular and oral symptoms and were screened for anti-SS-A/Ro, anti-SS-B/La antibodies and rheumatoid factor. …

CD4+ T cell-mediated cytotoxicity toward thyrocytes: the importance of Fas/Fas ligand interaction inducing apoptosis of thyrocytes and the inhibitory effect of thyroid-stimulating hormone.

The accumulation of activated CD4+ T cells and antigen (Ag)-dependent cellular interactions between thyrocytes and CD4+ T cells have been determined in thyroid gland from patients with Graves’ disease. The Fas/Fas ligand (FasL) interaction between antigen-presenting cells and T cells regulates the apoptosis of the former cells triggered by the latter cells. The inhibition of Fas-mediated apoptosis in thyrocytes could be a underlying mechanism of hyperplasia of thyrocytes in patients with Graves’ disease. We investigated the potential role of Fas/FasL interaction between thyrocytes and CD4+ T cells in the induction of Fas-mediated apoptosis of the former cells induced by the latter cells. The presence of only a few specific T cells responsive to a putative autoantigen has hampered the investigation of specific T cell activation toward antigen-presenting cells (APCs). Therefore, we used a superantigen, staphylococcal enterotoxin B (SEB), to examine specific T cell activation toward thyrocytes in vitro since it stimulates a large proportion of T cells with particular Vβ elements. Spontaneous apoptosis of thyrocytes in culture was not found even in the presence of various kinds of cytokines. In contrast, a clear induction of Fas-mediated apoptosis by anti-Fas IgM was determined in interferon-γ (IFN-γ)-stimulated thyrocytes. In addition, a significant cytotoxicity of purified CD4+ T cells toward IFN-γ-stimulated thyrocytes in the presence of SEB was induced, and the addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or blockade of the Fas/FasL interaction reduced this cytotoxicity. FasL expression of CD4+ T cells cocultured with IFN-γ-stimulated thyrocytes in the presence of SEB was clearly induced. Furthermore, the addition of mAbs against CD54 and CD58 inhibited both cytotoxicity and FasL expression of CD4+ T cells. The cytotoxicity of CD4+ T cells toward IFN-γ-stimulated, SEB-pulsed thyrocytes was markedly inhibited when we used thyrocytes cultured with IFN-γ in the presence of thyroid-stimulating hormone (TSH) as target cells. Our results suggest that 1) CD4+ T cells were activated by thyrocytes expressing MHC class II molecules in an SEB-dependent manner and then expressed FasL. 2) These activated FasL+ CD4+ T cells killed thyrocytes by interacting with Fas on thyrocytes and FasL on activated CD4+ T cells. The presence of costimulating molecules such as CD54 and CD58 on thyrocytes was also necessary to generate activated FasL+ CD4+ T cells. 3) Since the actions of thyroid stimulating antibody (TSAb) toward thyrocytes are similar to those of TSH, one goitrogenic activity of TSAb may, in part, be due to the inhibitory effect on Fas-mediated apoptosis of thyrocytes triggered by activated CD4+ T cells.

The association between chronic kidney disease and cardiovascular disease risk factors in atomic bomb survivors.

Atomic bomb (A-bomb) radiation is associated with cardiovascular disease (CVD) and metabolic CVD risk factors. Chronic kidney disease (CKD) is also known to be a risk factor for CVD and little is known whether CKD is associated with A-bomb radiation. To examine whether CKD is associated with CVD risk factors or with A-bomb radiation in A-bomb survivors, we classified renal dysfunction in 1,040 A-bomb survivors who were examined in 2004–2007 as normal [n = 121; estimated glomerular filtration rate (eGFR) ≥90 ml/min/1.73 m2]; mild (n = 686; eGFR 60–89 ml/min/1.73 m2); moderate (n = 217; eGFR 30–59 ml/min/1.73 m2); or severe (n = 16; eGFR <30 ml/min/1.73 m2). Also, we diagnosed subjects in the moderate and severe renal dysfunction groups as having CKD (n = 233; eGFR <59 ml/min/1.73 m2). After adjusting for age, gender, and smoking and drinking habits, we looked for an association between renal dysfunction and hypertension, diabetes mellitus (DM), hyperlipidemia, and metabolic syndrome (MetS), and between renal dysfunction and A-bomb radiation. Hypertension [odds ratio (OR), 1.57; 95% confidence interval (CI), 1.12–2.20, P = 0.009]; DM (OR, 1.79; 95% CI, 1.23–2.61, P = 0.002); hyperlipidemia (OR, 1.55; 95% CI, 1.12–2.14, P = 0.008); and MetS (OR, 1.86; 95% CI, 1.32–2.63, P < 0.001) were associated with CKD (moderate/severe renal dysfunction), and hyperlipidemia and MetS were also associated with mild renal dysfunction. CKD (OR/Gy, 1.29; 95% CI, 1.01–1.63, P = 0.038) and severe renal dysfunction (OR/Gy, 3.19; 95% CI, 1.63–6.25, P < 0.001) were significantly associated with radiation dose. CKD associated with radiation may have played a role in the development of CVD among A-bomb survivors.

