Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
Advance online publication
Showing 1-50 articles out of 58 articles from Advance online publication
  • Cheng-Chih Chung, Yung-Kuo Lin, Yu-Hsun Kao, Shyh-Hsiang Lin, Yi-Jen C ...
    Type: Original
    Article ID: EJ20-0344
    Published: 2020
    [Advance publication] Released: October 27, 2020
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    Testosterone deficiency is associated with poor prognosis among patients with chronic heart failure (HF). Physiological testosterone improves the exercise capacity of patients with HF. In this study, we evaluated whether treatment with physiological testosterone contributes to anti-fibrogenesis by modifying calcium homeostasis in cardiac fibroblasts and we studied the underlying mechanisms. Nitric oxide (NO) analyses, calcium (Ca2+) fluorescence, and Western blotting were performed in primary isolated rat cardiac fibroblasts with or without (control cells) testosterone (10, 100, 1,000 nmol/L) treatment for 48 hours. Physiological testosterone (10 nmol/L) increased NO production and phosphorylation at the inhibitory site of the inositol trisphosphate (IP3) receptor, thereby reducing Ca2+ entry, phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) expression, type I and type III pro-collagen production. Non-physiological testosterone-treated fibroblasts exhibited similar NO and collagen production capabilities as compared to control (testosterone deficient) fibroblasts. These effects were blocked by co-treatment with NO inhibitor (L-NG-nitro arginine methyl ester [L-NAME], 100 μmol/L). In the presence of the IP3 receptor inhibitor (2-aminoethyl diphenylborinate [2-APB], 50 μmol/L), testosterone-deficient and physiological testosterone-treated fibroblasts exhibited similar phosphorylated CaMKII expression. When treated with 2-APB or CaMKII inhibitor (KN93, 10 μmol/L), testosterone-deficient and physiological testosterone-treated fibroblasts exhibited similar type I, and type III collagen production. In conclusion, physiological testosterone activates NO production, and attenuates the IP3 receptor/Ca2+ entry/CaMKII signaling pathway, thereby inhibiting the collagen production capability of cardiac fibroblasts.

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  • Xiaosong Yuan, Jing Wang, Yanfang Gao, Huiyan Wang, Bin Yu
    Type: Original
    Article ID: EJ20-0377
    Published: 2020
    [Advance publication] Released: October 27, 2020
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    The purpose of this study was to explore the impact of maternal thyroid hormone dysfunction in late pregnancy on birth outcomes in a Chinese population. We retrospectively examined hospitalisation records and laboratory data between April 2016 and March 2017 and obtained results from 11,564 consecutive pregnant women with singleton births in which serum thyroid hormone had been examined together with birth outcomes. We assessed the association between maternal thyroid level and dysfunction with adverse birth outcomes based on regression analysis. Hyperthyroidism was associated with an increased risk of preterm birth (PTB, adjusted OR: 2.41, 95% CI: 1.83–3.17) and hypothyroidism was associated with an increased risk of small for gestational age (SGA, adjusted OR: 1.56, 95% CI: 1.10–2.22), while hyperthyroxinaemia was associated with a decreased risk of large for gestational age (LGA, adjusted OR: 0.64, 95% CI: 0.45–0.90). In addition, compared to women with normal FT3 and TSH (≥the 5th and ≤the 95th percentiles), women with high free triiodothyronine (FT3 >the 95th percentile) and low thyroid-stimulating hormone (TSH <the 95th percentile) had a 4.02- fold higher risk of PTB ‍(95% CI: 2.05–7.88), and women with low FT3 and high TSH had a 4.22- fold greater risk of SGA (95% CI: 1.59–11.23). Our study supports associations between multiple types of maternal thyroid dysfunction in late pregnancy and adverse birth ‍outcomes.

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  • Shihan Chen, Hui Liu, Panyu Luo, Yerong Yu
    Type: Original
    Article ID: EJ20-0395
    Published: 2020
    [Advance publication] Released: October 23, 2020
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    Primary aldosteronism (PA) is the most common cause of secondary hypertension, and a simpler non-invasive method for identification of aldosterone-producing adenoma (APA) is required to improve the standard of medical treatment for PA patients. We retrospectively analyzed the clinical data of hypertensive patients with an aldosterone/renin ratio (ARR) ≥30 (ng/dL)/(ng/mL/h), and surgical and/or adrenal venous sampling (AVS) results served as the gold standard for APA diagnosis. The study aimed to determine whether positive CCT and SIT results plus a unilateral adrenal nodule found by CT allow unambiguous identification of an APA with high diagnostic specificity. Clinical data from 71 APA and 47 non-APA patients were collected, and logistic regression analysis was performed to construct models. Receiver operating characteristic (ROC) curves were used to analyze the efficacy of diagnostic tests. The areas under the ROC curves (AUCs) were similar between the post-SIT plasma aldosterone concentration (PAC) and post-CCT PAC (p > 0.05). The optimal post-SIT and post-CCT PAC cutoff values were 17.2 and 21.2 ng/dL, respectively. Positive CT findings combined with a post-SIT PAC >17.2 ng/dL or post-CCT PAC >21.2 ng/dL provided specificities of 97.8% and 95.7% for predicting APA, respectively. Logistic diagnostic models 1 (M1, CT finding + post-SIT PAC) and 2 (M2, CT finding + post-CCT PAC) were built, which showed equivalent diagnostic value (AUC = 0.959 and 0.932, respectively) (p > 0.05). The models combining CT findings with post-SIT PACs or post-CCT PACs represent an easier method to distinguish APA patients from other hypertensive patients with positive upright ARR results, especially in primary care where AVS may be unavailable.

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  • Hanna Deguchi-Horiuchi, Hisashi Koide, Ikki Sakuma, Yue Gao, Seiichiro ...
    Type: Original
    Article ID: EJ20-0361
    Published: 2020
    [Advance publication] Released: October 21, 2020
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    Rathke’s cleft cyst (RCC) is a common incidental tumor in the hypothalamic-pituitary region. Some reports have shown that the clinical symptoms and endocrine functions of symptomatic RCCs are temporarily improved by glucocorticoid administration. However, it is still unknown whether glucocorticoid treatment is effective for symptomatic RCCs according to long-term observations. In this study, we describe the long-term clinical outcomes of two cases of glucocorticoid-treated biopsy-proven secondary hypophysitis caused by RCCs. We summarize the symptoms, imaging findings, and endocrine evaluations of two symptomatic RCC patients with concomitant hypophysitis before and after prednisolone treatment. In both evaluated cases, visual impairments and altered endocrine parameters were present due to chiasm and stalk compression; these outcomes improved after shrinkage of RCCs in response to prednisolone administration, and partial recovery of anterior pituitary hormone secretion was observed. However, in both cases, the deficits in anterior pituitary hormone secretion recurred, possibly due to persistent inflammatory infiltration in the RCCs and pituitary glands. After relapse of hypophysitis, anterior hormone secretion did not fully recover. In our cases of secondary hypophysitis caused by RCCs, prednisolone administration had an early effect of cyst shrinkage, followed by partial improvements in clinical symptoms and pituitary functions. However, long-term observation showed that prednisolone treatment did not contribute to complete improvement in anterior pituitary hormone dysfunction.

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  • Pengfei Yan, Yongbo Wang, Tao Fu, Yu Liu, Zhi-Jiang Zhang
    Type: Original
    Article ID: EJ20-0138
    Published: 2020
    [Advance publication] Released: October 20, 2020
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    Supplementary material

    Diabetes mellitus (DM) is widely considered to be associated with the risk of diverse cancers; however, the association between DM and the risk of leukemia is still controversial. Thus, a detailed meta-analysis of cohort studies was conducted to elucidate this association. Eligible studies were screened through the electronic searches in PubMed, Web of Science, and Embase from their inception to August 11, 2020. Summary relative risks (RRs) and 95% confidence intervals (CIs) were computed through the random-effects model. Eighteen articles involving 10,516 leukemia cases among a total of 4,094,235 diabetic patients were included in this meta-analysis. Overall, twenty-five RRs were synthesized for type 2 diabetes mellitus (T2DM) and yielded a summary RR of 1.33 (95%CI, 1.21–1.47; p < 0.001). For type 1 diabetes mellitus (T1DM), 7 RRs were combined, however, the pooled RR was insignificant (RR, 1.08; 95%CI, 0.87–1.34; p = 0.48). Interestingly, the summary RR for East Asia (RR, 1.83, 95%CI, 1.63–2.06) was significantly higher than that for Europe (RR, 1.11, 95%CI, 1.06–1.15), Western Asia (RR, 1.40, 95%CI, 1.25–1.54), North America (RR, 1.14, 95%CI, 1.08–1.20), and Australia (RR, 1.47, 95%CI, 1.25–1.71). Moreover, we found that patients with a shorter T2DM duration (1–5 years) had a higher risk of leukemia compared to those with a longer duration (5.1–10 years). Overall, this meta-analysis suggests there is a moderately increased risk of leukemia among T2DM patients, but not in T1DM patients. Further investigation is warranted.

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  • Qihuan Lv, Jian Zhou, Jiongjiong Liu, Dongmei Kang, Hongyu Zhang
    Type: Original
    Article ID: EJ20-0186
    Published: 2020
    [Advance publication] Released: October 20, 2020
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    Serum osteocalcin (OCN) is closely related to metabolic risk factors, and the relationship between OCN and atherosclerosis has been investigated. However, it is still controversial. Herein, we explored the potential correlation between serum total OCN and lower extremity atherosclerotic disease (LEAD) in 326 hospitalized Chinese patients with type 2 diabetes mellitus (T2DM). Femoral intima-media thickness (F-IMT) and lower limb atherosclerotic plaque were assessed through color Doppler ultrasound. Subjects with LEAD had significantly lower serum OCN levels compared with those without LEAD (14.54 [14.10–14.89] ng/mL versus 16.79 [15.86–18.04] ng/mL, p < 0.001). Spearman’s correlation analysis revealed that serum OCN levels were positively associated with high density lipoprotein cholesterol (HDL-C) and negatively associated with fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (2hPG), hemoglobin A1c (HbA1c), waist-to-hip ratio (WHR) and F-IMT. Multiple logistic analysis revealed that OCN (OR 0.938, 95% confidence interval (CI 0.933–0.950, p = 0.003) and glomerular filtration rate (GFR) (OR 0.990, 95% CI 0.985–0.996, p = 0.003) were independently and inversely associated with LEAD, while age (OR 1.140, 95% CI 1.127–1.148, p < 0.001), diabetes duration (OR 1.068, 95% CI 1.039–1.080, p < 0.005) and uric acid (UA) (OR 1.005, 95% CI 1.002–1.007, p = 0.032) were independently and positively associated with LEAD. Additionally, multiple linear regression analysis revealed that serum OCN levels were negatively associated with F-IMT (standardized β = –0.180, p = 0.002). In Chinese patients with T2DM, serum OCN levels were independently and inversely correlated with LEAD.

