We aimed to determine the optimal gestational weight gain (GWG) in Japanese women with a Body Mass Index (BMI) ≥25 kg/m2. The present retrospective study investigated singleton pregnancies in 6,781 Japanese women registered in the Japan Society of Obstetrics and Gynecology system in 2013. We divided overweight and obese women into four GWG categories based on the Institute of Medicine (IOM) recommended: weight loss, small weight gain, within IOM criteria, and above IOM criteria. The adjusted odds ratios and predicted probabilities of maternal and neonatal outcomes of interest with weight change were calculated. In overweight women, GWG was associated with neonatal birth weight. In the loss and small gain subgroups, there was a significant increase in small for gestational age (SGA) and low birth weight neonates (LBW). Predicted probabilities showed the lowest risk was observed in a weight gain of 0 kg; the risk sharply increased at a gain of 11.5 kg. In obese women, weight gain increased the prevalence of large for gestational age (LGA) neonates; however; SGA was not associated with GWG. Predicted probabilities showed an increase in the risk with weight gain. The observed optimal GWG was 0 to 11.5 kg in overweight, and weight loss in obese, pregnant Japanese women.
The pathogenesis of thyroid lymphoepithelial cysts is controversial, and two hypotheses have been proposed, namely derivation from branchial-derived remnants or from squamous metaplasia of the follicular cells. The aim of this study was to clarify the pathogenesis of thyroid lymphoepithelial cysts. We performed pathological and immunohistochemical examination of 21 thyroid lymphoepithelial cysts, 13 non-neoplastic squamous metaplasia samples without thyroid carcinoma, 13 solid cell nests, and 14 lateral cervical cysts. On ultrasound, half of thyroid lymphoepithelial cysts were interpreted as calcified nodules regardless of no calcification. Thyroid lymphoepithelial cysts and squamous metaplasia tended to be located in the central and lower portions of the thyroid, while solid cell nests were located in the upper and central portions (p < 0.05). In 95.2% of patients with thyroid lymphoepithelial cysts and all patients with squamous metaplasia, lesions were histologically associated with chronic thyroiditis forming lymph follicles. Hashimoto’s disease was serologically confirmed in 18 patients with lymphoepithelial cysts (85.7%) and 10 patients with squamous metaplasia (76.9%). Immunohistochemically, lymphoepithelial cysts showed nuclear positivity for PAX8, thyroid transcription factor 1, and p63. One lateral cervical cyst (7.1%) showed positive staining for PAX8, while solid cell nests were PAX8-negative. In three (14.3%) cases of thyroid lymphoepithelial cysts, squamous cells located on the superficial layer were focally and weakly positive for CEA. We concluded that thyroid lymphoepithelial cysts originate from follicular cells and are unrelated to solid cell nests and lateral cervical cysts arising from branchial-derived remnants.
The prevalence of obesity is increasing globally in patients with diabetes. This study aimed to examine 12-year trends of increasing obesity in Japanese patients with diabetes, and their clinical features. The study used results of the Shiga Diabetes Clinical Survey, which recorded medical performance in diabetic patients in 2000, 2006 and 2012. Data were analyzed from 14,205, 14,407 and 21,449 adult patients in these three years, respectively. Overweight and obesity prevalence and the clinical features of diabetes patients were examined, stratified by body mass index (BMI) and age. The prevalence of overweight (BMI 25–30 kg/m2) and obesity (BMI ≥30 kg/m2) were 27.0% and 5.1% in 2000, 28.9% and 7.3% in 2006 and 30.9% and 10.0% in 2012. Glycemic control, blood pressure and serum lipid profile improved over 12 years in all BMI categories. However, glycemic and triglyceride control were insufficient in obese patients aged <65 years (hemoglobin A1c 7.5 ± 1.4%, triglyceride 197.7 ± 178.4 mg/dL in 2012). The percentage of patients who used antihypertensive and lipid-lowering drugs increased and patients with higher BMI had increased frequency of using these drugs, both in young and old age groups. Higher BMI was significantly and positively associated with albuminuria. In summary, overweight and obesity have increased in Japanese diabetic patients, particularly for younger generations. Findings suggest that obesity may lead to poorer glycemic control, blood pressure and lipid profiles. Overweight and obesity are important modifiable risk factors for diabetes, suggesting that more active weight-control interventions are warranted.