Metabolic cardiovascular disease risk factors and their clustering in subclinical hypothyroidism

Objective  A possible association between subclinical hypothyroidism and cardiovascular disease (CVD) has been reported. Monitoring of atomic‐bomb survivors for late effects of radiation exposure at the Radiation Effects Research Foundation has provided the opportunity to examine associations between subclinical hypothyroidism and metabolic CVD risk factors. The objective of the study was to evaluate associations between subclinical hypothyroidism and metabolic CVD risk factors, and a cluster of these factors.

Risk for Progression to Overt Hypothyroidism in an Elderly Japanese Population with Subclinical Hypothyroidism

BACKGROUND Few population-based studies report the changes with time in thyroid function tests in patients with subclinical hypothyroidism. We compared the risk for developing overt hypothyroidism in patients with subclinical hypothyroidism and euthyroid controls from the same population of elderly Japanese. We also sought associations of selected parameters with the development of overt hypothyroidism in the subclinical hypothyroid and euthyroid groups. METHODS We measured thyrotropin (TSH) and free thyroxine (T4) levels at baseline examinations performed from 2000 to 2003 in the cohort of Japanese atomic-bomb survivors and identified 71 patients with spontaneous subclinical hypothyroidism (normal free T4 and TSH >4.5 mIU/L without a history of thyroid treatment, mean age 70 year) and 562 euthyroid controls. We re-examined TSH and free T4 levels an average of 4.2 years later (range, 1.9-6.9). RESULTS The risk for progression to overt hypothyroidism was significantly increased in subclinical hypothyroid patients (7.0%) compared with control subjects (1.6%) after adjusting for age and sex (odds ratio, 4.56; p=0.009). Higher baseline TSH levels were associated with progression from subclinical to overt hypothyroidism (p=0.02) in the multivariate analysis, including age, sex, antithyroid peroxidase antibody, and ultrasonography (US) findings. The analysis using binary TSH data suggested that a TSH level >8 mIU/L was a predictive value for development of overt hypothyroidism (p=0.005). On the other hand, serum TSH levels spontaneously normalized in 38 (53.5%) of the patients with subclinical hypothyroidism. In the multivariate analysis, normalization of TSH levels was associated with lower baseline TSH levels (p=0.004) and normal and homogenous thyroid US findings (p=0.04). Atomic-bomb radiation dose was not associated with subclinical hypothyroidism or its course. CONCLUSIONS Subclinical hypothyroidism was four times more likely to be associated with development of overt hypothyroidism than euthyroid controls in the sample population of Japanese elderly. TSH levels in half of the patients normalized spontaneously when assessed after an average follow-up period of 4.2 years. Baseline TSH level and thyroid US findings are potential predictors of future thyroid function in subclinical hypothyroidism.

Elevation of Serum Pro-Gastrin - Releasing Peptide in Patients with Medullary Thyroid Carcinoma and Small Cell Lung Carcinoma

Medullary thyroid carcinoma (MTC) arises from parafollicular or C cells of the thyroid gland and produces a variety of peptides such as calcitonin (CT) and gastrin-releasing peptide (GRP). Here we measured serum levels of pro-gastrin-releasing peptide (Pro-GRP), a more stable precursor of GRP, in 15 patients with MTC (4 males, 11 females) who did not show any clinical or radiologic signs of small cell lung cancer. Serum Pro-GRP levels were elevated in 80% (12/15) patients. Significant correlation was observed between serum Pro-GRP and CT (r = 0.52) and carcinoembryonic antigen (CEA) (r = 0.56). Serum Pro-GRP levels also correlated with tumor size (r = 0.70). Serum Pro-GRP levels also decreased below the cut-off range in one patient after surgical resection. Our data suggest that Pro-GRP, which is considered to be a specific marker for small cell lung carcinoma, seems to be also helpful and additional marker for the diagnosis and monitoring the response to therapy in patients with MTC in addition to calcitonin as the main tumor marker.

