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It has been controversial whether or not 1 mg overnight dexamethasone suppression test (DST) is superior to 0.5 mg DST in diagnosing subclinical adrenal Cushing syndrome. Sasaki et al. addressed this issue by measuring plasma dexamethasone concentration using liquid chromatography tandem mass spectrometry. Their results clearly showed that 1 mg DST dexamethasone suppression test is superior to 0.5 mg DST. This information is useful for the diagnosis of subclinical adrenal Cushing syndrome.

In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing’s syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry

Yosuke Sasaki, Takuyuki Katabami, Shiko Asai, Hisashi Fukuda, Yasushi Tanaka

Abstract

The low-dose dexamethasone suppression test (DST) is one of the commonly used initial tests for endogenous Cushing’s syndrome (CS). However, there are two loading dose regimens (0.5-mg and 1-mg), which may cause some confusion in daily practice in Japan; furthermore, there are no reports regarding whether 0.5-mg DST is a better loading dose for detecting adrenal subclinical CS (SCS) based on the plasma dexamethasone (DEX) levels. Therefore, the aims of this study were (a) to develop a novel assay to measure DEX by using liquid chromatography tandem-mass spectrometry (LC-MS/MS) and (b) to compare between the 0.5-mg and 1-mg DST for SCS diagnosis based on the DEX levels. The study retrospectively analyzed 52 consecutive subjects hospitalized for diagnosis of adrenal incidentaloma but who did not exhibit an overt CS phenotype; eight (15.4%) patients were affected with adrenal SCS. Inter-individual variability of DEX levels after the DST was high, but intra-individual variability was low. DEX levels after 1-mg loading in each patient was around two times higher than those after 0.5-mg loading (ρ = 0.853 and p < 0.001). There were 45 (86.5%) and 17 (32.7%) subjects with DEX levels ≤2.2 ng/mL after the 0.5-mg and 1-mg DST, respectively (p < 0.001). Twenty-eight (93.3%) of 30 subjects and four (21.1%) of 19 subjects with detectable ACTH levels after the 0.5-mg and 1.0-mg DST, respectively, did not exhibit DEX levels >2.2 ng/mL. These results clearly indicate that the 1-mg DST is superior to 0.5-mg loading for the diagnosis of adrenal SCS.


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Nakamura et al. investigated the complication of X-linked hypophosphatemia (XLH) other than skeletal and dental diseases. They examined retrospectively medical records of 22 patients with XLH, and found that hypertension was associated with XLH in 6 patients. The average onset of hypertension was 29.0 years and secondary hyperparathyroidism preceded the development of hypertension. In patients with hypertension, eGFR was significantly reduced compared to that of those without hypertension. These results suggest that early-onset hypertension is one of complications in patients with XLH.

Hypertension is a characteristic complication of X-linked hypophosphatemia

Yoshie Nakamura, Masaki Takagi, Ryojun Takeda, Kentaro Miyai, Yukihiro Hasegawa

Abstract

X-linked hypophosphatemia (XLH) is a group of rare disorders caused by defective proximal tubular reabsorption of phosphate. Mutations in the PHEX gene are responsible for the majority of cases. There are very few reports of long-term complications of XLH other than skeletal and dental diseases. The aim of this study was to identify the phenotypic presentation of XLH during adulthood including complications other than skeletal and dental diseases. The clinical and biochemical phenotype of 22 adult patients with a PHEX gene mutation were examined retrospectively from their medical records. 6 patients had hypertension. The average age of hypertension onset was 29.0 years. Secondary hyperparathyroidism preceded the development of hypertension in 5 patients. 1 patient developed tertiary hyperparathyroidism. 15 patients had nephrocalcinosis. 2 patients had chronic renal dysfunction. Patients with hypertension had a significantly lower eGFR (p=0.010) compared to patients without hypertension. No significant difference was found in any other parameters. To examine the genotype-phenotype correlation, 10 adult males were chosen for analysis. No significant genotype-phenotype correlation analysis was revealed in any of the complications. However, there was a possibility that the age at nephrocalcinosis onset was younger in the non-missense mutation group than in the missense mutation group (p=0.063). This study corroborated the view that early-onset hypertension could be one of the characteristic complications seen in XLH patients. Considering the limited number of our patients, further study is necessary to address a potential cause of hypertension. XLH patients require careful lifelong treatment.