Maternal Graves’ disease (GD) during pregnancy may influence thyroid function in fetuses. Neonates born to mothers with high serum TSH receptor antibody (TRAb) levels have been reported to develop ‘neonatal GD’. Therefore, evaluations of serum thyroid hormone and TRAb levels in neonates upon birth are crucial for a prompt diagnosis. At delivery, we measured TRAb with third-generation TRAb test using an M22 human monoclonal antibody in neonates by collecting umbilical cord blood in a blood collection tube with lithium-heparin, which provides a whole blood/plasma sample. In recent years, we have encountered positive TRAb levels (more than 2.0 IU/L) in nineteen neonates born to mothers with GD whose thyroid hormone levels were almost within the reference range and serum TRAb levels were less than 10 IU/L. All the neonates with positive TRAb levels did not exhibit thyrotoxicosis. However, when we measured TRAb levels with serum sample in six out of the nineteen cases, their serum TRAb levels were all negative, suggesting a discrepancy of TRAb levels between in lithium-heparin plasma from umbilical cord blood and serum. Moreover, this discrepancy was observed in neonates born to euthyroid mothers, adult active GD patients and healthy volunteers. Since lithium-heparin plasma from umbilical cord blood is widely used in laboratory tests at delivery, we may encounter ‘false-positive’ TRAb, which may, in turn, lead to a misdiagnosis of neonatal GD. This is a pitfall of third-generation TRAb measurements in neonates, particularly at delivery, and needs to be considered by obstetricians and neonatologists.
Oxidative stress caused free radical and mitochondrial damage plays a critical role in the progression of aging and age-related damage at the cellular and tissue levels. Antioxidant supplementation has received growing attention and the effects of antioxidant on aging are increasingly assessed in both animal and human studies. However, additional and more promising treatments that contribute to the expansion of anti-aging therapies are needed. Astaxanthin, a super antioxidant carotenoid and free radical scavenger, inhibits lipid peroxidation more potently than vitamin E. In the present study, we investigated the preventative effects of astaxanthin on aging using an accelerated aging model: mice chronically treated with a combination of D-galactose and jet lag. After 6 weeks of treatment, astaxanthin administration tended to protect the liver weight loss in aged mice. It is probably by upregulating the mRNA expression of galactose-1-phosphate uridyltransferase, which contribute to the enhancement of D-galactose metabolism. Astaxanthin supplementation also improved muscle endurance of aged mice in a swimming test. These results were associated with reduced oxidative stress in serum and increased anti-oxidative enzymes activities and mRNA expression in vivo. Moreover, astaxanthin reversed the dysregulation of aging-related gene expression caused by the combination of D-galactose and jet lag in the liver and kidney of mice. In conclusion, astaxanthin prevents liver weight loss, ameliorates locomotive muscular function, exerts significant anti-aging effects by reducing oxidative stress and improving the expression of age-related genes in D-galactose and jet lag-induced aging model.
There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145–222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9–1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7–4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.
The reported prevalence of complications in Turner Syndrome (TS) was highly variable because of the rarity and the limited numbers analyzed. Again, possible presence of other complications that are not described as specific for TS, is also speculated. To resolve these issues, a questionnaire survey was conducted in hGH treated 492 patients with adult TS (17–42 years). The possible association with these complications and karyotypes were also analyzed. The complications and their prevalence were as follows: chronic thyroiditis (25.2%), inflammatory bowel disease (1.8%), congenital cardiovascular anomaly (11.8%), urinary tract malformation (11.8%), low bone mineral density (BMD) (42.9%), scoliosis (8.4%), hearing loss (6.2%), epilepsy (2.8%) and schizophrenia (0.9%). The majority of prevalence of these diseases in TS was higher than in the general population. In distribution, the most frequent karyotype was 45,X monosomy (28.9%), followed by 45,X/46,X,Xi (16.9%), 46,X,Xi (9.1%), and 45,X/46,XX (6.3%), while other mosaic 45,X was noted in 29.9%. Regarding the karyotype, cardiovascular anomaly was more frequent in the 45,X group and less in the 46,X,Xi group. Urinary tract malformation and epilepsy were frequently associated with the chromosome 45,X. The prevalence of low BMD was noticed more in the chromosome 46,X,Xi and 45,X/46,X,Xi, and less in other mosaic 45,X. In conclusion, the more exact prevalence of diverse complications was clarified and it exceeded the prevalence of the majority of complications in general population. As novel findings, it was observed that the prevalence of epilepsy was significantly high, and epilepsy and low BMD were frequently associated with the specific karyotypes.
