The lack of isolation ward throughout Japan has long been limiting the 131I radioactive iodine (RAI) ablation for differentiated thyroid cancer (DTC) cases. The 30 mCi RAI ablation was only recently permitted for outpatient basis. However, no patient selection tool nor response predictor has been proposed. This study evaluated factors to find response predictor and determinant for the suitable patients. The retrospective study reviewed 47 eligible non-metastatic papillary DTC patients whose had first 30 mCi RAI ablation after total thyroidectomy. Age, gender, clinical stage, risk category, and pre-ablation serum thyroglobulin (Tg) level were among covariates analyzed to determine the patient selection factors; while the thyroid bed uptake on initial whole body scan (WBS) was later also included in determining RAI ablation response. Thirteen (28%) patients had a low risk (T1-2) while 23 (49%) and 11 (23%) had an intermediate (T3) or high risk (T4), respectively. Twenty-five patients were responders, and 22 were non-responders. All factors were similar between responders and non-responders except pre-ablation serum Tg level (p < 0.001). In multivariate analysis, pre-ablation serum Tg level was the only significant factor for both patient selection (odd ratio (OR) = 1.52, 95% confidence interval (CI) = 1.13–2.06) and response predictor (OR = 1.48; 95% CI = 1.12–1.95). With the cut-off of 5.4 ng/mL, pre-ablation serum Tg level predicts RAI ablation response with 92% specificity and 73% sensitivity. Pre-ablation serum Tg level may help patient selection and predict the response to outpatient 30 mCi RAI ablation among post total thyroidectomy non-metastatic DTC patients.
Thyroid hormones play a vital role in the human body for growth and differentiation, regulation of energy metabolism, and physiological function. Hypothyroidism is a common endocrine disorder, which generally results from diminished normal circulating concentrations of serum thyroxine (fT4) and triiodothyronine (fT3). The primary choice in hypothyroidism treatment is oral administration of levothyroxine (L-T4), a synthetic T4 hormone, as approximately 100–125 μg/day. Generally, dose adjustment is made by trial and error approach. However, there are several factors which might influence bioavailability of L-T4 treatment. Genetic background could be an important factor in hypothyroid patients as well as age, gender, concurrent medications and patient compliance. The concentration of thyroid hormones in tissue is regulated by both deiodinases enzyme and thyroid hormone transporters. In the present study, it was aimed to evaluate the effects of genetic differences in the proteins and enzymes (DIO1, DIO2, TSHR, THR and UGT) which are efficient in thyroid hormone metabolism and bioavailability of L-T4 in Turkish population. According to our findings, rs225014 and rs225015 variants in DIO2, which catalyses the conversion of thyroxine (pro-hormone) to the active thyroid hormone, were associated with TSH levels. It should be given lower dose to the patients with rs225014 TT and rs225015 GG genotypes in order to provide proper treatment with higher effectivity and lower toxicity.
Prolactinoma is a benign tumor of the pituitary gland that rarely occurs in children and adolescents; thus, the clinical spectrum and long-term prognosis in these patients remain unknown. This study was performed to investigate the long-term outcomes of medical treatment and the prognostic factors for remission and relapse in children and adolescents with prolactinoma. Three male subjects and four female subjects between the ages of 7- and 17-years-old were included in this study. The mean initial serum prolactin level was 443 ± 251.8 ng/mL (range, 152–946 ng/mL). During the follow-up period (range, 0.6–20 years), a dopamine agonist was administered, and surgery or radiotherapy was performed in cases of resistance to medical treatment or relapse. Unlike female subjects with macroadenoma who often exhibit a good clinical course, two male subjects with early onset macroadenoma presented with visual disturbances. These subjects showed resistance to medical therapy and relapsed, eventually requiring surgical removal and radiotherapy; one of the subjects manifested a metastatic thrombus in the internal jugular vein. In conclusion, pediatric prolactinoma exhibits a broad clinical spectrum, a relatively high incidence of macroadenoma, resistance to medical therapy, and frequent tumor relapses. In addition, a poor prognosis appears to be correlated with male sex, age at disease onset, and histopathological characteristics.
Primary macronodular adrenal hyperplasia (PMAH), also known in the past as bilateral macronodular adrenalhyperplasia or adrenocorticotropin (ACTH)-independent macronodular adrenal hyperplasia, is a rare type of Cushing’s syndrome (CS) and is associated with bilateralenlargement of the adrenal glands. It accounts for <1% of all endogenous cases of CS. In order toidentify the pathogenic mutations in the causative gene of (AIMAH pedigrees, Whole-genome sequencing of three patients in family I was used to retrieve candidate causative genes. Meanwhile, the causative gene was identified by Sanger sequencing from the two pedigrees. Sequencing of ARMC5 exons of three patients was carried out to identify somatic mutations. Moreover, haploid clone of one tumor DNA sample was conducted. ARMC5 was the causative gene of two pedigrees confirmed by whole-genome sequencing (WGA) and Sanger sequencing. The variant sites of the two families were c.C943T (p.R315W) and c.C1960T (p.R654X), respectively. Autosomal dominant inheritance of AIMAH was confirmed by genotypes of one family member. Several somatic mutations were discovered in tumor DNA samples. In addition, haploid clone of tumor DNA was confirmed by germline mutation and somaticmutation, which suggested the pathogenic mechanism of “two-hit-model.” ARMC5 was the causative gene of AIMAH pedigrees. This AIMAH in this study presented autosomal dominant inheritance, fitting to Mendelian inheritance law. However, the pathogenic mode of this disease showed as compound heterozygote.