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Matsuzawa et al. investigated the involvement of regulatory T cells in the pathophysiology of Graves' ophthalmopathy (GO). They analyzed peripheral blood mononuclear cells from patients with Graves' disease with overt GO, those with Graves' disease without GO (non-GO), and healthy controls. They found that GO had significantly higher frequency of effector T cells than non-GO and healthy controls. Regarding disease activity, patients with improved GO had lower frequencies of regulatory T cells than patients with stable or deteriorated GO. They conclude that expanded population of effector T cells may be associated with pathogenesis of GO and that decreased regulatory T cells in peripheral blood may predict a good clinical outcome.

Implications of FoxP3-positive and -negative CD4+ CD25+ T cells in Graves’ ophthalmopathy

Kazuhiko Matsuzawa, Shoichiro Izawa, Tsuyoshi Okura, Shinya Fujii, Kazuhisa Matsumoto, Kyoko Shoji, Risa Nakamura, Keisuke Sumi, Yohei Fujioka, Akio Yoshida, Chiaki Shigemasa, Masahiko Kato, Kazuhiro Yamamoto, Shin-ichi Taniguchi

Abstract

Graves’ ophthalmopathy (GO) is a common manifestation of Graves’ disease (GD); however, its pathogenesis is not well understood. Recently, the dysregulation of regulatory T cells (Tregs) has been thought to be closely associated with the pathogenesis and clinical symptoms of autoimmune disease. We therefore evaluated whether T cell subsets, including Tregs, are associated with GO pathogenesis and clinical symptoms. In this observational study we evaluated 35 GD patients with overt ophthalmopathy (GOs) and 28 patients without ophthalmopathy (non-GOs). Fifteen healthy euthyroid patients served as healthy controls (HCs). Peripheral blood mononuclear cells from GOs, non-GOs and HCs were analyzed for CD4, CD25, and FoxP3 expression using flow cytometry. We also evaluated their correlation with disease activity according to the clinical activity score (CAS) and magnetic resonance imaging (MRI) findings. Disease severity was evaluated using the NOSPECS score, and clinical progression of GO was followed for 24 weeks. The main outcome measures were the frequencies of FoxP3-positive and -negative CD4+ CD25+ T cells at study outset, namely Tregs and effector T cells (Teffs), respectively. GOs had higher frequencies of Teffs (30.8±8.4%) than non-GOs (19.4±7.1%) and HCs (22.7±7.9%). Notably, patients with improved GOs had lower frequencies of Tregs (5.8±1.1%) than patients with stable or deteriorated GOs (7.3±1.2%), although ophthalmic and radiological parameters were not significantly different at the start of the study. In conclusion, an expanded Teff population may be associated with GO pathogenesis. Additionally, decreased Tregs in peripheral blood may predict a good clinical outcome.


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Ono et al. reported a new method to induce fatal hypothyroidism in rabbits. They performed total thyroidectomy using a surgical microscope. After the total thyroidectomy, severe signs of hypothyroidism were observed. Most of the thyroidectomized rabbits died within 14 weeks presumably due to heart failure. This is an interesting animal model for fatal hypothyroidism and may be useful to establish a guideline for the treatment of myxedema coma, a life-threatening endocrine crisis.

A rabbit model of fatal hypothyroidism mimicking “myxedema coma” established by microscopic total thyroidectomy

Yosuke Ono, Masanori Fujita, Sachiko Ono, Sho Ogata, Shoichi Tachibana, Yuji Tanaka