Diabetic patients often suffer from muscle cramps. This study aimed to compare the quality of life (QOL) of diabetic patients with and without muscle cramps and to investigate the effect of L-carnitine supplementation in diabetic patients with muscle cramps. A total of 91 patients with diabetes were enrolled in this study: 69 patients with muscle cramps and 22 patients without muscle cramps. Muscle cramps and QOL were evaluated using the muscle cramp questionnaire and the Short Form 36 health survey version 2 (SF-36), respectively. Clinical characteristics were compared between diabetic patients with and without muscle cramps. In the prospective portion of the study, 25 diabetic patients with muscle cramps received L-carnitine supplementation (600 mg/day orally) for 4 months. The questionnaires were administered before and after supplementation. The SF-36 scores in diabetic patients with muscle cramps were lower than those in patients without muscle cramps on the subscales of physical function, role physical, bodily pain, vitality, general health, and social function. In the 25 patients with muscle cramps who received L-carnitine supplementation, the monthly frequency of muscle cramps and Wong-Baker FACES® Pain Rating Scale scores were significantly decreased. Scores on the following SF-36 subscales improved after L-carnitine supplementation: body pain, vitality, social function, and role emotional. This study demonstrated that muscle cramps decrease the QOL in patients with diabetes, and L-carnitine supplementation may improve the QOL by reducing the frequency and severity of muscle cramps in these patients.
Copy number variation (CNV) has emerged as another important genetic marker in addition to SNP for understanding etiology of complex disease. Kv channel interacting protein 1 (KCNIP1) is a Ca2+-dependent transcriptional modulator that contributes to the regulation of insulin secretion. Previous genome-wide CNV assay identified the KCNIP1 gene encompassing a CNV region, however, its further effect and risk rate on type 2 diabetes (T2D) have rarely been addressed, especially in Chinese population. The current study aims to detect and excavate genetic distribution profile of KCNIP1 CNV in Chinese T2D and control populations, and further to investigate the associations with clinical characteristics. Divergent patterns of the KCNIP1 CNV were identified (p < 0.01), in which the copy number gain was predominant in T2D, while the copy number normal accounted for the most in control group. Consistently, the individuals with copy number gain showed significant risk on T2D (OR = 4.550, p < 0.01). The KCNIP1 copy numbers presented significantly positive correlations with fasting plasma glucose and glycated hemoglobin in T2D. For OGTT test, the T2D patients with copy number gain had remarkably elevated glucose contents (60, 120, 180-min, p < 0.05 or p < 0.01) and diminished insulin levels (60, 120-min, p < 0.05) than those with copy number loss and normal, which suggested that the KCNIP1 CNV was correlated with the glucose and insulin action. This is the first CNV association study of the KCNIP1 gene in Chinese population, and these data indicated that KCNIP1 might function as a T2D-susceptibility gene whose dysregulation alters insulin production.
By biochemical and epidemiological similarity with type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM) has some overlap between prediction markers and risk factors of T2DM. The present study aimed to establish that secreted frizzled-related protein 4 (SFRP4) and ficolin-3 levels, which have been linked to insulin resistance and the development of T2DM, are elevated in GDM women. A longitudinal prospective cohort study of 86 GDM and 273 normal glucose tolerant (NGT) pregnant women was performed. The clinical parameters, lipid profiles, and serum SFRP4 and ficolin-3 levels were tested during the early and late second-trimester and third-trimester of pregnancy. Both SFRP4 and ficolin-3 levels were significantly higher in GDM women as compared to the NGT participants at three test points (p < 0.01). Spearman’s correlation analysis showed that serum SFRP4 levels were significantly positively correlated with ficolin-3 during the early and late second-trimester and third-trimester of pregnancy. The elevated SFRP4 and ficolin-3 concentrations at 16–18 weeks gestation significantly associated with GDM were conformed using binary logistic regression analysis after controlling for other variables [odds ratios (OR) with 95% confidence intervals (CI) for SFRP4: 2.84 (1.78–4.53), p < 0.01; for ficolin-3: 2.45 (1.55–3.88), p < 0.01]. In Conclusions, increased SFRP4 and ficolin-3 levels are significantly associated with GDM development and might be important risk factors for this pregnancy complication.