New insights in thyroid cancer biology propelled the development of targeted therapies as salvage treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC), and the tyrosine kinase inhibitor (TKI) lenvatinib has recently become available as a new line of therapy for RR-DTC. The aim of this study is to investigate clinical factors related to the efficacy of TKI therapy in recurrent RR-DTC patients and identify the optimal timing for the start of TKI therapy. The subjects consisted of 29 patients with progressive RR-DTC, 9 males and 20 females, median age 66 years. A univariate analysis was conducted in relation to progression free survival (PFS) and overall survival (OS) by the Kaplan-Meier method for the following variables: age, sex, histology of the primary tumor, thyroglobulin doubling time before the start of lenvatinib therapy, site of the target lesions, presence of a tumor-mediated symptom at the start of lenvatinib therapy, and baseline tumor size of the target lesions. Median duration of lenvatinib therapy was 14.7 months and median drug intensity was 9.5 mg. At the time of the data cut-off for the analysis, 9 patients (31.0%) have died of their disease (DOD), and a PR (partial response), SD (stable disease), and PD (progressive disease) were observed in 20 patients (69%), 6 patients (20.7%), 3 patients (10.3%), respectively. Univariate analyses showed that the presence of a symptom was the only factor significantly related to poorer PFS and OS. Clinical benefit of TKI therapy will be possibly limited when the therapy starts after tumor-mediated symptoms appear.
Previous studies showed that adenosine monophosphate-activated protein kinase (AMPK), which plays as an intracellular energy sensor, promotes the differentiation and mineralization of osteoblasts via enhancing expression of bone morphogenetic protein (BMP)-2, which is a potent inducer of osteoblastogenesis. Thus, the aim of this study was to examine the roles of AMPK in BMP-2-induced osteoblastogenesis. We used a murine osteoblastic cell line MC3T3-E1 and a murine marrow stromal cell line ST2. BMP-2 (50 and 100 ng/mL) stimulated alkaline phosphatase (ALP) activity and enhanced mineralization of MC3T3-E1 cells, while the effects of BMP-2 were partly abolished by an inhibitor of AMPK, ara-A (0.1 mM). Real-time PCR showed that BMP-2 significantly increased the mRNA expressions of Alp, osteocalcin (Ocn), Runx2, Osterix and Dlx-5 in MC3T3-E1 cells, while co-incubation of ara-A significantly decreased the BMP-2-stimulated expression of Alp, Ocn, and Runx2. Moreover, co-incubation of ara-A suppressed the BMP-2-induced upregulation of Alp and Ocn in ST2 cells. Western blot analysis showed that BMP-2 phosphorylated Smad1/5 although it did not affect AMPK phosphorylation in MC3T3-E1 cells. Furthermore, a BMP receptor inhibitor LDN-193189 inhibited the phosphorylation of Smad1/5, but did not affect AMPK. In addition, co-incubation of ara-A did not affect BMP-2-induced phosphorylation of Smad1/5. These findings suggest that the inhibition of AMPK activation reduces the osteo-inductive effects of BMP-2 by decreasing the expression of Alp, Ocn, and Runx2 through Smad-independent mechanisms in osteoblastic cells.
Frailty is a state of vulnerability and a consequence of cumulative decline in multiple physiological systems over a lifespan. The occurrence of frailty depends on deterioration in muscle and nerve function, declining cardiopulmonary reserve and loss of executive function. Diabetes mellitus (DM) often causes functional impairment in each of the above systems, thus leading to a loss of whole body homeostasis and deterioration in physical function. Inability of self-management in DM patients may also have considerable impact on the development of sarcopenia/frailty. Thus, there may be positive feedback between the progression of diabetic complications and frailty/sarcopenia. While various factors are involved in this process, insulin resistance or insulin depletion may be an important factor in the progression of frailty in diabetes patients since insulin is well known to be an anabolic hormone in muscle. Interestingly, in our study targeting elderly DM patients, low HbA1c was a significant and independent risk factor for frailty, as assessed using a broad sense frailty scale, the Clinical Frailty Scale (CSF), suggesting that reverse metabolism due to malnutrition in elderly type 2 DM patients might be involved. Therefore, an intervention that includes proper nutrition and exercise training may be essential for the prevention of frailty. The pathogenesis of frailty in DM patients is extensively discussed in this review.
Chronic kidney disease (CKD) is a common chronic microvascular complication and the major cause of death in diabetic patients. This study was conceived to explore the possible mechanisms of how hyperuricemia and obesity contribute to renal function impairment in type 2 diabetic (T2DM) patients. A cross-sectional study in 609 participants recruited from a T2DM population in North China was conducted. The multiplicative interaction between body mass index (BMI) and uric acid (UA) level was assessed using an interaction term in a logistic regression analysis. Our results indicate that male T2DM patients having higher BMI (OR 1.711, p = 0.038), blood urine nitrogen (BUN) (OR 1.100, p = 0.034), and 24-hour urinary micro-albumin levels (OR 1.004, p = 0.021) were much more likely to have high UA. Whereas, for female T2DM patients, the OR of BMI, BUN, and triglyceride were 1.169 (p = 0.001), 1.337 (p = 0.000), and 1.359 (p = 0.006), respectively. In this study population, obesity and elevated UA work together to increase the risk of renal injury. In vitro experiments indicate that reactive oxygen species (ROS) production increased with UA treatment in human renal glomerular endothelial cells (HRGECs), while endothelial nitric oxide synthase (eNOS) production level dropped. UA also increased monocyte chemotactic protein-1 (MCP-1) expression and nuclear factor kappa B (NF-κB) activation. Taken together, our results indicate that high concentrations of UA lead to endothelial dysfunction through the activation of the inflammatory response and induction of oxidative stress, even in non-obese T2DM patients.
Di-(2-ethylhexyl) phthalate (DEHP) is extensively used in many personal care and consumer products, which has resulted in widespread human exposure. Limited studies have suggested that exposure to DEHP may affect thyroid function, but little is known about the effect and mechanisms of DEHP exposure on the hypothalamic-pituitary-thyroid axis (HPTA). The present study was conducted to elucidate the potential mechanisms in which DEHP disrupts the function of the HPTA. Wistar rats were administered DEHP by gavage at 0, 5, 50, and 500 mg/kg/day for 28 days and then sacrificed within 24 h following the last dose. Hormones of HPTA was quantified with radioimmunoassay and enzyme-linked immunosorbent assay, protein levels of thyrotropin-releasing hormone receptor (TRHR) and thyroid-stimulating hormone receptor (TSHR) were analyzed by Western blot and immunohistochemistry, expression levels of TRHR and TSHR mRNA were measured by quantitative real-time PCR. Rats treated with DEHP resulted in increased bodyweight, on the HPTA, down-regulated the protein levels of TRH in the hypothalamus, up-regulated the protein and mRNA levels of TRHR in the pituitary, down-regulated mRNA expression of TSHR in the thyroid, while the difference of TSH in various dose groups was not statistically significant and T3, T4, FT3, FT4 levels in serum were decreased compared with control. DEHP could interfere with the balance of HPTA of adolescent rats, and increase the body weight, down-regulate the homeostasis of thyroid related hormones and receptors expression levels.