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  • Huan Li, Maoguang Yang, Hong Shen, Sisi Wang, Hanqing Cai
    Type: Original
    Article ID: EJ20-0448
    Published: 2020
    [Advance publication] Released: October 20, 2020
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    Werner syndrome, also called adult progeria, is a heritable autosomal recessive human disorder characterized by the premature onset of numerous age-related diseases including juvenile cataracts, dyslipidemia, diabetes mellitus (DM), osteoporosis, atherosclerosis, and cancer. Werner syndrome is a segmental progeroid syndrome whose presentation resembles accelerated aging. The most common causes of death for WS patients are atherosclerosis and cancer. A 40-year-old female presented with short stature, bird-like facies, canities with alopecia, scleroderma-like skin changes, and non-healing foot ulcers. The patient reported a history of delayed puberty, abortion, hypertriglyceridemia, and juvenile cataracts. A clinical diagnosis of WS was made and subsequently confirmed. We discovered two WRN gene mutations in the patient, Variant 1 was the most common WRN mutation, nonsense mutation (c.1105C>T:p.R369Ter) in exon 9, which caused a premature termination codon (PTC) at position 369. Variant 2 was a frameshift mutation (c.1134delA:p.E379KfsTer5) in exon 9, which caused a PTC at position 383 and has no published reports describing. Patients with WS can show a wide variety of clinical and biological manifestations in endocrine-metabolic systems (DM, thyroid dysfunction, and hyperlipidemia). Doctors must be cognizant of early manifestations of WS and treatment options.

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  • Yutaro Yamamoto, Yoshio Nagai, Shin Kawanabe, Yoshiaki Hishida, Koji H ...
    Type: Original
    Article ID: EJ20-0550
    Published: 2020
    [Advance publication] Released: October 17, 2020
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    Type 2 diabetes is associated with sarcopenia. Resistance training and appropriate nutritional therapy are reported to be effective for muscle strength and mass. This study aimed to evaluate the effect of resistance training using elastic bands at home combined with a leucine-rich amino acid supplement on muscle strength, physical function, and muscle mass in elderly type 2 diabetes. We conducted a 48-week prospective single-center randomized controlled trial in 60 patients who were randomly allocated to one of three groups: control (C), resistance exercise (R), and resistance exercise plus supplement (RL). R and RL groups performed daily bodyweight resistance training with elastic bands exercises at home, and the RL group also took 6 g of a leucine-rich amino acid supplement daily. Knee extension strength (muscle strength), grip strength, usual gait speed (physical function), muscle mass, and cognitive function were assessed at 0 and 48 weeks. Although the change in knee extension strength from baseline was significantly increased by 6.4 Nm (95% CI 1.0, 11.7) in the RL group (p = 0.036), no significant difference was observed among the three groups (p = 0.090). Physical function, muscle mass, and cognitive function also had no changes during the study period among the three groups. No additive effect of a leucine-rich amino acid supplement on muscle strength or mass was observed. Although a post hoc analysis comparing with or without resistance training (C group vs. R + RL group) found that knee extension strength was significantly increased (p = 0.028), and cognitive decline was less (p = 0.046) than in the C group.

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  • Shintaro Iwama, Hiroshi Arima
    Type: Review
    Article ID: EJ20-0436
    Published: 2020
    [Advance publication] Released: October 14, 2020
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    Autoimmunity contributes to the pathogenesis of hypophysitis, a chronic inflammatory disease in the pituitary gland. Although primary hypophysitis is rare, the number of pituitary dysfunction cases induced by immune checkpoint inhibitors (ICIs) is increasing. While it is difficult to prove the involvement of autoimmunity in the pituitary glands, circulating anti-pituitary antibodies (APAs) can be measured by indirect immunofluorescence and used as a surrogate marker of pituitary autoimmunity. APAs are present in several pituitary diseases, including lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis (LINH), IgG4-related hypophysitis, and pituitary dysfunction induced by ICIs. Mass spectrometry analysis of antigens targeted by APAs clarified rabphilin-3A as an autoantigen in LINH. This demonstrates that APAs can be applied as a probe to identify novel autoantigens in other pituitary autoimmune diseases, including pituitary dysfunction induced by ICIs, which can aid in biomarker discovery.

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  • Sung Keun Park, Ju Young Jung, Chang-Mo Oh, Joong-Myung Choi, Min-Ho K ...
    Type: Original
    Article ID: EJ20-0486
    Published: 2020
    [Advance publication] Released: October 10, 2020
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    Supplementary material

    Metabolic syndrome (MetS) consists of 5 metabolic components, which are recognized as risk factors for cerebral infarction. The present study was to evaluate the relative influence of individual metabolic component on incident cerebral infarction. Using a data of 209,339 Koreans registered in National Health Information Corporation, we evaluated the risk for incident cerebral infarction according to the number of metabolic component and each metabolic component for 4.37 years’ follow-up. Cox proportional hazards model was used to calculate hazard ratios (HRs) for cerebral infarction and their confidence interval (CI). The more metabolic components accompanied the worse metabolic profile, leading increased incidence of cerebral infarction. The risk of cerebral infarction increased proportionally to the number of present metabolic components (number 0: reference, number 1: 1.78 [1.42–2.23], number 2: 2.20 [1.76–2.74], number 3: 2.61 [2.09–3.25] and number 4–5: 3.18 [2.54–3.98]). Compared to subjects without metabolic component, the impact of each component on cerebral infarction was relatively higher in elevated fasting glucose (1.56 [1.14–2.13]) and elevated BP (2.13 [1.66–2.73]), indicating no statistical significance in low HDL-cholesterol (1.53 [0.96–2.44]), high triglyceride (1.24 [0.84–1.84]) and abdominal obesity (1.05 [0.63–1.73]). Proportional relationship was found between the number of metabolic component and risk of cerebral infarction. Out of metabolic components, fasting glucose and BP are more powerful predictor for cerebral infarction.

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  • Saisai Li, Weibo Li, Bo Sheng, Xueqiong Zhu
    Type: Original
    Article ID: EJ20-0340
    Published: 2020
    [Advance publication] Released: October 08, 2020
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    Uterine fibroids and thyroid nodules, both of which are crucially affected by estrogen, are common diseases among reproductive-age women. However, little attention has been paid to the association between the two diseases. This retrospective case-control study aimed to assess the relationships among thyroid nodules, thyroid function and uterine fibroids in China. We reviewed the electronic records of 853 reproductive-age women who attended health check-ups at the Second Affiliated Hospital of Wenzhou Medical University from July 1st, 2017, to June 30th, 2018. All subjects received transvaginal pelvic ultrasound, thyroid ultrasound, thyroid function, and other laboratory tests. We found that the prevalence of thyroid nodules in subjects with uterine fibroids was remarkably higher than that in subjects without fibroids. The proportion of thyroid nodules ≥1 cm in subjects with uterine fibroids was significantly higher than that in subjects without fibroids. Women with thyroid nodules had a higher proportion of multiple uterine fibroids than women without thyroid nodules. Among the parameters of thyroid function, the only statistically significant parameter was total triiodothyronine, i.e., women with uterine fibroids had lower total triiodothyronine levels than unaffected controls; however, the total triiodothyronine levels were within the normal ranges. Moreover, no significant difference was noted in thyroid hormone status between subjects with and without uterine fibroids. Our findings suggest that thyroid nodules are positively correlated with uterine fibroids among reproductive-age women in China. Further studies are needed to confirm this association and fully understand the common pathogenetic mechanism underlying the association between uterine fibroids and thyroid nodules.

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  • Natsuki Baba, Hiraku Kameda, Akinobu Nakamura, Kyu Yong Cho, Hiroshi N ...
    Type: Original
    Article ID: EJ20-0185
    Published: 2020
    [Advance publication] Released: October 06, 2020
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    A silent pituitary adenoma (SPA) is characterized by the expression of pituitary hormones, detected by immunohistochemical staining, in the absence of clinical signs or symptoms of hormonal excess. Compared with functional pituitary adenomas, little is known regarding the involvement of SPAs in metabolic disorders. This study aimed to examine the correlations between SPAs and metabolic disorders, including obesity, abnormal glucose tolerance, hypertension and dyslipidemia. Seventy-four patients with nonfunctional pituitary adenomas who underwent a pituitary adenomectomy in Hokkaido University Hospital from 2008 to 2016 were retrospectively examined. Pituitary adenomas were immunohistochemically classified into pituitary hormone positive or negative groups. Twenty whole hormone-negative pituitary adenomas were excluded because we couldn’t identify pituitary transcription factors which is necessary for the diagnosis of a null cell adenoma. The preoperative rates of obesity, abnormal glucose tolerance, hypertension and dyslipidemia were compared between each group. Twenty-seven GH positive adenomas (50.0%), 32 gonadotroph positive adenomas (59.3%), 28 TSH positive adenomas (51.9%) and 21 ACTH positive adenomas (38.9%) were identified. Evaluation of the preoperative clinical data showed 25 cases of obesity (46.2%), 16 cases of abnormal glucose tolerance (29.6%), 29 cases of hypertension (53.7%) and 35 cases of dyslipidemia (64.8%). The rate of hypertension was significantly lower in the GH positive group (37.0%) than the GH negative group (70.4%) (p = 0.0140). In the GH negative group, postoperative systolic and diastolic blood pressure levels were significantly lower than preoperative values. GH positive SPAs may affect the homeostasis of blood pressure.