Abstract

Myxedema coma (MC) is a life-threatening endocrine crisis caused by severe hypothyroidism. However, validated diagnostic criteria and treatment guidelines for MC have not been established owing to its rarity. Therefore, a valid animal model is required to investigate the pathologic and therapeutic aspects of MC. The aim of the present study was to establish an animal model of MC induced by total thyroidectomy. We utilized 14 male New Zealand White rabbits anesthetized via intramuscular ketamine and xylazine administration. A total of 7 rabbits were completely thyroidectomized under a surgical microscope (thyroidectomized group) and the remainder underwent sham operations (control group). The animals in both groups were monitored without thyroid hormone replacement for 15 weeks. Pulse rate, blood pressure, body temperature, and electrocardiograms (ECG) were recorded and blood samples were taken from the jugular vein immediately prior to the thyroidectomy and 2 and 4 weeks after surgery. The thyroidectomized rabbits showed a marked reduction of serum thyroxine levels at 4 weeks after the surgical procedure vs. controls (0.50±0.10 vs. 3.32±0.68 μg/dL, p<0.001). Additionally, thyroidectomized rabbits exhibited several signs of hypothyroidism such as hypothermia, systolic hypotension, bradycardia, and low voltage on ECGs, compared with controls. Of the 7 rabbits with severe hypothyroidism, 6 died from 4 to 14 weeks after the thyroidectomy possibly owing to heart failure, because histopathologic examinations revealed a myxedema heart. In summary, we have established a rabbit model of fatal hypothyroidism mimicking MC, which may facilitate pathophysiological and molecular investigations of MC and evaluations of new therapeutic interventions.


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In this review article, Horii and Hatada overviewed application of genome editing by using the CRISPR/Cas system. Using this new technology, it is rather easy to prepare knockout cells or animals. Additionally, this method enables us to generate multiple mutations and knock-in. In this article, application of the CRISPR/Cas system for the pluripotent stem cells and for preparation of genome-edited animals is presented.

Production of genome-edited pluripotent stem cells and mice by CRISPR/Cas

Takuro Horii, Izuho Hatada

Abstract

Clustered regularly at interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) nucleases, so-called CRISPR/Cas, was recently developed as an epoch-making genome engineering technology. This system only requires Cas9 nuclease and single-guide RNA complementary to a target locus. CRISPR/Cas enables the generation of knockout cells and animals in a single step. This system can also be used to generate multiple mutations and knockin in a single step, which is not possible using other methods. In this review, we provide an overview of genome editing by CRISPR/Cas in pluripotent stem cells and mice.


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Genome editing technology is a breakthrough in the field of life science and enables us to perform gene targeting in easy and reproducible ways. In this article, Hatada and Horii reviewed history, principles and application of the CRISPR/Cas9 system. Future prospects of the genome editing are also presented.

Genome editing: A breakthrough in life science and medicine

Izuho Hatada, Takuro Horii

Abstract

Genome editing technologies represent a major breakthrough that has dramatically altered strategies in a wide range of biological studies. Genome editing simplifies and accelerates the creation of animal disease models and enables construction of models in most animal species, even those that are not amenable to conventional gene targeting technology.


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Ozturk and colleagues investigated the prevalence of metabolic syndrome in patients with normocalcemic primary hyperparathyroidism (NC-PHPT) and compared to that in patients with hypercalcemic primary hyperparathyroidism (HC-PHPT). Compared to patients with HC-PHPT, patients with NC-PHPT had similar prevalence of metabolic syndrome, glucose intolerance and hypertension. Compared to control age- and gender-matched subjects, patients with NC-PHPT had significantly higher prevalence of glucose intolerance and hypertension. Patients with NC-PHPT should be followed up carefully because of the metabolic consequences.

Patients with normocalcemic primary hyperparathyroidism may have similar metabolic profile as hypercalcemic patients

Feyza Yener Ozturk, Selvinaz Erol, Muhammed Masum Canat, Savas Karatas, Idris Kuzu, Sezin Dogan Cakir, Yuksel Altuntas

Abstract

Primary hyperparathyroidism is well known to be associated with cardiovascular morbidity and mortality. However, it is unclear whether normocalcemic primary hyperparathyroidism (NC-PHPT) and hypercalcemic primary hyperparathyroidism (HC-PHPT) share the same risk factors. We aimed to determine prevalence of metabolic syndrome in NC-PHPT and compare metabolic syndrome parameters and insulin resistance in NC-PHPT subjects with those in HC-PHPT and control subjects. After excluding patients with secondary hyperparathyroidism, the study enrolled 25 patients with NC-PHPT, 24 patients with HC-PHPT and 30 age-gender matched controls. All participants were evaluated using the International Diabetes Federation (IDF)-2006 metabolic syndrome criteria. Compared with HC-PHPT patients, NC-PHPT patients had similar prevalence of metabolic syndrome, glucose intolerance, and previous history of hypertension/anti-hypertensive medications, but compared with controls, NC-PHPT patients had significantly higher prevalence of glucose intolerance and previous history of hypertension/anti-hypertensive medications. Not serum calcium but PTH concentration was found to be significantly higher in those with glucose intolerance. Serum fasting triglyceride concentration and waist circumference were found to be positively correlated only with serum PTH concentration. In conclusion, patients with NC-PHPT may be prone to similar metabolic disturbances linked to higher cardiovascular risk like patients with HC-PHPT. Although NC-PHPT is thought to occur early in the development of the classical disease, it should be monitored regularly because of its metabolic consequences.