Obesity in children is a serious public health problem in Japan. However, the prevalence of central fatness has not been well determined in Japanese youth. We studied the relationship between body mass index (BMI) and waist circumference (WC) using line of equality analysis in 5,787 boys and 4,639 girls aged 6 to 17 years who participated in the 1992–1994 national survey on body sizes. WC was measured at the level of maximum waist narrowing in girls (WC1) and at the level of the top of iliac crest in boys (WC2). Using the 1978–1981 national survey data as baseline reference, excess fatness was defined as measurements exceeding the 90th centile in WC or in BMI. Among boys, 2,466 (42.6%) had WC2 >90th centile and 1,029 (17.8%) BMI >90th centile; whereas among girls, 895 (19.3%) had WC1 >90th centile and 673 (14.5%) BMI >90th centile. WC2-standard deviation scores (SDS) exceeded BMI-SDS in 5,060 (87.4%) boys and WC1-SDS exceeded BMI-SDS in 3,168 (68.3%) girls, respectively. Our results suggested a much higher prevalence of central fatness than generally recognized for Japanese children and adolescents, in particular, in Japanese boys.
Primary hyperparathyroidism is the most common hormonal manifestation associated with multiple endocrine neoplasia 1 (MEN1). It is generally caused by parathyroid hyperplasia, and parathyroid carcinoma is rare. Here, we report a case of MEN1 with parathyroid carcinoma in two parathyroid glands causing primary hyperparathyroidism. A 40-year-old man with primary hyperparathyroidism due to MEN1 underwent a total parathyroidectomy. His corrected calcium and intact PTH (i-PTH) serum levels were 10.8 mg/dL and 203 pg/mL, respectively. Although three glands were successfully removed, the left upper parathyroid gland could not be detected. Since the right lower parathyroid lesion had invaded into the thyroid, right lobectomy was performed. A portion of the left lower parathyroid tissue was transplanted into his forearm. The histological findings of the left lower and the right upper parathyroid glands were consistent with hyperplasia while that of the right lower parathyroid gland was parathyroid carcinoma. Since the post-surgical i-PTH levels remained high, the intrathyroidal lesion of the left lobe, which was initally diagnosed as an adenomatous nodule, was suspected to contain parathyroid tumor. A fine needle aspiration of the tumor revealed a high concentration of i-PTH. One week after the first surgery, a left thyroid lobectomy was performed. The pathological diagnosis of the tumor was parathyroid carcinoma. After the surgery, calcium and i-PTH levels were normal. Although it is rare, parathyroid carcinoma should be considered as a cause of hyperparathyroidism in MEN1 patients. Since it is difficult to diagnose parathyroid carcinoma before surgery, intraoperative findings are important for the appropriate treatment.
Segmental progeroid syndromes with lipodystrophy are extremely rare, heterogeneous, and complex multi-system disorders that are characterized by phenotypic features of premature aging affecting various tissues and organs. In this study, we present a “sporadic/isolated” Japanese woman who was ultimately diagnosed with mandibular hypoplasia, deafness, progeroid features, and progressive lipodystrophy (MDPL) syndrome (MIM #615381) using whole exome sequencing analysis. She had been suspected as having atypical Werner syndrome and/or progeroid syndrome based on observations spanning a 30-year period; however, repeated genetic testing by Sanger sequencing did not identify any causative mutation related to various subtypes of congenital partial lipodystrophy (CPLD) and/or mandibular dysplasia with lipodystrophy (MAD). Recently, MDPL syndrome has been described as a new entity showing progressive lipodystrophy. Furthermore, polymerase delta 1 (POLD1) gene mutations on chromosome 19 have been identified in patients with MDPL syndrome. To date, 21 cases with POLD1-related MDPL syndrome have been reported worldwide, albeit almost entirely of European origin. Here, we identified a de novo mutation in exon 15 (p.Ser605del) of the POLD1 gene in a Japanese case by whole exome sequencing. To the best of our knowledge, this is the first identified case of MDPL syndrome in Japan. Our results provide further evidence that mutations in POLD1 are responsible for MDPL syndrome and serve as a common genetic determinant across different ethnicities.
Hyalinizing trabecular tumour (HTT) immunohistochemically shows cell membranous immunoreactivity for MIB-1. This aberrant immunoreactivity is an important factor for the diagnosis of HTT. However, fully automated stainers frequently fail to confirm the immunoreactivity. The aim of this study is to investigate the cause of false negative cell membranous immunoreactivity for MIB-1 in HTT using fully automated stainers, to determine potential reasons for the problem, and to establish methods confirming cell membranous immunoreactivity for MIB-1 in HTT. Six participating institutions examined immunoreactivity for MIB-1 in 10 HTT cases using two approaches: fully automated and semi-automated methods. In the latter, antigen retrieval was carried out using manual methods adopted for routine assays at each institute. The autostainers used included the BOND-MAX, BOND-III, Benchmark XT, and Omnis systems. Using fully automated methods, institute E showed cell membranous MIB-1 positivity in all HTT cases. In contrast, at institute D, all HTT cases were negative. The positive rates of the remaining four institutes ranged from 10% to 20%. The incidence of positive cases using semi-automated methods was 100%, 90%, 90%, 30%, 80%, and 100% at institutes A, B, C, D, E, and F, respectively. We assert that antigen retrieval should be conducted manually for diagnosis of HTT; furthermore, definitively diagnosed HTT should be prepared as the external positive control.
Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGL) are frequently associated with bone metastasis. Bone metastasis requires long-term management and may lead to skeletal-related events (SREs) that remarkably reduce patients’ quality of life (QOL). The aim of this study was to elucidate the risk factors for developing bone metastasis in patients with PPGL. The medical records of 40 consecutive adult patients with malignant PPGL at the National Hospital Organization Kyoto Medical Center between 2006 and 2016 were reviewed. SREs were defined as pathologic fracture, spinal cord compression, and the need for bone irradiation and/or surgery. PHEO (20/40) and PGL (20/40) were each present in 50% of the patients. Bone was the most frequent site of metastasis, detected in 60% (24/40). Bone metastasis was more frequent in patients with PGL (16/20, 80%) than in patients with PHEO (8/20, 40%) (p = 0.02). Half (12/24) of the patients with bone metastasis had at least one SRE. Extra-skeletal invasion of the spine, defined as local infiltration to the surrounding tissue beyond the cortical bone, was more frequently observed in patients with bone metastasis associated with SREs than without them (p = 0.001). Careful follow-up and management are warranted especially in patients with PGL as a risk factor for bone metastasis and with extra-skeletal invasion of the spine as risk factor of SREs.
The clinical influence of macroprolactin (MPRL) is not clearly understood and the rate of patients potentially affected by MPRL is unknown. We investigated the influence of MPRL on the onset of galactorrhea and estimated the rate of patients with a proportion of MPRL fraction that may possibly affect galactorrhea. Data of patients with obstetric or gynecological symptoms who had undergone PRL fractionation testing were retrospectively analyzed. To evaluate factors influencing galactorrhea, a multivariate logistic regression analysis was performed and the adjusted odds ratios of MPRL for galactorrhea were calculated. Cutoff values for the total PRL level and the proportion of MPRL fractions for galactorrhea were determined by ROC analysis using a multivariate logistic model. The prevalence of patients with a proportion of MPRL fraction greater than or equal to the cutoff value for galactorrhea was estimated. The median proportion of MPRL fraction was 30.1% and increased as PRL level increased. Total PRL and MPRL had a significant influence on the onset of galactorrhea and the adjusted odds ratio was 1.09 in total PRL and 0.94 in MPRL. The rate of patients with a proportion of MPRL fraction that may possibly affect galactorrhea was estimated to be 33.5% of the study population, and thus found to be twelve times or more the number of macroprolactinemia patients. Future prospects for hyperprolactinemia may require diagnostic criteria using free prolactin levels and so MPRL fraction measurement is important for the diagnosis and treatment of patients with obstetric and gynecological symptoms.
Osteoporosis not only increases bone fracture risk but also affects survival in postmenopausal women. Although osteoporosis is diagnosed based on low bone mineral density (BMD) determined by dual energy X-ray absorptiometry (DXA), BMD measurement is sometimes difficult because DXA is not widely available in the community. The Fracture Risk Assessment tool (FRAX) can predict 10-year major osteoporotic fracture risk and hip fracture risk with or without femoral neck BMD. The FRAX has not been investigated adequately in community-dwelling Japanese women. We administered the FRAX tool in 13,421 Japanese women who underwent DXA-based forearm BMD measurement in Chiba Bone Survey, a population-based, multicenter, cross-sectional study of postmenopausal osteoporosis conducted in Chiba, Japan. Mean age was 57.77 ± 9.24 years. Mean forearm BMD was 87.94 ± 17.00% of young adult mean (YAM). Mean FRAX major osteoporotic fracture risk without femoral neck BMD was 7.06 ± 5.22%. BMD decreased and percentage of osteoporosis increased from age 55 onward. Age distribution of percentage of subjects with FRAX major osteoporotic fracture risk >15% was similar to that of percentage of osteoporosis subjects. We identified the cutoff value of FRAX major osteoporotic fracture risk for diagnosis of osteoporosis as 7.2%. With this cutoff, the positive likelihood ratio was over 1.0 at age 55 and above but accuracy was low. In conclusion, FRAX without femoral neck BMD reflects bone status, and may be useful to diagnose osteoporosis in Japanese women aged 55 and above, although the sensitivity was low for osteoporosis screening, especially in middle-aged women.
With advancing maternal age, the number of prenatal genetic tests is increasing in many countries. Prenatal genetic tests, such as amniocentesis, chorionic villus sampling and non-invasive prenatal testing, can disclose fetal chromosomal sex, although these tests were originally designed to prenatally diagnose chromosomal aneuploidies, such as trisomy 21, 18 and 13. Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder caused by an androgen receptor dysfunction leading to hormone resistance. The affected individuals are genetic males as shown by 46,XY but present complete female external genitalia and normal breast development at puberty albeit without menstruation. CAIS is commonly diagnosed in adolescence based on primary amenorrhea or in childhood based on inguinal hernia or testis-like masses in the inguinal region. In the present report, we describe a baby in whom CAIS was diagnosed immediately after birth based on a mismatch between the fetal karyotype detected by amniocentesis and the external genitalia phenotype at birth. We speculate that the increase in the number of prenatal genetic tests is contributing to the early detection of 46,XY disorders of sex development, especially those previously called complete sex reversal, which is supposedly diagnosed during childhood or adolescence. Hence, it is necessary to understand the disease-specific hormone profile at each developmental stage for accurate diagnosis.
This randomized double-blind multicenter trial (NCT01927861) evaluated the growth-promoting effect and safety of Norditropin® (NN220; somatropin) in Japanese children with short stature due to Noonan syndrome. Prepubertal children aged 3–<11 years (boys) or 3–<10 years (girls) with Noonan syndrome were randomized to receive GH 0.033 mg/kg/day (n = 25, mean age 6.57 years, 11 females) or 0.066 mg/kg/day (n = 26, mean age 6.06 years, eight females) for 104 weeks. Change in height standard deviation score (HSDS) from baseline was analyzed based on an ANCOVA model. Baseline HSDS was –3.24. Estimated change in HSDS [95% CI] after 104 weeks’ treatment was 0.84 [0.66, 1.02] and 1.47 [1.29, 1.64] for the lower and higher doses, respectively; estimated mean difference 0.63 [0.38, 0.88], p < 0.0001. Rates and patterns of adverse events (AEs) were similar between groups. Most were mild and reported as unlikely to be related to Norditropin®. There were no withdrawals due to AEs. Insulin-like growth factor-I SDS increased from –1.71 to –0.64 (0.033 mg/kg/day) and to 0.63 (0.066 mg/kg/day). HbA1c increased slightly (0.033 mg/kg/day: +0.14%; 0.066 mg/kg/day: +0.13%); glucose profiles were almost unchanged; insulin profiles increased in both groups in the oral glucose tolerance test. There were no clinically significant abnormal electrocardiogram or echocardiography findings. We conclude that Norditropin® at doses of 0.033 mg/kg/day or 0.066 mg/kg/day for 104 weeks increases height in Japanese children with short stature due to Noonan syndrome, with a favorable safety profile. The effect was greater with 0.066 mg/kg/day compared with 0.033 mg/kg/day.