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  • Yoshiaki Soejima, Nahoko Iwata, Yasuhiro Nakano, Koichiro Yamamoto, At ...
    Type: Original
    Article ID: EJ20-0359
    Published: 2020
    [Advance publication] Released: October 06, 2020
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    Functional interactions between the levels of clock gene expression and adrenal steroidogenesis were studied in human adrenocortical H295R cells. Fluctuations of Bmal1, Clock, Per2 and Cry1 mRNA levels were found in H295R cells treated with forskolin (FSK) in a serum-free condition. The changes of clock gene expression levels were diverged, with Clock mRNA level being significantly higher than Cry1 and Per2 mRNA levels after 12-h stimulation with FSK. After FSK induction, mRNA levels of StAR and CYP11B2 were highest at 12 hours and CYP17 mRNA level reached a peak at 6 hours, but HSD3B1 mRNA level was transiently decreased at 3 hours. The expression levels of Clock mRNA showed a significant positive correlation with StAR among the interrelationships between mRNA levels of key steroidogenic factors and clock genes. Knockdown of Clock gene by siRNA led to a significant reduction of FSK-induced expression of StAR and CYP17 after 12-h treatment with FSK. BMP-6 and activin, which modulate adrenal steroidogenesis, had inhibitory effects on Clock mRNA expression, whereas treatment with follistatin, a binding protein of activin, increased Clock mRNA levels in the presence of FSK, suggesting an endogenous function of activin in regulation of Clock mRNA expression. Collectively, the results indicated that changes of Clock mRNA expression, being upregulated by FSK and suppressed by BMP-6 and activin, were tightly linked to StAR expression by human adrenocortical cells.

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  • Koji Shiraishi, Chietaka Ohmi, Hideyasu Matsuyama
    Type: Original
    Article ID: EJ20-0365
    Published: 2020
    [Advance publication] Released: October 03, 2020
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    Male hypogonadotropic hypogonadism (MHH) is effectively treated by gonadotropins with a high rate of ejaculate sperm and paternity; however, there is no information regarding the appropriate management, including patient-reported outcomes (PROs), of men with MHH who have finished infertility treatment. To compare health-related quality of life, erectile function and biochemical alterations in men with MHH who were treated with testosterone replacement therapy (TRT) or human chorionic gonadotropin (hCG). Twenty-six MHH patients (mean age: 34 years) who needed to improve their androgen deficiency symptoms underwent either hCG therapy (n = 16, started with self-injection of 2,000–7,500 IU per week) or TRT (n = 10, testosterone enanthate 250 mg every 3 weeks). The 36-item Short Form Health Survey (SF-36) questionnaire, five-item International Index of Erectile Function (IIEF-5) and hormonal and biochemical analyses were assessed every 3 months. Changes and comparison of each treatment regarding these parameters were analyzed. Both hCG and TRT significantly improved all domains of the SF-36, except for bodily pain and social functioning. hCG significantly improved the general and mental health domains compared with TRT. Significant improvements in IIEF-5 were observed with both treatments, showing significant improvement with hCG compared to TRT. TRT caused progressive testicular atrophy. There were significant decreases in waist circumference and triglycerides in both treatment groups and significant elevations in prostate-specific antigen and hematocrit. Both hCG and TRT are effective and safe, with preferable PROs by hCG, for treating androgen deficiency in men with MHH who do not need infertility treatment.

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  • Hidefumi Inaba, Hiroyuki Ariyasu, Hiroshi Iwakura, Chiaki Kurimoto, Ke ...
    Type: Original
    Article ID: EJ20-0371
    Published: 2020
    [Advance publication] Released: October 03, 2020
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    Supplementary material

    Immune-related adverse events in the thyroid glands (thyroid irAEs) during treatment with immune-checkpoint inhibitors (ICIs) are most frequent endocrine irAE. Thyroid irAE can be divided into that requiring continuous therapy for thyroid dysfunction (P-THY), and that requiring only temporal treatment (T-THY). However, predictive factors for those differential outcomes are unknown, and susceptibility of human leukocyte antigen (HLA) to thyroid irAE has never been investigated. This study aimed to elucidate clinical courses and prognosis of P-THY in comparison with T-THY in the aspect of thyroid immunity and HLA. Patients with P-THY (n = 15) that required L-T4 supplemental therapy for hypothyroidism for more than 3 months, and patients with T-THY who required no therapy or therapy within 1 month were enrolled in the study. Lower-value of TSH, higher-value of FT4, and lower value of TSH/FT4 were thought to be predictive markers to estimate P-THY. In addition, anti-thyroglobulin antibody (TgAb) levels were significantly higher in patients with P-THY than those in patients with T-THY. HLA-DPA1*01:03 and HLA-DPB1*02:01 allele, and their haplotype frequencies were significantly higher in patients with P-THY than those in controls. P-THY had better survival rate than T-THY. Pre-existing thyroid autoimmunity, the extent of thyroid dysfunction, and predisposing HLA were associated with the differential course of thyroid irAEs. It was suggested that thyroid function tests, TgAb, and HLA typing tests are useful for prediction of clinical course in thyroid irAEs.

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  • Hongcui Diao, Xiaolong Yu, Chengqian Li, Yanjun Guo, Baoming Shen, Wen ...
    Type: Original
    Article ID: EJ20-0286
    Published: 2020
    [Advance publication] Released: October 01, 2020
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    Supplementary material

    We undertook a systematic review and meta-analysis to assess the effects and safety of activators of glucokinase (GKAs) in patients with type 2 diabetes mellitus (T2DM). 11 RCTs, including 2,429 participants, are enrolled in our study. According to different doses, we divided the studies into 3 groups: low-dose group, medium-dose group and high-dose group for subgroup analysis. There were decreases of HbA1c in all dose group (WMD = –0.27, 95%CI (–0.51~ –0.03), Z = 2.17, p = 0.03; WMD = –0.37, 95%CI (–0.58~ –0.16), Z = 3.41, p = 0.0006; WMD = –0.60, 95%CI (–0.86~ –0.33), Z = 4.43, p < 0.00001). Though the total risk of hypoglycemia is absolutely low, in the high-dose group higher hypoglycemia than the placebo can be observed (RR = 0.03, 95%CI (0.00~0.06), Z = 2.27, p = 0.02). In addition, the study found that the drug was less likely to have adverse reactions such as diarrhea, headache and dizziness, nasopharyngitis and upper respiratory tract infection (RR = 0.76, 95%CI (0.36~1.60), Z = 0.73, p = 0.47; RR = 1.26, 95%CI (0.73~2.17), Z = 0.83, p = 0.41; RR = 0.71, 95%CI (0.41~1.22), Z = 1.25, p = 0.21; RR = 1.61, 95%CI (0.77~3.36), Z = 1.26, p = 0.21). It concludes that GKAs are relatively effective and safe in the treatment of patients with T2DM, but in consideration of the potential risk of hypoglycemia in the high-dose group, the low-dose and medium-dose group, in the clinical practice, can be an excellent choice.

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  • Asako Tsunemi, Toyoyoshi Uchida, Keiji Kuroda, Yuko Ikemoto, Asako Och ...
    Type: Original
    Article ID: EJ20-0380
    Published: 2020
    [Advance publication] Released: October 01, 2020
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    Recent randomized controlled studies have revealed that levothyroxine (LT4) treatment improves pregnancy outcomes only in infertile women with subclinical hypothyroidism who have thyroid autoantibodies (TAs), but not for those with high TSH levels within the normal range who have TAs. Here, we retrospectively investigated pregnancy outcomes in infertile Japanese women with 2.5 μIU/mL ≤ TSH < upper reference limit (URL). Between 2012 and 2018, 286 patients diagnosed with infertility were followed for more than 1 year at our institution. Among them, we included 106 patients with 2.5 μIU/mL ≤ TSH < URL. We divided these patients into four groups based on the combination of TA positivity and LT4 treatment status to assess the effects of LT4 treatment considering TA positivity on the incidence of pregnancy or miscarriage. In this study, we did not find any significant differences in the rates of pregnancy or miscarriage among the four groups (p = 0.81 and 0.52, respectively). In addition, logistic regression analysis showed that age and history of miscarriage were associated with the incidence of pregnancy, but presence of TAs and LT4 treatment status were not and that no variables examined were associated with the incidence of miscarriage. In summary, we were not able to demonstrate the benefit of LT4 treatment for pregnancy outcomes in Japanese euthyroid infertile women with 2.5 μIU/mL ≤ TSH < URL regardless of TA status in this study.

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  • Marino Hiruma, Yoshiyuki Sasano, Natsuko Watanabe, Ai Yoshihara, Satos ...
    Type: Original
    Article ID: EJ20-0184
    Published: 2020
    [Advance publication] Released: September 29, 2020
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    Propylthiouracil (PTU)-induced otitis media with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is an extremely rare adverse event associated with anti-thyroid drugs and is not well recognized. A 42-year-old woman with Graves’ disease undergoing PTU therapy for 8 years visited our hospital because of earache and congested feeling in her left ear. Blood tests, a computed tomography scan and pure tone audiometry revealed otitis media and moderate mixed hearing impairment. Antibiotics, ear drops with antibiotics and painkillers were administered. However, her earache and hearing loss gradually got worse and symptoms of facial nerve palsy appeared. At several weeks after initiation of the treatment, a high serum level of myeloperoxidase (MPO)-ANCA, 75.6 U/mL, was revealed. After excluding other causes, she was diagnosed with OMAAV. PTU was suspected as the cause of her OMAAV and was immediately discontinued, and prednisolone was started. Hearing impairment in her left ear gradually got better and showed substantial improvement. Facial nerve palsy disappeared. Although PTU-induced OMAAV is an extremely rare disease, it is important to recognize the disease, as delayed treatment can lead to irreversible hearing loss, hypertrophic pachymeningitis, and subarachnoid hemorrhage. When patients taking anti-thyroid drugs, especially PTU, are diagnosed with refractory otitis media or hearing loss, it is possible that OMAAV might be the cause and thus serum ANCA levels should be evaluated.