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Hayashi et al. reported a patient with type 2 diabetes associated with anti-insulin antibody. The patient was treated with insulin but the glycemic control was poor characterized by frequent episodes of nocturnal hypoglycemia and daytime hyperglycemia. Administration of a DPP4 inhibitor was not effective whereas ipragliflozin, an SGLT2 inhibitor, markedly improved glycemic control and hypoglycemic episodes were disappeared. Anti-insulin antibody was greatly improved. These results suggest that SGLT2 inhibitors provide a therapeutic option for diabetes associated with anti-insulin antibody.

SGLT2 inhibitors provide an effective therapeutic option for diabetes complicated with insulin antibodies

Akinori Hayashi, Koji Takano, Sayuki Kawai, Masayoshi Shichiri

Abstract

Diabetes mellitus complicated with insulin antibodies is rare in clinical practice but usually difficult to control. A high amount of insulin antibodies, especially with low affinity and high binding capacity, leads to unstable glycemic control characterized by hyperglycemia unresponsive to large volume of insulin and unanticipated hypoglycemia. There are several treatment options, such as changing insulin preparation, immunosupression with glucocorticoids, and plasmapheresis, most of which are of limited efficacy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of drug which decrease renal glucose reabsorption and lowers plasma glucose level independent of insulin action. We report here a case with diabetes complicated with insulin antibodies who was effectively controlled by an SGLT2 inhibitor. A 47-year-old man with type 2 diabetes treated with insulin had very poor glycemic control characterized by postprandial hyperglycemia unresponsive to insulin therapy and repetitive hypoglycemia due to insulin antibodies. Treatment with ipragliflozin, an SGLT2 inhibitor, improved HbA1c from 8.4% to 6.0% and glycated albumin from 29.4% to 17.9%. Continuous glucose monitoring revealed improvement of glycemic profile (average glucose level from 212 mg/dL to 99 mg/dL and glycemic standard deviation from 92 mg/dL to 14 mg/dL) with disappearance of hypoglycemic events. This treatment further ameliorated the characteristics of insulin antibodies and resulted in reduced insulin requirement. SGLT2 inhibitors may offer an effective treatment option for managing the poor glycemic control in diabetes complicated with insulin antibodies.


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Sasaki et al. analyzed a transgenic mouse line expressing human insulin receptor after crossing the line with db/db mice. They unexpectedly found that these mice have improvements in hyperphagia and glucose tolerance without improved insulin sensitivity. Leptin receptor signaling may contribute to the discordant regulation between glucose tolerance and insulin sensitivity.

Overexpression of insulin receptor partially improves obese and diabetic phenotypes in db/db mice

Tsutomu Sasaki, Mitsutaka Kuroko, Sawako Sekine, Sho Matsui, Osamu Kikuchi, Vina Yanti Susanti, Masaki Kobayashi, Yoshinori Tanaka, Tomoyuki Yuasa, Tadahiro Kitamura

Abstract

Type 2 diabetes mellitus (T2DM) is one of the major health concern among the world. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues, and improving insulin sensitivity by insulin sensitizers. However, increasing the amount of insulin receptor in insulin-target tissues has not been explored. In order to test the efficacy of insulin receptor overexpression for improving glucose control, we established a transgenic mouse line expressing human insulin receptor (INSR). We analyzed, growth, energy balance, and glucose control of INSR-overexpressing db/db mice (INSR; db/db), which we produced by mating INSR transgenic mice with db/db mice, a genetic model of obesity due to insufficient leptin signaling. Compared to db/db mice, INSR; db/db mice were rescued from hyperphagia and obesity, leading to improved blood glucose levels. Unexpectedly, however, INSR; db/db mice presented with stunted growth, accompanied by decreased plasma levels of free IGF1 and IGFBP-3, indicating the down-regulation of GH/IGF1 axis. These phenotypes were observed in INSR; db/db mice but not in INSR littermates. Meanwhile, bone defects observed in db/db male mice were not rescued. Moreover, improved blood glucose was not accompanied by improved insulin sensitivity. Therefore, overexpression of insulin receptor improves obese and diabetic phenotypes in db/db mice, with consequences on growth.