Erythropoietin (EPO) is known to stimulate erythropoiesis after binding with its specific receptor. In clinics, EPO is widely used in hemodialyzed patients with diabetes. However, changes in the expression of the erythropoietin receptor (EPOR) under diabetic conditions are still unclear. Therefore, we investigated EPOR expression both in vivo and in vitro. Streptozotocin-induced type 1-like diabetic rats (STZ rats) were used to evaluate the blood glucose-lowering effects of EPO. The expression and activity of the transducer and activator of transcription 3 (STAT3), the potential signaling molecule, was investigated in cultured rat skeletal myoblast (L6) cells incubated in high-glucose (HG) medium to mimic the in vivo changes. The EPO-induced reduction in hyperglycemia was more pronounced in diabetic rats. The increased EPOR expression in the soleus muscle of diabetic rats was reversed by the reduction in hyperglycemia. Glucose uptake was also increased in high-glucose (HG)-treated L6 cells. Western blotting results indicated that the EPO-induced hyperglycemic activity was enhanced mainly through an increase in EPOR expression. Increased EPOR expression was associated with the enhanced nuclear expression of STAT3 in HG-exposed L6 cells. In addition, treatment with siRNA specific to STAT3 reversed the increased expression of EPOR observed in these cells. Treatment with Stattic at a dose sufficient to inhibit STAT3 reduced the expression level of EPOR in STZ rats. In conclusion, the increased expression of EPOR by hyperglycemia is mainly associated with an augmented expression of nuclear STAT3, which was identified both in vivo and in vitro in the present study.
Hashimoto’s thyroiditis with heavy lymphoplasmacytic infiltration is a common comorbidity of immunoglobulin G4 (IgG4)-related thyroiditis and Warthin-like papillary thyroid carcinoma (WL-PTC). We hypothesized that WL-PTC may have a strong association with IgG4-related thyroiditis. To validate this hypothesis, we clinically and immunohistochemically studied 17 WL-PTC cases. Fourteen patients (82.4%) had anti-thyroglobulin antibody and were confirmed to have Hashimoto’s thyroiditis through microscopic analysis. Among them, five (29.4%) had disease consistent with IgG4-related thyroiditis but did not exhibit a “storiform” pattern or obliterative phlebitis. IgG4-related diseases were not found in other organs. No cases with serum IgG4 level of >135 mg/dL were noted. A total of 94.1% of WL-PTC cases had IgG4-positive plasma cells (+PCs) in the stroma, and cases with rich IgG4+PCs were more frequently associated with Hashimoto’s thyroiditis than those with poor IgG4+PCs. In this study, all three cases without Hashimoto’s thyroiditis had poor IgG4+PCs, and one of them did not exhibit IgG4+PCs in the stroma of WL-PTC and Hashimoto’s thyroiditis. Nodal metastatic lesions were seen in eight cases, all of which were not WL-PTC. As such, we should consider that the Hashimoto’s disease with rich IgG4+PCs seen in our cases is representative of non-IgG4-related disease and not IgG4-related disease involving multiple organs. This study is the first to demonstrate the presence of IgG4+PCs in the stroma of WL-PTC. We concluded that the appearance of IgG4+PCs in the stroma of WL-PTC may be related to Hashimoto’s thyroiditis with rich IgG4+PC.
We compared treatment satisfaction between daily dipeptidyl peptidase-4 (DPP-4) inhibitors and a weekly DPP-4 inhibitor in patients with type 2 diabetes. The study was a 12-week, open-label, randomized, multicenter, controlled trial. Participants were Japanese patients with type 2 diabetes who had received daily DPP-4 inhibitors for more than 3 months. Patients were randomly assigned to a treatment cohort: (1) a group that continued taking daily DPP-4 inhibitors (daily group); or (2) a group that switched from daily DPP-4 inhibitors to a weekly DPP-4 inhibitor, trelagliptin (weekly group). The primary outcome was the change in treatment satisfaction levels from baseline to 12 weeks between the two groups, according to Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Diabetes Therapy-Related Quality of Life (DTR-QOL) questionnaire scores. The changes in glycemic control and body weight were also assessed. Of 49 patients initially enrolled in the study, 47 completed the study. The change in DTSQ scores in the weekly group was not significantly different from that in the daily group. However, the improvements in total score and subscale domains 1 and 2 in the DTR-QOL analysis, which relate to burden on social/daily activities and anxiety/dissatisfaction with treatment, were significantly greater in the weekly group than the daily group (p = 0.048, 0.013 and 0.045, respectively). Mean changes in glycated hemoglobin levels and body weight were comparable between the groups. Switching from daily DPP-4 inhibitors to a weekly DPP-4 inhibitor, trelagliptin, could partially improve treatment satisfaction levels in patients with type 2 diabetes without affecting glycemic control.
This study aimed to determine the prevalence of colorectal neoplasms and to investigate the rate of and time required for cecal intubation in patients with acromegaly. A database search performed at our institution identified 29 patients with acromegaly who underwent colonoscopy. Data regarding the endoscopic, biological, and pathological examinations performed were retrospectively reviewed from the clinical records. Subsequently, the rate of and time required for cecal intubation were investigated in 23 patients with acromegaly and compared with the corresponding data of the control group. Control subjects were selected from a 2:1 matched historical control cohort, according to baseline characteristics. The mean age of the acromegaly group (17 female and 12 male) was 60.4 ± 12.6 years. Twelve patients had adenoma (41.4%), eight patients had hyperplastic polyps (27.6%), three patients had sessile serrated adenoma/polyps (10.3%), and three patients had colon cancer (10.3%). Successful cecal intubation was achieved in all patients in both groups. The difference in the time required for successful intubation between the acromegaly group (15.7 ± 9.8 minutes) and the control group (8.7 ± 6.0 minutes) was statistically significant. Linear regression analysis revealed that increased patient age was significantly related to longer colonoscope insertion times. In conclusion, although cecal intubation during colonoscopy was successful in all participants, it required a longer time in patients with acromegaly. Our results underscore the importance of and certain technical difficulties involved in colonoscopy procedures in patients with acromegaly, especially in older patients.