Association of radiation dose with prevalence of thyroid nodules among atomic bomb survivors exposed in childhood (2007-2011).

IMPORTANCE Few studies have evaluated the association of radiation dose with thyroid nodules among adults exposed to radiation in childhood. OBJECTIVE To evaluate radiation dose responses on the prevalence of thyroid nodules in atomic bomb survivors exposed in childhood. DESIGN, SETTING, AND PARTICIPANTS This survey study investigated 3087 Hiroshima and Nagasaki atomic bomb survivors who were younger than 10 years at exposure and participated in the thyroid study of the Adult Health Study at the Radiation Effects Research Foundation. Thyroid examinations including thyroid ultrasonography were conducted between October 2007 and October 2011, and solid nodules underwent fine-needle aspiration biopsy. Data from 2668 participants (86.4% of the total participants; mean age, 68.2 years; 1213 men; and 1455 women) with known atomic bomb thyroid radiation doses (mean dose, 0.182 Gy; median dose, 0.018 Gy; dose range, 0-4.040 Gy) were analyzed. MAIN OUTCOMES AND MEASURES The prevalence of all thyroid nodules having a diameter of 10 mm or more (consisting of solid nodules [malignant and benign] and cysts), prevalence of small thyroid nodules that were less than 10 mm in diameter detected by ultrasonography, and atomic bomb radiation dose-responses. RESULTS Thyroid nodules with a diameter of 10 mm or more were identified in 470 participants (17.6%): solid nodules (427 cases [16.0%]), malignant tumors (47 cases [1.8%]), benign nodules (186 cases [7.0%]), and cysts (49 cases [1.8%]), and all were significantly associated with thyroid radiation dose. Excess odds ratios per gray unit were 1.65 (95% CI, 0.89-2.64) for all nodules, 1.72 (95% CI, 0.93-2.75) for solid nodules, 4.40 (95% CI, 1.75-9.97) for malignant tumors, 2.07 (95% CI, 1.16-3.39) for benign nodules, and 1.11 (95% CI, 0.15-3.12) for cysts. The interaction between age at exposure and the dose was significant for the prevalence of all nodules (P = .003) and solid nodules (P < .001), indicating that dose effects were significantly higher with earlier childhood exposure. No interactions were seen for sex, family history of thyroid disease, antithyroid antibodies, or seaweed intake. No dose-response relationships were observed for small (<10-mm diameter) thyroid nodules. CONCLUSIONS AND RELEVANCE Radiation effects on thyroid nodules exist in atomic bomb survivors 62 to 66 years after their exposure in childhood. However, radiation exposure is not associated with small thyroid nodules.

Right bundle branch block without overt heart disease predicts higher risk of pacemaker implantation: The study of atomic-bomb survivors☆☆☆

BACKGROUND We investigated the clinical course of complete right bundle branch block (RBBB) or RBBB with axis deviation (AD) in terms of subsequent pacemaker implantation for high-degree atrioventricular (AV) block or sick sinus syndrome (SSS). METHODS AND RESULTS Among the 16,170 atomic-bomb survivors in our biennial health examination between July 1967 and December 2010, we detected 520 newly-acquired RBBB subjects with no organic heart disease, and selected 1038 age- (at RBBB diagnosis) and sex-matched subjects without RBBB to serve as comparison subjects. Multivariate Cox regression analysis was used to estimate the hazard ratios (HRs) for the risk of pacemaker implantation due to all causes, AV block or SSS between RBBB and comparison subjects and between RBBB subjects with and without AD. The risk of pacemaker implantation for RBBB was 4.79 (95% confidence interval [CI] 1.89-12.58; P=0.001), 3.77 (95% CI, 1.09-13.07; P=0.036), and 6.28 (95% CI, 1.24-31.73, P=0.026) when implantation was for all causes, AV block and SSS, respectively. RBBB subjects with AD had a higher risk for all-cause pacemaker implantation than subjects without AD (HR, 3.03; 95% CI, 1.00-9.13, P=0.049). RBBB subjects with AD were younger than subjects without AD at the time of RBBB diagnosis (59.4±7.6 vs 74.4±3.1 years old, P=0.019), and their progression from diagnosis to pacemaker implantation took longer (15.1±6.6 vs 6.4±3.0 years, P=0.032). CONCLUSIONS RBBB, especially with AD, progresses to AV block and SSS that requires pacemaker implantation; the mechanisms by which the conduction defect progresses differ among patients with and without AD.