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Fukumoto and colleagues summarized the definition and pathogenesis of rickets and osteomalacia, two metabolic disorders due to impaired mineralization of bone matrix. They also presented diagnostic criteria and flowchart for differential diagnosis, which are very useful for endocrinologists.

Pathogenesis and diagnostic criteria for rickets and osteomalacia — Proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society [Opinion]

Seiji Fukumoto, Keiichi Ozono, Toshimi Michigami, Masanori Minagawa, Ryo Okazaki, Toshitsugu Sugimoto, Yasuhiro Takeuchi, Toshio Matsumoto

Abstract

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations revealed that the causes for rickets and osteomalacia are quite variable. While these diseases can severely impair the quality of life of the affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose the diagnostic criteria and a flowchart for the differential diagnosis of various causes for these diseases. We hope that these criteria and flowchart are clinically useful for the proper diagnosis and management of patients with these diseases.


Recommendation from Editors/Reviewers

Sasaki et al. analyzed a transgenic mouse line expressing human insulin receptor after crossing the line with db/db mice. They unexpectedly found that these mice have improvements in hyperphagia and glucose tolerance without improved insulin sensitivity. Leptin receptor signaling may contribute to the discordant regulation between glucose tolerance and insulin sensitivity.

Overexpression of insulin receptor partially improves obese and diabetic phenotypes in db/db mice

Tsutomu Sasaki, Mitsutaka Kuroko, Sawako Sekine, Sho Matsui, Osamu Kikuchi, Vina Yanti Susanti, Masaki Kobayashi, Yoshinori Tanaka, Tomoyuki Yuasa, Tadahiro Kitamura

Abstract

Type 2 diabetes mellitus (T2DM) is one of the major health concern among the world. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues, and improving insulin sensitivity by insulin sensitizers. However, increasing the amount of insulin receptor in insulin-target tissues has not been explored. In order to test the efficacy of insulin receptor overexpression for improving glucose control, we established a transgenic mouse line expressing human insulin receptor (INSR). We analyzed, growth, energy balance, and glucose control of INSR-overexpressing db/db mice (INSR; db/db), which we produced by mating INSR transgenic mice with db/db mice, a genetic model of obesity due to insufficient leptin signaling. Compared to db/db mice, INSR; db/db mice were rescued from hyperphagia and obesity, leading to improved blood glucose levels. Unexpectedly, however, INSR; db/db mice presented with stunted growth, accompanied by decreased plasma levels of free IGF1 and IGFBP-3, indicating the down-regulation of GH/IGF1 axis. These phenotypes were observed in INSR; db/db mice but not in INSR littermates. Meanwhile, bone defects observed in db/db male mice were not rescued. Moreover, improved blood glucose was not accompanied by improved insulin sensitivity. Therefore, overexpression of insulin receptor improves obese and diabetic phenotypes in db/db mice, with consequences on growth.


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Shimatsu et al. analyzed possible predictors for QOL improvement during GH replacement therapy in 83 patients with adult GH deficiency. The results show that physical, mental and social component scores were negatively correlated with the changes in fasting plasma glucose concentration (FPG). Short-term changes in FPG and IGF-I were correlated with long-term changes in QOL. These results may provide an insight into our understanding of the efficacy of GH replacement therapy for the treatment of adult GH deficiency.