Kisspeptin/neurokinin B (NKB)/dynorphin (Dyn) (KNDy) neuron in hypothalamic arcuate nucleus plays a key role in GnRH/LH pulsatile secretion. We aimed to determine whether stimulation of NKB/neurokinin 3 receptor (NK3R) signaling and inhibition of Dyn/kappa-opioid receptor (KOR) signaling recover LH secretion that is suppressed by acute fasting in male rats. Furthermore, we determined dose dependent effect of NKB/NK3R signaling on serum LH level under acute fasting condition in male mice. Mature male rats were injected saline (0.1 mL) and senktide (20 μg/kg), a NK3R agonist, or nor-BNI (800 μg/kg), a KOR antagonist intraperitoneally (ip) after 72 h fasting. And mature male mice were injected multiple doses of senktide, ip after 48 h fasting. Blood and brain sample were collected 90 min after injections for LH measurement and hypothalamic mRNA expressions. All three studies showed significantly lower LH concentration in fasted groups than non-fasted groups. Senktide did not recover LH suppressed by acute fasting in male rats, whereas nor-BNI injected male rats showed significantly higher LH than 72 h fasted male rats (p < 0.05). Mice study showed significantly higher LH concentration in higher doses senktide groups than 48 h fasted group and one of lower doses senktide group. These results suggest that stimulation of NKB/NK3R signaling and attenuation of Dyn/KOR signaling could recover suppressed LH secretion under acute fasting condition in male rodents.
Glucose promotes insulin secretion primarily via its metabolism and the production of metabolic coupling factors in beta-cells. The activation of AMP-activated protein kinase (AMPK), an energy sensor, results in a decrease in insulin secretion from beta-cells, but its mechanism remains largely unknown. Berberine, an oral anti-diabetic drug, has been shown to activate AMPK in multiple peripheral tissues. Here, we examined the effects of berberine and AMPK activation on insulin secretion and glucose oxidation in rat islets. Our results showed that berberine inhibited glucose-stimulated insulin secretion from rat islets with AMPK activation. When glucose concentration was elevated to 25 mmol/L, the inhibitory action of berberine on insulin secretion disappeared. Furthermore, berberine significantly decreased oxygen consumption rate (OCR) and ATP production induced by high glucose in rat islets. Although adenovirus-mediated overexpression of constituent-activated AMPK markedly decreased GSIS and OCR in rat islets, the inhibition of AMPK by compound C did not reverse berberine-suppressed OCR. In addition, berberine attenuated glucose-stimulated expression of fatty acid synthase. These results indicate that berberine-mediated deceleration of glucose oxidation is tightly link to the decreased insulin secretion in islets independent of AMPK activation and inhibition of fatty acid synthesis may also contribute to the effect of berberine on insulin secretion.
Obstructive sleep apnea syndrome (OSAS) is often associated with metabolic disorders such as obesity and type 2 diabetes and may contribute to cardiovascular events. A novel class of antidiabetic drugs, the sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce body weight (BW), although there is limited data on their impact on OSAS. We therefore evaluated the effect of SGLT2i on OSAS in patients with type 2 diabetes. The presented study was a retrospective design in 18 patients with type 2 diabetes with OSAS (4 males, age range 39–81 yr) administrated a SGLT2i. HbA1c, BW, body mass index (BMI), blood pressure (BP) and apnea hypopnea index (AHI) were evaluated before and after SGLT2i administration. The relationships between the reduction in AHI and the other variables were examined using Pearson correlation analysis. We have got result that SGLT2i reduced AHI from 31.9 ± 18.0 to 18.8 ± 11.5 events per hr (p = 0.003). HbA1c, BW and BMI decreased significantly, whereas BP did not. The Pearson correlation analysis showed a significant relationship between the reduction in AHI and pre-administration of AHI. In conclusion, SGLT2i reduced not only HbA1c, BW and BMI but also AHI significantly and therefore has potential as an effective treatment of OSAS.