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  • Chihiro Munekawa, Yukako Hosomi, Yoshitaka Hashimoto, Takuro Okamura, ...
    Type: Original
    Article ID: EJ20-0426
    Published: 2020
    [Advance publication] Released: September 29, 2020
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    Supplementary material

    To investigate the acute effects of the coronavirus disease 2019 (COVID-19) on the lifestyle and metabolic parameters in patients with type 2 diabetes mellites. This cross-sectional and retrospective cohort study induced 203 patients who completed a questionnaire regarding stress levels and lifestyles. Data regarding stress levels, sleep time, exercise, and total diet, snack, and prepared food intake were obtained from the questionnaires. The changes in the body weight or HbA1c levels were determined by comparing the values at the time the questionnaire was administered to those noted 3 months ago. Increased levels of stress and decreased exercise levels were reported in approximately 40% and >50%. During the COVID-19 pandemic. There was a negative correlation between stress and exercise (r = –0.285, p < 0.001) and a positive correlation between stress and prepared food intake (r = 0.193, p = 0.009). Decreased exercise levels (r = –0.33, p < 0.001) and increased snack consumption (r = 0.24, p = 0.002) were associated with increased body weight. Furthermore, increased total diet intake (r = 0.16, p = 0.031) was associated with increased HbA1c levels. These relationships remained significant for patients aged <65 years and patients who did not engage in regular exercise. Many patients experienced stress and lifestyle changes due to the COVID-19 pandemic, and these changes were associated with increased body weight and HbA1c levels.

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  • Tetsuro Niri, Ichiro Horie, Hiromi Kawahara, Takao Ando, Noriaki Fukuh ...
    Type: Note
    Article ID: EJ20-0300
    Published: 2020
    [Advance publication] Released: September 19, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Idiopathic hypothalamitis is a rare condition that can cause anterior pituitary dysfunction and central diabetes insipidus (CDI), occasionally accompanied by a disturbance of autonomic regulation known as hypothalamic syndrome. This condition has been described as a subtype of autoimmune (lymphocytic) hypophysitis; however, some cases of isolated hypothalamic involvement with no inflammatory lesions in either the pituitary gland or infundibulum have been reported. The detailed epidemiology and pathophysiology of isolated hypothalamitis have not been clarified. We herein report a case of a solitary hypothalamic lesion in a young woman who showed spontaneous development of CDI and panhypopituitarism accompanied by hyperphagia. The hypothalamic lesion increased from 11 × 7 to 17 × 7 mm over 16 months based on the sagittal slices of magnetic resonance imaging examinations. The negative results for anti-pituitary antibodies and anti-Rabphilin-3A antibodies suggested that upward extension of lymphocytic adenohypophysitis or infundibulo-neurohypophysitis was unlikely. Infectious disease, granulomatosis, Langerhans cell histiocytosis, vasculitis, and systemic neoplastic diseases were excluded by the findings of a laboratory investigation, cerebrospinal fluid examination, and imaging studies. To make a definitive diagnosis, we performed a ventriculoscopic biopsy of the hypothalamic lesion. Histology revealed an infiltration of nonspecific lymphoplasmacytes with no evidence of neoplasm, which was consistent with a diagnosis of idiopathic hypothalamitis. Subsequently, the patient was treated with methylprednisolone pulse therapy followed by oral prednisolone. The hypothalamic lesion improved and remained undetectable after withdrawal of the prednisolone, suggesting that the glucocorticoid treatment was effective for isolated hypothalamitis while the patient remains dependent on the replacement of multiple hormones.

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  • Kazunori Kageyama, Rie Hagiwara, Kanako Niioka, Shinobu Takayasu, Mako ...
    Type: Original
    Article ID: EJ20-0251
    Published: 2020
    [Advance publication] Released: September 18, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Autonomous production of adrenocorticotropic hormone (ACTH) from pituitary corticotroph adenomas is the primary cause of Cushing’s disease. Somatostatin receptor, a G protein-coupled receptor (GPCR), types 2 (SSTR2) and 5 (SSTR5) mRNA expression is greater than that of other SSTR subtypes in human corticotroph adenomas. Further, the multiligand SOM230 shows potent effects in decreasing ACTH plasma levels and urinary free cortisol levels in patients with Cushing’s disease. We previously showed that both Sstr2 and Sstr5 mRNA levels were unaffected by SOM230 treatment, suggesting that both receptors might not be downregulated by the agonist. Intracellular molecules, such as β-arrestins, modulate ligand activated-receptor responses. In the present study, we determined regulation of β-arrestin1 and β-arrestin2 by SOM230 and dexamethasone in murine AtT-20 corticotroph tumor cells. In addition, we examined the effects of β-arrestin1 and β-arrestin2 on Sstr mRNA and their protein levels. SOM230 treatment increased β-arrestin1 mRNA levels and did not alter β-arrestin2 mRNA levels. SOM230 treatment could induce β-arrestin1 production in corticotroph tumor cells. Dexamethasone treatment decreased β-arrestin2 mRNA levels. β-arrestin2 knockdown increased proopiomelanocortin, and both Sstr2 and Sstr5 mRNA and their protein levels. The β-arrestin2 knockdown-increased proopiomelanocortin mRNA levels were canceled by SOM230 treatment.

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  • Jiajun Li, Yue Wang, Xiao Zheng, Jie Sheng, Hui Guo, Wenlin Long, Yao ...
    Type: Original
    Article ID: EJ20-0239
    Published: 2020
    [Advance publication] Released: September 17, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Type 2 diabetes (T2D) is a chronic endocrine disorder with rapidly increasing prevalence worldwide. Genetic instability leading to metabolic dysfunction plays an important role in T2D susceptibility and progression. Structural alteration in genome, that is, copy number variation (CNV) is emerging as the inherent marker for disease identification. Previous genomic CNV array revealed that protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene was overlapped with a CNV region, however, whether this CNV affected T2D risk remains to be further elucidated. In this study, we first identified divergent distributions of the PTPN22 copy number (CN) between T2D patients and healthy controls in Chinese population (p < 0.01). Risk assessment analysis revealed that the CN gain (OR = 3.28, p < 0.001) was the promising risk factor for T2D. Also, significantly positive correlations of the PTPN22 CNV with fasting plasma glucose and glycated hemoglobin were demonstrated in T2D patients. Statistical association analysis investigated that the T2D individuals carrying CN gain showed higher plasma glucose and lower insulin levels than those carrying CN normal and loss at 60 min/120 min/180 min during an OGTT test. In addition, the PTPN22 CNV had an effect on total cholesterol, and the CN gain presented higher values than the other two CN types. These results suggested that the CN gain types of the PTPN22 gene accompany with the glycometabolism dysregulation, and finally predispose their carriers to T2D; therefore, the PTPN22 CNV may be a promising biomarker for predicting T2D risk, or a clinical target for T2D diagnosis and therapy.

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  • Jianxin Li, Jing Li, Zhongyan Shan, Wenying Yang, Jie Liu, Haoming Tia ...
    Type: Original
    Article ID: EJ20-0006
    Published: 2020
    [Advance publication] Released: September 10, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Using the data from the trial of Metformin and AcaRbose in Chinese as the initial Hypoglycemic treatment (MARCH), this study was performed to compare the differential effects of acarbose and metformin on glucose metabolism after stratification by gender. Six hundred and forty patients who had finished the whole 48-week follow-up were included. The reduction of haemoglobin A1c (HbA1c) was comparable between acarbose- and metformin-treated patients among either females or males, and it was also similar between males and females treated with either acarbose or metformin for 24 and 48 weeks. The dropping of fasting plasma glucose (FPG) in acarbose-treated females was significantly less than that in metformin-treated females at both 24 and 48 weeks. Furthermore, the decrease of 2-hour postprandial glucose (2hPPG) in acarbose-treated males was significantly greater than that in metformin-treated males at both 24 and 48 weeks. Multiple linear regression analysis showed that drug selection was an independent factor affecting the decrease of FPG in female patients while it independently influenced 2hPPG in males at week 24 and 48. The reductions of FPG and 2hPPG at week 24 and 48 were also significantly different between metformin-treated females and metformin-treated males although gender was not an independent regulating factor. Our study indicates that there might be gender-differential effects on FPG and 2hPPG reduction when the comparisons are made between acarbose and metformin treatments.

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  • Yoshimi Morita, Haruya Ohno, Kazuhiro Kobuke, Kenji Oki, Masayasu Yone ...
    Type: Original
    Article ID: EJ20-0366
    Published: 2020
    [Advance publication] Released: September 10, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Japanese Americans living in the United States are genetically identical to Japanese people, but have undergone a rapid and intense westernization of their lifestyle. This study investigated variability in glucagon secretion after glucose loading among Japanese Americans with normal glucose tolerance (NGT) according to obesity status. The 75-g oral glucose tolerance test (OGTT) was performed for 138 Japanese Americans (aged 40–75 years) living in Los Angeles. Plasma glucagon levels measured using the sandwich enzyme-linked immunosorbent assay were compared according to body mass index (BMI) categories among 119 individuals with NGT. The individuals were classified into three categories according to their BMI values: <22 kg/m2 (n = 37), 22–24.9 kg/m2 (n = 46), and ≥25 kg/m2 (n = 36). Fasting plasma glucagon levels and glucagon-area under the curve levels during the OGTT were the highest in the BMI ≥25 kg/m2 group. Fasting glucagon levels were correlated with BMI (r = 0.399, p < 0.001), fasting insulin levels (r = 0.275, p = 0.003) and the homeostasis model assessment-insulin resistance (r = 0.262, p = 0.004). In conclusion, our findings suggest that fasting hyperglucagonemia is associated with obesity and insulin resistance even during the NGT stage in the Japanese American population.

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  • Yohei Masunaga, Yasuko Fujisawa, Mayumi Muramatsu, Hiroyuki Ono, Takan ...
    Type: Note
    Article ID: EJ20-0291
    Published: 2020
    [Advance publication] Released: September 03, 2020
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    SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5–6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GH-treated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of ‍IRDM.