Possible predictors for QOL improvement following GH replacement therapy in adult GHD

Akira Shimatsu, Noriyuki Iwamoto, Toshiaki Tanaka, Akira Teramoto, Masanori Taketsuna, Katsuichiro Ihara, Jumpei Funai, Minoru Irie, Kazuo Chihara

Abstract

In addition to impaired physical activity, adult GH deficiency (GHD) can decrease quality of life (QOL). Hence, assessment of QOL is important to evaluate the efficacy of GH replacement therapy. This study aimed to identify factors that may be predictive of long-term improvement in QOL among clinical/laboratory variables during GH replacement therapy. The analysis included 83 Japanese adults with GHD who participated in the Hypopituitary Control and Complications Study (HypoCCS). Correlations between the change from baseline in clinical/laboratory variables at 6 months and the change from baseline in Quality of life (Short-Form 36 [SF-36] component scores) at 12 months were examined. Unexpectedly, all component scores were negatively correlated with the change in fasting plasma glucose concentration (FPG) (physical component summary [PCS], r = -0.456; mental component summary [MCS], r = -0.523; role/social component summary [RCS], r = -0.433). The change in MCS was positively correlated with the change in insulin-like growth factor-1 standard deviation score (IGF-1 SDS) (r = 0.417). The change in PCS was positively correlated with the change in body fat (r = 0.551). The change in RCS was positively correlated with the change in waist circumference (r = 0.528). Short-term changes in several clinical/laboratory variables, most notably FPG and IGF-1 SDS, were correlated with long-term changes in QOL. The clinical importance of these correlations for predicting GH replacement treatment efficacy warrants further investigation.


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Yoshihara et al. investigated the serum levels of hCG and thyroid hormones in patients with gestational transient thyrotoxicosis (GTT) in an attempt to differentiate between active Graves' disease and GTT. Their results show that the serum hCG level is high in patients with GTT but is not a good parameter for differentiating between active Graves' disease and GTT. Instead, the FT3/FT4 ratio is a better parameter for differentiation.

Serum human chorionic gonadotropin levels and thyroid hormone levels in gestational transient thyrotoxicosis: Is the serum hCG level useful for differentiating between active Graves' disease and GTT?

Ai Yoshihara, Jaeduk Yoshimura Noh, Koji Mukasa, Miho Suzuki, Hidemi Ohye, Masako Matsumoto, Yo Kunii, Natsuko Watanabe, Nami Suzuki, Toshiaki Kameda, Kiminori Sugino and Koichi Ito

Abstract

Gestational transient thyrotoxicosis (GTT) is defined as transient thyrotoxicosis caused by the stimulating effect of human chorionic gonadotropin (hCG) during pregnancy. We attempted to identify the serum hCG level that causes GTT, and we compared the serum hCG levels and thyroid hormone levels of GTT patients according to whether they had a background of thyroid disease. We also evaluated serum hCG as a parameter for differentiating between active Graves’ disease (GD) and GTT. We reviewed the 135 cases of pregnant women who came to our hospital to be evaluated for thyrotoxicosis during their 7th to 14th week of pregnancy, and their serum hCG level was measured at that time. Among the 135 pregnant women with thyrotoxicosis; 103 of the women had GTT, and the other 32 women had active GD. There were no correlations between their serum hCG levels and free thyroid hormone levels. There were no significant differences in thyroid hormone levels or hCG levels among the GTT groups with different thyroid disease backgrounds; i.e., the GTT group without thyroid disease, GTT group with chronic thyroiditis, GTT group with non-functioning thyroid nodules, and GTT group with GD in remission. The serum hCG level of the GTT group was significantly higher than in the active GD group, but it was not a good parameter for differentiating between the two groups. The FT3/FT4 ratio of the active GD was significantly higher than in GTT group, and was a better parameter for differentiation.


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Maejima et al. reported a case of DEND syndrome caused by a mutation in the Kir6.2 subunit of the ATP-sensitive potassium channel. The patient was responsive to sulfonylurea and, interestingly, was associated with water intake disorder. This raises a possibility that the ATP-sensitive potassium channel in the brain is involved in the regulation of water intake and/or osmoregulation.