Children born small for gestational age (SGA) are at a higher risk for metabolic disorders later in life. In this study, we aimed to characterize young SGA children without catch-up growth and evaluate the effects of GH treatment on endocrinological, metabolic, and immunological parameters. Study design is a one-year single hospital-based study included prospective observation of SGA patients during 12 months of GH treatment. Clinical and laboratory profiles of SGA children at baseline were compared with controls born appropriate size for age. Twenty-six SGA children (median age, 3.4 years) and 26 control children (median age, 3.8 years) were enrolled. Anthropometric, hematologic, biochemical, immunological, and endocrinological parameters were assessed at baseline and 1, 3, 6, 9, and 12 months after the start of GH treatment. As a result, median height SD score (SDS) of SGA children increased by +0.42 with 12-month GH treatment. Body mass index SDS was lower in SGA children than in controls. Serum apolipoprotein A1 increased, whereas apolipoprotein B decreased during GH treatment. Serum leptin and resistin levels, which were lower in SGA children than in controls at baseline, did not change remarkably with GH treatment. Monocyte counts, which were lower in SGA patients at baseline, increased after GH treatment. Neutrophil counts significantly increased after GH treatment. Natural killer cell ratios, which were higher in SGA patients, decreased after GH treatment. In conclusion, there was no evidence suggesting metabolic abnormalities in SGA children. Serum apolipoprotein changes might predict the beneficial role of GH treatment in lowering cardiometabolic risk.
We describe a very rare case of concurrent variant type 3 autoimmune polyglandular syndrome (APS) and pulmonary arterial hypertension (PAH). A previously healthy 65-year-old Japanese woman was referred to our university hospital with a 2-month history of general fatigue and hyperglycemia. Laboratory tests revealed severe hyperglycemia (plasma glucose 543 mg/dL and HbA1c 10.7%) with ketonuria (3+). Glutamic acid decarboxylase (GAD) and IA-2 antibodies were positive, and the serum C peptide level was markedly decreased to 0.2 ng/mL. Accordingly, type 1 diabetes was diagnosed. Hashimoto’s thyroiditis was also diagnosed because she had a diffuse goiter and a mild hypothyroidism (TSH 8.20 μU/mL, and FT4 0.80 ng/mL) with positive autoantibodies for thyroid peroxidase and thyroglobulin. There was neither adrenal insufficiency nor hypocalcemia. In addition, chest X ray showed a suspicious PAH by a dilation of both pulmonary arteries, especially right descending artery, and right heart catheterization confirmed the presence of PAH. HLA Class II genotyping revealed DRB1-DQB1*0901-*0303, a common susceptibility haplotype in Japanese patients with type 3 APS or acute-onset type 1 diabetes. The combination of variant type 3 APS and PAH is extremely rare and to the best of knowledge, this is the first case reported in a Japanese patient.
Thyroid metastasis from head and neck squamous cell carcinoma (SCC) is a very rare form of rarely observed metastatic thyroid tumor. We herein report a case of thyroid metastasis from oropharyngeal SCC (OSCC). The patient was a 68-year-old male diagnosed with p16-positive tonsillar OSCC on the right side with multiple lymph node metastases and a thyroid mass, which was determined as metastatic p16-positive OSCC by immunohistochemistry of specimens collected by fine-needle aspiration cytology (FNAC). He received one cycle of induction chemotherapy followed by concurrent chemoradiotherapy. No visible primary lesions were observed after treatment. The disappearance of the tonsillar lesion was considered to be a complete response by the magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT). The thyroid lesion was also decreased, but a solid lesion with unclear boundaries in the right thyroid lobe remained. Therefore, the patient underwent total thyroidectomy to remove any residual tumor. Postoperative pathological evaluation revealed no residual viable carcinoma cells in the resected specimen. As illustrated in this case, immunohistochemistry of the FNAC specimen for p16 was successful in determining the thyroid tumor as a metastatic lesion from the oropharynx. Although radical radiotherapy might be sufficient to control thyroid gland metastasis of OSCC, in this case, early-stage remedial surgery was thought to be necessary for a secure radical cure.
Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) sub-family, plays a major role in angiogenesis and vasculogenesis. Previous study demonstrated that PlGF-overexpressing transgenic (Tg) mice had gestational loss. In addition, PlGF secretion was up-regulated in isolated T lymphocytes (T-cell) upon CD3/CD28 stimulation, suggesting that PlGF could be a regulator of T-cell differentiation and development. T-cells are well known to play a critical role in obesity-induced inflammation. Therefore, to verify the possible link of diet-induced obesity (DIO) with inflammation and related metabolic disorders, such as insulin resistance, we fed high-fat diet (HFD) to Tg mice for 16 weeks. Adiposity and glucose intolerance significantly increase in Tg mice fed a HFD (Tg HFD) compared to wild-type (WT) mice fed HFD (WT HFD). In addition, macrophage infiltrations were significantly higher in the epididymal white adipose tissue (EWAT), liver, and pancreatic islets of Tg HFD mice compared to WT HFD mice. In the in vitro study, we showed that isolated CD4+ T-cells from Tg mice further differentiate into type 1 (Th1) and type 17 (Th17) helper T-cells via CD3/CD28 stimulation. Furthermore, we observed that the pro-inflammatory cytokines IL-6, IL-17, and TNFα, are remarkably increased in Tg mice compared to WT mice. These findings demonstrate that PlGF overexpression in T-cells might lead to inflammatory T-cell differentiation and accumulation in adipose tissue (AT) or metabolism-related tissues, contributing to the development of systemic metabolic disorders. Thus, PlGF may provide an effective therapeutic target in the management of obesity-induced inflammation and related metabolic disorders.
Various noninvasive algorithms have been developed for predicting the presence of nonalcoholic fatty liver disease (NAFLD). The evaluation of the indexes’ diagnostic performance has been reported in Europe and Asia over the past decade; however, external validation of them in China is rare. This study was aimed to evaluate various indexes for NAFLD in western China. It was a retrospective cross-sectional study, using data from a large-scale health check-up project at Sichuan provincial hospital. Receiver operating characteristic (ROC) curves of eight indexes, including the fatty liver index (FLI), the hepatic steatosis index, lipid accumulation product and etc., were developed to predict ultrasonographic NAFLD. There were 13,122 subjects in this study (2,692 NAFLD patients and 10,430 non-NAFLD participants). The area under ROC curve of FLI for predicting NAFLD was 0.880 (95% confidence interval, 0.874–0.886), which was significantly higher than other seven indexes. Accuracy, sensitivity and specificity of FLI for NAFLD were good (cut-off value = 30, 0.782, 0.832, 0.770 and cut-off value = 60, 0.838, 0.443, 0.940, respectively). Furthermore, FLI also presented advantages in expenditure and accessibility, compared with other indexes. It supports FLI as an easily accessible index for physicians and a reliable predictor for NAFLD screening in western China.
We report three cases of thyroid sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE), which is an extremely rare variant of mucoepidermoid carcinoma (MEC). The aims of this report were to describe the clinicopathological findings, including results from immunohistochemical and fluorescence in situ hybridization analysis of thyroid SMECE, as well as to discuss the distinction between thyroid SMECE and its salivary counterpart. The cases included a 63-year-old female, a 44-year-old male, and a 66-year-old female, with all patients presenting with Hashimoto’s thyroiditis. Nodal metastasis was not found in any of the three cases. Neither regional recurrences nor distant metastases were found in any patient during the follow-up, which was 20 years, 3 years, and 18 months, respectively. Histologically, tumors were composed of epidermoid carcinoma cells, intermediate type carcinoma cells, and goblet cell-type mucus-secreting carcinoma cells, with all tumors displaying a sclerotic stroma with eosinophilic and lymphocytic infiltration. The formation of eosinophilic abscess in the tumor nests that might be a novel characteristic finding of SMECE was observed. Immunohistochemically, the carcinoma cells were positive for cytokeratin 34βE12, TTF-1, and PAX8, but negative for thyroglobulin. In two cases, increased IgG4-positive plasma cells were observed. Mastermind-like transcriptional coactivator 2 (MAML2), according to fluorescence in situ hybridization, was intact in all cases. In conclusion, thyroid SMECE has favorable outcomes and seems to be genetically different from salivary MEC. This is the first report to describe the presence of increased IgG4-positive plasma cells in the stroma of SMECE.