The purpose of this study is to evaluate the potential synergic effect of BRAFV600E mutation and multifocality on central lymph nodes metastasis (CLNM) in the patients with unilateral papillary thyroid carcinoma (PTC). We enrolled 413 patients with unilateral PTCs who accepted prophylactic unilateral or bilateral central lymph node dissection (LND). Univariate and multivariate analyses were made to determine the association between related factors and CLNM. Then, all patients were divided into 4 groups based on their status of BRAFV600E mutation and multifocality. Relative excess risk of interaction (RERI), attributable proportion (AP) of interaction and synergy index (SI) were applied to evaluate the interactive effect of these two factors on CLNM. Results showed that BRAFV600E mutation and multifocality were independent risk factors for CLNM. A further study revealed that unilateral PTCs accompanying multifocality with BRAFV600E mutation had the highest incidence of CLNM compared with other subgroups. Besides, RERI was 4.323 (95% CI = 1.276–7.369), AP was 0.523 (95% CI = 0.364–0.682) and SI was 2.469 (95% CI = 1.607 to 3.794), indicating a significant additive interaction of BRAFV600E mutation and multifocality on CLNM. The present study has confirmed that BRAFV600E mutation and multifocality are risk factors for CLNM in unilateral PTC. Additionally, unilateral PTC patients accompanying multifocality with BRAFV600E mutation may have an increased risk of CLNM in clinically negative CLNM.
Patients with growth hormone deficiency (GHD) have an increased risk of atherosclerosis and vascular mortality. Evidence suggests that endothelial dysfunction is involved in all stages of atherogenesis. This study examined the effect of growth hormone (GH) replacement therapy on diacron-reactive oxygen metabolites (d-ROMs) and endothelial function in Japanese patients with GHD, using peripheral arterial tonometry. This was an open-label, prospective, case-control study. Nine patients with GHD who had not previously received any GH replacement therapy were enrolled. The following parameters were evaluated at baseline (before treatment), and after 24 weeks of GH replacement therapy: endothelial function using the reactive hyperemia index (RHI; EndoPAT® system), d-ROMs, blood pressure, and fasting lipid levels. Plasma GH and insulin-like growth factor-1 (IGF-1) levels were measured at baseline and after 24 weeks of GH replacement therapy. We also enrolled eight controls with pituitary disease but no GH deficiency. Over 24 weeks of GH replacement therapy, the serum IGF-1 levels normalized with significant improvement in the RHI (from 1.65 ± 0.33 to 1.92 ± 0.26, p < 0.05) and decreased d-ROM levels (from 356.8 ± 64.1 to 303.1 ± 43.3 U.CARR, p < 0.05). There were no significant improvements in the RHI or d-ROM levels in controls. GH replacement therapy in Japanese patients with GHD may be mediated by the reduced oxidative stress and the d-ROMs associated with the treatment.
Ghrelin functions as a neuroprotective agent and saves neurons from various insults include ischemic injury. However, it remains to be elucidated whether ghrelin protects neuronal cells against ischemic injury-induced excessive autophagy. Autophagy is required for the maintenance of neural stem cell homeostasis. However, regarding autophagic cell death, it is commonly assumed that excessive autophagy leads to self-elimination of mammalian cells. The purpose of this study was to investigate the potential neuroprotection effects of ghrelin from excessive autophagy in adult rat hippocampal neural stem cells (NSCs). Oxygen-Glucose Deprivation (OGD) strongly induces autophagy in adult rat hippocampal NSCs. Ghrelin treatment inhibited OGD-induced cell death of adult rat hippocampal NSCs assessed by cell-counting-kit-8 assay. Ghrelin also suppressed OGD-induced excessive autophagy activity. The protective effect of ghrelin was accompanied by an increased expression levels of Bcl-2, p-62 and decreased expression level of LC3-II, Beclin-1 by Western blot. Furthermore, ghrelin reduced autophagosome formation and number of GFP-LC3 transfected puncta. In conclusion, our data suggest that ghrelin protects adult rat hippocampal NSCs from excessive autophagy in experimental stroke (oxygen-glucose deprivation) model. Regulating autophagic activity may be a potential optimizing target for promoting adult rat hippocampal NSCs based therapy for stroke.
Oxidative status is attributed to endothelial dysfunction and might be one of the key mechanisms of endothelial dysfunction in acromegaly. In this study, we aimed to investigate the effect of acromegaly on superoxide dismutase (SOD) and total antioxidant capacity (TAC) levels, and the possible influence of human manganese superoxide dismutase (MnSOD) polymorphism on these levels. 51 acromegaly patients and 57 age and sex matched healthy subjects were recruited to the study in Bezmialem Vakif University Hospital between 2011 and 2014. The median SOD and TAC levels were 42.7 (33–60) pg/mL and 1,313.7 (155–1,902) μM in acromegaly; and 46.3 (38–95) pg/mL and 1,607.3 (195–1,981) μM in healthy subjects (p < 0.001, p < 0.001). SOD levels were decreased in controlled and uncontrolled patients compared to healthy subjects (p = 0.05 and p = 0.002, respectively). Controlled and uncontrolled acromegaly displayed significantly decreased levels of TAC compared to healthy subjects (p < 0.05 and p < 0.001, respectively). SOD levels were not associated with MnSOD polymorphisms in acromegaly. In conclusion, this study showed that acromegaly was associated with decreased levels of SOD and TAC, and controlling the disease activity could not adequately improve these levels.