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  • Shoji Takagi, Mitsuyoshi Hirokawa, Kenji Nagashima, Miyoko Higuchi, Ky ...
    Type: Original
    Article ID: EJ19-0501
    Published: 2020
    [Advance publication] Released: September 02, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and invasive encapsulated follicular variant of papillary thyroid carcinoma (EFV-PTC) are indistinguishable preoperatively. CD26 expression in follicular tumor-uncertain malignant potential (FT-UMP) is reported to be clearly higher than in that without capsular invasion. To verify the diagnostic significance of CD26 immunostaining in EFV-PTC, we examined the expression pattern of CD26 in non-invasive EFV-PTC (NIFTP) and invasive EFV-PTC. We performed immunohistochemical analysis using CD26 antibody for 37 NIFTPs and 54 EFV-PTCs (34 minimally invasive EFV-PTCs and 20 widely invasive EFV-PTCs). Most NIFTP samples showed an apical membranous pattern or a cytoplasmic diffuse pattern of expression. Invasive EFV-PTCs more frequently showed a cytoplasmic dot-like pattern, and the labeling indices of tumor cells with cytoplasmic dot-like patterns were significantly higher than those in NIFTPs. The sizes of dots seen in NIFTPs (mean: 1.12 μm) were significantly smaller than in invasive EFV-PTCs (1.33 μm), minimally invasive EFV-PTC (1.27 μm), and widely invasive EFV-PTC (1.38 ‍μm). We, therefore, conclude that cytoplasmic diffuse and/or cytoplasmic dot-like CD26 expression, particularly the larger CD26-positive dots, could be useful markers for capsular invasion in EFV-PTC. CD26 immunostaining, using cell blocks or cytological specimens, may preoperatively distinguish between NIFTP and invasive EFV-PTC.

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  • Otgontsetseg Erdenebayar, Takeshi Kato, Takako Kawakita, Kana Kasai, Y ...
    Type: Original
    Article ID: EJ19-0586
    Published: 2020
    [Advance publication] Released: September 02, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Recent studies have revealed that the administration of oxytocin has beneficial effects on the regulation of body weight, food intake, and metabolic functions, especially in obese individuals. Obesity is common in women after the menopause and drives many components of metabolic syndrome. Weight gain in menopausal women has been frequently reported. Although obesity and associated metabolic disorders are frequently observed in peri- and postmenopausal women, there are few medical interventions for these conditions. In this study, we evaluated the effects of chronic oxytocin administration on appetite, body weight, and fat mass in peri- and postmenopausal female rats. Sixteen naturally premenopausal or menopausal rats were intraperitoneally injected with oxytocin (1,000 μg/day) for 12 days. The daily changes in their body weight and food intake were measured at the same time as the oxytocin and vehicle injections. Intraperitoneally administering oxytocin for 12 days significantly reduced food intake, body weight, and visceral adipocyte size. In addition, oxytocin administration caused reductions in serum triglyceride and low-density lipoprotein-cholesterol levels, while it did not disturb hepatic or renal functions or locomotor activity. This is the first study to show the effects of oxytocin on the metabolic and feeding functions of peri- and postmenopausal female rats. Oxytocin might be a useful treatment for metabolic disorders caused by the menopause or aging.

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  • Tsukasa Kawakami, Haruki Fujisawa, Shogo Nakayama, Yasumasa Yoshino, S ...
    Type: Original
    Article ID: EJ20-0289
    Published: 2020
    [Advance publication] Released: September 02, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Recently, chronic hyponatremia, even mild, has shown to be associated with poor quality of life and high mortality. The mechanism by which hyponatremia contributes to those symptoms, however, remains to be elucidated. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a primary cause of hyponatremia. Appropriate animal models are crucial for investigating the pathophysiology of SIADH. A rat model of SIADH has been generally used and mouse models have been rarely used. In this study, we developed a mouse model of chronic SIADH in which stable and sustained hyponatremia occurred after 3-week continuous infusion of the vasopressin V2 receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) and liquid diet feeding to produce chronic water loading. Weight gain in chronic SIADH mice at week 2 and 3 after starting dDAVP injection was similar to that of control mice, suggesting that the animals adapted to chronic hyponatremia and grew up normally. AQP2 expression in the kidney, which reflects the renal action of vasopressin, was decreased in dDAVP-infused water-loaded mice as compared with control mice that received the same dDAVP infusion but were fed pelleted chow. These results suggest that “vasopressin escape” occurred, which is an important process for limiting potentially fatal severe hyponatremia. Behavioral analyses using the contextual and cued fear conditioning test and T-maze test demonstrated cognitive impairment, especially working memory impairment, in chronic SIADH mice, which was partially restored after correcting hyponatremia. Our results suggest that vasopressin escape occurred in chronic SIADH mice and that chronic hyponatremia contributed to their memory impairment.

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  • Erkan Somuncu, Yasin Kara
    Type: Original
    Article ID: EJ20-0417
    Published: 2020
    [Advance publication] Released: September 02, 2020
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    Quality of life (QoL) typically improves with a parathyroidectomy (PTx) in cases of primary hyperparathyroidism (PHPT), but the effect of surgery on QoL is not yet fully understood. This study evaluated the impact of PTx on health-related QoL (HRQoL). Patients who underwent PTx for PHPT between January 2016 and December 2019 were asked to complete the 36-Item Short Form Health Survey (SF-36) and the Primary Hyperparathyroidism Quality of Life (PHPQoL) questionnaire before surgery and 1 year later. A 5-point Likert scale was used: negative responses received a lower score and positive responses scored high. Forty-one of 50 patients completed the questionnaires before and 12 months after the surgery. The median patient age was 64 years (min–max: 32–83 years). In the study group, 33 were female, and 8 were male. The SF-36 results indicated that significant improvements had been observed in all 8 domains a year after surgery, particularly in the physical functioning and role, general health, energy, and mental health scales. The PHPQoL scores also improved significantly after PTx (p < 0.05). The improvement in the physical and mental health components was 50% and 76%, respectively. In conclusion, this study demonstrated that PTx for PHPT improved QoL.

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  • Hiroshi Arima, Koichi Goto, Tomohisa Motozawa, Makoto Mouri, Ryo Watan ...
    Type: Original
    Article ID: EJ20-0216
    Published: 2020
    [Advance publication] Released: August 29, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    The purpose of this study was to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This multicenter, open-label, dose-escalation, phase III study enrolled Japanese patients (20–85 years old) with hyponatremia secondary to SIADH who were unresponsive to fluid restriction. Oral tolvaptan was administered for up to 30 days, initially at 7.5 mg/day, but escalated daily as necessary, based on the serum sodium concentration and safety, over the first 10 days until the optimal maintenance dose was determined for each patient (maximum 60 mg/day). The primary endpoint was the proportion of patients with normalized serum sodium concentration on the day after the final tolvaptan dose. Secondary endpoints included the mean change in serum sodium concentration from baseline on the day after the final dose. Sixteen patients (male, 81.3%; mean ± standard deviation age 71.9 ± 6.1 years) received tolvaptan treatment and 11 patients completed the study with one patient re-administered tolvaptan in the treatment period. Serum sodium concentrations normalized in 13 of 16 (81.3%) patients on the day after the final tolvaptan dose. The mean change in serum sodium concentration from baseline on the day after the final dose was 11.0 ± 4.3 mEq/L. Adverse events considered related to tolvaptan (10 [62.5%] patients) were generally of mild to moderate severity. Oral tolvaptan corrects hyponatremia in Japanese patients with SIADH with a similar efficacy and safety profile as that noted in non-Japanese patients.

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  • Sae Ishihara, Naoyoshi Onoda, Satoru Noda, Yukie Tauchi, Tamami Morisa ...
    Type: Original
    Article ID: EJ20-0287
    Published: 2020
    [Advance publication] Released: August 29, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Anaplastic thyroid cancer (ATC) is a rarely occurring refractory disease. While recent clinical trials have demonstrated the efficacy of tyrosine kinase inhibitor (TKI) therapy for ATC, evidence is scarce in clinical practice. In this study, we reviewed our initial experiences with TKI treatment in ATC patients with the aim of revealing the efficacy and safety of the same in clinical practice. We retrospectively reviewed our experiences with TKI treatment use in ATC patients diagnosed at our institute from 2014 to 2019. Changes in the patients’ neutrophil-to-lymphocyte ratio (NLR) by TKI therapy introduction as well as their clinical factors to indicate the efficacy were examined. Seven patients showed no indication for TKI treatment, while 13 (65%) received treatment. The median duration of TKI treatment was 1.9 months. All patients died, and the overall survival period from diagnosis was 4.7 (95% confidence interval: 2.0–11.5) months. Adverse events ≥Grade 3 were observed commonly (92.3%), and resulted in the termination of TKI treatment in six cases (46.1%). Existence of multiple unfavorable characteristics (higher Prognostic Index) was associated with poor survival. The NLR decreased after the introduction of TKIs and increased again when treatment failed. The response rate to TKI among the ATC patients were approximately 30% in practice. Although the duration of the response was short, several patients demonstrated long survival durations when TKI treatment was provided after successful multidisciplinary treatment to control local disease. Decreases in high NLR values during treatment may suggest the continued effect of TKIs.

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  • Guoqiang Fan, Yanfei Li, Fuli Ma, Ruqian Zhao, Xiaojing Yang
    Type: Original
    Article ID: EJ20-0179
    Published: 2020
    [Advance publication] Released: August 28, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Skeletal muscle is the most abundant tissue in the adult body and plays an essential role in maintaining heat production for the entire body. Recently, muscle-derived non-shivering thermogenesis under cold conditions has received much attention. Zinc-α2-glycoprotein (ZAG) is an adipokine that was shown to influence energy metabolism in the adipose tissue. We used ZAG knock-out (ZAG KO) and wild-type (WT) mice to investigate the effect of ZAG on the lipid metabolism of skeletal muscle upon exposure to a low temperature (6°C) for one week. The results show that cold stress significantly increases the level of lipolysis, energy metabolism, and fat browning-related proteins in the gastrocnemius muscle of WT mice. In contrast, ZAG KO mice did not show any corresponding changes. Increased expression of β3-adrenoceptor (β3-AR) and protein kinase A (PKA) might be involved in the ZAG pathway in mice exposed cold stress. Furthermore, expression of lipolysis-related proteins (ATGL and p-HSL) and energy metabolism-related protein (PGC1α, UCP2, UCP3 and COX1) was significantly enhanced in ZAG KO mice after injection of ZAG-recombinant plasmids. These results indicate that ZAG promotes lipid-related metabolism in the skeletal muscle when the animals are exposed to low temperatures. This finding provides a promising target for the development of new therapeutic approaches to improve skeletal muscle energy metabolism.