Water intake disorder in a DEND syndrome afflicted patient with R50P mutation

Yuko Maejima, Shinji Hasegawa, Shoichiro Horita, Kensuke Kumamoto, Juris Galbanovskis, Seiichi Takenoshita, Kenju Shimomura

Abstract

In this study, we present a case of developmental delay, epilepsy and neonatal diabetes (DEND) syndrome in a young male patient with the R50P mutation located in the Kir6.2 subunit of the ATP-sensitive K+ (KATP) channel. Whereas most patients with DEND syndrome are resistant to sulfonylurea therapy, our patient was responsive to sulfonylurea, lacked the most common neurological symptoms, such as epilepsy, but refused to drink water. His serum electrolytes and plasma osmolarity were normal but the serum vasopressin level was increased. To investigate the underlying mechanism of his water intake disorder, a 5 µl aliquot of 340 µM KATP channel opener diazoxide or 100 µM KATP channel inhibitor glibenclamide was injected into the third ventricle of the rat brain, and water intake was monitored. Although the injection of glibenclamide had no effect, injection of diazoxide significantly increased water intake by about 1.5 fold without affecting food intake. This result indicates that the KATP channel activity in the brain may have an influence on water intake. Here, we present the first case of a DEND syndrome-afflicted patient with water intake disorder and increased serum vasopressin level, possibly related to altered KATP channel activity.


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Kim et al. demonstrate by using ghrelin knockout mice that ghrelin is required for neurogenesis in hippocampus induced by dietary restriction.

Ghrelin is required for dietary restriction-induced enhancement of hippocampal neurogenesis: lessons from ghrelin knockout mice

Kim Y, Kim SH, Kim CY, Sato T, Kojima M, Park SJ.

Abstract

Neurogenesis occurs in the adult hippocampus and is enhanced by dietary restriction (DR), and neurogenesis enhancement is paralleled by circulating ghrelin level enhancement. We have previously reported that ghrelin modulates adult neurogenesis in the hippocampus. In order to investigate the possible role of ghrelin in DR-induced hippocampal neurogenesis in adult mice, ghrelin knockout (GKO) mice and wild-type (WT) mice were maintained for 3 months on DR or ad libitum (AL) diets. Protein levels of ghrelin in the stomach and the hippocampus were increased by DR in WT mice. One day after BrdU administration, the number of BrdU-labeled cells in the hippocampal dentate gyrus was decreased in GKO mice maintained on the AL diet. DR failed to alter the proliferation of progenitor cells in both WT and GKO mice. Four weeks after BrdU injection, the number of surviving cells in the dentate gyrus was decreased in AL-fed GKO mice. DR increased survival of newborn cells in WT mice, but not in GKO mice. Levels of brain-derived neurotrophic factor protein in the hippocampus were similar between WT and GKO mice, and were increased by DR both in WT and GKO mice. These results suggest that elevated levels of ghrelin during DR may have an important role in the enhancement of neurogenesis induced by DR.


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Leonova et al. investigated the effects of long-term TSH suppression therapy and Calcium-D3 supplementation on bone mineral density in 124 young female patients treated for differentiated thyroid cancer at a mean age of 14 years and followed up for an average of 10 years. No effects of L-T4 and radioiodine therapies on bone mineral density was found. In addition, bone mineral density was significantly higher in patients receiving Calium-D3 medication. They conclude that long-term TSH suppression does not affect bone mineral density in women treated for differentiated thyroid cancer at young age.

Bone mineral density in treated at a young age for differentiated thyroid cancer after Chernobyl female patients on TSH-suppressive therapy receiving or not Calcium-D3 supplementation

Leonova TA, Drozd VM, Saenko VA, Mine M, Biko J, Rogoinovitch TI, Takamura N, Reiners C, Yamashita S.

Abstract

Long-term management of patients with differentiated thyroid cancer (DTC) commonly includes TSH-suppressive therapy with L-T4 and, in case of postsurgical hypoparathyroidism, Calcium-D3 supplementation, both of which may affect skeletal health. Experience with female patients treated for DTC at a young age and who were then receiving long-term therapy with L-T4 and Calcium-D3 medication is very limited to date. This cross-sectional study set out to investigate effects of Calcium-D3 supplementation and TSH-suppressive therapy on bone mineral density (BMD) in 124 young female patients treated for DTC at a mean age of 14 years and followed-up for an average of 10 years. BMD was found to be significantly higher in patients receiving Calcium-D3 medication than in patients not taking supplements. The level of ionized calcium was the strongest factor determining lumbar spine BMD in patients not receiving Calcium-D3 supplementation. Pregnancy ending in childbirth and HDL-cholesterol were associated with a weak adverse effect on spine and femoral BMD. No evidence of adverse effects of L-T4 and of radioiodine therapies on BMD was found. We conclude that Calcium-D3 medication has a beneficial effect on BMD, and that TSH-suppressive therapy does not affect BMD in women treated for DTC at young age, at least after 10 years of follow-up.