This study evaluates the efficacy and safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors as add-on to metformin and sulfonylurea treatment for type 2 diabetes management. The literature search was conducted in electronic databases and meta-analyses of mean differences in the changes from baseline in selected disease endpoints (efficacy endpoints) or odds ratios (for safety endpoints) were performed to compare outcomes between SGLT2 inhibitor- and placebo-/comparator-treatments. Seven studies (5,143 patients; age 56.75 years [95% CI: 56.19, 57.37]; body mass index 29.53 kg/m2 [28.23, 30.83]; and 51.87% [50.46, 53.57] males) were included. Compared to placebo, SGLT2 inhibitors significantly (p < 0.00001) reduced glycated hemoglobin (HbA1c; –0.79% [95% CI: –0.90, –0.68]), fasting plasma glucose (FPG; –1.73 mmol/L [–1.86, –1.60]) and body weight (–1.85 kg [–2.11, –1.59]) after 52–78 weeks of treatment. There were no significant differences in reduction of either HbA1c, FPG or body weight between 18–24 weeks and after 52–76 weeks of treatment. Treatment with SGLT2 inhibitors as add-on to metformin and sulfonylurea was also associated with significant reductions in blood pressure and triglycerides and increase in high-density lipoprotein-cholesterol. Incidence of hypoglycemia was significantly higher, but incidence of hyperglycemia was significantly lower in SGLT2 inhibitor group. Overall, drug-related adverse events were more common in SGLT2 group mainly due to higher incidence of genital tract infections.
Skipping breakfast or irregular breakfast is associated with poor glycemic control. However, a relationship between the timing of dinner and glycemic control in people with type 2 diabetes remains indefinite. Therefore, we investigated the relationship between late-night-dinner and glycemic control in people with type 2 diabetes. We performed questionnaire survey for lifestyle factors in this cross-sectional study. We defined having dinner later than eight pm as late-night-dinner. We examined the differences in clinical and metabolic parameters between those who have late-night-dinner and those who do not have. We also examined the relationship between late-night-dinner and HbA1c, using multiple regression analysis. Ninety-five people (23.2%) had a late-night-dinner, among 409 people with type 2 diabetes. Metabolic parameters (mean (SD) or median (interquartile range)) of people with late-night-dinner were worse than those of without, including body mass index (BMI) (24.4 (4.0) vs. 23.2 (3.4) kg/m2, p = 0.006), triglycerides (1.5 (1.1–2.1) vs. 1.2 (0.8–1.7) mmol/L, p < 0.001), HDL-cholesterol (1.4 (0.4) vs. 1.6 (0.4) mmol/L, p = 0.004) and hemoglobin A1c (58.1 (13.3) vs. 55.2 (10.2) mmol/mol, (7.5 (1.2) vs. 7.2 (0.9) %), p = 0.023)). Late-night-dinner (standardized regression coefficient = 0.13, p = 0.028) was associated with hemoglobin A1c after adjusting for age, BMI, sex, duration of diabetes, smoking, exercise, alcohol, snacking after dinner, nighttime sleep duration, time from dinner to bedtime, skipping breakfast, and medication for diabetes. Late-night-dinner is independently associated with poor glycemic control in people with type 2 diabetes.
Recently, we reported that linagliptin had equivalent efficacy to voglibose in reducing postprandial blood glucose levels in drug-naïve patients with type 2 diabetes (L-STEP Study). As a sub-study of the L-STEP Study we examined the effect of linagliptin on postprandial lipids profile. Between October 2012 and April 2014, the study enrolled patients with type 2 diabetes mellitus who had inadequate glycemic control. Patients were randomly assigned to either the linagliptin group (5 mg once daily, n = 85) or the voglibose group (0.2 mg/meal thrice daily, n = 71). Meal tolerance tests were performed at baseline (week 0) and endpoint (week 12). The increments in 4-h postprandial triglyceride, remnant lipoprotein cholesterol (RLP-C), and apolipoprotein B48 (ApoB48) from baseline to endpoint in the linagliptin group were lower (p < 0.001, p = 0.025 and p < 0.001). 4-h postprandial ApoB48 at endpoint was lower in the linagliptin group (p = 0.007), and positive correlation was detected between change of ApoB48 and changes in both triglyceride (r = 0.67, p < 0.001) and RLP-C (r = 0.73, p < 0.001) at 4 h. This study revealed that in drug-naïve Japanese patients with relatively mild type 2 diabetes mellitus, linagliptin improves not only postprandial blood glucose level but also levels of lipids such as TG and RLP-C by reducing the ApoB48 level compared with voglibose.