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  • Takehiro Kitagawa, Tatsuya Ohtonari, Junkoh Yamamoto, Nobuharu Nishiha ...
    Type: Original
    Article ID: EJ20-0292
    Published: 2020
    [Advance publication] Released: August 28, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Metastatic paraganglioma (MPG) of the spine is a rare condition, with no established management. Herein, we report the longest survival case of a primary neck tumor that caused spinal MPG with a succinate dehydrogenase subunit B (SDHB) mutation (c.470delT, p.L157X) which could have promoted its malignancy. This male patient initially presented with ‍a left neck PG which was diagnosed by a biopsy when he was 54 years-old. Simultaneously performed additional examinations revealed the spinal metastatic tumors on the T5-7 vertebrae and L3 vertebra-sacrum. These primary neck and metastatic spinal tumors’ growths were once suppressed under the radiation therapy. Nineteen years later, he developed acute progressive paraparesis due to a mass located at the T2-3 level, tightly compressing the spinal cord, and protruding into the left thoracic cavity. We resected the maximum possible area of tumor in the spinal canal, confirmed MPG by histological examination, and then, we administered radiation therapy of 40 Gy in 20 fractions. Eventually, the patient was able to walk unaided with no evidential tumor recurrence for 3 years after treatment. Generally, clinical feature of MPG with SDHB mutation from abdominal lesion is thought to be poor prognosis. However, our case suggests the possibility of long-term control of spinal MPG with the adequate combination of radiation therapy and resection if metastatic lesions from primary-neck lesion with an SDHB mutation are remained to spine.

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  • Norio Wada, Arina Miyoshi, Hiroaki Usubuchi, Satoshi Terae, Yui Shibay ...
    Type: Original
    Article ID: EJ20-0329
    Published: 2020
    [Advance publication] Released: August 26, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Captopril challenge test (CCT) is a simple and safe confirmatory test for primary aldosteronism (PA). We investigated the effectiveness of the indices after captopril administration for prediction of unilateral hyperaldosteronism (UHA) on adrenal vein sampling (AVS). We studied 238 patients with PA who had CCT and successful AVS between July 2007 and December 2019 in Sapporo City General Hospital. Receiver operating characteristic (ROC) curve analysis showed that the diagnostic performance for prediction of UHA on AVS in regard to the reduction rate of plasma aldosterone concentration (PAC) after captopril administration was inferior to aldosterone to renin ratio (ARR) and PAC (area under the ROC curve 0.72 vs. 0.84, 0.72 vs. 0.89, respectively, both p < 0.01). Based on the optimal cut-off values in ARR (897 pg/mL/ng/mL/h, sensitivity 64.6%, specificity 93.0%) and PAC (203 pg/mL, sensitivity 73.9%, specificity 93.0%) after captopril administration, the patients were divided into three groups: (1) both positive, (2) one positive, and (3) both negative. The prevalence of UHA on AVS in the three groups were 90.0%, 52.9%, and 7.3%, respectively. In the first group, 31 of 32 patients with unilateral nodular lesion on CT had an ipsilateral unilateral AVS. In conclusion, the combination of post-captopril ARR and PAC is useful for prediction of laterality diagnosis on AVS. AVS is strongly recommended in patients with both positive or one positive results for the optimal cut-off values of post-captopril ARR and PAC and is weakly recommended in patients with both negative results.

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  • Daisuke Otani, Takaaki Murakami, Takeshi Matsubara, Masato Hojo, Takur ...
    Type: Note
    Article ID: EJ20-0173
    Published: 2020
    [Advance publication] Released: August 20, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Acromegaly is characterized by autonomous excessive growth hormone (GH) secretion, generally due to GH-producing pituitary adenoma, and is associated with various systemic comorbidities including diabetes mellitus. Polycystic kidney disease (PKD) is characterized by the growth of numerous cysts in the kidneys that deteriorate renal function. While possible renal effects of excessive GH exposure have been a current issue in experimental medicine, only five cases of coexisting acromegaly and PKD have been reported previously, and little is known regarding the influence of acromegaly on renal disease. We treated a 50-year-old male with diabetes mellitus who showed a sudden and rapid decline of renal function along with increasing proteinuria, which led to diagnoses of PKD and acromegaly. His urinary protein levels were increased together with excessive GH secretion and worsening glycemic control. An increase of total kidney volume was also noted. Transsphenoidal surgery for the pituitary adenoma was successfully performed. Marked improvement of hyperglycemia and proteinuria were observed after the surgery, but renal function was unchanged. The patient’s clinical course suggested common aspects of excessive GH secretion as an accelerating factor of the progression of diabetic nephropathy and PKD via direct and indirect pathways. Although coexisting acromegaly and PKD is clinically rare, vigilance for early diagnosis of acromegaly is appropriate in patients with diabetes and/or PKD, especially in those showing unexpected exacerbation of renal dysfunction.

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  • Atsuhiko Sakamoto, Takashi Matsuzuka, Yukie Yamaya, Satoru Suzuki, Man ...
    Type: Original
    Article ID: EJ20-0235
    Published: 2020
    [Advance publication] Released: August 20, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    The Fukushima Daiichi Nuclear Power Plant accident occurred on March 11 2011, following the Great East Japan Earthquake and tsunami. Radioactive materials, including I-131, were released into the environment after the accident. Shortly after, the prefectural government initiated the Fukushima Health Management Survey for monitoring the long-term health conditions of the residents of Fukushima Prefecture. In the survey, thyroid ultrasonography was scheduled for all people aged 18 years or younger who were living in Fukushima Prefecture at the time of disaster. The total number of examinees was approximately 370,000 in the Preliminary Baseline Survey (PBLS), and 380,000 in the first Full-scale Survey (FSS). First, thyroid ultrasonography was performed as the Primary Examination. When a thyroid nodule that meets the fine needle aspiration cytology (FNAC) guideline is detected, thyroid FNAC is performed. By the end of June 2017, the cytological specimens of 187 examinees had been interpreted as Malignant or Suspicious for Malignancy (SFM). In this article, the cytological results of whole categories are presented using the criteria of The Bethesda System for Reporting Thyroid Cytopathology. The total numbers of examinees with SFM or Malignant in PBLS and at the first FSS were 106 (62.0%) and 71 (38.0%), respectively. The data of the cytological results of SFM and Malignant were already reported. However, this is the first report of cytological data from categories other than SFM and Malignant. The results of the current study will contribute to future research into the thyroid conditions of children and adolescents.

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  • Reina Yamamoto, Kyota Akasaki, Masataka Horita, Makoto Yonezawa, Hirok ...
    Type: Original
    Article ID: EJ20-0304
    Published: 2020
    [Advance publication] Released: August 19, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Werner syndrome (WS), a type of progeria, is a hereditary condition caused by a mutation in the WRN gene. A 62-year-old Japanese woman was diagnosed with WS at the age of 32 and has been visiting the hospital for follow-up since the last 30 years. The patient developed diabetes at the age of 46, and at the age of 60, her body mass index increased from 20.1 to 22.7 kg/m2 owing to her unhealthy eating habits; her visceral fat area at the age of 61 was 233 cm2. With dietary control, her body weight, including the visceral fat and subcutaneous fat, decreased at the age of 62, and her insulin secretion, obesity, and fatty liver improved. We conducted the oral glucose challenge test four times, including at the prediabetic stage, to evaluate the insulin-secretion ability. The patient’s insulin resistance gradually increased for more than 14 years, and her insulin secretion ability began to decrease 14 years after her diabetes diagnosis. Despite a remarkable decrease in body weight and fat mass with dietary management, the psoas muscle index did not decrease significantly in proportion to the body weight or fat mass. However, muscle mass monitoring is important for preventing the progression of sarcopenia. Hence, gradual reduction of visceral fat and weight by dietary management may be useful in treating diabetes in patients with WS, particularly in those whose visceral fat is significantly increased.

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  • Takaaki Oba, Tatsunori Chino, Ai Soma, Tadafumi Shimizu, Mayu Ono, Tok ...
    Type: Original
    Article ID: EJ20-0171
    Published: 2020
    [Advance publication] Released: August 18, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    The tyrosine kinase inhibitors (TKIs) sorafenib, lenvatinib, vandetanib, and cabozantinib are currently used for thyroid cancer treatment; however, the differences in their clinical efficacy and toxicity remain unclear. This meta-analysis assessed the efficacy and toxicity of these four TKIs based on 34 studies. The pooled incidence of partial response (PR), stable disease (SD), TKI-related adverse events (AEs), and pooled median progression-free survival (PFS) were calculated with 95% confidence intervals (CI). Complete response to TKIs was extremely rare (0.3%). The highest PR rate and longest PFS were observed for lenvatinib in differentiated thyroid cancer (69%, 95% CI: 57–81 and 19 months, 95% CI: 9–29, respectively) and vandetanib in medullary thyroid cancer (40%, 95% CI: 25–56 and 31 months, 95% CI: 19–43, respectively). Although the discontinuation rate due to AEs was similar for each TKI, there was a difference in the most frequently observed AE for each TKI (hand-foot syndrome for sorafenib, hypertension and proteinuria for lenvatinib, and QTc prolongation for vandetanib). The identified differences in the TKI efficacy and AE profiles may provide a better understanding of thyroid cancer treatment. Although TKIs are promising agents for thyroid cancer treatment, they are unlikely to lead to a cure. Thus, even in the TKI era, a multimodal treatment including surgery, radioiodine therapy, external beam radiotherapy, and TKIs is required to optimize patient chances of improved survival.