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Kiyota et al. identified an antigen with molecular weight of 51 KDa in pituitary extract recognized by sera from patients with isolated ACTH deficiency. By LC-MS/MS analysis, they identified the 51 KDa protein to be Rab GDI. Rab GDI may be a candidate of autoantigen involved in the pathogenesis of isolated ACTH deficiency.

Identification of the novel autoantigen candidate Rab GDP dissociation inhibitor alpha in isolated adrenocorticotropin deficiency

Kiyota A, Iwata S, Sugimura Y, Takeuchi S, Takagi H, Iwata N, Nakashima K, Suzuki H,
Nishioka T, Kato T, Enomoto A, Arima H, Kaibuchi K, Oiso Y.

Abstract

Isolated adrenocorticotropin deficiency (IAD) is characterized by low or absent adrenocorticotropic hormone (ACTH) production. IAD is presumed to be caused in part by an autoimmune mechanism, and several lines of evidence have suggested the presence of anti-pituitary antibodies in IAD. However, the exact autoantigens remain unknown. The present study was designed to identify the autoantigen(s) in IAD using chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Rat anterior pituitary lysate was subjected to SDS-PAGE, and immunoblotting was performed using the sera from two patients with IAD and from a healthy subject. The bands detected by the patient serum samples, but not by the healthy subject sample, were excised, in-gel digested using trypsin, and subjected to LC-MS/MS analysis. On immunoblots, a 51-kDa band in the insoluble pellet was detected by the sera from the IAD patients but not from the healthy subject. Mass spectrometric analysis revealed the 51-kDa band contained Rab guanine nucleotide dissociation inhibitor (GDI) alpha. Consistent with the mass spectrometric analysis, a recombinant full-length human Rab GDI alpha was recognized by the two IAD patient samples but not by the healthy subject sample using immunoblotting. In total, anti-Rab GDI alpha antibodies were detected in serum samples from three of five patients with IAD (60%) but were absent in 5 healthy subjects. In addition, Rab GDI alpha was expressed in the anterior pituitary. In conclusion, it appears that Rab GDI alpha is a candidate autoantigen involved in IAD, and that anti-Rab GDI alpha antibodies are present predominantly in patients with IAD.


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Kawate et al. demonstrate that patients with subclinical Cushing's syndrome, especially those with bilateral lesions, have a risk of extra-adrenal malignancy. Screening of malignancies may be necessary in patients with bilateral adrenal tumors suspected of autonomous hypersecretion of cortisol from both sides.

Long-term study of subclinical Cushing's syndrome shows high prevalence of extra-adrenal malignancy in patients with functioning bilateral adrenal tumors

Hisaya Kawate, Michiko Kohno, Yayoi Matsuda, Yuko Akehi, Makito Tanabe, Toshihiro
Horiuchi, Keizo Ohnaka, Masatoshi Nomura, Toshihiko Yanase, Ryoichi Takayanagi

Abstract

Subclinical Cushing's syndrome (SCS) is characterized by subtle autonomous cortisol secretion from adrenal tumors without specific signs and symptoms of hypercortisolism. Patients with SCS have a high prevalence of "lifestyle-related diseases," such as hypertension, diabetes mellitus, dyslipidemia, and osteoporosis. Long-term follow-up of SCS patients is reportedly indispensable for establishing indications for surgical treatment of SCS. We performed a follow-up survey of 27 patients with SCS (median: 5.3 years) and compared those who had undergone surgical treatment (n=15) with those who had not (n=12). The mean diameter of tumors was 31 mm; 16 (59%) patients had unilateral lesions and 11 (41%) carried bilateral ones. In 67% and 60% of the treatment group, respectively, hypertension and diabetes mellitus improved. We also noticed that eight of 11 (73%) SCS patients with bilateral adrenal tumors had extra-adrenal malignancies in various tissues. Interestingly, among nine SCS patients who had malignancies, eight showed bilateral adrenal uptake in 131I-aldosterol scintigraphy. The results imply that surgical treatment can reduce cardiovascular risks in SCS patients. Screening for malignancy may be necessary in patients with bilateral adrenal tumors suspected of autonomous hypersecretion of cortisol from both sides.

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