Ferritin is a universal intracellular protein that acts as an iron carrier. Several studies have indicated that iron deficiency affects thyroid function in non-pregnant women. Our objective was to assess the relationship between serum ferritin levels and thyroid function in pregnant women during the second trimester. Pregnant women with sufficient iodine intake and normal antithyroid antibodies during the second trimester were recruited from the obstetric outpatient department of the Fifth People’s Hospital of Fudan University. Serum ferritin (SF) levels, thyroid function, anti-thyroid antibodies and vitamin B12 were determined by electrochemiluminescence immunoassay kit. Maternal serum iron (Fe), unsaturated iron binding capacity (UIBC), hemoglobin (Hb), creatinine (Cr), fasting blood glucose (FBG), and alanine aminotransferase (ALT) were also evaluated. Stepwise regressions performed to evaluate the associations between SF and other maternal parameters. In the second trimester, 11.4% pregnant women had a SF concentration less than 12 μg/L, and 7.6% pregnant women were anemic. SF levels were negatively correlated with serum TSH levels (r = –0.219, p < 0.05), and positively correlated with FT4 levels (r = 0.203, p < 0.05). Linear regression analysis showed only SF, age, week of gestation were significant predictors of regression with TSH as the dependent variable (β: –0.007, –0.059, and 0.118 respectively; all p < 0.05). However consistent relation between the SF levels and FT4 was not observed in stepwise linear regression. Maternal iron status is a determinant of TSH concentrations during pregnancy in pregnant women during the second trimester.
Recent studies have suggested that decreased pancreatic β-cell function and mass are common features of patients with type 2 diabetes mellitus. Pancreatic β-cell homeostasis is regulated by various types of signaling molecules and stress responses. Sequestosome 1/p62 (SQSTM1, hereafter referred to as p62) is a ubiquitin-binding adaptor protein involved in cell signaling, oxidative stress, and autophagy. Because p62 appears to play an important role in maintaining mitochondrial quality control, it is possible that the loss of p62 in pancreatic β cells contributes to mitochondrial dysfunction, and thus leading to impaired glucose tolerance. In this study we investigated the physiological roles of p62 by inactivating p62 in a β-cell specific manner. We found that firstly, rat insulin-2 promoter-Cre (RIP-Cre)-mediated p62 inactivation did not cause body weight gain, although ubiquitous inactivation of p62 was previously shown to result in severe obesity. Secondly, we found no gross structural disorganization of the islets of p62-deficient mice. Consistent with normal islet morphology, no impairment in glucose tolerance was observed in mice with RIP-Cre-mediated p62 deletion. These results suggest that p62 is dispensable for normal islet organization and β-cell function.
Obesity and increased arterial stiffness are risk factors for cardiovascular disease. A well-known characteristic of obesity is the chronic low-grade inflammatory state, and it causes elevation of arterial stiffness. Weight-loss reduces arterial stiffness and inflammatory level in obese individuals. However, it is unclear which inflammatory factor is most related to weight loss-induce decreases in arterial stiffness in overweight and obese men. Thus, the aim of this study was to determine which circulating cytokine level has the most effect on decreasing arterial stiffness after lifestyle modification. Twenty overweight and obese men completed a 12-week period of lifestyle modifications (combination of aerobic exercise training and dietary modification). We measured brachial-ankle pulse wave velocity (baPWV) as an index of arterial stiffness, and circulating cytokine levels using comprehensive analysis. After the 12-week lifestyle modifications, body mass was markedly decreased. Also, baPWV and the levels of several circulating cytokines significantly decreased after the lifestyle modifications. We observed a positive correlation between changes in baPWV and circulating interleukin-6 (IL-6) levels. Furthermore, multiple liner regression analysis revealed that change in baPWV was significantly associated with that in IL-6 levels after consideration of changes in systolic blood pressure and body mass index. These results suggest that for overweight and obese men, a 12-week period of lifestyle modifications-induced a decrease in circulating cytokine levels (especially IL-6 levels), leads to decreased baPWV.
Drug-induced hypersensitivity syndrome (DIHS) is a severe systemic adverse drug reaction. Previous studies showed that DIHS is associated with the onset of fulminant type 1 diabetes mellitus (FT1D). Although genetic background and abnormalities in immune response or viral infection are considered to be associated with pathogenesis of FT1D, it remains unclear whether virus infection and specific human leukocyte antigen (HLA) typing are involved in DIHS-associated FT1D. Here, we report a case of a 78-year-old female patient with FT1D after DIHS treatment. She was diagnosed as DIHS caused by carbamazepine, and treatment with predonisolone was initiated. After 46 days from the occurrence of DIHS, she was admitted to our hospital because of type 1 diabetes mellitus and diabetic ketoacidosis. Although her Hemoglobin A1c (HbA1c) was elevated by predonisolone treatment (HbA1c: 9.2%), we diagnosed her as fulminant type 1 diabetes mellitus considering the abrupt onset of the ketoacidosis. Her general condition was improved by treatment with fluid infusion and insulin administration. During her clinical course, the infection of coxsackie B4 virus was observed. In addition, the examination of HLA typing showed HLA-A24 haplotype. These findings suggest that the coxsackie B4 virus infection may be involved in the pathogenesis of DIHS-induced FT1D, and that HLA-A24 haplotype might relate to DIHS-associated FT1D.
Neuropeptide Y (NPY) is an important neurotransmitter in the control of energy metabolism. Several studies have shown that obesity is associated with increased levels of NPY in the hypothalamus. We hypothesized that the release of NPY has coordinated and integrated effects on energy metabolism in different tissues, such as adipocyte tissue, resulting in increased energy storage and decreased energy expenditure. Whether NPY has role in the molecular mechanism of human adipocyte tissue remains unclear. We established the model of human adipose derived stem cells (hADSCs) from human adipose tissue and differentiated it into adipocytes in the presence of NPY at different concentrations (10–15–10–6 mmol/L). We then assessed hADSCs proliferation and differentiation by quantifying lipid accumulation and examining the expression levels of related adipocyte markers after differentiation. Furthermore, the specific markers of white adipocyte tissue (WAT) in hADSCs were also analyzed. The results showed that low doses of NPY stimulated hADSCs proliferation (p < 0.05), while high doses of NPY inhibited hADSCs proliferation (p < 0.05). NPY significantly promoted lipid accumulation and increased the size of lipid droplets during human adipogenic differentiation; the levels of adipocyte markers PPAR-γ and C/EBPα were also increased. At the same time, NPY also increased the levels of WAT markers Cidec and RIP140 after adipocyte differentiation. The results suggested high dose NPY inhibits the proliferation of hADSCs while promotes adipocyte differentiation and increases the expression of WAT markers. This may be the reason why increased levels of NPY can lead to a rise in body weight.