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  • Kazutoshi Sugiyama, Sakiko Kobayashi, Isao Kurihara, Kazutoshi Miyashi ...
    Type: Original
    Article ID: EJ20-0307
    Published: 2020
    [Advance publication] Released: August 18, 2020
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    Amiodarone is an effective antiarrhythmic drug. However, it is associated with changes in thyroid function in euthyroid patients due to its high iodine content and intrinsic drug effects. Studies have been conducted in iodine-deficient and iodine-sufficient countries; however, data from countries with excessive iodine intake are lacking. Thus, this study aimed to evaluate the effect of long-term amiodarone treatment on thyroid function in euthyroid Japanese patients. Japanese adults aged ≥18 years who were treated with amiodarone for at least 90 consecutive days were included in this retrospective chart review. Patients with abnormal thyroid function test results at baseline were excluded. Serial changes in thyroid function tests at baseline and at days 30, 90, 180, 270, and 360 were analyzed using a mixed-effects model for repeated measures. In total, 46 patients with a mean age of 63.7 years were evaluated. The mean TSH level significantly increased from 1.62 μIU/mL at baseline to 3.43, 2.75, 2.84, 2.78, and 2.65 μIU/mL at days 30, 90, 180, 270, and 360, respectively. The mean free T4 level significantly increased from 1.3 ng/dL at baseline to 1.4, 1.5, 1.5, 1.5, and 1.5 ng/dL at days 30, 90, 180, 270, and 360, respectively. The mean free T3 level significantly decreased from 2.8 pg/mL at baseline to 2.4, 2.3, 2.3, 2.4, and 2.4 pg/mL at days 30, 90, 180, 270, and 360, respectively. In conclusion, significant changes in thyroid function persisted not only in the acute phase but also in the chronic phase of long-term amiodarone treatment.

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  • Nozomi Matsuda, Kei Takasawa, Yasuhisa Ohata, Shigeru Takishima, Takuo ...
    Type: Original
    Article ID: EJ20-0203
    Published: 2020
    [Advance publication] Released: August 08, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Hypophosphatasia (HPP; OMIM 241510, 241500, and 146300) is an inherited metabolic disease characterized by defects of bone and tooth mineralization, which is caused by loss-of-function mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP). In the last three decades, several studies have focused on the genotype-phenotype correlation in hypophosphatasia (HPP). In particular, functional tests based on in vitro analysis for the residual enzymatic activities of mutations have revealed a clear but imperfect genotype-phenotype correlation, suggesting that multiple potential factors modulate the phenotype. One of the missense variants identified in the tissue non-specific alkaline phosphatase (ALPL) gene, c.787T>C, has been considered as a benign polymorphism in HPP; however, its pathogenicity and role in disease manifestation remain controversial. We here report our recent experience of three unrelated families harboring the c.787T>C variant, suggesting clinical implications regarding the controversial pathogenicity of c.787T>C. First, despite the lack of obvious clinical phenotypes, homozygous c.787T>C would decrease the serum level of ALP activity. Second, c.‍787T>C might deteriorate phenotypes of a patient harboring another ALPL variant, especially one that has thus far presumed to be benign, e.g., the c.1144G>A variant. These cases contribute to the recent advances in understanding HPP to facilitate clinical recognition of more subtle phenotypes, further providing insights into the pathogenesis of HPP.

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  • Nobuhiko Akazawa, Koichiro Tanahashi, Keisei Kosaki, Hiroshi Kumagai, ...
    Type: Original
    Article ID: EJ20-0211
    Published: 2020
    [Advance publication] Released: August 01, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    An increase in arterial stiffness with advance aging is a risk for cardiovascular disease. Cardiovascular dysfunction is associated with the imbalance of adrenal cortex hormones, especially with the cortisol/dehydroepiandrosterone sulfate (DHEAs) ratio. However, the impact of aerobic fitness on arterial stiffness and cortisol/DHEAs ratio is unclear. The aim of this study was to investigate the relationship between aerobic fitness, arterial stiffness, and cortisol/DHEAs ratio. A total of 198 middle-aged and older adults (aged 50–79 years old) participated in this study. The aerobic fitness evaluated by peak oxygen consumption (VO2peak), carotid-femoral pulse wave velocity (cfPWV) as an indicator of arterial stiffness, and serum cortisol and DHEAs and their ratio were measured. The subjects were divided into the lower (n = 100) and the higher (n = 98) aerobic fitness groups based on the median value of VO2peak. There were no significant differences in serum cortisol and DHEAs concentration alone between the lower and higher fitness groups. However, the cortisol/DEHAs ratio and cfPWV in the higher fitness group was smaller than in the lower fitness group (p < 0.05). The cortisol/DHEAs ratio was significantly correlated with cfPWV (r = 0.159, p < 0.05). These findings suggest that the cortisol/DHEAs ratio is associated with aerobic fitness and arterial stiffness in middle-aged and older adults.

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  • Karine Tremblay, Diane Brisson, Daniel Gaudet
    Type: Note
    Article ID: EJ20-0123
    Published: 2020
    [Advance publication] Released: July 29, 2020
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    A fasting triglyceridemia >10 mmol/L is associated with chylomicronemia (CM) and an increased recurrent acute pancreatitis (RAP) risk. The number of pancreatitis episodes varies significantly between patients with CM. The objective of this study was to investigate gene expression profiles of RAP in patients with CM. A total of 47 CM subjects participated in this study. Prior to the analyses, all patients were divided into three groups covering a wide spectrum of RAP: 0 (n = 21), 1–3 (n = 10) or >4 (n = 16) pancreatitis episodes. Gene expression profiles were compared to those of 15 healthy normolipidemic controls. Differential expression moderated T-tests between studied groups were performed using a linear model of the Bioconductor package Limma. The False discovery rate was controlled using the Benjamini-Hochberg procedure. At a p-value <0.01, a false discovery rate of 5% and a >2-fold change expression significance levels, a set of 41 probes have been found differentially expressed in CM subjects with no pancreatitis, 103 in the CM group with 1 to 3 pancreatitis, and 94 in the group with ≥4 pancreatitis compared to healthy controls. Of the identified annotated probes, 14 are shared by all CM groups; 3 are specific to CM with no pancreatitis; 11 are specific to CM with 1 to 3 pancreatitis, and 17 are specific to CM with ≥4 pancreatitis. Most of the annotated biomarkers are involved in inflammatory, immune, lipoprotein kinetics or signalling biological pathways. These results reveal gene expression signatures of RAP in patients with CM.

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  • Wook Yi, Bo Hyun Kim, Mijin Kim, So Ree Ryang, Min Hee Jang, Jeong Mi ...
    Type: Original
    Article ID: EJ20-0242
    Published: 2020
    [Advance publication] Released: July 28, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    After thyroidectomy in differentiated thyroid cancer (DTC), radioactive iodine (RAI) treatment is often used for remnant ablation. However, RAI treatment has been associated with bone marrow suppression, and leukopenia, anemia, and thrombocytopenia may occur after a single RAI administration. In this study, we examined the change in complete blood counts at 1 week after RAI administration; this is less well studied. A group of 189 DTC patients who received RAI treatment and underwent blood tests before and after treatment, were included. Peripheral blood counts at baseline were compared to those obtained at 1 week, 1–6 months, and 6–12 months after RAI treatment in order to test for bone marrow suppression. At 1 week after RAI treatment, there was a significant decrease in the white blood cell count (WBC, 5.8 ± 1.6 × 109/L vs. 5.4 ± 1.5 × 109/L, p < 0.001) and hemoglobin level (Hb, 13.5 ± 1.7 g/dL vs. 13.3 ± 1.4 g/dL, p = 0.001). The WBC decrease was mostly due to lymphocyte counts (2.2 ± 0.6 × 109/L vs. 1.6 ± 0.5 × 109/L, p < 0.001), with no decrease in the neutrophil count. Although not significantly changed at 1 week, platelets counts were altered within 6 months (265 ± 69 × 109/L vs. 239 ± 53 × 109/L, p < 0.001). The decline in the WBC count recovered within 6 months; lymphocyte and platelet counts recovered within 12 months. In conclusion, RAI treatment after a thyroidectomy was associated with a statistically significant but temporary decline in WBC counts and Hb levels at 1 week. Physicians treating DTC patients should not decrease usage of moderate dose RAI treatments.

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  • Fan Zhang, Xinyue Lin, Xiaohui Yu
    Type: Original
    Article ID: EJ20-0163
    Published: 2020
    [Advance publication] Released: July 23, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing syndrome (CS). In many cases of the PMAH family, variant in ARMC5, a putative tumor suppressor gene, are thought to induce the disease. The purpose of this study was to report a large Chinese family, in which a new germline heterozygous variant of ARMC5 (c.52C>T (p.Gln18X)) was found. A 64-year-old female patient (proband) was admitted to the hospital due to bilateral adrenal masses. In order to clarify the nature and function of adrenal masses, the proband completed several relevant screening tests of the adrenal function. After an ectopic receptor screening test and genetic testing, a new ARMC5 gene variant was found that might had led to the occurrence of PMAH. Because of its characteristic of autosomal dominant inheritance, the proband’s relatives were recommended to conduct the genetic test. We collected the family members’ genetic information, in which have 27 individuals, the proband tested the whole exon sequence, and 12 participants tested the Sanger sequence. Finally, 7 individuals were found have the same germline variant of ARMC5 as the proband. Subsequent computer analysis predicted that the variant significantly impaired protein function and resulted in inactivation of ARMC5. We found a new germline ARMC5 variant (c.52C>T (p.Gln18X)), which may induced PMAH. ARMC5 sequencing can improve the identification of clinical forms of PMAH and allow early diagnosis of the disease.