The molecular mechanism involved in the exocytosis of arginine vasopressin (AVP) is not fully known. Rabphilin-3A has been suggested as a novel autoantigen in infundibulo-neurohypophysitis (LINH), which leads to central diabetes insipidus through insufficient secretion of AVP. However, the role of rabphilin-3A in the pathogenesis of LINH remains unclear. Thus, the aim of the present study was to identify proteins binding rabphilin-3A in the posterior pituitary. Using glutathione S-transferase (GST)-pulldown assays and proteomic analyses, cullin-associated NEDD8-dissociated protein 1 (CAND1) was identified as a rabphilin-3A-binding protein in the posterior pituitary. Co-immunoprecipitation assays indicated that CAND1 interacted endogenously with rabphilin-3A. In addition, immunohistochemistry experiments showed that CAND1 immunoreactivity was detected mainly in the posterior pituitary, intermediate lobe, and the supraoptic nucleus in the hypothalamus, and less in the anterior lobe, partially co-localizing with rabphilin-3A. Overexpression of CAND1 resulted in deubiquitylation of rabphilin-3A in PC12 cells. Moreover, overexpression of CAND1 in PC12 cells co-transfected with AVP enhanced both basal and KCl-stimulated AVP secretion. The findings indicate that CAND1 inhibits the ubiquitylation of rabphilin-3A and positively regulates AVP secretion. These data shed light on a novel potential mechanism involving rabphilin-3A in AVP secretion, and suggest a new role of CAND1 as a regulator of hormone or neurotransmitter secretion.
Diabetic foot ulcer is a chronic, refractory, frequent complication in diabetic patient. Its treatment often requires multidisciplinary joint efforts, diverse strategies have been adopted to address this annoying issue, including stem cell-based therapy/acellular dermal matrix/negative pressure wound therapy etc. However, consensus has not been reached. To assess the current evidence regarding the efficiency and potential advantages of stem cell-based therapy compared with conventional standard treatment and/or placebo in the treatment of diabetic foot ulcer. A comprehensive search in PubMed, EmBase, Cochrane Central and Web of Science databases was conducted during December 2016 and a systematic review and meta-analysis of all relevant studies were performed. A total of 7 studies that involved 224 diabetic foot patients, classified as Wagner grades 1–5, were analyzed. The pooled results confirmed the benefits of using the stem cell treatment. Partial and/or complete healing were significantly higher in the stem cell group compared with the control group (77.4% vs. 31.9%; RR: 2.22; 95% CI, 1.65–2.98). Subgroup analysis on ABI and TCP02 also confirmed the results. The present meta-analysis indicates that stem cell-based therapy can enhance the healing of diabetic foot ulcers and is associated with lesser pain, lower amputation rate and improved prognosis compared with normal treatment. Well-designed randomized controlled trials are required in the future in order to confirm and update these findings.
To assess the efficacy, safety, and pharmacokinetics of metyrosine (an inhibitor of catecholamine synthesis) in patients with pheochromocytoma/paraganglioma (PPGL), we conducted a prospective, multi-center, open-label study at 11 sites in Japan. We recruited PPGL patients aged ≥12 years requiring preoperative or chronic treatment, receiving α-blocker treatment, having baseline urinary metanephrine (uMN) or normetanephrine (uNMN) levels ≥3 times the upper limit of normal values, and having symptoms associated with excess catecholamine. Metyrosine treatment was started at 500 mg/day and modified according to dose-adjustment criteria up to 4,000 mg/day. The main outcome measure was the proportion of patients who achieved at least 50% reduction in uMN or uNMN levels from baseline. Sixteen patients (11 males/5 females) aged 12–86 years participated. After 12 weeks of treatment and at the last evaluation of efficacy, the primary endpoint was achieved in 31.3% of all patients, including 66.7% of those under preoperative treatment and 23.1% of those under chronic treatment. Sedation, anemia, and death were reported in 1 patient each as serious adverse drug reactions during the 24-week treatment. Metyrosine was shown to be tolerated and to relieve symptoms by reducing excess catecholamine in PPGL patients under both preoperative and chronic treatment.
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.
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.
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.