Although somatostatin analogues (SSAs) are recommended as the first-line medical therapy for acromegaly, dopamine agonists (DAs) are also a therapeutic option for treatment. We aimed to assess and compare the efficacies of DAs and SSAs in treating acromegaly in clinical practice. We included 89 patients with acromegaly who took DAs (bromocriptine [BCT], n = 63; cabergoline [CAB], n = 11) or SSAs (n = 15) as a primary medical therapy for more than 3 months in the Seoul National University Hospital. The CAB (45.5%) and SSA (33.3%) groups achieved random GH levels of <2.5 ng/mL and the normal IGF-1 levels were significantly higher than in the BCT group (11.1%) (p = 0.009). We further included all the patients with acromegaly (n = 132) who had taken CAB, BCT, and SSAs as first- or second-line medical therapy. The CAB group showed similar efficacy as the SSA group in terms of the GH and insulin-like growth factor-1 (IGF-1) levels (57.6% for random GH level <2.5 ng/mL, 42.4% for normal IGF-1 levels, 36.4% for both). Logistic regression analysis revealed that medications, age, GH level, or IGF-1 level before medication, hyperprolactinemia, and prior gamma-knife surgery or radiation therapy, did not affect the therapeutic response. High pretreatment GH levels predicted poor treatment outcomes (odds ratio [95% confidence interval] = 0.95 [0.90–0.99]). CAB was effective in treating acromegaly at a relatively lower cost in patients with low pretreatment GH levels.
Aim of this study was to examine the association between the severity of obstructive sleep apnea (OSA) and dysglycemia in Japanese individuals with and without type 2 diabetes (T2DM). We enrolled 115 individuals diagnosed with OSA with an apnea hypopnea-index (AHI) ≥ 20 in whom continuous positive airway pressure (CPAP) therapy was introduced (N = 115, 44 with T2DM, age 62 ± 11 years, BMI 27.0 ± 4.4 kg/m2 and AHI median 36.1; interquartile range 27.2–48.1). During admission, the severity of OSA was evaluated by polysomnography, and its association with glycated hemoglobin (HbA1c) level was examined. Continuous glucose monitoring (CGM) was also conducted during the admission in 94 individuals. Apnea-hypopnea index (AHI), non-rapid eye movement (REM) AHI, minimum peripheral capillary oxygen saturation (SpO2) and percentage of sleep time (%TST) with SpO2 < 90% were significantly associated with HbA1c level in total and non-diabetic individuals (all p < 0.05) but not in those with T2DM, the majority of whom were treated with anti-diabetic medications. The associations of the non-REM AHI and %TST with SpO2 < 90% with HbA1c level remained significant after adjustment for age, sex and BMI in non-diabetic and T2DM subjects treated with dietary therapy only. Mean glucose level, but not SD or coefficient of variation of glucose, assessed by CGM was significantly associated with AHI and non-REM AHI in non-diabetic subjects after adjustment for age, sex and BMI. In conclusion, the severity of OSA was associated with increased HbA1c level independently of BMI in Japanese individuals, especially in those without diabetes.
The pathophysiology is distinct in various state of glucose metabolism abnormalities. As the defect of individuals with normal oral glucose tolerance (NGT) but isolated high glycosylated hemoglobin (HbA1c), i.e. iHH, was ambiguous, we aimed to investigate the insulin sensitivity and β-cell function of iHH. According to the ADA criteria of HbA1c cut-off point (5.7%), 3,517 subjects with NGT screened from a total of 7,855 middle-aged and elderly Chinese without known diabetes were divided into two groups, 1,877 subjects with HbA1c < 5.7% and 1,640 with HbA1c ≥ 5.7% (i.e. iHH). A variety of indexes from blood glucose and insulin levels of oral glucose tolerance were calculated to evaluate insulin sensitivity and β-cell function. Compared with subjects with HbA1c < 5.7%, individuals with iHH had increased homeostasis model assessment of insulin resistance (HOMA-IR), early-phase and total insulin release indexes (insulin release index 30 min and 120 min, i.e. INRS30 and INSR120), and decreased Matsuda insulin sensitivity index (Matsuda ISI) and early-phase disposition index (DI30). After adjustment for confounding factors, the significant difference of HOMA-IR and INSR30 between the two groups vanished, however, Matsuda ISI and DI30 remained significantly lower and INSR120 was still higher in iHH group compared with HbA1c < 5.7%. In conculsion, subjects with NGT may not be perfectly healthy in glycometabolism, those with iHH have impaired early-phase β-cell function and decreased insulin sensitivity.
The aim of the present study was to evaluate the association of irisin with obesity and metabolic syndrome (MetS) in Korean prepubertal children. A total of 96 children and adolescents aged 6 to 10 years (56 males) were included in this study. Subjects were divided into 3 groups: normal weight (n = 54), overweight (n = 16), and obese (n = 26). In the subgroup analyses, overweight/obese children were further divided based on their MetS status (with MetS vs. without MetS). Children with obesity tended to exhibit a lower mean irisin concentration compared to those with normal weight (p = 0.028). Using Pearson’s correlation coefficient to compare all the children in the study, there was a significant inverse correlation between irisin and body mass index (BMI) standard deviation scores (SDS) (r = –0.210, p = 0.041), waist circumference SDS (r = –0.203, p = 0.049), and glucose (r = –0.296, p = 0.004). In the subgroup analyses of overweight/obese children, irisin exhibited a significant inverse correlation with glucose (r = –0.507, p = 0.001) and triglycerides (r = –0.331, p = 0.033). Children with MetS exhibited lower irisin concentrations than those without MetS (14.70 ng/mL vs. 22.02 ng/mL, p = 0.001), and these associations were significant after adjusting for age, gender, and BMI SDS (14.51 ng/mL vs. 22.06 ng/mL, p = 0.002). The irisin level of 15.43 ng/mL was determined to be a possible cutoff to distinguish children with metabolic syndrome from overweight/obese children, with a sensitivity of 75% and a specificity of 94% (p < 0.001). Our results suggest that decreased irisin levels may be associated with MetS in prepubertal children and that irisin might be a biomarker for MetS in prepubertal children.