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  • Yu-Shu Yen, Harn-Shen Chen
    Type: Original
    Article ID: EJ20-0159
    Published: 2020
    [Advance publication] Released: July 22, 2020
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    Supplementary material

    The surgical treatment of acromegaly reduces mortality, however its impact on cardiovascular risk factors is unclear. This study was carried out to determine the changes in cardiovascular risk factors in patients with acromegaly who received trans-sphenoidal surgery. We recruited 127 patients with acromegaly who received trans-sphenoidal adenomectomy between August 2003 and May 2014 and follow-up for 12 months. Fasting GH and IGF-1 levels were evaluated every 3 months, and cardiovascular risk factors were assessed before and 12 months after surgery. The main outcomes were changes in cardiovascular risk factors after surgery. One year after trans-sphenoidal adenomectomy, 68 patients (53.5%) had a fasting GH level <2.0 ng/mL, IGF-1 was normalized in 74 patients (58.3%), and both fasting GH and IGF-1 were under control in 51 patients (40.2%). Levels of glycated hemoglobin (HbA1c) (8.57 ± 3.19 vs. 6.66 ± 0.90%, p = 0.001) and triglycerides (130.6 ± 61.5 vs. 108.0 ± 47.5 mg/dL, p = 0.027) were significantly decreased and serum creatinine was significantly increased (0.665 ± 0.222 vs. 0.754 ± 0.223 mg/dL, p = 0.001) after trans-sphenoidal adenomectomy. However, there were no significant changes in body weight, systolic blood pressure, diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol and cardiovascular risk score after trans-sphenoidal adenomectomy. In the patient with high cardiovascular risk before surgery, systolic blood pressure, total cholesterol, fasting glucose, triglycerides and high-density lipoprotein cholesterol improved after trans-sphenoidal adenomectomy. In this study, HbA1c and triglycerides were significantly decreased after trans-sphenoidal adenomectomy in the patients with acromegaly irrespective of endocrinological outcomes. The other traditional cardiovascular factors might be improved after trans-sphenoidal adenomectomy in the patients with a high cardiovascular risk.

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  • Daham Kim, Namki Hong, Yonggeun Cho, Sang-Guk Lee, Yumie Rhee
    Type: Original
    Article ID: EJ20-0349
    Published: 2020
    [Advance publication] Released: July 22, 2020
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    The adoptive transfer of ex vivo-expanded natural killer (NK) cells has recently been employed as an alternative cancer treatment in certain institutions. However, the safety profiles of this strategy remain uncharacterized. We evaluated three patients who exhibited elevated serum parathyroid hormone (PTH) levels without the relevant clinical manifestations and had a history of autologous NK cell therapy. The serum PTH concentration was measured using a second-generation PTH assay, and the serum thyroglobulin concentration was measured using a second-generation thyroglobulin assay. Subsequently, the PTH or thyroglobulin concentration obtained using heterophile-blocking tube (HBT) for a secondary confirmation assay was measured and compared with the result of the initial assay. The three patients had falsely elevated serum PTH and thyroglobulin levels owing to heterophile antibody interference associated with NK cell therapy that persisted for at least up to 12 months after the treatment and was confirmed by normalization of hormone levels after HBT treatment. We propose that certain types of mouse monoclonal antibodies used to stimulate NK cells can induce heterophile antibodies. Abnormal laboratory test results in individuals administered NK cell therapy without the relevant clinical manifestations must be examined in the context of heterophile antibody interference to avoid misdiagnosis and unnecessary testing.

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  • Qinpei Ding, Yubo Zhou, Shu Zhang, Min Liang
    Type: Original
    Article ID: EJ20-0071
    Published: 2020
    [Advance publication] Released: July 17, 2020
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    This retrospective study aimed to investigate the relationship between hemoglobin (Hb) levels and non-alcoholic fatty liver disease (NAFLD) in patients with young-onset type 2 diabetes mellitus (T2DM). Data were collected for 296 patients with young-onset T2DM admitted to the first Affiliated Hospital of Guangxi Medical University from May 2017 to January 2020. Subjects were divided into NAFLD (n = 186) and non-NAFLD groups (n = 110). Patients with NAFLD had significantly higher Hb levels (p = 0.001). According to logistic regression analysis, Hb levels were significantly correlated with NAFLD after adjusting for confounding factors [odds ratio (OR) = 1.024, 95% confidence interval = 1.003–1.046, p = 0.028]. Subjects were also grouped according to Hb quartiles. After adjusting for sex and body mass index (BMI), the OR (95%CI) for NAFLD significantly increased with increasing Hb levels (p for trend = 0.009). Patients were also divided into lean (BMI <25 kg/m2, n = 139) and overweight/obese groups (BMI ≥25 kg/m2, n = 157), with adjusted ORs (95%CI) for the highest quartiles of 1.797 (0.559–5.776) and 6.009 (1.328–27.181), respectively. Further quartile classification of Hb according to sex showed adjusted OR (95%CI) for the highest compared with the lowest quartile of 2.796 (1.148–6.814) for males and 2.945 (0.482–17.997) for females. In conclusion, high Hb levels were associated with the presence of NAFLD in patients with young-onset T2DM, especially in males and overweight/obese patients.

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  • Xiao-hua Wang, Feng Xu, Ming Cheng, Xing Wang, Dong-mei Zhang, Li-hua ...
    Type: Original
    Article ID: EJ20-0201
    Published: 2020
    [Advance publication] Released: July 17, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
    Supplementary material

    Type 2 diabetes (T2D) is characterized by islet β-cell dysfunction and impaired suppression of glucagon secretion of α-cells in response to oral hyperglycaemia. Bile acid (BA) metabolism plays a dominant role in maintaining glucose homeostasis. So we evaluated the association of fasting serum total bile acids (S-TBAs) with insulin sensitivity, islet β-cell function and glucagon levels in T2D. Total 2,952 T2D patients with fasting S-TBAs in the normal range were recruited and received oral glucose tolerance tests for determination of fasting and postchallenge glucose, C-peptide and glucagon. Fasting and systemic insulin sensitivity were assessed by homeostasis model assessment (HOMA) and Matsuda index using C-peptide, i.e., ISHOMA-cp and ISIM-cp, respectively. Islet β-cell function was assessed by the insulin-secretion-sensitivity-index-2 using C-peptide (ISSI2cp). The area under the glucagon curve (AUCgla) was used to assess postchallenge glucagon. The results showed ISHOMA-cp, ISIM-cp and ISSI2cp decreased, while AUCgla notably increased, across ascending quartiles of S-TBAs but not fasting glucagon. Moreover, S-TBAs were inversely correlated with ISHOMA-cp, ISIM-cp and ISSI2cp (r = –0.21, –0.15 and –‍0.25, respectively, p < 0.001) and positively correlated with AUCgla (r = 0.32, p < 0.001) but not with fasting glucagon (r = 0.033, p = 0.070). Furthermore, after adjusting for other clinical covariates by multiple linear regression analyses, the S-TBAs were independently associated with ISHOMA-cp (β = –0.04, t = –2.82, p = 0.005), ISIM-cp (β = –0.11, t = –7.05, p < 0.001), ISSI2cp (β = –0.15, t = –10.26, p < 0.001) and AUCgla (β = 0.29, t = 19.08, p < 0.001). Increased fasting S-TBAs are associated with blunted fasting and systemic insulin sensitivity, impaired islet β-cell function and increased glucagon levels in response to glucose challenge in T2D.

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  • Maki Oshita, Yasuhiro Ito, Tomoko Miyamoto, Hisashi Ota, Tomohiko Naka ...
    Type: Original
    Article ID: EJ20-0254
    Published: 2020
    [Advance publication] Released: July 16, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a new entity adopted by the newest World Health Organization classification. It is differentiated from follicular variant papillary thyroid carcinoma (FVPTC) and regarded as non-malignant disease. Here, we compared the ultrasound findings of NIFTP (n = 40) with those of FVPTC (n = 94) and encapsulated PTC (encap-PTC) (n = 157). The NIFTP group showed benign findings on ultrasound significantly more frequently than the FVPTC group based on the Japan Society of Ultrasonics in Medicine criteria: a regular shape (p < 0.001), well edge definition (p = 0.007), smooth character (p < 0.001), isoechoic and homogeneous internal echoes (p < 0.001), lack of punctate microcalcification (p = 0.027), and a regular marginal hypoechoic zone (p < 0.001). Compared to encap-PTC, NIFTP has a significantly higher incidence of benign findings: isoechoic and homogeneous internal echoes (p < 0.001), lack of punctate microcalcification (p < 0.001), and a regular marginal hypoechoic zone (p = 0.004). Based on the ultrasound classification (USC) system at Kuma Hospital, no cases were classified as malignant (USC ≥3.5), but 55.4% of the FVPTCs and 53.5% of the encap-PTCs were diagnosed as malignancy. However, on cytology, the incidence of NIFTP classified as Bethesda-V or -VI (PTC) was very high at 86.9%. All patients underwent surgical treatment, but none of the NIFTP patients showed postoperative recurrence. Although avoiding surgery might be difficult because of the high incidence of malignant cytology, overtreatment (including extensive surgery) for NIFTP can be avoided by paying close attention to the lack of malignant findings on ultrasound.

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  • Shuhei Aoyama, Yuya Nishida, Yoshio Fujitani, Ayako Fukunaka, Takeshi ...
    Type: Original
    Article ID: EJ20-0326
    Published: 2020
    [Advance publication] Released: July 16, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Autophagy has been reported to play a crucial role in the maintenance of intracellular homeostasis, including in pancreatic beta cells. Rubicon, which interacts with the phosphoinositide 3-kinase (PI3K) complex, through autophagy-related 14 (ATG14), is among the few autophagy regulators that have been reported to inhibit autophagic flux to date and the deletion of Rubicon has been shown to increase autophagic flux. Based on previous results showing a causal relationship between autophagic dysfunction and pancreatic beta-cell impairment, we hypothesized that the deletion of Rubicon in pancreatic beta cells would improve cell integrity and confer protective effects. To test this hypothesis, we first confirmed that Rubicon knockdown (KD) promoted autophagic flux in βTC3 pancreatic beta-cell line. Next, we generated pancreatic beta-cell-specific Rubicon knockout (βKO) mice, by administering tamoxifen to Rubiconflox/flox:MIP-Cre-ERT mice, which showed normal glucose tolerance and insulin secretion under a normal chow diet, despite successful gene recombination. We also attempted to increase insulin resistance by feeding the mice with a high-fat diet for an additional 2 months to find little differences among the parameters evaluated for glucose metabolism. Finally, severe insulin resistance was induced with insulin receptor antagonist treatment, which resulted in comparable glucose homeostasis measurements between Rubicon βKO and control mice. In summary, these results suggest that in pancreatic beta cells, Rubicon plays a limited role in the maintenance of systemic glucose homeostasis.

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